Download PDF

Clinical Trial Results:
A Phase 1/2 Study of the Highly-selective RET Inhibitor, BLU-667, in Patients with Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other Advanced Solid Tumors

Summary
EudraCT number	2016-004390-41
Trial protocol	GB DE NL BE
Global end of trial date	21 Mar 2024

Results information
Results version number	v1(current)
This version publication date	04 Apr 2025
First version publication date	04 Apr 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

BO42863

ISRCTN number

US NCT number

NCT03037385

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse, 124, Basel, Switzerland, CH-4058

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

21 Mar 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

21 Mar 2024

Was the trial ended prematurely?

Main objective of the trial

The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antineoplastic activity of pralsetinib (BLU-667) administered orally in participants with medullary thyroid cancer (MTC), rearranged during transfection (RET)-altered NSCLC and other RET-altered solid tumors.

Protection of trial subjects

All study participants were required to read and sign an Informed Consent Form (ICF).

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Mar 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

China: 111

Country: Number of subjects enrolled

Germany: 39

Country: Number of subjects enrolled

Spain: 37

Country: Number of subjects enrolled

France: 45

Country: Number of subjects enrolled

United Kingdom: 13

Country: Number of subjects enrolled

Italy: 40

Country: Number of subjects enrolled

Korea, Republic of: 59

Country: Number of subjects enrolled

Netherlands: 15

Country: Number of subjects enrolled

Singapore: 12

Country: Number of subjects enrolled

Taiwan: 10

Country: Number of subjects enrolled

United States: 207

Worldwide total number of subjects

590

EEA total number of subjects

178

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

405

From 65 to 84 years

180

85 years and over

Subject disposition

Top of page

Recruitment details

A total of 590 participants with rearranged during transfection (RET) fusion-positive NSCLC, RET mutation-positive MTC (also known as RET-mutant MTC), RET fusion-positive thyroid cancer (TC) and other advanced solid tumors took part in the study at 74 investigative sites across 13 countries from 17 March 2017 to 21 March 2024.

Screening details

The study was divided into two phases. In Phase 1 (Dose Escalation), participants received pralsetinib at varying doses. In Phase 2 (Dose Expansion), participants received fixed dose of pralsetinib.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase I: Pralsetinib 30 mg

Arm description

Participants received pralsetinib 30 milligrams (mg), orally, once a day (QD) until discontinuation due to toxicity, disease progression, or other reasons.

Arm type

Experimental

Investigational medicinal product name

Pralsetinib

Investigational medicinal product code

RO7499790

Other name

BLU-667

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pralsetinib, 30 mg, orally was administered to participants, QD.

Phase I: Pralsetinib 60 mg

Arm description

Participants received pralsetinib 60 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Arm type

Experimental

Investigational medicinal product name

Pralsetinib

Investigational medicinal product code

RO7499790

Other name

BLU-667

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pralsetinib, 60 mg, orally was administered to participants, QD.

Phase I: Pralsetinib 100 mg

Arm description

Participants received pralsetinib 100 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Arm type

Experimental

Investigational medicinal product name

Pralsetinib

Investigational medicinal product code

RO7499790

Other name

BLU-667

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pralsetinib, 100 mg, orally was administered to participants, QD.

Phase I: Pralsetinib 200 mg

Arm description

Participants received pralsetinib 200 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Arm type

Experimental

Investigational medicinal product name

Pralsetinib

Investigational medicinal product code

RO7499790

Other name

BLU-667

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pralsetinib, 200 mg, orally was administered to participants, QD.

Phase I: Pralsetinib 300 mg

Arm description

Participants received pralsetinib 300 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Arm type

Experimental

Investigational medicinal product name

Pralsetinib

Investigational medicinal product code

RO7499790

Other name

BLU-667

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pralsetinib, 300 mg, orally was administered to participants, QD.

Phase I: Pralsetinib 400 mg

Arm description

Participants received pralsetinib 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Arm type

Experimental

Investigational medicinal product name

Pralsetinib

Investigational medicinal product code

RO7499790

Other name

BLU-667

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pralsetinib, 400 mg, orally was administered to participants, QD.

Phase I: Pralsetinib 600 mg

Arm description

Participants received pralsetinib 600 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Arm type

Experimental

Investigational medicinal product name

Pralsetinib

Investigational medicinal product code

RO7499790

Other name

BLU-667

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pralsetinib, 600 mg, orally was administered to participants, QD.

Phase I: Pralsetinib 100/100 mg

Arm description

Participants received pralsetinib 100 mg, orally, twice a day (BID) until discontinuation due to toxicity, disease progression, or other reasons.

Arm type

Experimental

Investigational medicinal product name

Pralsetinib

Investigational medicinal product code

RO7499790

Other name

BLU-667

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pralsetinib, 100 mg, orally was administered to participants, BID.

Phase I: Pralsetinib 200/100 mg

Arm description

Participants received pralsetinib 200 mg in the morning and then 100 mg in the evening orally until discontinuation due to toxicity, disease progression, or other reasons.

Arm type

Experimental

Investigational medicinal product name

Pralsetinib

Investigational medicinal product code

RO7499790

Other name

BLU-667

Pharmaceutical forms

Tablet, Tablet

Routes of administration

Oral use, Oral use

Dosage and administration details

Pralsetinib, 200 mg in the morning and then 100 mg in the evening was administered to participants, orally.

Phase II: Pralsetinib 400 mg

Arm description

Participants with advanced NSCLC, advanced non-resectable TC and other advanced non-resectable solid tumors with various RET-alterations were enrolled in this arm to receive pralsetinib, 400 mg, QD until discontinuation due to toxicity, disease progression, or other reasons.

Arm type

Experimental

Investigational medicinal product name

Pralsetinib

Investigational medicinal product code

RO7499790

Other name

BLU-667

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pralsetinib, 400 mg, orally was administered to participants, QD.

Number of subjects in period 1	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg	Phase II: Pralsetinib 400 mg
Started	2	6	5	13	11	12	4	6	3	528
Completed	0	0	0	0	0	0	0	0	0	0
Not completed	2	6	5	13	11	12	4	6	3	528
Initiation Of Another Therapy	1	-	-	-	-	-	-	1	-	2
Consent withdrawn by subject	-	-	1	2	1	3	-	-	-	52
Physician decision	-	-	-	-	-	-	-	-	-	1
Adverse Event	-	-	1	-	-	-	-	-	-	6
Death	1	4	2	2	5	2	1	5	2	240
Reason Not Specified	-	1	-	4	3	6	2	-	1	181
Progressive Disease	-	1	1	5	2	-	1	-	-	30
Lost to follow-up	-	-	-	-	-	1	-	-	-	16

Baseline characteristics

Top of page

Reporting group title

Phase I: Pralsetinib 30 mg

Reporting group description

Participants received pralsetinib 30 milligrams (mg), orally, once a day (QD) until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 60 mg

Reporting group description

Participants received pralsetinib 60 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 100 mg

Reporting group description

Participants received pralsetinib 100 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 200 mg

Reporting group description

Participants received pralsetinib 200 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 300 mg

Reporting group description

Participants received pralsetinib 300 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 400 mg

Reporting group description

Participants received pralsetinib 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 600 mg

Reporting group description

Participants received pralsetinib 600 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 100/100 mg

Reporting group description

Participants received pralsetinib 100 mg, orally, twice a day (BID) until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 200/100 mg

Reporting group description

Participants received pralsetinib 200 mg in the morning and then 100 mg in the evening orally until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase II: Pralsetinib 400 mg

Reporting group description

Reporting group values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg	Phase II: Pralsetinib 400 mg	Total
Number of subjects	2	6	5	13	11	12	4	6	3	528	590
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	54.5 ( 9.2 )	49.5 ( 18.0 )	51.2 ( 13.2 )	53.8 ( 13.6 )	60.6 ( 11.0 )	49.2 ( 17.8 )	59.5 ( 9.1 )	63.7 ( 10.7 )	60.0 ( 21.9 )	57.7 ( 12.6 )	-
Sex: Female, Male
Units: participants
Female	1	3	4	5	4	3	3	2	1	257	283
Male	1	3	1	8	7	9	1	4	2	271	307
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	2	2	1	1	0	3	0	0	0	19	28
Not Hispanic or Latino	0	4	4	12	11	9	4	4	3	465	516
Unknown or Not Reported	0	0	0	0	0	0	0	2	0	44	46
Race/Ethnicity, Customized
Units: Subjects
Asian	0	1	2	0	0	2	0	1	0	203	209
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0	2	2
Black or African American	0	0	0	1	0	1	0	0	0	4	6
White	0	3	2	11	11	9	4	4	3	284	331
Other	0	0	0	0	0	0	0	0	0	3	3
Unknown or Not Reported	2	2	1	1	0	0	0	1	0	32	39

End points

Top of page

Reporting group title

Phase I: Pralsetinib 30 mg

Reporting group description

Participants received pralsetinib 30 milligrams (mg), orally, once a day (QD) until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 60 mg

Reporting group description

Participants received pralsetinib 60 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 100 mg

Reporting group description

Participants received pralsetinib 100 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 200 mg

Reporting group description

Participants received pralsetinib 200 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 300 mg

Reporting group description

Participants received pralsetinib 300 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 400 mg

Reporting group description

Participants received pralsetinib 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 600 mg

Reporting group description

Participants received pralsetinib 600 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 100/100 mg

Reporting group description

Participants received pralsetinib 100 mg, orally, twice a day (BID) until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase I: Pralsetinib 200/100 mg

Reporting group description

Participants received pralsetinib 200 mg in the morning and then 100 mg in the evening orally until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Phase II: Pralsetinib 400 mg

Reporting group description

Subject analysis set title

Phase 1: All Participants QD

Subject analysis set type

Per protocol

Subject analysis set description

Participants received pralsetinib at varying doses at a QD schedule until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

Pralsetinib ≤ 300 mg QD

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received pralsetinib, 300 mg or less, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

Pralsetinib 400 mg QD

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received pralsetinib, 400 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

Pralsetinib BID Dosing Schedule

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received pralsetinib, 100 mg, orally, BID or 200 mg in the morning and then 100 mg in the evening, orally, until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

RET- fusion Positive NSCLC With Prior Platinum Treatment

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET-fusion positive NSCLC previously treated with platinum-based chemotherapies received pralsetinib, 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

RET-fusion Positive NSCLC With Non-platinum Systemic Treatment

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET-fusion positive NSCLC previously treated with non-platinum or systemic therapies received pralsetinib, 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

RET-fusion NSCLC With No Prior Systemic/Platinum Treatment

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET-fusion positive NSCLC not previously treated with systemic or platinum-based chemotherapies received pralsetinib, 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET- mutation positive MTC previously treated with either cabozantinib and/or vandetanib therapies received pralsetinib, 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

RET-mutation MTC With No Cabozantinib/Vandetanib Treatment

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET- mutation positive MTC not previously treated with cabozantinib or vandetanib therapies received pralsetinib, 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

RET-fusion Positive TC

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET-fusion positive TC received pralsetinib, 400 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

RET-fusion Positive Solid Tumors Other Than NSCLC and TC

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had other RET-positive solid tumors other than NSCLC and TC received pralsetinib, 400 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

RET-altered Solid Tumors Previously Treated With RET Inhibitor

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET-altered (fusion or mutation) solid tumors previously treated with a selective RET tyrosine kinase inhibitor (TKI) received pralsetinib, 400 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

RET-mutation Positive Tumors Other Than MTC

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET-mutation positive solid tumors received pralsetinib, 400 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

RET- fusion Positive NSCLC Participants

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET-fusion positive NSCLC received pralsetinib, 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons. This arm was specifically planned for reporting PK data.

Subject analysis set title

Tumor-agnostic Participants

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET-fusion positive NSCLC or TC, or RET-mutation positive MTC, each with different genetic mutations received pralsetinib, 400 mg orally, QD until discontinuation due to toxicity, disease progression, or other reasons. This arm was specifically planned for reporting PK data.

Subject analysis set title

RET-altered Solid Tumors Participants

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET-altered (fusion or mutation) solid tumors previously treated with a selective RET TKI received pralsetinib, 400 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons. This arm was specifically planned for reporting PK data.

Subject analysis set title

RET-mutation Positive Tumors other than MTC Participants

Subject analysis set type

Per protocol

Subject analysis set description

Participants who had RET-mutation positive solid tumors received Pralsetinib 400 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons. This arm was specifically planned for reporting PK data.

Subject analysis set title

Phase I: Pralsetinib 200/100 mg

Subject analysis set type

Per protocol

Subject analysis set description

Participants received pralsetinib 200 mg in the morning and then 100 mg in the evening orally until discontinuation due to toxicity, disease progression, or other reasons.

Subject analysis set title

Pralsetinib All Doses

Subject analysis set type

Safety analysis

Subject analysis set description

Participants received pralsetinib at varying doses at the QD and BID schedule until discontinuation due to toxicity, disease progression, or other reasons.

Primary: Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib

Top of page

End point title

Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib ^[1]

End point description

MTD was defined as the highest tolerated dose of pralsetinib without causing dose limiting toxicities (DLTs). DLT was defined as any Grade ≥3 adverse event (AE) occurring during Cycle 1 during Phase 1 (dose escalation) that is not clearly caused by something other than pralsetinib. RP2D was defined as the highest dose with acceptable toxicity as determined from dose-escalation phase. Dose-determining population included all participants in the dose-escalation part who have received ≥75% (21 days) of the study drug and completed safety evaluations through Cycle 1 Day 28 or experienced a DLT.

End point type

Primary

End point timeframe

Up to approximately 30.8 months

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistics was planned for this endpoint.

End point values	Phase 1: All Participants QD
Number of subjects analysed	51
Units: mg
MTD	400
RP2D	400

No statistical analyses for this end point

Primary: Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs)

Top of page

End point title

Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs) ^[2]

End point description

AE=any untoward medical occurrence associated with use of drug in humans, whether or not considered drug related. AE can be any unfavorable & unintended sign, symptom/disease temporally associated with use of drug, without any judgment about causality. SAE=any significant hazard, contraindication, side effect that is fatal/life-threatening, requires hospitalization/prolongation of existing hospitalization, results in persistent/significant disability, is congenital anomaly/birth defect, is medically significant/requires intervention to prevent the outcomes listed above. Safety Population included all participants who have received at least 1 dose of the study drug regardless of starting dose levels. As pre-specified in the SAP, safety data was to be analyzed and reported as per the pre-planned grouped dose level II (SAP section 3.6.5.2). Hence, per dose safety data is not presented for this study.

End point type

Primary

End point timeframe

From Cycle 1 Day 1 up to 30 days after the final dose of study drug (up to approximately 6.7 years)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistics was planned for this endpoint.

End point values	Pralsetinib ≤ 300 mg QD	Pralsetinib 400 mg QD	Pralsetinib BID Dosing Schedule	Pralsetinib All Doses
Number of subjects analysed	37	540	9	590
Units: percentage of participants
number (not applicable)
AEs	37	540	9	590
SAEs	26	381	7	416

No statistical analyses for this end point

Primary: Phase 2: Overall Response Rate (ORR)

Top of page

End point title

Phase 2: Overall Response Rate (ORR) ^[3]

End point description

ORR=percentage of participants with a confirmed complete response (CR)/partial response (PR) for at least 2 assessments with at least 28 days apart & no disease progression (PD) in between. Per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), CR=disappearance of all target lesions/any pathological lymph nodes (whether target/non-target) having a reduction in short axis to <10 millimeters(mm). PR=at least 30% decrease in sum of diameters (SOD) of all target lesions, taking as reference baseline SOD, in absence of CR. PD=at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study (including baseline). RET-altered measurable disease population=participants in efficacy population who had measurable (target) disease per RECIST v1.1 at baseline according to blinded central review (BICR) &sufficient evidence of RET alteration. As prespecified in SAP, Phase 1 participants treated at 400 mg QD were included in Phase 2 efficacy analysis.

End point type

Primary

End point timeframe

Up to approximately 79.8 months

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No formal statistics was planned for this endpoint.

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment	RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment	RET-mutation MTC With No Cabozantinib/Vandetanib Treatment	RET-fusion Positive TC	RET-fusion Positive Solid Tumors Other Than NSCLC and TC	RET-altered Solid Tumors Previously Treated With RET Inhibitor	RET-mutation Positive Tumors Other Than MTC
Number of subjects analysed	130	23	106	60	72	27	28	21	13
Units: percentage of participants
number (confidence interval 95%)	63.1 (54.2 to 71.4)	73.9 (51.6 to 89.8)	78.3 (69.2 to 85.7)	56.7 (43.2 to 69.4)	77.8 (66.4 to 86.7)	85.2 (66.3 to 95.8)	46.4 (27.5 to 66.1)	19.0 (5.4 to 41.9)	7.7 (0.99 to 36.0)

No statistical analyses for this end point

Secondary: Phase 1: ORR

Top of page

End point title

Phase 1: ORR ^[4]

End point description

ORR was defined as percentage of participants with a confirmed CR or PR for at least two assessments with at least 28 days apart and no PD in between. Per RECIST v1.1, CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to <10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). ORR and its two-sided 95% CI, based on the exact binomial distribution (Clopper-Pearson), was presented. Efficacy population includedall participants who have been exposed to at least one dose of the study on/prior to 11 July 2019. -0.9999&9999=The lower and upper limit of 95% confidence interval (CI) was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Up to approximately 28 months

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report data for Phase I of the study only. Hence, Phase II arm is not included.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	6	5	13	11	12	4	5	4
Units: percentage of participants
number (confidence interval 95%)	0 (-0.9999 to 9999)	50.0 (11.8 to 88.2)	40.0 (5.3 to 85.3)	38.5 (13.9 to 68.4)	45.5 (16.7 to 76.6)	41.7 (15.2 to 72.3)	25.0 (0.99 to 80.6)	80.0 (28.4 to 99.5)	75.0 (19.4 to 99.4)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants with Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants with Specific RET Gene Status

End point description

Oncogenic RET rearrangements have been identified in 1−2% of NSCLC. These rearrangements typically produce chimeric transcripts encoding fusion protein consisting of RET kinase domain coupled to a protein with dimerization domain (eg Kinesin family member 5B(KIF5B), coiled-coil domain containing 6(CCDC6), nuclear receptor coactivator 4(NCOA4). RET genotypes determined by local testing/central analysis of circulating tumor deoxyribonucleic acid(ctDNA). ORR=% of participants with confirmed CR/PR for at least 2 assessments 28 days apart & no PD in between. CR/PR/PD: defined per RECIST as outlined in description for ORR endpoint (EP). RET-altered measurable disease (RAMD) population. As prespecified in SAP, Phase 1 participants treated at 400 mg are pooled with Phase 2 participants for efficacy analysis. n=number of participants with specified mutation. 9999=95% CI was not estimable due to insufficient number of participants with events. 99999=no participants had the specified mutation.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment
Number of subjects analysed	130	23	106
Units: percentage of participants
number (confidence interval 95%)
KIF5B(n=91,17,76)	63.7 (53.0 to 73.6)	82.4 (56.6 to 96.2)	78.9 (68.1 to 87.5)
CCDC6(n=25,4,19)	68.0 (46.5 to 85.1)	75.0 (19.4 to 99.4)	84.2 (60.4 to 96.6)
NCOA4(n=1,0,0)	100 (2.5 to 100)	99999 (99999 to 99999)	99999 (99999 to 99999)
Other(n=13,2,11)	46.2 (19.2 to 74.9)	0 (-9999 to 9999)	63.6 (30.8 to 89.1)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status

End point description

Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing and/or central analysis of ctDNA. ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for ORR EP. RAMD population. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. n=number of participants with the specified mutation. -0.9999&9999=Since only 1 participant was analyzed upper and lower limit of 95% CI was not evaluable..

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment	RET-mutation MTC With No Cabozantinib/Vandetanib Treatment
Number of subjects analysed	60	72
Units: percentage of participants
number (confidence interval 95%)
M918T (n=41,43)	53.7 (37.4 to 69.3)	74.4 (58.8 to 86.5)
Cysteine Rich Domain(n=13,25)	46.2 (19.2 to 74.9)	88.0 (68.8 to 97.5)
V804X(n=2,1)	100 (15.8 to 100)	0 (-0.9999 to 9999)
Other(n=4,3)	100 (39.8 to 100)	66.7 (9.4 to 99.2)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status

End point description

Oncogenic RET activation has been implicated as a driver in both MTC and differentiated TC (DTC). These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing and/or central analysis of ctDNA. ORR was assessed in participants having specific RET rearrangements. ORR was defined as the percentage of participants with a confirmed CR or PR for at least 2 assessments with at least 28 days apart and no PD in between. CR, PR, and PD were defined per RECIST as outlined in the description for ORR EP. RAMD population. As prespecified in the SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. n=number of participants with the specified mutation. 9999=no participants exhibited the specified mutation.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET-fusion Positive TC
Number of subjects analysed	27
Units: percentage of participants
number (confidence interval 95%)
KIF5B(n=0)	9999 (9999 to 9999)
CCDC6(n=17)	82.4 (56.6 to 96.2)
NCOA4(n=6)	100 (54.1 to 100)
Other(n=4)	75.0 (19.4 to 99.4)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status

End point description

Oncogenic RET rearrangements have been identified in 1%−2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode fusion protein consisting of RET kinase domain coupled to a protein with a dimerization domain. RET genotypes were determined by local testing/central analysis of ctDNA. CBR was defined as percentage of participants with confirmed CR, PR or stable disease (SD) which has been lasting at least 16 weeks from 1st dose date. CR, PR & PD were defined per RECIST as outlined in description for ORR EP. SD=neither sufficient shrinkage to qualify for CR/PR nor sufficient increase to qualify for PD. RAMD population. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. n=number of participants with specified mutation. 9999=95% CI was not estimable due to insufficient number of participants with events. 99999=no participants exhibited the specified mutation.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment
Number of subjects analysed	130	23	106
Units: percentage of participants
number (confidence interval 95%)
KIF5B(n=91,17,76)	76.9 (66.9 to 85.1)	88.2 (63.6 to 98.5)	81.6 (71.0 to 89.5)
CCDC6(n=25,4,19)	76.0 (54.9 to 90.6)	75.0 (19.4 to 99.4)	84.2 (60.4 to 96.6)
NCOA4(n=1,0,0)	100 (2.5 to 100)	99999 (99999 to 99999)	99999 (99999 to 99999)
Other(13,2,11)	53.8 (25.1 to 80.8)	0 (-9999 to 9999)	63.6 (30.8 to 89.1)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status

End point description

Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode fusion protein consisting of RET kinase domain coupled to a protein with a dimerization domain(e.g. M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing/central analysis of ctDNA. CBR was defined aspercentage of participants with confirmed CR, PR or SD which has been lasting at least 16 weeks from first dose date. CR and PR were defined per RECIST as outlined in description for EP 3. SD was defined asneither sufficient shrinkage to qualify for CR/PR nor sufficient increase to qualify for PD. PD was defined asat least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study (including baseline). RAMD population. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. n=number of participants with specified mutation.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment	RET-mutation MTC With No Cabozantinib/Vandetanib Treatment
Number of subjects analysed	60	72
Units: percentage of participants
number (confidence interval 95%)
M918T(n=41,43)	78.0 (62.4 to 89.4)	86.0 (72.1 to 94.7)
Cysteine Rich Domain(n=13,25)	76.9 (46.2 to 95.0)	96.0 (79.6 to 99.9)
V804X(n=2,1)	100 (15.8 to 100)	100 (2.5 to 100)
Other(n=4,3)	100 (39.8 to 100)	100 (29.2 to 100)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status

End point description

Oncogenic RET activation has been implicated as a driver in both MTC & DTC. These rearrangements typically produce chimeric transcripts that encode fusion protein consisting of RET kinase domain coupled to protein with a dimerization domain(e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing/central analysis of ctDNA. CBR=percentage of participants with a confirmed CR/PR/SD which has been lasting at least 16 weeks from first dose date. CR & PR were defined per RECIST as outlined in description for ORR EP. SD=neither sufficient shrinkage to qualify for CR/PR nor sufficient increase to qualify for PD. PD=at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). RAMD population. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. n=number of participants with specified mutation. 9999=no participants exhibited the specified mutation.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET-fusion Positive TC
Number of subjects analysed	27
Units: percentage of participants
number (confidence interval 95%)
KIF5B(n=0)	9999 (9999 to 9999)
CCDC6(n=17)	82.4 (56.6 to 96.2)
NCOA4(n=6)	100 (54.1 to 100)
Other(n=4)	75.0 (19.4 to 99.4)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status

End point description

Oncogenic RET rearrangements have been identified in 1-2% of NSCLC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing/central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR=percentage of participants with confirmed CR/PR/SD. CR & PR were defined per RECIST as outlined in the description for ORR EP. SD=neither sufficient shrinkage to qualify for CR/PR nor sufficient increase to qualify for PD. PD=at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). RAMD population. As per SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. n=number of participants with specified mutation. 9999=no participants exhibited the specified mutation.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment
Number of subjects analysed	130	23	106
Units: percentage of participants
number (confidence interval 95%)
KIF5B(n=91,17,76)	93.4 (86.2 to 97.5)	94.1 (71.3 to 99.9)	88.2 (78.7 to 94.4)
CCDC6(n=25,4,19)	88.0 (68.8 to 97.5)	100 (39.8 to 100)	89.5 (66.9 to 98.7)
NCOA4(n=1,0,0)	100 (2.5 to 100)	9999 (9999 to 9999)	9999 (9999 to 9999)
Other(n=13,2,11)	84.6 (54.6 to 98.1)	50.0 (1.3 to 98.7)	100 (71.5 to 100)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status

End point description

Oncogenic RET activation has been implicated as a driver in MTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of the RET kinase domain coupled to a protein with a dimerization domain (e.g., M918T, cysteine rich domain, V804X). RET genotypes were determined by local testing/central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR=percentage of participants with a confirmed CR/PR/SD. CR & PR were defined per RECIST as outlined in the description for ORR EP. SD=neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD=at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). RAMD population. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. n=number of participants with specified mutation.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment	RET-mutation MTC With No Cabozantinib/Vandetanib Treatment
Number of subjects analysed	60	72
Units: percentage of participants
number (confidence interval 95%)
M918T(n=41,43)	95.1 (83.5 to 99.4)	90.7 (77.9 to 97.4)
Cysteine Rich Domain(n=13,25)	92.3 (64.0 to 99.8)	96.0 (79.6 to 99.9)
V804X(n=2,1)	100 (15.8 to 100)	100 (2.5 to 100)
Other(n=4,3)	100 (39.8 to 100)	100 (29.2 to 100)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status

End point description

Oncogenic RET activation has been implicated as a driver in both MTC & DTC. These rearrangements typically produce chimeric transcripts that encode a fusion protein consisting of RET kinase domain coupled to protein with a dimerization domain(e.g., KIF5B, CCDC6, NCOA4). RET genotypes were determined by local testing/central analysis of ctDNA. DCR was assessed in participants having specific RET rearrangements. DCR=percentage of participants with confirmed CR/PR/SD. CR & PR were defined per RECIST as outlined in the description for ORR EP. SD=neither sufficient shrinkage to qualify for CR/PR nor sufficient increase to qualify for PD. PD=at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). RAMD population. As per SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. n=number of participants with specified mutation. 9999=no participants exhibited the specified mutation.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET-fusion Positive TC
Number of subjects analysed	27
Units: percentage of participants
number (confidence interval 95%)
KIF5B(n=0)	9999 (9999 to 9999)
CCDC6(n=17)	94.1 (71.3 to 99.9)
NCOA4(n=6)	100 (54.1 to 100)
Other(n=4)	100 (39.8 to 100)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation MTC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation MTC Participants With Specific RET Gene Status

End point description

Oncogenic RET activation has been implicated as a driver in MTC. RET genotypes were determined by local testing/central analysis of ctDNA. DOR=time from first documented CR/PR to date of first documented PD/death due to any cause, whichever occurs first. CR, PR and PD were defined per RECIST as outlined in description for ORR EP. DOR was analyzed using the Kaplan-Meier (KM) method. RAMD population. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Participants with a response of CR/PR were analyzed. n=number of participants with specified mutation. 9999=upper limit of 95% CI was not estimable due to insufficient number of participants with events. 99999=median & upper limit of 95% CI was not estimable due to insufficient number of participants with events. 999999=median & 95% CI was not estimable due to insufficient number of participants with events. 9999999=no participants exhibited the specified mutation.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment	RET-mutation MTC With No Cabozantinib/Vandetanib Treatment
Number of subjects analysed	34	56
Units: months
median (confidence interval 95%)
M918T(n=22,32)	18.4 (15.1 to 25.8)	51.8 (40.0 to 9999)
Cysteine Rich Domain(n=6,22)	29.5 (8.9 to 9999)	36.8 (23.1 to 9999)
V804X(n=2,0)	21.8 (14.2 to 29.4)	9999999 (9999999 to 9999999)
Other(n=4,2)	99999 (14.5 to 99999)	999999 (999999 to 999999)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: DOR in RET-mutation NSCLC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: DOR in RET-mutation NSCLC Participants With Specific RET Gene Status

End point description

Oncogenic RET rearrangements have been identified in 1%−2% of NSCLC. RET genotypes were determined by local testing and/or central analysis of ctDNA. DOR=time from first documented CR/PR to date of first documented PD/death due to any cause, whichever occurs first. CR, PR and PD were defined per RECIST as outlined in description for ORR EP. DOR was analyzed using the KM method. RAMD population. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Participants with a response of CR/PR were analyzed. n=number of participants with specified mutation. 9999=upper limit of 95% CI was not estimable due to insufficient number of participants with events. 0.999=lower limit of 95% CI was not estimable due to insufficient number of participants with events. 99999=no participants exhibited the specified mutation.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment
Number of subjects analysed	82	17	83
Units: months
median (confidence interval 95%)
KIF5B (n=58,14,60)	15.1 (8.8 to 34.2)	21.5 (9.3 to 9999)	9.2 (7.4 to 13.4)
CCDC6 (n=17,34,16)	46.7 (33.7 to 9999)	29.6 (11.3 to 47.9)	0.999 (-9999 to 9999)
NCOA4 (n=1,0,0)	0.999 (-9999 to 9999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Other (n=6,0,7)	35.2 (10.6 to 9999)	99999 (99999 to 99999)	41.2 (27.9 to 9999)

No statistical analyses for this end point

Secondary: Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status

Top of page

End point title

Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status

End point description

Oncogenic RET activation has been implicated as a driver in MTC. RET genotypes were determined by local testing/central analysis of ctDNA. DOR=time from first documented CR or PR to date of first documented PD or death due to any cause, whichever occurs first. CR and PR were defined per RECIST v1.1 as outlined in description for ORR EP. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study (including baseline). DOR was analyzed using the KM method. RAMD population. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Participants who had a response of CR/PR were analyzed in this outcome measure. n=number of participants with specified mutation. 9999=upper limit of 95% CI was not estimable due to insufficient number of participants with events. 99999=median and upper limit of 95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET-fusion Positive TC
Number of subjects analysed	23
Units: months
median (confidence interval 95%)
CCDC6(n=14)	99999 (11.2 to 99999)
NCOA4(n=6)	15.2 (6.9 to 9999)
Other(n=3)	99999 (23.6 to 99999)

No statistical analyses for this end point

Secondary: Phase 2: DOR

Top of page

End point title

Phase 2: DOR

End point description

DOR was defined as time from first documented response (CR/PR) to the date of first documented PD or death due to any cause, whichever occurs first. CR and PR were defined as per RECIST v1.1 as outlined in description for ORR endpoint. PD was defined asat least a 20% increase in SOD of target lesions, taking as reference smallest SOD on study (including baseline). DOR was analyzed using KM methods. RAMD population. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. Participants who had a response of CR/PR were analyzed in this endpoint. 9999=upper limit of 95% CI was not estimable due to insufficient number of participants with events. 999 =median & upper limit of 95% CI was not estimable due to insufficient number of participants with events. 0.999 and 999999=95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment	RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment	RET-mutation MTC With No Cabozantinib/Vandetanib Treatment	RET-fusion Positive TC	RET-fusion Positive Solid Tumors Other Than NSCLC and TC	RET-altered Solid Tumors Previously Treated With RET Inhibitor	RET-mutation Positive Tumors Other Than MTC
Number of subjects analysed	82	17	83	34	56	23	13	4	1
Units: months
median (confidence interval 95%)	31.8 (15.1 to 40.4)	22.6 (11.1 to 47.9)	13.4 (9.4 to 21.7)	21.7 (15.1 to 34.8)	51.8 (36.8 to 9999)	999 (12.9 to 999)	11.1 (5.5 to 25.1)	99999 (6.0 to 99999)	5.5 (0.999 to 999999)

No statistical analyses for this end point

Secondary: Phase 2: CBR

Top of page

End point title

Phase 2: CBR

End point description

CBR was defined as the percentage of participants with CR or PR, or SD which has been lasting at least 16 weeks (i.e. 4 cycles if 28 days are in one cycle) from the first dose date. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to <10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). CBR and its two-sided 95% CI, which is based on the exact binomial distribution (Clopper-Pearson), were presented. RAMD population. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment	RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment	RET-mutation MTC With No Cabozantinib/Vandetanib Treatment	RET-fusion Positive TC	RET-fusion Positive Solid Tumors Other Than NSCLC and TC	RET-altered Solid Tumors Previously Treated With RET Inhibitor	RET-mutation Positive Tumors Other Than MTC
Number of subjects analysed	130	23	106	60	72	27	28	21	13
Units: percentage of participants
number (confidence interval 95%)	74.6 (66.2 to 81.8)	78.3 (56.3 to 92.5)	80.2 (71.3 to 87.3)	80.0 (67.7 to 89.2)	90.3 (81.0 to 96.0)	85.2 (66.3 to 95.8)	60.7 (40.6 to 78.5)	28.6 (11.3 to 52.2)	23.1 (5.0 to 53.8)

No statistical analyses for this end point

Secondary: Phase 2: DCR

Top of page

End point title

Phase 2: DCR

End point description

DCR was defined as the percentage of participants with a confirmed CR/PR, or SD, per RECIST v1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to <10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. SD was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). DCR and its two-sided 95% CI, which is based on the exact binomial distribution (Clopper-Pearson), were presented. RAMD population. As prespecified in SAP, Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment	RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment	RET-mutation MTC With No Cabozantinib/Vandetanib Treatment	RET-fusion Positive TC	RET-fusion Positive Solid Tumors Other Than NSCLC and TC	RET-altered Solid Tumors Previously Treated With RET Inhibitor	RET-mutation Positive Tumors Other Than MTC
Number of subjects analysed	130	23	106	60	72	27	28	21	13
Units: percentage of participants
number (confidence interval 95%)	91.5 (85.4 to 95.7)	91.3 (72.0 to 98.9)	89.6 (82.2 to 94.7)	95.0 (86.1 to 99.0)	93.1 (84.5 to 97.7)	96.3 (81.0 to 99.9)	75.0 (55.1 to 89.3)	42.9 (21.8 to 66.0)	69.2 (38.6 to 90.9)

No statistical analyses for this end point

Secondary: Phase 2: Progression-free Survival (PFS)

Top of page

End point title

Phase 2: Progression-free Survival (PFS)

End point description

PFS was defined as the time from the first dose of pralsetinib to the date of first documented PD or death due to any cause, whichever occurred first. PD was defined as at least a 20% increase in SOD of target lesions, taking as reference the smallest SOD on study (including baseline). PFS was analyzed using KM methods. Efficacy population included all participants who have been exposed to at least one dose of the study drug at the RP2D. As pre-specified in the SAP, PFS was to be assessed in participants with RET-fusion positive NSCLC, RET-mutation MTC, RET-fusion TC, and RET-fusion solid tumors other than NSCLC and TC. Hence, only the data for these arms is presented here. Number analyzed is the number of participants with data available for analysis. 9999=upper limit of 95% CI was not estimable due to insufficient number of participants with events. 99999=median & upper limit of 95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Up to approximately 7 years

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment	RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment	RET-mutation MTC With No Cabozantinib/Vandetanib Treatment	RET-fusion Positive TC	RET-fusion Positive Solid Tumors Other Than NSCLC and TC
Number of subjects analysed	141	24	116	67	78	31	28
Units: months
median (confidence interval 95%)	16.4 (11.4 to 23.5)	13.0 (9.3 to 35.1)	12.1 (9.2 to 16.6)	24.9 (19.9 to 35.0)	55.3 (37.2 to 9999)	99999 (14.7 to 99999)	7.0 (3.9 to 12.8)

No statistical analyses for this end point

Secondary: Phase 2: Overall Survival (OS)

Top of page

End point title

Phase 2: Overall Survival (OS)

End point description

OS was defined as the time from the first dose of pralsetinib to the date of death due to any causes. Efficacy population included all participants who have been exposed to at least one dose of the study drug at the RP2D. As pre-specified in the SAP, OS was to be assessed in participants with RET-fusion positive NSCLC, RET-mutation MTC, RET-fusion TC, and RET-fusion solid tumors other than NSCLC and TC. Hence, only the data for these arms is presented here. 9999=upper limit of 95% CI was not estimable due to insufficient number of participants with events. 99999=median and 95% CI was not estimable due to insufficient number of participants with events. 999999=median and upper limit of 95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Up to approximately 7 years

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment	RET-mutation MTC With Cabozantinib and/or Vandetanib Treatment	RET-mutation MTC With No Cabozantinib/Vandetanib Treatment	RET-fusion Positive TC	RET-fusion Positive Solid Tumors Other Than NSCLC and TC
Number of subjects analysed	141	24	116	67	78	31	29
Units: months
median (confidence interval 95%)	39.7 (27.8 to 53.2)	46.0 (19.1 to 62.4)	50.1 (28.3 to 9999)	42.2 (31.2 to 9999)	99999 (99999 to 99999)	999999 (19.4 to 999999)	10.3 (6.8 to 25.2)

No statistical analyses for this end point

Secondary: Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants

Top of page

End point title

Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants

End point description

ORR=percentage of participants with CR/PR for at least 2 assessments, ≥28 days apart, with no PD in between. CR=disappearance of all target CNS/brain lesions (including brainstem/cerebellum) and non-target lesions identified at baseline, with no new CNS/brain lesions. PR=at least 30% decrease in the SOD of any CNS/brain lesion identified as RECIST 1.1 target lesions, with no progression of non-target CNS/brain lesions or new lesions. PD= ≥20% increase in the SOD of target CNS/brain lesions, with a reference to the smallest sum on study, or unequivocal progression of non-target lesions or new lesions. RAMD population. As specified in the SAP, ORR was to be assessed in RET-fusion CNS metastases sub-population (participants with CNS metastases) only. Hence only NSCLC arms are presented here. Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. -0.9999 & 9999=95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment
Number of subjects analysed	13	1	1
Units: percentage of participants
number (confidence interval 95%)	53.8 (25.1 to 80.8)	100 (2.5 to 100)	0 (-0.9999 to 99999)

No statistical analyses for this end point

Secondary: Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants

Top of page

End point title

Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants

End point description

CBR=percentage of participants with CR/PR/SD lasting ≥16 weeks from 1st dose date. CR=disappearance of all target CNS/brain lesions (including brainstem/cerebellum) & non-target lesions identified at baseline, with no new CNS/brain lesions. PR=at least 30% decrease in SOD of any CNS/brain lesion identified as RECIST 1.1 target lesions, with no progression of non-target CNS/brain lesions/new lesions. SD=neither sufficient shrinkage for PR or increase for PD for target/non-target CNS/brain lesion, with reference to smallest SOD on study. PD= ≥20% increase in SOD of target CNS/brain lesions, with a reference to smallest sum on study/unequivocal progression of non-target lesions/new lesions. As specified in SAP, CBR was in RET-fusion CNS metastases sub-population only. Hence only NSCLC arms are presented here. Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants. -0.9999 and 9999=95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment
Number of subjects analysed	13	1	1
Units: percentage of participants
number (confidence interval 95%)	61.5 (31.6 to 86.1)	100 (2.5 to 100)	0 (-0.9999 to 9999)

No statistical analyses for this end point

Secondary: Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants

Top of page

End point title

Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants

End point description

DCR=percentage of participants with a confirmed CR/PR, or SD. CR=disappearance of all target CNS/brain lesions (including brainstem/cerebellum) & non-target lesions identified at baseline, with no new CNS/brain lesions. PR=at least 30% decrease in SOD of any CNS/brain lesion identified as RECIST 1.1 target lesions, with no progression of non-target CNS/brain lesions/new lesions. SD=neither sufficient shrinkage for PR or increase for PD for target/non-target CNS/brain lesion, with reference to smallest SOD on study. PD=≥20% increase in SOD of target CNS/brain lesions, reference to smallest sum on study/unequivocal progression of non-target lesions/new lesions. As specified in SAP, DCR was assessed in RET-fusion CNS metastases sub-population (participants with CNS metastases) only. Hence only NSCLC arms are presented. Phase 1 participants treated at 400 mg are pooled with Phase 2 participants. -0.9999&9999=95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment
Number of subjects analysed	13	1	1
Units: percentage of participants
number (confidence interval 95%)	76.9 (46.2 to 95.0)	100 (2.5 to 100)	0 (-0.9999 to 9999)

No statistical analyses for this end point

Secondary: Phase 2: Intracranial DOR in RET-fusion Positive NSCLC CNS Metastases Participants

Top of page

End point title

Phase 2: Intracranial DOR in RET-fusion Positive NSCLC CNS Metastases Participants

End point description

DOR=time from first documented CR/PR to the date of first documented PD/death due to any cause, whichever occurs first. CR and PR were defined per RECIST as outlined in the description for endpoint 23. PD=either at least 20% increase in SOD of target CNS/brain lesion, taking as reference smallest sum on study. Unequivocal progression of any CNS/brain lesion nontarget lesions at baseline, or identification of new CNS/brain lesion. DOR was analyzed using the KM methods. RAMD population. As specified in SAP, DOR was to be assessed in RET-fusion CNS metastases sub-population only. Hence only NSCLC arms are presented here. Participants with a CR/PR were assessed for this OM. Phase 1 participants treated at 400 mg QD are pooled with Phase 2 participants for efficacy analysis. 9999=upper limit of 95% CI was not estimable due to insufficient number of participants with events. -0.9999=lower limit of 95% CI was not estimable due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Up to approximately 79.8 months

End point values	RET- fusion Positive NSCLC With Prior Platinum Treatment	RET-fusion Positive NSCLC With Non-platinum Systemic Treatment	RET-fusion NSCLC With No Prior Systemic/Platinum Treatment
Number of subjects analysed	7	1	0 ^[5]
Units: months
median (confidence interval 95%)	28.3 (10.5 to 9999)	11.3 (-0.9999 to 9999)	( to )

Notes
[5] - No participants in this arm exhibited a CR/PR.

No statistical analyses for this end point

Secondary: Phase 1: Maximum Plasma Concentration (Cmax)

Top of page

End point title

Phase 1: Maximum Plasma Concentration (Cmax) ^[6]

End point description

Pharmacokinetic (PK)-evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. n=number of participants with data available for analysis at the specified timepoint. 9999=Values were LTR for 1 participant. Since data was evaluable only for 1 participant geometric co-efficient of variation was not evaluable. 99999=Since data was available only for 1 participant geometric co-efficient of variation was not evaluable.

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report PK data for Phase I of the study.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	6	5	13	11	12	4	6	3
Units: nanograms per milliliters (ng/mL)
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1(n=2,6,5,13,11,12,4,6,3)	346 ( 9999 )	335 ( 52.8 )	198 ( 99.8 )	459 ( 52.3 )	688 ( 53.3 )	1210 ( 85.3 )	1820 ( 63.8 )	569 ( 42.0 )	715 ( 64.1 )
Cycle 1 Day 15(n=1,6,3,12,9,10,2,5,2)	130 ( 99999 )	420 ( 56.9 )	586 ( 47.8 )	525 ( 72.5 )	1390 ( 35.3 )	1930 ( 66.7 )	4330 ( 9999 )	1080 ( 43.8 )	1780 ( 9999 )

No statistical analyses for this end point

Secondary: Phase 1: Time to Maximum Plasma Concentration (Tmax)

Top of page

End point title

Phase 1: Time to Maximum Plasma Concentration (Tmax) ^[7]

End point description

PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. n=number of participants with data available for analysis at the specified timepoint.

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report PK data for Phase I of the study.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	6	5	13	11	12	4	6	3
Units: hour
median (full range (min-max))
Cycle 1 Day 1(n=2,6,5,13,11,12,4,6,3)	3.04 (2.08 to 4.00)	2.04 (1.98 to 4.00)	2.03 (2.00 to 6.03)	2.07 (0.983 to 7.98)	2.02 (1.72 to 7.90)	3.00 (2.00 to 6.03)	2.00 (2.00 to 2.00)	12.5 (12.2 to 14.8)	12.0 (2.07 to 12.3)
Cycle 1 Day 15(n=1,6,3,12,9,10,2,5,2)	1.87 (1.87 to 1.87)	2.00 (1.97 to 4.13)	3.97 (3.90 to 4.00)	2.97 (1.05 to 4.08)	2.23 (0.983 to 24.0)	3.03 (2.00 to 7.85)	6.00 (4.00 to 8.00)	2.00 (0.500 to 3.95)	4.03 (1.98 to 6.08)

No statistical analyses for this end point

Secondary: Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast)

Top of page

End point title

Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast) ^[8]

End point description

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report PK data for Phase I of the study.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	6	5	13	11	12	4	6	3
Units: hours
median (full range (min-max))
Cycle 1 Day 1(n=2,6,5,13,11,12,4,6,3)	24.0 (24.0 to 24.0)	24.0 (23.1 to 24.4)	24.0 (7.88 to 24.1)	24.0 (21.9 to 25.7)	23.8 (7.88 to 24.0)	23.8 (22.6 to 24.6)	23.9 (23.4 to 24.0)	12.5 (12.2 to 14.8)	12.3 (12.0 to 14.4)
Cycle 1 Day 15(n=1,6,3,12,9,10,2,5,2)	23.8 (23.8 to 23.8)	24.1 (23.9 to 24.4)	24.3 (23.6 to 27.8)	24.0 (8.00 to 26.6)	24.0 (22.2 to 24.8)	24.0 (7.38 to 25.4)	24.1 (24.0 to 24.2)	12.2 (7.88 to 15.7)	12.5 (10.1 to 14.8)

No statistical analyses for this end point

Secondary: Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24)

Top of page

End point title

Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24) ^[9]

End point description

End point type

Secondary

End point timeframe

24 hours postdose on Day 1 (1 cycle = 28 days)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report PK data for Phase I of the study.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	6	3	11	6	8	3	0 ^[10]	0 ^[11]
Units: hours-nanograms/milliliters(hr-ng/mL)
geometric mean (geometric coefficient of variation)	4450 ( 9999 )	3620 ( 50.8 )	3010 ( 84.8 )	5260 ( 46.2 )	8470 ( 54.5 )	14700 ( 60.3 )	27700 ( 94.1 )	( )	( )

Notes
[10] - No participants in this arm were available for PK analysis.
[11] - No participants in this arm were available for PK analysis.

No statistical analyses for this end point

Secondary: Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr)

Top of page

End point title

Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr) ^[12]

End point description

PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Number analysed is the number of participants with data available for analysis. n=number of participants with data available for analysis at the specified timepoint. 9999=Values were LTR for 1 participant. Since data was evaluable only for 1 participant geometric co-efficient of variation was not evaluable. 99999=since data was available only for 1 participant geometric co-efficient of variation was not evaluable.

End point type

Secondary

End point timeframe

24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report PK data for Phase I of the study.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	6	3	11	9	8	3	0 ^[13]	0 ^[14]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=2,6,3,11,6,8,3,0,0)	110 ( 9999 )	69.2 ( 81.0 )	65.8 ( 59.6 )	104 ( 76.6 )	221 ( 64.2 )	376 ( 74.1 )	715 ( 75.9 )	( )	( )
Cycle 1 Day 15 (n=1,6,3,10,9,8,2,0,0)	55.9 ( 99999 )	94.2 ( 123 )	175 ( 31.3 )	137 ( 132 )	713 ( 42.2 )	977 ( 107 )	1950 ( 9999 )	( )	( )

Notes
[13] - No participants in this arm were available for PK analysis.
[14] - No participants in this arm were available for PK analysis.

No statistical analyses for this end point

Secondary: Phase 1: Apparent Volume of Distribution (Vz/F)

Top of page

End point title

Phase 1: Apparent Volume of Distribution (Vz/F) ^[15]

End point description

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report PK data for Phase I of the study.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	5	3	10	5	7	3	0 ^[16]	0 ^[17]
Units: liters
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1(n=2,5,3,10,5,7,3,0,0)	96.1 ( 9999 )	230 ( 37.1 )	458 ( 125 )	499 ( 50.8 )	543 ( 82.6 )	430 ( 62.6 )	350 ( 115 )	( )	( )
Cycle 1 Day 15(1,4,3,9,5,5,1,0,0)	355 ( 99999 )	171 ( 176 )	232 ( 43.7 )	622 ( 67.3 )	367 ( 86.6 )	418 ( 19.9 )	181 ( 99999 )	( )	( )

Notes
[16] - No participants in this arm were available for PK analysis.
[17] - No participants in this arm were available for PK analysis.

No statistical analyses for this end point

Secondary: Phase 1: Terminal Elimination Half‑life (t½)

Top of page

End point title

Phase 1: Terminal Elimination Half‑life (t½) ^[18]

End point description

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report PK data for Phase I of the study.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	5	3	10	5	7	3	0 ^[19]	1
Units: hours
median (full range (min-max))
Cycle 1 Day 1 (n=2,5,3,10,5,7,3,0,1)	16.3 (11.8 to 20.8)	9.87 (8.98 to 18.3)	14.3 (8.12 to 31.5)	12.6 (6.69 to 34.9)	12.2 (9.53 to 34.5)	16.5 (10.2 to 48.7)	19.7 (12.8 to 36.1)	( to )	10.7 (10.7 to 10.7)
Cycle 1 Day 15(n=1,4,3,9,5,5,1,0,0)	17.6 (17.6 to 17.6)	8.10 (5.25 to 39.6)	13.4 (12.5 to 14.4)	13.2 (10.1 to 21.8)	20.4 (9.91 to 27.3)	20.9 (9.21 to 33.6)	13.0 (13.0 to 13.0)	( to )	9999 (9999 to 9999)

Notes
[19] - No participants in this arm were available for PK analysis.

No statistical analyses for this end point

Secondary: Phase 1: Apparent Oral Clearance (CL/F)

Top of page

End point title

Phase 1: Apparent Oral Clearance (CL/F) ^[20]

End point description

PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Number analysed is the number of participants with data available for analysis. n=number of participants with data available for analysis at the specified timepoint. 9999=Values were LTR for 1 participant. Since data was evaluable only for 1 participant geometric co-efficient of variation was not evaluable. 99999=Since data was available only for 1 participant geometric co-efficient of variation was not evaluable.

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report PK data for Phase I of the study.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	6	3	10	9	8	3	0 ^[21]	0 ^[22]
Units: liters per hour (L/hr)
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1(n=2,5,3,10,5,7,3,0,0)	4.26 ( 9999 )	14.7 ( 42.3 )	20.6 ( 48.1 )	27.3 ( 60.3 )	23.3 ( 40.2 )	15.2 ( 88.1 )	11.6 ( 81.3 )	( )	( )
Cycle 1 Day 15(n=1,6,3,10,9,8,2,0,0)	14.0 ( 99999 )	11.3 ( 51.2 )	12.0 ( 38.9 )	31.4 ( 97.8 )	13.2 ( 33.0 )	11.1 ( 72.2 )	8.57 ( 9999 )	( )	( )

Notes
[21] - No participants in this arm were available for PK analysis.
[22] - No participants in this arm were available for PK analysis.

No statistical analyses for this end point

Secondary: Phase 1: Accumulation Ratio for Cmax (RCmax)

Top of page

End point title

Phase 1: Accumulation Ratio for Cmax (RCmax) ^[23]

End point description

PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Number analyzed is the number of participants with data available for analysis. 9999=Since data was available only for 1 participant geometric co-efficient of variation was not evaluable. 99999=Values were LTR for 1 participant. Since data was evaluable only for 1 participant geometric co-efficient of variation was not evaluable.

End point type

Secondary

End point timeframe

24 hours postdose on Day 15 of Cycle 1 (1 cycle = 28 days)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report PK data for Phase I of the study.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	1	6	3	12	9	10	2	4	1
Units: ratio
geometric mean (geometric coefficient of variation)	1.04 ( 9999 )	1.25 ( 27.6 )	3.20 ( 114 )	1.17 ( 110 )	1.87 ( 40.5 )	1.62 ( 102 )	2.97 ( 99999 )	1.91 ( 40.7 )	1.41 ( 9999 )

No statistical analyses for this end point

Secondary: Phase 1: Accumulation Ratio for AUC (RAUC)

Top of page

End point title

Phase 1: Accumulation Ratio for AUC (RAUC) ^[24]

End point description

PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Number analysed is the number of participants with data available for analysis. 9999=since data was available only for 1 participant geometric co-efficient of variation was not evaluable. 99999=Values were LTR for 1 participant. Since data was evaluable only for 1 participant geometric co-efficient of variation was not evaluable.

End point type

Secondary

End point timeframe

24 hours postdose on Day 15 of Cycle 1 (1 cycle = 28 days)

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report PK data for Phase I of the study.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	1	6	1	8	4	6	1	2	1
Units: ratio
geometric mean (geometric coefficient of variation)	1.43 ( 9999 )	1.47 ( 11.1 )	3.22 ( 9999 )	1.31 ( 147 )	2.33 ( 11.4 )	2.75 ( 70.9 )	2.48 ( 9999 )	4.28 ( 99999 )	1.21 ( 9999 )

No statistical analyses for this end point

Secondary: Phase 2: Cmax

Top of page

End point title

Phase 2: Cmax

End point description

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

End point values	RET- fusion Positive NSCLC Participants	Tumor-agnostic Participants	RET-altered Solid Tumors Participants	RET-mutation Positive Tumors other than MTC Participants
Number of subjects analysed	98	5	3	4
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1(n=98,5,0,3,4)	1680 ( 69.4 )	1380 ( 65.4 )	2450 ( 164 )	1770 ( 87.2 )
Cycle 1 Day 15(n=87,5,0,3,4)	2840 ( 50.7 )	2200 ( 36.7 )	3440 ( 93.9 )	2430 ( 55.3 )

No statistical analyses for this end point

Secondary: Phase 2: Tmax

Top of page

End point title

Phase 2: Tmax

End point description

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

End point values	RET- fusion Positive NSCLC Participants	Tumor-agnostic Participants	RET-altered Solid Tumors Participants	RET-mutation Positive Tumors other than MTC Participants
Number of subjects analysed	98	5	3	4
Units: hours
median (full range (min-max))
Cycle 1 Day 1(n=98,5,0,3,4)	4.00 (1.90 to 23.7)	3.90 (2.0 to 6.0)	4.0 (4.0 to 6.0)	2.05 (2 to 8)
Cycle 1 Day 15(n=87,5,0,3,4)	4.00 (1.00 to 8.10)	5.00 (2.0 to 8.0)	4.00 (2.00 to 6.00)	3.05 (2 to 6)

No statistical analyses for this end point

Secondary: Phase 2: Tlast

Top of page

End point title

Phase 2: Tlast

End point description

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

End point values	RET- fusion Positive NSCLC Participants	Tumor-agnostic Participants	RET-altered Solid Tumors Participants	RET-mutation Positive Tumors other than MTC Participants
Number of subjects analysed	98	5	3	4
Units: hours
median (full range (min-max))
Cycle 1 Day 1(n=98,5,0,3,4)	23.9 (2.40 to 24.8)	8.00 (7.8 to 23.5)	23.10 (8.0 to 24.0)	8.05 (8.0 to 24.0)
Cycle 1 Day 15(n=87,5,0,3,4)	23.8 (7.80 to 26.5)	23.70 (7.9 to 24.0)	24.00 (7.9 to 24.0)	24.00 (23.8 to 24.0)

No statistical analyses for this end point

Secondary: Phase 2: AUC0-24

Top of page

End point title

Phase 2: AUC0-24

End point description

PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Number analysed is the number of participants with data available for analysis. n=number of participants with data available for analysis at the specified timepoint. 9999=Since data was available only for 1 participant geometric co-efficient of variation was not evaluable.

End point type

Secondary

End point timeframe

24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

End point values	RET- fusion Positive NSCLC Participants	Tumor-agnostic Participants	RET-altered Solid Tumors Participants	RET-mutation Positive Tumors other than MTC Participants
Number of subjects analysed	70	3	2	4
Units: hr-ng/ mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n=70,2,0,1,3)	20400 ( 64.2 )	17400 ( 152 )	103000 ( 9999 )	18400 ( 69.8 )
Cycle 1 Day 15(n=50,3,0,2,4)	40100 ( 59.5 )	33900 ( 27.4 )	91100 ( 46.8 )	32000 ( 90.8 )

No statistical analyses for this end point

Secondary: Phase 2: C24hr

Top of page

End point title

Phase 2: C24hr

End point description

End point type

Secondary

End point timeframe

24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

End point values	RET- fusion Positive NSCLC Participants	Tumor-agnostic Participants	RET-altered Solid Tumors Participants	RET-mutation Positive Tumors other than MTC Participants
Number of subjects analysed	92	5	3	4
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1(n=92,5,0,3,3)	540 ( 75.4 )	519 ( 197 )	1020 ( 225 )	415 ( 140 )
Cycle 1 Day 15(n=82,5,0,2,4)	1150 ( 69 )	797 ( 42.8 )	1400 ( 207 )	1050 ( 94.0 )

No statistical analyses for this end point

Secondary: Phase 2: t½

Top of page

End point title

Phase 2: t½

End point description

PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Number analysed is the number of participants with data available for analysis. n=number of participants with data available for analysis at the specified timepoint. 9999=since data was available only for 1 participant geometric co-efficient of variation was not evaluable.

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

End point values	RET- fusion Positive NSCLC Participants	Tumor-agnostic Participants	RET-altered Solid Tumors Participants	RET-mutation Positive Tumors other than MTC Participants
Number of subjects analysed	57	2	1	3
Units: hours
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1(n=57,2,0,1,3)	13.4 ( 44.1 )	18.4 ( 98.8 )	20.8 ( 9999 )	11.0 ( 55.8 )
Cycle 1 Day 15(n=47,2,0,1,2)	17.9 ( 58.8 )	16.5 ( 44.6 )	25.8 ( 9999 )	63.0 ( 882 )

No statistical analyses for this end point

Secondary: Phase 2: CL/F

Top of page

End point title

Phase 2: CL/F

End point description

PK evaluable population included all participants who received at least one dose of pralsetinib and from whom at least one post dose PK sample was collected. Number analysed is the number of participants with data available for analysis. n=number of participants with data available for analysis at the specified timepoint. 9999=since data was available only for 1 participant geometric co-efficient of variation was not evaluable.

End point type

Secondary

End point timeframe

Predose on 0.5, 1, 2, 4, 6, 8 and 24 hours postdose on Days 1 and 15 of Cycle 1 (1 cycle = 28 days)

End point values	RET- fusion Positive NSCLC Participants	Tumor-agnostic Participants	RET-altered Solid Tumors Participants	RET-mutation Positive Tumors other than MTC Participants
Number of subjects analysed	47	2	1	3
Units: liters per hour (L/hr)
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1(n=30,2,0,1,3)	13.4 ( 56.8 )	12.7 ( 347 )	2.00 ( 9999 )	16.1 ( 43.3 )
Cycle 1 Day 15(n=47,2,0,1,2)	9.91 ( 58.9 )	7.49 ( 64.4 )	2.92 ( 9999 )	1.39 ( 1220 )

No statistical analyses for this end point

Secondary: Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6)

Top of page

End point title

Phase 1: Percent Change From Baseline in Dual Specificity Phosphatase 6 (DUSP6) ^[25]

End point description

The dose dependent change in a mitogen-activated protein kinases (MAPK) pathway expression signature was analyzed for all available samples of MTC and NSCLC participants. Participants with archived sample (used as baseline) and on treatment Cycle 2 Day 1 (1 cycle = 28 days) tumor tissues with greater than 20% tumor cells are included in the analysis. The changes in tumor biomarker DUSP6 levels was explored. Safety Population included all participants who have received at least 1 dose of the study drug regardless of starting dose levels. Participants are presented per the planned treatment arm for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 4

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report data for Phase I of the study only. Hence, Phase II arm is not included.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	6	5	13	11	12	4	5	4
Units: percent change
arithmetic mean (standard deviation)	0 ( 0 )	54.26 ( 88.318 )	0 ( 0 )	-20.27 ( 42.971 )	-74.87 ( 15.707 )	-13.32 ( 82.394 )	0 ( 0 )	-81.57 ( 3.057 )	-61.96 ( 39.141 )

No statistical analyses for this end point

Secondary: Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4)

Top of page

End point title

Phase 1: Percent Change From Baseline in Sprout Receptor Tyrosine Kinase Signaling Antagonist 4 (SPRY4) ^[26]

End point description

The dose dependent change in a MAPK pathway expression signature was analyzed for all available samples of MTC and NSCLC participants. Participants with archived sample (used as baseline) and on treatment Cycle 2 Day 1 (1 cycle = 28 days) tumor tissues with greater than 20% tumor cells are included in the analysis. The changes in tumor biomarker SPRY4 levels was explored. Safety Population included all participants who have received at least 1 dose of the study drug regardless of starting dose levels. Participants are presented per the planned treatment arm for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 4

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned to report data for Phase I of the study only. Hence, Phase II arm is not included.

End point values	Phase I: Pralsetinib 30 mg	Phase I: Pralsetinib 60 mg	Phase I: Pralsetinib 100 mg	Phase I: Pralsetinib 200 mg	Phase I: Pralsetinib 300 mg	Phase I: Pralsetinib 400 mg	Phase I: Pralsetinib 600 mg	Phase I: Pralsetinib 100/100 mg	Phase I: Pralsetinib 200/100 mg
Number of subjects analysed	2	6	5	13	11	12	4	5	4
Units: percent change
arithmetic mean (standard deviation)	0 ( 0 )	210.16 ( 309.468 )	0 ( 0 )	-34.98 ( 29.569 )	-69.00 ( 28.731 )	-3.26 ( 99.349 )	0 ( 0 )	-75.65 ( 10.944 )	124.93 ( 311.210 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

AEs and SAEs: From Cycle 1 Day 1 up to 30 days after the final dose of study drug (up to approximately 6.7 years) All-cause Mortality: Up to approximately 7 years

Adverse event reporting additional description

Safety Population included all participants who have received at least 1 dose of the study drug regardless of starting dose levels. As pre-specified in the SAP, safety data was to be analyzed and reported as per the pre-planned grouped dose level II (SAP section 3.6.5.2). Hence, per dose safety data is not presented for this study.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Pralsetinib ≤ 300 mg QD

Reporting group description

Participants received pralsetinib, 300 mg or less, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Pralsetinib All Doses

Reporting group description

Participants received pralsetinib at varying doses at the QD and BID schedule until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Pralsetinib BID Dosing Schedule

Reporting group description

Participants received pralsetinib, 100 mg, orally, BID or 200 mg in the morning and then 100 mg in the evening, orally, until discontinuation due to toxicity, disease progression, or other reasons.

Reporting group title

Pralsetinib 400 mg QD

Reporting group description

Participants received pralsetinib, 400 mg, orally, QD until discontinuation due to toxicity, disease progression, or other reasons.

Serious adverse events	Pralsetinib ≤ 300 mg QD	Pralsetinib All Doses	Pralsetinib BID Dosing Schedule	Pralsetinib 400 mg QD
Total subjects affected by serious adverse events
subjects affected / exposed	26 / 37 (70.27%)	416 / 590 (70.51%)	7 / 9 (77.78%)	381 / 540 (70.56%)
number of deaths (all causes)	15	268	7	245
number of deaths resulting from adverse events	0	10	0	9
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Diffuse large B-cell lymphoma
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder cancer
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung cancer metastatic
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
Anaplastic large-cell lymphoma
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Bone neoplasm
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Brain neoplasm
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Medullary thyroid cancer
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
Non-small cell lung cancer
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Neoplasm progression
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Neoplasm malignant
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Metastatic neoplasm
subjects affected / exposed	0 / 37 (0.00%)	7 / 590 (1.19%)	0 / 9 (0.00%)	7 / 540 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 7	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
Metastasis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	0 / 37 (0.00%)	6 / 590 (1.02%)	0 / 9 (0.00%)	6 / 540 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 37 (2.70%)	27 / 590 (4.58%)	0 / 9 (0.00%)	26 / 540 (4.81%)
occurrences causally related to treatment / all	0 / 1	0 / 31	0 / 0	0 / 30
deaths causally related to treatment / all	0 / 1	0 / 22	0 / 0	0 / 21
Malignant neoplasm progression
subjects affected / exposed	1 / 37 (2.70%)	5 / 590 (0.85%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 4	0 / 0	0 / 3
Malignant pleural effusion
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paraneoplastic syndrome
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour necrosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid cancer metastatic
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
Thyroid cancer
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
Vascular disorders
Peripheral embolism
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Haematoma
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 37 (0.00%)	8 / 590 (1.36%)	0 / 9 (0.00%)	8 / 540 (1.48%)
occurrences causally related to treatment / all	0 / 0	5 / 9	0 / 0	5 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	2 / 4	0 / 0	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Internal haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jugular vein thrombosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Peripheral ischaemia
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Spinal decompression
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Calcinosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Face oedema
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug withdrawal syndrome
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Malaise
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Granuloma
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Fatigue
subjects affected / exposed	1 / 37 (2.70%)	4 / 590 (0.68%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 1	2 / 5	0 / 0	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Condition aggravated
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 37 (0.00%)	6 / 590 (1.02%)	0 / 9 (0.00%)	6 / 540 (1.11%)
occurrences causally related to treatment / all	0 / 0	2 / 6	0 / 0	2 / 6
deaths causally related to treatment / all	0 / 0	2 / 6	0 / 0	2 / 6
Disease progression
subjects affected / exposed	0 / 37 (0.00%)	10 / 590 (1.69%)	0 / 9 (0.00%)	10 / 540 (1.85%)
occurrences causally related to treatment / all	0 / 0	0 / 10	0 / 0	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 5	0 / 0	0 / 5
Oedema peripheral
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 37 (0.00%)	15 / 590 (2.54%)	0 / 9 (0.00%)	15 / 540 (2.78%)
occurrences causally related to treatment / all	0 / 0	5 / 21	0 / 0	5 / 21
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Performance status decreased
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Abnormal uterine bleeding
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Heavy menstrual bleeding
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 37 (0.00%)	10 / 590 (1.69%)	0 / 9 (0.00%)	10 / 540 (1.85%)
occurrences causally related to treatment / all	0 / 0	1 / 14	0 / 0	1 / 14
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
Cough
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chylothorax
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asphyxia
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
Laryngeal oedema
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 37 (0.00%)	6 / 590 (1.02%)	0 / 9 (0.00%)	6 / 540 (1.11%)
occurrences causally related to treatment / all	0 / 0	9 / 12	0 / 0	9 / 12
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
Acute respiratory failure
subjects affected / exposed	0 / 37 (0.00%)	6 / 590 (1.02%)	1 / 9 (11.11%)	5 / 540 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
Pneumothorax spontaneous
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 37 (0.00%)	6 / 590 (1.02%)	0 / 9 (0.00%)	5 / 540 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis aspiration
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Pneumonitis
subjects affected / exposed	2 / 37 (5.41%)	29 / 590 (4.92%)	0 / 9 (0.00%)	27 / 540 (5.00%)
occurrences causally related to treatment / all	3 / 3	32 / 35	0 / 0	29 / 32
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
Pleural effusion
subjects affected / exposed	2 / 37 (5.41%)	14 / 590 (2.37%)	1 / 9 (11.11%)	11 / 540 (2.04%)
occurrences causally related to treatment / all	0 / 2	0 / 15	0 / 1	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung consolidation
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	4 / 37 (10.81%)	12 / 590 (2.03%)	0 / 9 (0.00%)	8 / 540 (1.48%)
occurrences causally related to treatment / all	0 / 4	0 / 12	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	2 / 37 (5.41%)	9 / 590 (1.53%)	1 / 9 (11.11%)	6 / 540 (1.11%)
occurrences causally related to treatment / all	0 / 2	2 / 10	0 / 1	2 / 7
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 2
Respiratory distress
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 37 (2.70%)	3 / 590 (0.51%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device issue
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 37 (0.00%)	5 / 590 (0.85%)	0 / 9 (0.00%)	5 / 540 (0.93%)
occurrences causally related to treatment / all	0 / 0	4 / 5	0 / 0	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	3 / 4	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bilirubin conjugated increased
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inflammatory marker increased
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphocyte count decreased
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	15 / 15	0 / 0	15 / 15
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Chemical peritonitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 7	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 37 (2.70%)	3 / 590 (0.51%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seroma
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 7	0 / 0	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Radiation pneumonitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pneumothorax
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immunisation reaction
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periprosthetic fracture
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis radiation
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic haematoma
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Angina pectoris
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stress cardiomyopathy
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 37 (2.70%)	4 / 590 (0.68%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 2	0 / 5	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Myocardial injury
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Cardiac failure congestive
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac discomfort
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Cardiac arrest
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Bradycardia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral infarction
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Cerebral haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haematoma
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ataxia
subjects affected / exposed	1 / 37 (2.70%)	3 / 590 (0.51%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Epilepsy
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 37 (0.00%)	5 / 590 (0.85%)	0 / 9 (0.00%)	5 / 540 (0.93%)
occurrences causally related to treatment / all	0 / 0	1 / 6	0 / 0	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant spinal cord compression
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord paralysis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertebral artery thrombosis
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 37 (0.00%)	7 / 590 (1.19%)	0 / 9 (0.00%)	7 / 540 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 10	0 / 0	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Radiculopathy
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radicular pain
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Polyneuropathy chronic
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia of malignant disease
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia macrocytic
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	1 / 37 (2.70%)	34 / 590 (5.76%)	1 / 9 (11.11%)	32 / 540 (5.93%)
occurrences causally related to treatment / all	0 / 1	33 / 52	0 / 1	33 / 50
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood loss anaemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Eosinophilia
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 37 (0.00%)	5 / 590 (0.85%)	0 / 9 (0.00%)	5 / 540 (0.93%)
occurrences causally related to treatment / all	0 / 0	5 / 6	0 / 0	5 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	62 / 62	0 / 0	62 / 62
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bicytopenia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 37 (0.00%)	8 / 590 (1.36%)	0 / 9 (0.00%)	8 / 540 (1.48%)
occurrences causally related to treatment / all	0 / 0	11 / 11	0 / 0	11 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphopenia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Keratitis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	1 / 9 (11.11%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 37 (0.00%)	8 / 590 (1.36%)	1 / 9 (11.11%)	7 / 540 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 1	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal mass
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aphthous ulcer
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	2 / 37 (5.41%)	9 / 590 (1.53%)	0 / 9 (0.00%)	7 / 540 (1.30%)
occurrences causally related to treatment / all	0 / 2	4 / 9	0 / 0	4 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 37 (2.70%)	5 / 590 (0.85%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 1	3 / 7	0 / 0	3 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 37 (0.00%)	6 / 590 (1.02%)	0 / 9 (0.00%)	6 / 540 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Noninfective sialoadenitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 37 (5.41%)	3 / 590 (0.51%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	8 / 590 (1.36%)	1 / 9 (11.11%)	7 / 540 (1.30%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 1	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	1 / 9 (11.11%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	3 / 4	0 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal perforation
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumoperitoneum
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 5	0 / 0	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 37 (5.41%)	7 / 590 (1.19%)	0 / 9 (0.00%)	5 / 540 (0.93%)
occurrences causally related to treatment / all	0 / 3	0 / 8	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Proctitis ulcerative
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 37 (2.70%)	8 / 590 (1.36%)	0 / 9 (0.00%)	7 / 540 (1.30%)
occurrences causally related to treatment / all	0 / 1	0 / 9	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver injury
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	4 / 4	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
Liver disorder
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertransaminasaemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	4 / 4	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subcapsular hepatic haematoma
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus urinary
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	1 / 37 (2.70%)	6 / 590 (1.02%)	0 / 9 (0.00%)	5 / 540 (0.93%)
occurrences causally related to treatment / all	0 / 1	2 / 7	0 / 0	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive nephropathy
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypercalcaemia of malignancy
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adrenal insufficiency
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 37 (5.41%)	6 / 590 (1.02%)	1 / 9 (11.11%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 2	0 / 6	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 37 (0.00%)	9 / 590 (1.53%)	0 / 9 (0.00%)	9 / 540 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 11	0 / 0	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma muscle
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest wall haematoma
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 37 (0.00%)	8 / 590 (1.36%)	0 / 9 (0.00%)	8 / 540 (1.48%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
Rotator cuff syndrome
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal disorder
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Arthritis infective
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute sinusitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal infection
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atypical mycobacterial pneumonia
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronavirus infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 37 (2.70%)	4 / 590 (0.68%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 3	0 / 6	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	1 / 4	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	1 / 37 (2.70%)	14 / 590 (2.37%)	0 / 9 (0.00%)	13 / 540 (2.41%)
occurrences causally related to treatment / all	0 / 1	0 / 19	0 / 0	0 / 18
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
COVID-19
subjects affected / exposed	1 / 37 (2.70%)	17 / 590 (2.88%)	0 / 9 (0.00%)	16 / 540 (2.96%)
occurrences causally related to treatment / all	0 / 1	0 / 19	0 / 0	0 / 18
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis bacterial
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 37 (2.70%)	9 / 590 (1.53%)	0 / 9 (0.00%)	8 / 540 (1.48%)
occurrences causally related to treatment / all	0 / 1	0 / 9	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterobacter bacteraemia
subjects affected / exposed	1 / 37 (2.70%)	1 / 590 (0.17%)	0 / 9 (0.00%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterococcal bacteraemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis intestinal perforated
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	3 / 37 (8.11%)	6 / 590 (1.02%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 3	0 / 6	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella urinary tract infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymph node tuberculosis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	2 / 4	0 / 0	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemophilus infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis B reactivation
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal candidiasis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis enterococcal
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	5 / 37 (13.51%)	94 / 590 (15.93%)	1 / 9 (11.11%)	87 / 540 (16.11%)
occurrences causally related to treatment / all	0 / 5	30 / 127	0 / 1	29 / 120
deaths causally related to treatment / all	0 / 1	3 / 13	0 / 0	2 / 11
Osteomyelitis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic abscess
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 37 (2.70%)	6 / 590 (1.02%)	0 / 9 (0.00%)	5 / 540 (0.93%)
occurrences causally related to treatment / all	0 / 1	5 / 7	0 / 0	5 / 6
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
Meningitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Pneumonia legionella
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia influenzal
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	1 / 9 (11.11%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia haemophilus
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia cytomegaloviral
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Pneumonia bacterial
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
Pneumonia staphylococcal
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psoas abscess
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomembranous colitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal tuberculosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scrotal cellulitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 37 (5.41%)	25 / 590 (4.24%)	3 / 9 (33.33%)	20 / 540 (3.70%)
occurrences causally related to treatment / all	0 / 2	4 / 30	0 / 5	4 / 23
deaths causally related to treatment / all	0 / 0	0 / 5	0 / 1	0 / 4
Septic arthritis staphylococcal
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spontaneous bacterial peritonitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis bacterial
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis aspergillus
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	2 / 4	0 / 0	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 37 (5.41%)	26 / 590 (4.41%)	1 / 9 (11.11%)	23 / 540 (4.26%)
occurrences causally related to treatment / all	0 / 2	4 / 43	0 / 1	4 / 40
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Varicella
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	0 / 9 (0.00%)	2 / 540 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	4 / 4	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	1 / 37 (2.70%)	5 / 590 (0.85%)	0 / 9 (0.00%)	4 / 540 (0.74%)
occurrences causally related to treatment / all	0 / 1	3 / 5	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour lysis syndrome
subjects affected / exposed	2 / 37 (5.41%)	3 / 590 (0.51%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences causally related to treatment / all	1 / 2	2 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pseudohyperkalaemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 37 (2.70%)	10 / 590 (1.69%)	1 / 9 (11.11%)	8 / 540 (1.48%)
occurrences causally related to treatment / all	0 / 1	2 / 16	0 / 1	2 / 14
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 37 (0.00%)	5 / 590 (0.85%)	0 / 9 (0.00%)	5 / 540 (0.93%)
occurrences causally related to treatment / all	0 / 0	3 / 8	0 / 0	3 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	0 / 9 (0.00%)	1 / 540 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	3 / 5	0 / 0	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	0 / 9 (0.00%)	3 / 540 (0.56%)
occurrences causally related to treatment / all	0 / 0	5 / 5	0 / 0	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Pralsetinib ≤ 300 mg QD	Pralsetinib All Doses	Pralsetinib BID Dosing Schedule	Pralsetinib 400 mg QD
Total subjects affected by non serious adverse events
subjects affected / exposed	36 / 37 (97.30%)	585 / 590 (99.15%)	9 / 9 (100.00%)	536 / 540 (99.26%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 37 (0.00%)	6 / 590 (1.02%)	1 / 9 (11.11%)	5 / 540 (0.93%)
occurrences all number	0	9	1	8
Skin papilloma
subjects affected / exposed	0 / 37 (0.00%)	5 / 590 (0.85%)	1 / 9 (11.11%)	4 / 540 (0.74%)
occurrences all number	0	8	2	6
Vascular disorders
Haematoma
subjects affected / exposed	0 / 37 (0.00%)	7 / 590 (1.19%)	1 / 9 (11.11%)	6 / 540 (1.11%)
occurrences all number	0	7	1	6
Vasodilatation
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	1	1	0
Hypotension
subjects affected / exposed	2 / 37 (5.41%)	15 / 590 (2.54%)	0 / 9 (0.00%)	13 / 540 (2.41%)
occurrences all number	2	18	0	16
Intermittent claudication
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	1	1	0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	0	2	1	1
Peripheral vascular disorder
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	0	2	1	1
Thrombosis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	0	2	1	1
Hypertension
subjects affected / exposed	9 / 37 (24.32%)	206 / 590 (34.92%)	4 / 9 (44.44%)	189 / 540 (35.00%)
occurrences all number	12	530	11	499
General disorders and administration site conditions
Peripheral swelling
subjects affected / exposed	4 / 37 (10.81%)	22 / 590 (3.73%)	1 / 9 (11.11%)	17 / 540 (3.15%)
occurrences all number	5	25	1	19
Oedema peripheral
subjects affected / exposed	9 / 37 (24.32%)	117 / 590 (19.83%)	4 / 9 (44.44%)	104 / 540 (19.26%)
occurrences all number	10	154	4	140
Non-cardiac chest pain
subjects affected / exposed	4 / 37 (10.81%)	27 / 590 (4.58%)	2 / 9 (22.22%)	21 / 540 (3.89%)
occurrences all number	4	28	2	22
Mucosal inflammation
subjects affected / exposed	3 / 37 (8.11%)	43 / 590 (7.29%)	0 / 9 (0.00%)	40 / 540 (7.41%)
occurrences all number	4	60	0	56
Malaise
subjects affected / exposed	0 / 37 (0.00%)	34 / 590 (5.76%)	0 / 9 (0.00%)	33 / 540 (6.11%)
occurrences all number	0	45	0	44
Localised oedema
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	1 / 9 (11.11%)	3 / 540 (0.56%)
occurrences all number	0	4	1	3
Fatigue
subjects affected / exposed	12 / 37 (32.43%)	169 / 590 (28.64%)	2 / 9 (22.22%)	154 / 540 (28.52%)
occurrences all number	17	309	2	289
Face oedema
subjects affected / exposed	1 / 37 (2.70%)	43 / 590 (7.29%)	0 / 9 (0.00%)	42 / 540 (7.78%)
occurrences all number	1	58	0	57
Chills
subjects affected / exposed	4 / 37 (10.81%)	32 / 590 (5.42%)	0 / 9 (0.00%)	28 / 540 (5.19%)
occurrences all number	4	34	0	30
Chest discomfort
subjects affected / exposed	1 / 37 (2.70%)	18 / 590 (3.05%)	1 / 9 (11.11%)	16 / 540 (2.96%)
occurrences all number	1	21	1	19
Calcinosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	2	2	0
Asthenia
subjects affected / exposed	1 / 37 (2.70%)	90 / 590 (15.25%)	0 / 9 (0.00%)	88 / 540 (16.30%)
occurrences all number	1	194	0	192
Pyrexia
subjects affected / exposed	7 / 37 (18.92%)	176 / 590 (29.83%)	3 / 9 (33.33%)	164 / 540 (30.37%)
occurrences all number	11	286	7	266
Reproductive system and breast disorders
Breast calcifications
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	1	1	0
Erectile dysfunction
subjects affected / exposed	2 / 37 (5.41%)	32 / 590 (5.42%)	0 / 9 (0.00%)	30 / 540 (5.56%)
occurrences all number	2	36	0	34
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional
subjects affected / exposed	1 / 37 (2.70%)	24 / 590 (4.07%)	1 / 9 (11.11%)	22 / 540 (4.07%)
occurrences all number	1	34	1	32
Cough
subjects affected / exposed	9 / 37 (24.32%)	161 / 590 (27.29%)	2 / 9 (22.22%)	149 / 540 (27.59%)
occurrences all number	11	236	2	222
Dysphonia
subjects affected / exposed	1 / 37 (2.70%)	49 / 590 (8.31%)	1 / 9 (11.11%)	47 / 540 (8.70%)
occurrences all number	1	57	1	55
Dyspnoea
subjects affected / exposed	12 / 37 (32.43%)	127 / 590 (21.53%)	2 / 9 (22.22%)	112 / 540 (20.74%)
occurrences all number	15	165	3	146
Epistaxis
subjects affected / exposed	2 / 37 (5.41%)	43 / 590 (7.29%)	0 / 9 (0.00%)	41 / 540 (7.59%)
occurrences all number	2	51	0	49
Oropharyngeal pain
subjects affected / exposed	4 / 37 (10.81%)	45 / 590 (7.63%)	0 / 9 (0.00%)	41 / 540 (7.59%)
occurrences all number	4	58	0	54
Pleural effusion
subjects affected / exposed	2 / 37 (5.41%)	18 / 590 (3.05%)	0 / 9 (0.00%)	16 / 540 (2.96%)
occurrences all number	2	38	0	36
Pneumonitis
subjects affected / exposed	7 / 37 (18.92%)	59 / 590 (10.00%)	1 / 9 (11.11%)	51 / 540 (9.44%)
occurrences all number	11	109	1	97
Productive cough
subjects affected / exposed	0 / 37 (0.00%)	36 / 590 (6.10%)	1 / 9 (11.11%)	35 / 540 (6.48%)
occurrences all number	0	40	1	39
Rhinorrhoea
subjects affected / exposed	1 / 37 (2.70%)	7 / 590 (1.19%)	1 / 9 (11.11%)	5 / 540 (0.93%)
occurrences all number	1	7	1	5
Upper respiratory tract congestion
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	1	1	0
Wheezing
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	1 / 9 (11.11%)	3 / 540 (0.56%)
occurrences all number	0	4	1	3
Nasal congestion
subjects affected / exposed	4 / 37 (10.81%)	24 / 590 (4.07%)	1 / 9 (11.11%)	19 / 540 (3.52%)
occurrences all number	4	27	1	22
Psychiatric disorders
Anxiety
subjects affected / exposed	4 / 37 (10.81%)	32 / 590 (5.42%)	0 / 9 (0.00%)	28 / 540 (5.19%)
occurrences all number	4	35	0	31
Depression
subjects affected / exposed	2 / 37 (5.41%)	21 / 590 (3.56%)	0 / 9 (0.00%)	19 / 540 (3.52%)
occurrences all number	2	22	0	20
Insomnia
subjects affected / exposed	2 / 37 (5.41%)	52 / 590 (8.81%)	2 / 9 (22.22%)	47 / 540 (8.70%)
occurrences all number	2	61	2	56
Investigations
Alanine aminotransferase increased
subjects affected / exposed	16 / 37 (43.24%)	232 / 590 (39.32%)	3 / 9 (33.33%)	212 / 540 (39.26%)
occurrences all number	31	495	4	459
Aspartate aminotransferase increased
subjects affected / exposed	17 / 37 (45.95%)	295 / 590 (50.00%)	3 / 9 (33.33%)	273 / 540 (50.56%)
occurrences all number	41	739	3	693
Blood alkaline phosphatase increased
subjects affected / exposed	8 / 37 (21.62%)	78 / 590 (13.22%)	1 / 9 (11.11%)	68 / 540 (12.59%)
occurrences all number	9	125	1	112
Blood bilirubin increased
subjects affected / exposed	2 / 37 (5.41%)	61 / 590 (10.34%)	1 / 9 (11.11%)	58 / 540 (10.74%)
occurrences all number	5	172	1	166
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 37 (0.00%)	97 / 590 (16.44%)	0 / 9 (0.00%)	97 / 540 (17.96%)
occurrences all number	0	445	0	445
Blood creatinine increased
subjects affected / exposed	11 / 37 (29.73%)	158 / 590 (26.78%)	3 / 9 (33.33%)	143 / 540 (26.48%)
occurrences all number	17	310	4	288
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 37 (0.00%)	47 / 590 (7.97%)	0 / 9 (0.00%)	47 / 540 (8.70%)
occurrences all number	0	72	0	72
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 37 (0.00%)	32 / 590 (5.42%)	0 / 9 (0.00%)	31 / 540 (5.74%)
occurrences all number	0	40	0	39
Electrocardiogram repolarisation abnormality
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	1	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 37 (0.00%)	38 / 590 (6.44%)	0 / 9 (0.00%)	38 / 540 (7.04%)
occurrences all number	0	108	0	108
Hepatic enzyme increased
subjects affected / exposed	2 / 37 (5.41%)	5 / 590 (0.85%)	1 / 9 (11.11%)	2 / 540 (0.37%)
occurrences all number	4	9	1	4
Lymphocyte count decreased
subjects affected / exposed	6 / 37 (16.22%)	98 / 590 (16.61%)	1 / 9 (11.11%)	90 / 540 (16.67%)
occurrences all number	18	379	3	345
Neutrophil count decreased
subjects affected / exposed	5 / 37 (13.51%)	153 / 590 (25.93%)	1 / 9 (11.11%)	146 / 540 (27.04%)
occurrences all number	16	558	1	539
Platelet count decreased
subjects affected / exposed	3 / 37 (8.11%)	72 / 590 (12.20%)	0 / 9 (0.00%)	67 / 540 (12.41%)
occurrences all number	5	173	0	166
Weight decreased
subjects affected / exposed	2 / 37 (5.41%)	38 / 590 (6.44%)	0 / 9 (0.00%)	36 / 540 (6.67%)
occurrences all number	2	52	0	50
Weight increased
subjects affected / exposed	2 / 37 (5.41%)	64 / 590 (10.85%)	0 / 9 (0.00%)	62 / 540 (11.48%)
occurrences all number	4	174	0	170
White blood cell count decreased
subjects affected / exposed	14 / 37 (37.84%)	175 / 590 (29.66%)	2 / 9 (22.22%)	157 / 540 (29.07%)
occurrences all number	41	636	3	579
Injury, poisoning and procedural complications
Abdominal injury
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	1	2	1	0
Fall
subjects affected / exposed	1 / 37 (2.70%)	21 / 590 (3.56%)	2 / 9 (22.22%)	18 / 540 (3.33%)
occurrences all number	2	26	3	21
Hip fracture
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	1	1	0
Incision site haematoma
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	1	1	0
Joint injury
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	0	3	2	1
Procedural nausea
subjects affected / exposed	1 / 37 (2.70%)	2 / 590 (0.34%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	1	2	1	0
Procedural pain
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	1 / 9 (11.11%)	3 / 540 (0.56%)
occurrences all number	0	4	1	3
Cardiac disorders
Left ventricular hypertrophy
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	1	1	0
Left ventricular dysfunction
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	0	2	1	1
Nervous system disorders
Hypoaesthesia
subjects affected / exposed	5 / 37 (13.51%)	40 / 590 (6.78%)	0 / 9 (0.00%)	35 / 540 (6.48%)
occurrences all number	5	51	0	46
Dizziness
subjects affected / exposed	7 / 37 (18.92%)	94 / 590 (15.93%)	2 / 9 (22.22%)	83 / 540 (15.37%)
occurrences all number	9	115	2	101
Dysgeusia
subjects affected / exposed	2 / 37 (5.41%)	77 / 590 (13.05%)	0 / 9 (0.00%)	74 / 540 (13.70%)
occurrences all number	4	102	0	97
Headache
subjects affected / exposed	8 / 37 (21.62%)	110 / 590 (18.64%)	1 / 9 (11.11%)	100 / 540 (18.52%)
occurrences all number	8	152	1	140
Memory impairment
subjects affected / exposed	1 / 37 (2.70%)	15 / 590 (2.54%)	1 / 9 (11.11%)	13 / 540 (2.41%)
occurrences all number	1	20	1	18
Paraesthesia
subjects affected / exposed	0 / 37 (0.00%)	33 / 590 (5.59%)	0 / 9 (0.00%)	33 / 540 (6.11%)
occurrences all number	0	35	0	35
Peripheral sensory neuropathy
subjects affected / exposed	0 / 37 (0.00%)	22 / 590 (3.73%)	1 / 9 (11.11%)	21 / 540 (3.89%)
occurrences all number	0	27	1	26
Neuropathy peripheral
subjects affected / exposed	4 / 37 (10.81%)	32 / 590 (5.42%)	0 / 9 (0.00%)	26 / 540 (4.81%)
occurrences all number	4	43	0	36
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	4 / 37 (10.81%)	61 / 590 (10.34%)	1 / 9 (11.11%)	55 / 540 (10.19%)
occurrences all number	11	239	1	226
Lymphopenia
subjects affected / exposed	7 / 37 (18.92%)	77 / 590 (13.05%)	2 / 9 (22.22%)	67 / 540 (12.41%)
occurrences all number	29	359	8	321
Neutropenia
subjects affected / exposed	8 / 37 (21.62%)	135 / 590 (22.88%)	2 / 9 (22.22%)	124 / 540 (22.96%)
occurrences all number	22	456	6	422
Thrombocytopenia
subjects affected / exposed	3 / 37 (8.11%)	48 / 590 (8.14%)	1 / 9 (11.11%)	44 / 540 (8.15%)
occurrences all number	6	105	1	98
Anaemia
subjects affected / exposed	16 / 37 (43.24%)	310 / 590 (52.54%)	6 / 9 (66.67%)	285 / 540 (52.78%)
occurrences all number	45	1168	15	1098
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	0	2	1	1
Eye disorders
Vision blurred
subjects affected / exposed	1 / 37 (2.70%)	37 / 590 (6.27%)	1 / 9 (11.11%)	34 / 540 (6.30%)
occurrences all number	1	52	1	49
Growth of eyelashes
subjects affected / exposed	0 / 37 (0.00%)	5 / 590 (0.85%)	1 / 9 (11.11%)	4 / 540 (0.74%)
occurrences all number	0	5	1	4
Eye disorder
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	0	2	1	1
Corneal epithelial microcysts
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	1	1	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	5 / 37 (13.51%)	74 / 590 (12.54%)	0 / 9 (0.00%)	68 / 540 (12.59%)
occurrences all number	5	95	0	89
Abdominal pain upper
subjects affected / exposed	1 / 37 (2.70%)	49 / 590 (8.31%)	2 / 9 (22.22%)	46 / 540 (8.52%)
occurrences all number	1	59	2	56
Ascites
subjects affected / exposed	1 / 37 (2.70%)	23 / 590 (3.90%)	2 / 9 (22.22%)	19 / 540 (3.52%)
occurrences all number	1	35	2	31
Chronic gastritis
subjects affected / exposed	0 / 37 (0.00%)	5 / 590 (0.85%)	1 / 9 (11.11%)	4 / 540 (0.74%)
occurrences all number	0	5	1	4
Constipation
subjects affected / exposed	12 / 37 (32.43%)	255 / 590 (43.22%)	2 / 9 (22.22%)	238 / 540 (44.07%)
occurrences all number	16	351	2	329
Diarrhoea
subjects affected / exposed	10 / 37 (27.03%)	207 / 590 (35.08%)	4 / 9 (44.44%)	189 / 540 (35.00%)
occurrences all number	19	407	7	373
Dry mouth
subjects affected / exposed	2 / 37 (5.41%)	96 / 590 (16.27%)	1 / 9 (11.11%)	92 / 540 (17.04%)
occurrences all number	3	110	1	103
Dyspepsia
subjects affected / exposed	3 / 37 (8.11%)	32 / 590 (5.42%)	0 / 9 (0.00%)	29 / 540 (5.37%)
occurrences all number	5	41	0	36
Dysphagia
subjects affected / exposed	2 / 37 (5.41%)	47 / 590 (7.97%)	1 / 9 (11.11%)	44 / 540 (8.15%)
occurrences all number	2	53	1	50
Gastritis
subjects affected / exposed	0 / 37 (0.00%)	11 / 590 (1.86%)	1 / 9 (11.11%)	10 / 540 (1.85%)
occurrences all number	0	11	1	10
Gastrointestinal wall thickening
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	1 / 9 (11.11%)	3 / 540 (0.56%)
occurrences all number	0	4	1	3
Abdominal distension
subjects affected / exposed	2 / 37 (5.41%)	29 / 590 (4.92%)	0 / 9 (0.00%)	27 / 540 (5.00%)
occurrences all number	2	35	0	33
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 37 (0.00%)	37 / 590 (6.27%)	2 / 9 (22.22%)	34 / 540 (6.30%)
occurrences all number	0	44	2	41
Abdominal discomfort
subjects affected / exposed	2 / 37 (5.41%)	11 / 590 (1.86%)	0 / 9 (0.00%)	9 / 540 (1.67%)
occurrences all number	2	13	0	11
Toothache
subjects affected / exposed	0 / 37 (0.00%)	15 / 590 (2.54%)	1 / 9 (11.11%)	14 / 540 (2.59%)
occurrences all number	0	16	1	15
Stomatitis
subjects affected / exposed	3 / 37 (8.11%)	37 / 590 (6.27%)	0 / 9 (0.00%)	33 / 540 (6.11%)
occurrences all number	3	57	0	53
Paraesthesia oral
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	1 / 9 (11.11%)	2 / 540 (0.37%)
occurrences all number	0	3	1	2
Nausea
subjects affected / exposed	10 / 37 (27.03%)	126 / 590 (21.36%)	1 / 9 (11.11%)	114 / 540 (21.11%)
occurrences all number	17	182	1	163
Mouth ulceration
subjects affected / exposed	0 / 37 (0.00%)	15 / 590 (2.54%)	2 / 9 (22.22%)	13 / 540 (2.41%)
occurrences all number	0	19	2	17
Vomiting
subjects affected / exposed	7 / 37 (18.92%)	95 / 590 (16.10%)	0 / 9 (0.00%)	88 / 540 (16.30%)
occurrences all number	10	123	0	113
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	2 / 37 (5.41%)	19 / 590 (3.22%)	1 / 9 (11.11%)	16 / 540 (2.96%)
occurrences all number	4	25	1	20
Acne
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	1 / 9 (11.11%)	3 / 540 (0.56%)
occurrences all number	0	5	1	4
Actinic keratosis
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	0	2	1	1
Alopecia
subjects affected / exposed	2 / 37 (5.41%)	37 / 590 (6.27%)	0 / 9 (0.00%)	34 / 540 (6.30%)
occurrences all number	2	40	0	37
Dermatitis acneiform
subjects affected / exposed	3 / 37 (8.11%)	22 / 590 (3.73%)	2 / 9 (22.22%)	17 / 540 (3.15%)
occurrences all number	3	23	2	18
Dry skin
subjects affected / exposed	3 / 37 (8.11%)	25 / 590 (4.24%)	1 / 9 (11.11%)	21 / 540 (3.89%)
occurrences all number	3	29	1	25
Hyperhidrosis
subjects affected / exposed	2 / 37 (5.41%)	11 / 590 (1.86%)	0 / 9 (0.00%)	9 / 540 (1.67%)
occurrences all number	2	12	0	10
Perioral dermatitis
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	1 / 9 (11.11%)	3 / 540 (0.56%)
occurrences all number	0	4	1	3
Rash
subjects affected / exposed	3 / 37 (8.11%)	61 / 590 (10.34%)	0 / 9 (0.00%)	58 / 540 (10.74%)
occurrences all number	3	74	0	71
Rash erythematous
subjects affected / exposed	3 / 37 (8.11%)	8 / 590 (1.36%)	0 / 9 (0.00%)	5 / 540 (0.93%)
occurrences all number	3	8	0	5
Rash maculo-papular
subjects affected / exposed	0 / 37 (0.00%)	15 / 590 (2.54%)	1 / 9 (11.11%)	14 / 540 (2.59%)
occurrences all number	0	17	1	16
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 37 (2.70%)	19 / 590 (3.22%)	1 / 9 (11.11%)	17 / 540 (3.15%)
occurrences all number	1	23	1	21
Dysuria
subjects affected / exposed	1 / 37 (2.70%)	29 / 590 (4.92%)	0 / 9 (0.00%)	28 / 540 (5.19%)
occurrences all number	1	35	0	34
Renal failure
subjects affected / exposed	1 / 37 (2.70%)	10 / 590 (1.69%)	1 / 9 (11.11%)	8 / 540 (1.48%)
occurrences all number	1	12	2	9
Urinary incontinence
subjects affected / exposed	0 / 37 (0.00%)	3 / 590 (0.51%)	1 / 9 (11.11%)	2 / 540 (0.37%)
occurrences all number	0	3	1	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 37 (18.92%)	100 / 590 (16.95%)	3 / 9 (33.33%)	90 / 540 (16.67%)
occurrences all number	9	130	3	118
Back pain
subjects affected / exposed	6 / 37 (16.22%)	95 / 590 (16.10%)	1 / 9 (11.11%)	88 / 540 (16.30%)
occurrences all number	6	126	1	119
Muscle spasms
subjects affected / exposed	2 / 37 (5.41%)	46 / 590 (7.80%)	0 / 9 (0.00%)	42 / 540 (7.78%)
occurrences all number	2	54	0	50
Muscular weakness
subjects affected / exposed	2 / 37 (5.41%)	21 / 590 (3.56%)	0 / 9 (0.00%)	19 / 540 (3.52%)
occurrences all number	2	25	0	23
Myalgia
subjects affected / exposed	1 / 37 (2.70%)	69 / 590 (11.69%)	0 / 9 (0.00%)	67 / 540 (12.41%)
occurrences all number	1	123	0	121
Neck pain
subjects affected / exposed	2 / 37 (5.41%)	36 / 590 (6.10%)	0 / 9 (0.00%)	34 / 540 (6.30%)
occurrences all number	2	41	0	39
Pain in extremity
subjects affected / exposed	6 / 37 (16.22%)	72 / 590 (12.20%)	0 / 9 (0.00%)	66 / 540 (12.22%)
occurrences all number	6	111	0	105
Infections and infestations
COVID-19
subjects affected / exposed	2 / 37 (5.41%)	66 / 590 (11.19%)	0 / 9 (0.00%)	64 / 540 (11.85%)
occurrences all number	4	75	0	71
Cellulitis
subjects affected / exposed	1 / 37 (2.70%)	12 / 590 (2.03%)	1 / 9 (11.11%)	9 / 540 (1.67%)
occurrences all number	1	13	1	10
Ear infection
subjects affected / exposed	1 / 37 (2.70%)	4 / 590 (0.68%)	1 / 9 (11.11%)	2 / 540 (0.37%)
occurrences all number	1	4	1	2
Folliculitis
subjects affected / exposed	0 / 37 (0.00%)	7 / 590 (1.19%)	1 / 9 (11.11%)	6 / 540 (1.11%)
occurrences all number	0	8	2	6
Wound infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 590 (0.17%)	1 / 9 (11.11%)	0 / 540 (0.00%)
occurrences all number	0	2	2	0
Urinary tract infection
subjects affected / exposed	5 / 37 (13.51%)	87 / 590 (14.75%)	1 / 9 (11.11%)	80 / 540 (14.81%)
occurrences all number	10	182	4	167
Upper respiratory tract infection
subjects affected / exposed	1 / 37 (2.70%)	53 / 590 (8.98%)	1 / 9 (11.11%)	51 / 540 (9.44%)
occurrences all number	1	63	1	61
Skin candida
subjects affected / exposed	1 / 37 (2.70%)	3 / 590 (0.51%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	1	3	1	1
Sinusitis
subjects affected / exposed	3 / 37 (8.11%)	22 / 590 (3.73%)	1 / 9 (11.11%)	18 / 540 (3.33%)
occurrences all number	5	24	1	18
Pneumonia aspiration
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	0	2	1	1
Pneumonia
subjects affected / exposed	4 / 37 (10.81%)	68 / 590 (11.53%)	0 / 9 (0.00%)	64 / 540 (11.85%)
occurrences all number	4	111	0	107
Oropharyngeal candidiasis
subjects affected / exposed	0 / 37 (0.00%)	4 / 590 (0.68%)	1 / 9 (11.11%)	3 / 540 (0.56%)
occurrences all number	0	4	1	3
Oral candidiasis
subjects affected / exposed	2 / 37 (5.41%)	21 / 590 (3.56%)	1 / 9 (11.11%)	17 / 540 (3.15%)
occurrences all number	2	30	1	26
Lower respiratory tract infection
subjects affected / exposed	2 / 37 (5.41%)	7 / 590 (1.19%)	1 / 9 (11.11%)	4 / 540 (0.74%)
occurrences all number	2	7	1	4
Influenza
subjects affected / exposed	1 / 37 (2.70%)	15 / 590 (2.54%)	1 / 9 (11.11%)	13 / 540 (2.41%)
occurrences all number	1	16	1	14
Fungal foot infection
subjects affected / exposed	0 / 37 (0.00%)	2 / 590 (0.34%)	1 / 9 (11.11%)	1 / 540 (0.19%)
occurrences all number	0	2	1	1
Bronchitis
subjects affected / exposed	1 / 37 (2.70%)	25 / 590 (4.24%)	1 / 9 (11.11%)	23 / 540 (4.26%)
occurrences all number	2	31	1	28
Metabolism and nutrition disorders
Hypoalbuminaemia
subjects affected / exposed	5 / 37 (13.51%)	89 / 590 (15.08%)	0 / 9 (0.00%)	84 / 540 (15.56%)
occurrences all number	6	234	0	228
Dehydration
subjects affected / exposed	2 / 37 (5.41%)	12 / 590 (2.03%)	0 / 9 (0.00%)	10 / 540 (1.85%)
occurrences all number	2	14	0	12
Hypercalcaemia
subjects affected / exposed	2 / 37 (5.41%)	24 / 590 (4.07%)	1 / 9 (11.11%)	21 / 540 (3.89%)
occurrences all number	3	36	1	32
Hyperglycaemia
subjects affected / exposed	2 / 37 (5.41%)	39 / 590 (6.61%)	0 / 9 (0.00%)	37 / 540 (6.85%)
occurrences all number	2	61	0	59
Hyperkalaemia
subjects affected / exposed	3 / 37 (8.11%)	33 / 590 (5.59%)	1 / 9 (11.11%)	29 / 540 (5.37%)
occurrences all number	3	54	1	50
Hyperphosphataemia
subjects affected / exposed	4 / 37 (10.81%)	109 / 590 (18.47%)	3 / 9 (33.33%)	101 / 540 (18.70%)
occurrences all number	4	186	4	177
Decreased appetite
subjects affected / exposed	6 / 37 (16.22%)	124 / 590 (21.02%)	3 / 9 (33.33%)	113 / 540 (20.93%)
occurrences all number	6	175	3	164
Hypocalcaemia
subjects affected / exposed	7 / 37 (18.92%)	138 / 590 (23.39%)	1 / 9 (11.11%)	130 / 540 (24.07%)
occurrences all number	12	336	3	321
Hypomagnesaemia
subjects affected / exposed	4 / 37 (10.81%)	58 / 590 (9.83%)	0 / 9 (0.00%)	54 / 540 (10.00%)
occurrences all number	5	110	0	105
Hyponatraemia
subjects affected / exposed	5 / 37 (13.51%)	79 / 590 (13.39%)	3 / 9 (33.33%)	70 / 540 (12.96%)
occurrences all number	5	135	6	122
Hypophosphataemia
subjects affected / exposed	6 / 37 (16.22%)	84 / 590 (14.24%)	3 / 9 (33.33%)	75 / 540 (13.89%)
occurrences all number	16	151	4	131
Hypokalaemia
subjects affected / exposed	4 / 37 (10.81%)	103 / 590 (17.46%)	1 / 9 (11.11%)	98 / 540 (18.15%)
occurrences all number	19	185	3	163

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

09 Jan 2017

The following changes were made as per amendment 1: The inclusion criteria included only participants with unresectable disease; The exclusion criteria excluded participants with NSCLC with a targetable mutation in estimated glomerular filtration rate (EGFR), anaplastic lymphoma kinase (ALK), or ROS1; An enrollment stopping rule was incorporated that terminated further enrollment to the study if there was an excess of permanent treatment discontinuations due to study drug-related AEs; Strong inhibitors of cytochrome P450 family 1 subfamily A polypeptide 2 (CYP1A2), cytochrome P450 family 2 subfamily D member 6 (CYP2D6), and cytochrome P450 family 3 subfamily A member 4 (CYP3A4), as well as inducers of CYP3A4 and strong dual permeability glycoprotein (P-gp) and CYP3A4 inhibitors were included in the list of prohibited medications; An electrocardiogram (ECG) measurement was added at Day 1 and Day 15, 4 hours post-dose.

02 Feb 2018

The following change was made as per amendment 2: Exclusion criterion 1 was revised to exclude NSCLC participants with known BRAF mutations.

25 Jul 2018

The following changes were made as per amendment 4.1: Based on the favorable tolerability and encouraging efficacy observed in Phase 1, the sample size of Phase 2 was increased; A summary of Phase 1 was added, including determination of the MTD, overall safety, and preliminary efficacy for Phase 1; The overall enrollment for Phase 2 was increased to further evaluate the safety, efficacy, and PK of pralsetinib in RET-altered patients treated at the MTD/RP2D; Group 6 was added in Phase 2 to assess pralsetinib safety and efficacy in paarticipants previously treated with a selective RET inhibitor; The allowed eastern cooperative oncology group (ECOG) performance status was changed to be 0 to 1; Quality of life assessments added.

12 Dec 2018

The following changes were made as per amendment 7: Phase 2: -Definitions of Groups 1 to 4 were adjusted to reflect previous treatment with approved standard of care agents. -Group 5 was split into new Group 5 and new Group 7 to reflect that solid tumor participants with RET fusions and RET mutations may be distinct clinical and/or regulatory populations; Phase 2: - Sample size was 80 participants in Group 1, 40 participants in Group 2, 60 participants in Group 3, and 40 participants in Group 5 to test the efficacy hypotheses for each group (increasing the study’s total sample size to 360 participants); Phase 2: - Safety Review Committee was added; Two new exclusion criteria were added to exclude participants with Grade 2 or serum phosphorus at baseline or with clinically significant interstitial lung disease or interstitial pneumonitis and exclusion criterion 7 was revised to clarify the washout period duration.

03 Jul 2019

The following changes were made as per amendment 9: The study phase was updated from “1” to “1/2” to better describe the study design with the increased participant population and hypothesis testing; The Phase 2 Group 2 sample size was increased to 200 participants due to the encouraging initial data in treatment naïve RET fusion-positive NSCLC participants, to allow for enrollment of RET fusion-positive NSCLC participants with no prior treatment (increasing the study’s total sample size to 527); Clarification was added that participants enrolled in Phase 1 and treated at the RP2D were pooled together with the appropriate Phase 2 groups for analyses; Statistics section was updated to align with the SAP.

08 Jul 2020

The following changes were made as per amendment 13: Group 5: To more accurately characterize the activity of pralsetinib across various RET fusion-positive solid tumor types, the sample size of Group 5 has increased from N ~ 40 to N ~ 100 participants (increasing the study's total sample size to 647 participants); Phase 2 secondary objective in NSCLC participants and exploratory objective in participants with tumor types other than NSCLC have been updated to assess brain metastases activity in participants with measurable (target by RECIST v1.1) lesions in the brain by BICR (brain metastases sub-population) and assess the time to intracranial progression in all participants; An additional analysis population, the RET-altered Measurable Disease Population, was added to provide an assessment of the activity of pralsetinib in a mechanistically relevant population. This will be the primary analysis population for ORR, DOR, CBR and DCR, while the remaining efficacy endpoints will be examined using the Efficacy Population; Pharmacodynamic parameters of pralsetinib included changes in tumor/blood including, but not limited to, changes in blood calcitonin and CEA and biochemical response rate (MTC participants only); Group 2: The primary intent of this cohort was to assess the activity of pralsetinib in the treatment-naïve participants with NSCLC; therefore, text was added to clarify that this group will include no more than 30 participants with prior systemic therapy; Updated study visit frequency after Cycle 17, all study visits after Cycle 17 will occur at every 4 cycles (16 weeks) (e.g. Cycle 21, Cycle 25…).

28 May 2022

The following changes were made as per amendment 14: End of study and duration of participant participation was added; Detail was provided regarding reporting of serious adverse events and reference safety information document.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase 1/2 Study of the Highly-selective RET Inhibitor, BLU-667, in Patients with Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other Advanced Solid Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib

Primary: Phase 1 : Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of Pralsetinib

Primary: Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs)

Primary: Phase 1 and Phase 2: Number of Participants With AEs and Serious AEs (SAEs)

Primary: Phase 2: Overall Response Rate (ORR)

Primary: Phase 2: Overall Response Rate (ORR)

Secondary: Phase 1: ORR

Secondary: Phase 1: ORR

Secondary: Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants with Specific RET Gene Status

Secondary: Phase 1 and Phase 2: ORR in RET-fusion Positive NSCLC Participants with Specific RET Gene Status

Secondary: Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: ORR in RET-mutation MTC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: ORR in RET-fusion Positive TC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: Clinical Benefit Rate (CBR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: CBR in RET-mutation MTC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: CBR in RET-fusion Positive TC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: Disease Control Rate (DCR) in RET-fusion Positive NSCLC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: DCR in RET-mutation MTC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: DCR in RET-fusion Positive TC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation MTC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: Duration of Response (DOR) in RET-mutation MTC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: DOR in RET-mutation NSCLC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: DOR in RET-mutation NSCLC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status

Secondary: Phase 1 and Phase 2: DOR in RET-fusion Positive TC Participants With Specific RET Gene Status

Secondary: Phase 2: DOR

Secondary: Phase 2: DOR

Secondary: Phase 2: CBR

Secondary: Phase 2: CBR

Secondary: Phase 2: DCR

Secondary: Phase 2: DCR

Secondary: Phase 2: Progression-free Survival (PFS)

Secondary: Phase 2: Progression-free Survival (PFS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants

Secondary: Phase 2: Intracranial ORR in RET-fusion Positive NSCLC Central Nervous System (CNS) Metastases Participants

Secondary: Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants

Secondary: Phase 2: Intracranial CBR in RET-fusion Positive NSCLC CNS Metastases Participants

Secondary: Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants

Secondary: Phase 2: Intracranial DCR in RET-fusion Positive NSCLC CNS Metastases Participants

Secondary: Phase 2: Intracranial DOR in RET-fusion Positive NSCLC CNS Metastases Participants

Secondary: Phase 2: Intracranial DOR in RET-fusion Positive NSCLC CNS Metastases Participants

Secondary: Phase 1: Maximum Plasma Concentration (Cmax)

Secondary: Phase 1: Maximum Plasma Concentration (Cmax)

Secondary: Phase 1: Time to Maximum Plasma Concentration (Tmax)

Secondary: Phase 1: Time to Maximum Plasma Concentration (Tmax)

Secondary: Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast)

Secondary: Phase 1: Time of Last Quantifiable Plasma Drug Concentration (Tlast)

Secondary: Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24)

Secondary: Phase 1: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours Postdose (AUC0-24)

Secondary: Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr)

Secondary: Phase 1: Plasma Drug Concentration at 24 Hours Postdose (C24hr)

Secondary: Phase 1: Apparent Volume of Distribution (Vz/F)

Secondary: Phase 1: Apparent Volume of Distribution (Vz/F)

Secondary: Phase 1: Terminal Elimination Half‑life (t½)

Secondary: Phase 1: Terminal Elimination Half‑life (t½)

Secondary: Phase 1: Apparent Oral Clearance (CL/F)

Secondary: Phase 1: Apparent Oral Clearance (CL/F)

Secondary: Phase 1: Accumulation Ratio for Cmax (RCmax)

Secondary: Phase 1: Accumulation Ratio for Cmax (RCmax)

Secondary: Phase 1: Accumulation Ratio for AUC (RAUC)

Secondary: Phase 1: Accumulation Ratio for AUC (RAUC)

Clinical Trial Results:
A Phase 1/2 Study of the Highly-selective RET Inhibitor, BLU-667, in Patients with Thyroid Cancer, Non-Small Cell Lung Cancer (NSCLC) and Other Advanced Solid Tumors