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Clinical Trial Results:
An open-label multi-cohort Phase 1b/2 study of derazantinib and atezolizumab in patients with urothelial cancer expressing activating molecular FGFR aberrations (FIDES-02)

Summary
EudraCT number	2019-000359-15
Trial protocol	ES IT
Global end of trial date	04 Oct 2022

Results information
Results version number	v1(current)
This version publication date	07 Oct 2023
First version publication date	07 Oct 2023
Other versions

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

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Trial information

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Sponsor protocol code

DZB-CS-201

ISRCTN number

US NCT number

NCT04045613

WHO universal trial number (UTN)

Sponsor organisation name

Basilea Pharmaceutica International Ltd, Allschwil

Sponsor organisation address

Hegenheimermattweg 167b, Allschwil, Switzerland, 4123

Public contact

Manuel Haeckl, Basilea Pharmaceutica International Ltd, Allschwil, +41 76 302 53 10 , medical.information@basilea.com

Scientific contact

Study Director, Basilea Pharmaceutica International Ltd, Allschwil, +41 76 302 53 10 , manuel.haeckl@basilea.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

02 Nov 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

04 Oct 2022

Global end of trial reached?

Yes

Global end of trial date

04 Oct 2022

Was the trial ended prematurely?

Main objective of the trial

Primary objectives for Substudies 1, 3, 4 and 5 To evaluate the objective response rate (ORR) of derazantinib monotherapy (in Substudies 1 and 5, and Cohort 4a of Substudy 4) and of derazantinib-atezolizumab in combination (in Substudy 3 and Cohort 4b of Substudy 4) in patients with metastatic urothelial cancer (mUC) expressing fibroblast growth factor receptor genomic alterations (FGFR1–3 GAs). Primary objective for Substudy 2 •To determine the recommended Phase 2 dose (RP2D) of derazantinib in combination with atezolizumab.

Protection of trial subjects

The study was conducted according to the ethical principles that have their origins in the World Medical Association’s Declaration of Helsinki, the International Council for Harmonisation (ICH) E6 Good Clinical Practice, and all applicable national and local laws and regulations for the conduct of clinical research.

Background therapy

In this Phase 1b/2 study (FIDES-02), the FGFR inhibitor derazantinib, as monotherapy and in combination with the immune-checkpoint inhibitor (ICI) atezolizumab was evaluated in the treatment of patients with unresectable or mUC and FGFR1, FGFR2, or FGFR3 mutations and rearrangements/fusions. The addition of an FGFR inhibitor to an ICI was based on the assumption of an enhanced efficacy of checkpoint inhibition through immunomodulatory effects (CSF1R-inhibition by the kinase inhibitor derazantinib) on the tumor microenvironment.

Evidence for comparator

Not applicable

Actual start date of recruitment

02 Aug 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 6

Country: Number of subjects enrolled

Spain: 16

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

Switzerland: 3

Country: Number of subjects enrolled

United States: 15

Country: Number of subjects enrolled

Australia: 1

Country: Number of subjects enrolled

Korea, Republic of: 9

Country: Number of subjects enrolled

France: 15

Country: Number of subjects enrolled

Germany: 12

Country: Number of subjects enrolled

Hungary: 2

Country: Number of subjects enrolled

Italy: 8

Worldwide total number of subjects

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

A total of 95 patients entered the study and were assigned treatment. All patients assigned treatment were dispensed study drug and received at least one dose of derazantinib or atezolizumab

Screening details

From August, 2019 to September, 2022, 321 patients underwent molecular screening and 131 underwent clinical screening.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Not applicable

Are arms mutually exclusive

Yes

Substudy 1: Derazantinib

Arm description

Derazantinib 300 mg once daily monotherapy Derazantinib was administered orally at a dose of 300 mg once daily

Arm type

Experimental

Investigational medicinal product name

Derazantinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Derazantinib was supplied as 100 mg immediate-release powder-filled capsules for oral administration.

Substudy 2 (Dose-Level 1): Derazantinib + atezolizumab

Arm description

Derazantinib 200 mg once daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 200 mg once daily in combination with atezolizumab 1200 mg every 3 weeks

Arm type

Experimental

Investigational medicinal product name

Derazantinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Derazantinib was supplied as 100 mg immediate-release powder-filled capsules for oral administration.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Atezolizumab is an authorised medicinal product which was supplied as 1200 mg/20 mL concentrate solution for intravenous (IV) infusion. The atezolizumab dose for all patients receiving the combination treatment was 1200 mg every 3 weeks

Substudy 2 (Dose-Level 2): Derazantinib + atezolizumab

Arm description

Derazantinib 300 mg once daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 300 mg once daily in combination with atezolizumab 1200 mg every 3 weeks

Arm type

Experimental

Investigational medicinal product name

Derazantinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Derazantinib was supplied as 100 mg immediate-release powder-filled capsules for oral administration.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Substudy 3: Derazantinib + atezolizumab

Arm description

Derazantinib 200 mg twice daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 200 mg twice daily in combination with atezolizumab 1200 mg every 3 weeks

Arm type

Experimental

Investigational medicinal product name

Derazantinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Derazantinib was supplied as 100 mg immediate-release powder-filled capsules for oral administration.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Substudy 4 (Cohort 4a): Derazantinib

Arm description

Derazantinib 300 mg once daily monotherapy (QD) Derazantinib was administered orally at a dose of 300 mg once daily

Arm type

Experimental

Investigational medicinal product name

Derazantinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Derazantinib was supplied as 100 mg immediate-release powder-filled capsules for oral administration.

Substudy 4 (Cohort 4b): Derazantinib + atezolizumab

Arm description

Derazantinib 300 mg once daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 300 mg once daily in combination with atezolizumab 1200 mg every 3 weeks

Arm type

Experimental

Investigational medicinal product name

Derazantinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Derazantinib was supplied as 100 mg immediate-release powder-filled capsules for oral administration.

Investigational medicinal product name

Atezolizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Substudy 5: Derazantinib

Arm description

Derazantinib 200 mg twice daily monotherapy Derazantinib was administered orally at a dose of 200 mg twice daily

Arm type

Experimental

Investigational medicinal product name

Derazantinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Derazantinib was supplied as 100 mg immediate-release powder-filled capsules for oral administration.

Number of subjects in period 1	Substudy 1: Derazantinib	Substudy 2 (Dose-Level 1): Derazantinib + atezolizumab	Substudy 2 (Dose-Level 2): Derazantinib + atezolizumab	Substudy 3: Derazantinib + atezolizumab	Substudy 4 (Cohort 4a): Derazantinib	Substudy 4 (Cohort 4b): Derazantinib + atezolizumab	Substudy 5: Derazantinib
Started	32	14	12	2	8	10	17
Completed	0	0	0	0	0	0	0
Not completed	32	14	12	2	8	10	17
Adverse event, serious fatal	3	-	-	-	-	-	1
Physician decision	2	-	-	-	1	-	-
Consent withdrawn by subject	-	5	-	-	-	1	-
Adverse event, non-fatal	2	2	1	1	-	-	1
Other reasons	-	1	-	-	-	-	1
Progressive disease: Radiological progression	24	6	8	-	6	6	11
Progressive disease: Clinical progression	1	-	3	1	1	3	3

Baseline characteristics

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Reporting group title

Substudy 1: Derazantinib

Reporting group description

Derazantinib 300 mg once daily monotherapy Derazantinib was administered orally at a dose of 300 mg once daily

Reporting group title

Substudy 2 (Dose-Level 1): Derazantinib + atezolizumab

Reporting group description

Derazantinib 200 mg once daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 200 mg once daily in combination with atezolizumab 1200 mg every 3 weeks

Reporting group title

Substudy 2 (Dose-Level 2): Derazantinib + atezolizumab

Reporting group description

Derazantinib 300 mg once daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 300 mg once daily in combination with atezolizumab 1200 mg every 3 weeks

Reporting group title

Substudy 3: Derazantinib + atezolizumab

Reporting group description

Derazantinib 200 mg twice daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 200 mg twice daily in combination with atezolizumab 1200 mg every 3 weeks

Reporting group title

Substudy 4 (Cohort 4a): Derazantinib

Reporting group description

Derazantinib 300 mg once daily monotherapy (QD) Derazantinib was administered orally at a dose of 300 mg once daily

Reporting group title

Substudy 4 (Cohort 4b): Derazantinib + atezolizumab

Reporting group description

Derazantinib 300 mg once daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 300 mg once daily in combination with atezolizumab 1200 mg every 3 weeks

Reporting group title

Substudy 5: Derazantinib

Reporting group description

Derazantinib 200 mg twice daily monotherapy Derazantinib was administered orally at a dose of 200 mg twice daily

Reporting group values	Substudy 1: Derazantinib	Substudy 2 (Dose-Level 1): Derazantinib + atezolizumab	Substudy 2 (Dose-Level 2): Derazantinib + atezolizumab	Substudy 3: Derazantinib + atezolizumab	Substudy 4 (Cohort 4a): Derazantinib	Substudy 4 (Cohort 4b): Derazantinib + atezolizumab	Substudy 5: Derazantinib	Total
Number of subjects	32	14	12	2	8	10	17	95
Age categorical
Units: Subjects
Adults (18-64 years)	7	5	11	1	4	3	11	42
From 65-84 years	23	9	1	1	4	7	6	51
85 years and over	2	0	0	0	0	0	0	2
Gender categorical
Units: Subjects
Female	11	4	8	1	4	6	4	38
Male	21	10	4	1	4	4	13	57
Site of primary tumor at diagnosis
Units: Subjects
Bladder	19	2	1	2	7	7	11	49
Renal pelvis	9	0	0	0	0	2	4	15
Ureter	3	0	1	0	1	1	2	8
Missing	1	0	0	0	0	0	0	1
Other site of primary tumor	0	12	10	0	0	0	0	22
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
Measure Description: The ECOG PS scale indicates increasing levels of disability, with 0 indicating fully active; 1, restricted in strenuous activity; 2, restricted in work activity but ambulatory and capable of self-care
Units: Subjects
Scale 0	14	4	2	1	0	2	8	31
Scale 1	15	8	9	1	6	7	9	55
Scale 2	3	2	1	0	2	1	0	9
Number of previous anti-cancer treatments
Units: Subjects
One treatment	5	4	3	0	0	1	7	20
Two treatments	9	4	4	0	0	0	6	23
Three or more treatments	18	6	5	1	8	9	4	51
No treatment	0	0	0	1	0	0	0	1
Prior immune checkpoint inhibitor treatment
Units: Subjects
Prior immune checkpoint inhibitor treatment	26	1	4	0	8	10	12	61
No prior immune checkpoint inhibitor treatment	6	13	8	2	0	0	5	34
Reason previous therapy ended
Units: Subjects
Treatment completed	4	2	0	0	1	1	2	10
Progressive disease	23	10	12	0	6	8	12	71
Toxicity	1	0	0	1	1	0	0	3
Other	2	1	0	0	0	0	2	5
Unknown	2	1	0	0	0	1	1	5
No previous therapy	0	0	0	1	0	0	0	1
Race
Units: Subjects
Asian	4	0	2	0	2	1	0	9
Native Hawaiian or Other Pacific Islander	1	0	0	0	0	0	0	1
Black or African American	0	1	0	0	1	0	0	2
White	18	12	5	2	2	7	12	58
More than one race	0	0	0	0	0	0	1	1
Unknown or Not Reported	9	1	5	0	3	2	4	24

End points

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Reporting group title

Substudy 1: Derazantinib

Reporting group description

Derazantinib 300 mg once daily monotherapy Derazantinib was administered orally at a dose of 300 mg once daily

Reporting group title

Substudy 2 (Dose-Level 1): Derazantinib + atezolizumab

Reporting group description

Derazantinib 200 mg once daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 200 mg once daily in combination with atezolizumab 1200 mg every 3 weeks

Reporting group title

Substudy 2 (Dose-Level 2): Derazantinib + atezolizumab

Reporting group description

Derazantinib 300 mg once daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 300 mg once daily in combination with atezolizumab 1200 mg every 3 weeks

Reporting group title

Substudy 3: Derazantinib + atezolizumab

Reporting group description

Derazantinib 200 mg twice daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 200 mg twice daily in combination with atezolizumab 1200 mg every 3 weeks

Reporting group title

Substudy 4 (Cohort 4a): Derazantinib

Reporting group description

Derazantinib 300 mg once daily monotherapy (QD) Derazantinib was administered orally at a dose of 300 mg once daily

Reporting group title

Substudy 4 (Cohort 4b): Derazantinib + atezolizumab

Reporting group description

Derazantinib 300 mg once daily + atezolizumab 1200 mg Derazantinib was administered orally at a dose of 300 mg once daily in combination with atezolizumab 1200 mg every 3 weeks

Reporting group title

Substudy 5: Derazantinib

Reporting group description

Derazantinib 200 mg twice daily monotherapy Derazantinib was administered orally at a dose of 200 mg twice daily

Subject analysis set title

mITT Population

Subject analysis set type

Modified intention-to-treat

Subject analysis set description

Efficacy analyses were performed using the modified Intent-to-Treat (mITT) population: all patients who received at least one dose of derazantinib or atezolizumab, and had at least one post-baseline imaging assessment in accordance with RECIST 1.1, or documented clinical progression

Subject analysis set title

The safety/ITT population

Subject analysis set type

Safety analysis

Subject analysis set description

The safety/intent-to-treat (ITT) population consisted of all patients who received at least one dose of derazantinib or atezolizumab

Subject analysis set title

Substudy 2 Combined (Dose-Level 1 and 2) ITT

Subject analysis set type

Sub-group analysis

Subject analysis set description

Patients with solid tumors were treated with derazantinib 200 mg or 300 mg once daily in combination with atezolizumab 1200 mg given every 3 weeks as IV infusion

Subject analysis set title

MTD-determining population

Subject analysis set type

Sub-group analysis

Subject analysis set description

The maximum tolerated dose (MTD)-determining population included all patients enrolled in the MTD Part of each dose level who met the following minimum criteria during the DLT period: • received at least one dose of derazantinib and atezolizumab and has experienced a DLT; • received ≥ 90% of the derazantinib and atezolizumab dose, respectively, in Cycle 1 and did not experience a DLT, have been observed for ≥ 21 days following the first dose, and have been evaluated for safety

Subject analysis set title

Substudy 2 Combined (Dose-Level 1 and 2) mITT

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Objective Response Rate (ORR) Based on RECIST 1.1 (Substudies 1,3,4 and 5)

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End point title

Objective Response Rate (ORR) Based on RECIST 1.1 (Substudies 1,3,4 and 5) ^[1] ^[2]

End point description

ORR was defined as the proportion of patients who achieved a confirmed clinical response (CR) or partial response (PR) by blinded investigator central review (BICR) using the internationally recognized criteria for the radiological assessment in tumor response of solid tumors (RECIST) Version 1.1

End point type

Primary

End point timeframe

From first dose up to 2 years

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: This study was not powered for formal statistical analysis
[2] - 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 study was not powered for formal statistical analysis

End point values	Substudy 1: Derazantinib	Substudy 3: Derazantinib + atezolizumab	Substudy 4 (Cohort 4a): Derazantinib	Substudy 4 (Cohort 4b): Derazantinib + atezolizumab	Substudy 5: Derazantinib	mITT Population
Number of subjects analysed	32	2	7	10	17	91
Units: Proportion of patients
number (confidence interval 95%)
ORR	9.4 (2.0 to 25.0)	0.0 (0.0 to 84.2)	14.3 (0.4 to 57.9)	0.0 (0.0 to 30.8)	5.9 (0.1 to 28.7)	7.7 (3.1 to 15.2)

No statistical analyses for this end point

Primary: Recommended Phase 2 Dose (RP2D) of Derazantinib-atezolizumab in Combination Based on DLT Criteria, Safety and Efficacy Data (Substudy 2)

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End point title

Recommended Phase 2 Dose (RP2D) of Derazantinib-atezolizumab in Combination Based on DLT Criteria, Safety and Efficacy Data (Substudy 2) ^[3]

End point description

Patients with solid tumors were treated with derazantinib 200 mg or 300 mg once daily in combination with atezolizumab 1200 mg given every 3 weeks as IV infusion

End point type

Primary

End point timeframe

From first dose up to 2 years

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: This study was not powered for formal statistical analysis

End point values	Substudy 2 Combined (Dose-Level 1 and 2) ITT
Number of subjects analysed	26
Units: mg
number (not applicable)
Recommended Phase 2 Dose (RP2D)	300

No statistical analyses for this end point

Primary: Number of Patients With Dose-limiting Toxicities (DLTs) in Substudy 2

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End point title

Number of Patients With Dose-limiting Toxicities (DLTs) in Substudy 2 ^[4] ^[5]

End point description

In Substudy 2, the primary endpoint was the number of patients with Dose-limiting Toxicities (DLTs=. A DLT was defined as a clinically-significant adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications. Any DLT had to be a toxicity considered at least possibly related to derazantinib or the combination of derazantinib and atezolizumab

End point type

Primary

End point timeframe

From first dose up to 2 years

Notes
[4] - 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: This study was not powered for formal statistical analysis
[5] - 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 study was not powered for formal statistical analysis

End point values	Substudy 2 (Dose-Level 1): Derazantinib + atezolizumab	Substudy 2 (Dose-Level 2): Derazantinib + atezolizumab	MTD-determining population
Number of subjects analysed	6	5	11
Units: Subjects
Number of Patients With DLTs	0	0	0

No statistical analyses for this end point

Secondary: ORR Based on RECIST 1.1 (Substudy 2)

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End point title

ORR Based on RECIST 1.1 (Substudy 2) ^[6]

End point description

End point type

Secondary

End point timeframe

From first dose up to 2 years

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 study was not powered for formal statistical analysis

End point values	Substudy 2 (Dose-Level 1): Derazantinib + atezolizumab	Substudy 2 (Dose-Level 2): Derazantinib + atezolizumab	Substudy 2 Combined (Dose-Level 1 and 2) mITT
Number of subjects analysed	11	12	23
Units: Percentage of participants
number (confidence interval 95%)
ORR Based on RECIST 1.1	0.0 (0.0 to 28.5)	16.7 (2.1 to 48.4)	8.7 (1.1 to 28.0)

No statistical analyses for this end point

Secondary: Progression-free Survival (PFS) by RECIST

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End point title

Progression-free Survival (PFS) by RECIST

End point description

PFS was calculated as the time from cohort assignment until disease progression as assessed by BICR, or death from any cause, whichever came first

End point type

Secondary

End point timeframe

From first dose up to 2 years

End point values	Substudy 1: Derazantinib	Substudy 2 (Dose-Level 1): Derazantinib + atezolizumab	Substudy 2 (Dose-Level 2): Derazantinib + atezolizumab	Substudy 3: Derazantinib + atezolizumab	Substudy 4 (Cohort 4a): Derazantinib	Substudy 4 (Cohort 4b): Derazantinib + atezolizumab	Substudy 5: Derazantinib	mITT Population
Number of subjects analysed	32	11	12	2	7	10	17	91
Units: Months
median (confidence interval 95%)
PFS	2.0 (1.9 to 2.1)	2.0 (1.5 to 2.1)	4.2 (0.7 to 10.8)	2.5 (0.6 to 4.4)	2.0 (0.6 to 4.7)	1.9 (0.2 to 4.1)	2.1 (2.1 to 7.0)	2.1 (2.0 to 2.1)

No statistical analyses for this end point

Secondary: Number of Patients With at Least Grade 3 Adverse Events (AEs)

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End point title

Number of Patients With at Least Grade 3 Adverse Events (AEs)

End point description

Common Terminology Criteria for Adverse Events (CTCAE) displayed by increasing severity grades 3 to 5 (CTCAE grade 3/4/5 )

End point type

Secondary

End point timeframe

From first dose and until 90 days following the last dose

End point values	Substudy 1: Derazantinib	Substudy 2 (Dose-Level 1): Derazantinib + atezolizumab	Substudy 2 (Dose-Level 2): Derazantinib + atezolizumab	Substudy 3: Derazantinib + atezolizumab	Substudy 4 (Cohort 4a): Derazantinib	Substudy 4 (Cohort 4b): Derazantinib + atezolizumab	Substudy 5: Derazantinib	The safety/ITT population
Number of subjects analysed	32	14	12	2	8	10	17	95
Units: Number of patients
Number of patients with only unrelated CTCAE Grade	11	5	7	0	2	5	3	33
Number of patients with related CTCAE Grade ≥3	11	3	3	2	2	4	9	34
Number of patients without CTCAE Grade ≥3	10	6	2	0	4	1	5	28

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first administration of study medication up to 90 days after the last administration

Adverse event reporting additional description

Treatment-emergent adverse events and serious adverse events

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

SS2 - DZB 200 mg + AZB 1200 mg

Reporting group description

SS2 - DZB 200 mg + AZB 1200 mg

Reporting group title

SS3 - DZB 200 mg BID + AZB 1200 mg

Reporting group description

SS3 - DZB 200 mg BID + AZB 1200 mg

Reporting group title

SS5 - DZB 200 mg BID

Reporting group description

SS5 - DZB 200 mg BID

Reporting group title

SS4 - DZB 300 mg

Reporting group description

SS4 - DZB 300 mg

Reporting group title

SS4 - DZB 300 mg + AZB 1200 mg

Reporting group description

SS4 - DZB 300 mg + AZB 1200 mg

Reporting group title

SS1 - DZB 300 mg

Reporting group description

SS1 - DZB 300 mg

Reporting group title

SS2 - DZB 300 mg + AZB 1200 mg

Reporting group description

SS2 - DZB 300 mg + AZB 1200 mg

Serious adverse events	SS2 - DZB 200 mg + AZB 1200 mg	SS3 - DZB 200 mg BID + AZB 1200 mg	SS5 - DZB 200 mg BID	SS4 - DZB 300 mg	SS4 - DZB 300 mg + AZB 1200 mg	SS1 - DZB 300 mg	SS2 - DZB 300 mg + AZB 1200 mg
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 14 (28.57%)	1 / 2 (50.00%)	8 / 17 (47.06%)	3 / 8 (37.50%)	6 / 10 (60.00%)	17 / 32 (53.13%)	6 / 12 (50.00%)
number of deaths (all causes)	7	2	10	4	7	25	8
number of deaths resulting from adverse events	3	1	1	0	4	8	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Embolism
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	2 / 17 (11.76%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypothermia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	2 / 14 (14.29%)	1 / 2 (50.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	4 / 10 (40.00%)	7 / 32 (21.88%)	3 / 12 (25.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 4	0 / 7	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 4	0 / 7	0 / 3
Pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 2 (50.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eastern Cooperative Oncology Group performance status worsened
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fracture
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Nausea
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	1 / 8 (12.50%)	0 / 10 (0.00%)	3 / 32 (9.38%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic cytolysis
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Urinary retention
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephritis
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 14 (0.00%)	1 / 2 (50.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypercalcaemia of malignancy
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Endocarditis
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oral fungal infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cachexia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 2 (50.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	SS2 - DZB 200 mg + AZB 1200 mg	SS3 - DZB 200 mg BID + AZB 1200 mg	SS5 - DZB 200 mg BID	SS4 - DZB 300 mg	SS4 - DZB 300 mg + AZB 1200 mg	SS1 - DZB 300 mg	SS2 - DZB 300 mg + AZB 1200 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	14 / 14 (100.00%)	2 / 2 (100.00%)	17 / 17 (100.00%)	8 / 8 (100.00%)	10 / 10 (100.00%)	30 / 32 (93.75%)	12 / 12 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 32 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	0	1
Vascular disorders
Hypertension
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	3 / 17 (17.65%)	1 / 8 (12.50%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	1	0	3	1	0	2	0
Lymphoedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 14 (14.29%)	0 / 2 (0.00%)	5 / 17 (29.41%)	3 / 8 (37.50%)	3 / 10 (30.00%)	8 / 32 (25.00%)	5 / 12 (41.67%)
occurrences all number	2	0	5	4	4	8	6
Fatigue
subjects affected / exposed	5 / 14 (35.71%)	0 / 2 (0.00%)	6 / 17 (35.29%)	1 / 8 (12.50%)	3 / 10 (30.00%)	8 / 32 (25.00%)	2 / 12 (16.67%)
occurrences all number	5	0	6	1	3	9	2
Mucosal inflammation
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 32 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	1	0	0	2
Oedema
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 32 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1	0	0	1
Oedema peripheral
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 2 (50.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	2 / 12 (16.67%)
occurrences all number	0	1	0	0	0	2	2
Pyrexia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 32 (3.13%)	3 / 12 (25.00%)
occurrences all number	0	0	0	0	1	2	3
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	1 / 8 (12.50%)	1 / 10 (10.00%)	3 / 32 (9.38%)	1 / 12 (8.33%)
occurrences all number	0	0	1	1	1	3	1
Cough
subjects affected / exposed	2 / 14 (14.29%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	1	0	0	0
Productive cough
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	1
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 14 (0.00%)	1 / 2 (50.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 32 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	0	1	0	1
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	3 / 17 (17.65%)	1 / 8 (12.50%)	2 / 10 (20.00%)	6 / 32 (18.75%)	0 / 12 (0.00%)
occurrences all number	0	0	3	1	3	6	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	2	0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 14 (7.14%)	1 / 2 (50.00%)	2 / 17 (11.76%)	1 / 8 (12.50%)	1 / 10 (10.00%)	4 / 32 (12.50%)	2 / 12 (16.67%)
occurrences all number	2	1	2	1	1	4	2
Aspartate aminotransferase increased
subjects affected / exposed	2 / 14 (14.29%)	0 / 2 (0.00%)	4 / 17 (23.53%)	2 / 8 (25.00%)	2 / 10 (20.00%)	12 / 32 (37.50%)	3 / 12 (25.00%)
occurrences all number	2	0	4	2	3	12	3
Amylase increased
subjects affected / exposed	1 / 14 (7.14%)	1 / 2 (50.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	4 / 32 (12.50%)	2 / 12 (16.67%)
occurrences all number	1	1	0	0	1	4	2
Alanine aminotransferase increased
subjects affected / exposed	2 / 14 (14.29%)	0 / 2 (0.00%)	5 / 17 (29.41%)	2 / 8 (25.00%)	2 / 10 (20.00%)	10 / 32 (31.25%)	5 / 12 (41.67%)
occurrences all number	2	0	5	2	2	10	5
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	4 / 32 (12.50%)	2 / 12 (16.67%)
occurrences all number	1	0	1	0	0	4	2
Platelet count decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	2	2
Transaminases increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	2 / 17 (11.76%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	1	0
Weight decreased
subjects affected / exposed	2 / 14 (14.29%)	0 / 2 (0.00%)	2 / 17 (11.76%)	0 / 8 (0.00%)	1 / 10 (10.00%)	3 / 32 (9.38%)	0 / 12 (0.00%)
occurrences all number	2	0	2	0	1	3	0
Lipase increased
subjects affected / exposed	2 / 14 (14.29%)	1 / 2 (50.00%)	1 / 17 (5.88%)	1 / 8 (12.50%)	2 / 10 (20.00%)	4 / 32 (12.50%)	1 / 12 (8.33%)
occurrences all number	2	1	1	1	2	5	1
Haemoglobin decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	1 / 10 (10.00%)	2 / 32 (6.25%)	1 / 12 (8.33%)
occurrences all number	0	0	3	0	1	2	1
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	4 / 32 (12.50%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	0	4	1
C-reactive protein increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Blood phosphorus increased
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	4 / 32 (12.50%)	4 / 12 (33.33%)
occurrences all number	0	0	0	1	0	4	4
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	2	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 32 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1	0	0	2
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	1	0	0
Nervous system disorders
Balance disorder
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Tremor
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	1 / 10 (10.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	1	2	0
Dizziness
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 32 (3.13%)	1 / 12 (8.33%)
occurrences all number	0	0	1	0	1	1	1
Dysgeusia
subjects affected / exposed	2 / 14 (14.29%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	1 / 10 (10.00%)	3 / 32 (9.38%)	0 / 12 (0.00%)
occurrences all number	2	0	1	0	1	3	0
Sciatica
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 2 (0.00%)	1 / 17 (5.88%)	1 / 8 (12.50%)	3 / 10 (30.00%)	7 / 32 (21.88%)	2 / 12 (16.67%)
occurrences all number	2	0	1	3	3	7	2
Lymphopenia
subjects affected / exposed	2 / 14 (14.29%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	3 / 32 (9.38%)	1 / 12 (8.33%)
occurrences all number	2	0	0	0	0	4	1
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Central serous chorioretinopathy
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Dry eye
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	3 / 32 (9.38%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	4	1
Keratitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	2	0
Maculopathy
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Punctate keratitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Vision blurred
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	3 / 32 (9.38%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	3	1
Visual acuity reduced
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	2 / 17 (11.76%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Xerophthalmia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	6 / 14 (42.86%)	1 / 2 (50.00%)	5 / 17 (29.41%)	1 / 8 (12.50%)	3 / 10 (30.00%)	14 / 32 (43.75%)	4 / 12 (33.33%)
occurrences all number	7	2	7	1	4	14	5
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 32 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	1	0	0	1
Gastritis
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 32 (3.13%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	1	1
Dyspepsia
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	2 / 17 (11.76%)	1 / 8 (12.50%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	1	0	2	1	0	1	0
Dry mouth
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	2 / 17 (11.76%)	1 / 8 (12.50%)	1 / 10 (10.00%)	7 / 32 (21.88%)	2 / 12 (16.67%)
occurrences all number	1	0	2	1	1	7	2
Diarrhoea
subjects affected / exposed	4 / 14 (28.57%)	1 / 2 (50.00%)	5 / 17 (29.41%)	2 / 8 (25.00%)	4 / 10 (40.00%)	7 / 32 (21.88%)	3 / 12 (25.00%)
occurrences all number	4	1	7	2	4	7	4
Constipation
subjects affected / exposed	1 / 14 (7.14%)	1 / 2 (50.00%)	3 / 17 (17.65%)	3 / 8 (37.50%)	3 / 10 (30.00%)	10 / 32 (31.25%)	1 / 12 (8.33%)
occurrences all number	1	2	3	3	4	10	1
Ascites
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	0	0	2
Abdominal pain upper
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Abdominal pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	1 / 17 (5.88%)	1 / 8 (12.50%)	2 / 10 (20.00%)	2 / 32 (6.25%)	2 / 12 (16.67%)
occurrences all number	1	0	1	1	2	2	3
Abdominal distension
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	0	0	0
Stomatitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	1 / 8 (12.50%)	2 / 10 (20.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	2	1	0
Vomiting
subjects affected / exposed	4 / 14 (28.57%)	1 / 2 (50.00%)	4 / 17 (23.53%)	0 / 8 (0.00%)	3 / 10 (30.00%)	6 / 32 (18.75%)	3 / 12 (25.00%)
occurrences all number	5	3	5	0	3	6	3
Hepatobiliary disorders
Hepatic cytolysis
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	1	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)	1 / 32 (3.13%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	2	1	1
Pruritus
subjects affected / exposed	1 / 14 (7.14%)	1 / 2 (50.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	1	2	0	0	0	1	0
Nail dystrophy
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	2 / 17 (11.76%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Nail disorder
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 32 (3.13%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	1	1
Dry skin
subjects affected / exposed	0 / 14 (0.00%)	1 / 2 (50.00%)	2 / 17 (11.76%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	1	2	0	0	1	0
Eczema
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	0	0	1
Renal and urinary disorders
Urinary retention
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Pollakiuria
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Haematuria
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	2 / 17 (11.76%)	1 / 8 (12.50%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	1	0	2	1	0	2	0
Dysuria
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	3 / 32 (9.38%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	3	1
Back pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	3 / 17 (17.65%)	0 / 8 (0.00%)	0 / 10 (0.00%)	4 / 32 (12.50%)	2 / 12 (16.67%)
occurrences all number	1	0	3	0	0	4	2
Groin pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Bone pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	0
Pain in extremity
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	1	1	0	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	3 / 17 (17.65%)	0 / 8 (0.00%)	1 / 10 (10.00%)	3 / 32 (9.38%)	0 / 12 (0.00%)
occurrences all number	0	0	6	0	2	3	0
Pneumonia
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	1	0
Oral candidiasis
subjects affected / exposed	0 / 14 (0.00%)	1 / 2 (50.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	1 / 12 (8.33%)
occurrences all number	0	1	0	0	0	1	1
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 2 (50.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	1	0	1	0	1	0
Hypoglycaemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 2 (0.00%)	0 / 17 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Hypocalcaemia
subjects affected / exposed	2 / 14 (14.29%)	0 / 2 (0.00%)	1 / 17 (5.88%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	1	1	0	0	0
Hypoalbuminaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	2 / 8 (25.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	1	0	0	2	0	1	0
Hyperphosphataemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	1 / 10 (10.00%)	3 / 32 (9.38%)	0 / 12 (0.00%)
occurrences all number	2	0	1	0	1	3	0
Hyperkalaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	1 / 17 (5.88%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	0	1	0
Hyperglycaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	2 / 32 (6.25%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	2	0
Hypercalcaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	1 / 8 (12.50%)	1 / 10 (10.00%)	3 / 32 (9.38%)	1 / 12 (8.33%)
occurrences all number	0	0	1	1	1	3	1
Dehydration
subjects affected / exposed	4 / 14 (28.57%)	0 / 2 (0.00%)	1 / 17 (5.88%)	2 / 8 (25.00%)	0 / 10 (0.00%)	0 / 32 (0.00%)	0 / 12 (0.00%)
occurrences all number	4	0	1	2	0	0	0
Decreased appetite
subjects affected / exposed	3 / 14 (21.43%)	1 / 2 (50.00%)	6 / 17 (35.29%)	1 / 8 (12.50%)	2 / 10 (20.00%)	9 / 32 (28.13%)	3 / 12 (25.00%)
occurrences all number	3	1	7	1	3	10	4
Cachexia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 32 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1	0	0	1
Hypomagnesaemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	1 / 32 (3.13%)	1 / 12 (8.33%)
occurrences all number	1	0	0	1	0	2	1
Hyponatraemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	0 / 17 (0.00%)	3 / 8 (37.50%)	2 / 10 (20.00%)	4 / 32 (12.50%)	0 / 12 (0.00%)
occurrences all number	0	0	0	3	2	4	0
Hypophosphataemia
subjects affected / exposed	1 / 14 (7.14%)	0 / 2 (0.00%)	0 / 17 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	1	0	0	1	1	1	0
Vitamin D deficiency
subjects affected / exposed	0 / 14 (0.00%)	0 / 2 (0.00%)	1 / 17 (5.88%)	1 / 8 (12.50%)	0 / 10 (0.00%)	1 / 32 (3.13%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	1	0

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Were there any global substantial amendments to the protocol? Yes

10 May 2019

Protocol amendment 1 was implemented in Protocol Version 2 prior to screening of the first study patient. This amendment included the following: • updated definition of a dose-limiting toxicity applicable to Substudy 2, • implemented a new dose modification and discontinuation criteria / additional information on hyperphosphatemia, • modified the schedule for ophthalmologic examinations and added a management of retinal AEs, • amended concomitant medications, • updated clinical safety laboratory blood tests, • clarification of inclusion criterion 4 in Substudy 4, • all references to impaired renal function were clarified as requiring calculation of creatinine clearance using the Cockcroft-Gault formula, • references to molecular testing protocols throughout the protocol were broadened, • rescreening timeframe for assessing the inclusion and exclusion criteria was specified for clarity, • procedures for on-treatment ECGs were clarified, • the storage and future use of biological samples was clarified, • a table listing the inducers, inhibitors and substrates of CYP2C8 was added to Appendix 6 and definitions amended.

04 Oct 2019

Protocol amendment 2 was implemented in Protocol Version 3. This amendment included the following: • broadened the target population for Substudy 2 by removing the requirement for patients to have a tumor harboring any FGFR genetic aberrations, • introduced time windows for PK sampling, • clarified that for enrollment in Substudy 3 patients needed PD-L1 expression < 5%, • requirements for molecular tests conducted in the EU were clarified, • appropriate methods of birth control were clarified, • an exclusion criterion was added for hypersensitivity to atezolizumab or to any of the excipients, • study drug discontinuation criteria were amended, • a tuberculosis blood test and serology for HCV/HBV/HIV at screening were added, • live, attenuated vaccines within 28 days prior to enrollment were added as a prohibited medication, • added a requirement for patients in Substudy 2 to have no ‘standard’ treatment alternative rather than no ‘satisfactory’ treatment alternative, • added serum electrolyte abnormalities as exclusion criterion 6, • addition of measurements of amylase and lipase to the clinical safety laboratory tests, • to provide continued study treatment at the time of study closure to patients who continued to derive benefit, • modification of the schedule for ophthalmologic examinations to require a complete ophthalmological examination at End of Treatment visit.

20 Aug 2020

Protocol amendment 3 was implemented in Protocol Version 4. This amendment included the following: • changes to potential risks for derazantinib, • removal of phototoxicity from the list of AEs of special interest (AESIs), • deletion of translational clinical study groups planned for Substudies 1, 3, and 4 and associated molecular translational analyses from the protocol, • clarification of inclusion criterion 4: the definition of ‘PD-L1-low’, a low PD-L1 expression level, • change to inclusion criterion 5: for enrollment into Substudy 4, a positive central FGFR1–3 genetic aberration test result was not required if the patient had documented FGFR1–3 GA status from prior FGFR inhibiting treatment, • clarification of which pathway-targeting agents were the subject of exclusion criteria 3 and 4, • clarification that the corneal or retinal disorder referred to in exclusion criterion 5 must be clinically significant and likely to increase the risk of eye toxicity, • clarification of exclusion criteria 14: revised to state that patients with chronic hepatitis B were only eligible with an HBV DNA < 100 IU/mL and if taking an antiviral therapy, • change to eligible FGFR genetic aberrations, • amendments to screening where local FGFR testing was performed as routine institutional practice, • change to estimated objective response rate for the Substudy 1 hypothesis, • clarification of the requirements for informed consent for pre-screening and study participation, • changes to requirements for bone scans, • clarification of the ethical basis of the study (GCP), • changes to administration of derazantinib with food in the event of nausea or vomiting.

08 Mar 2021

Protocol amendment 4 was implemented in Protocol Version 5. This amendment included the following: • addition of Substudy 5 (a new substudy in patients with advanced or mUC expressing FGFR1–3 GAs who had progressed on at least one standard chemotherapy and/or immune-checkpoint blockade and had not received prior FGFR inhibiting treatment), replacing Substudy 1, • modification of Substudy 3 (revised the strategy for exploring the efficacy of derazantinib in first-line cisplatin mUC patients expressing FGFR1–3 GAs and removing the monotherapy cohort in this patient population), • modification of inclusion criterion 4 for Substudy 3 (to permit enrolment of patients with mUC with any PD-L1 status), • addition of an exclusion criterion taking into account the prognostic ‘Bellmunt score’, • clarification of exclusion criterion 15 (patients with active/chronic hepatitis B and active hepatitis C), • addition of pharmacodynamics cohorts to Substudies 3, 4, and 5, • amendments to molecular testing for eligibility (to permit positive FGFR1–3 GA test results obtained from local NGS testing), • clarification of AST/ALT elevations (as DLT), • revised dose modifications guidance for atezolizumab.

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.

The following secondary endpoints could not be shown due to the restrictions of the EudraCT system; duration of response, overall survival and disease control rate. The figures are on CT.gov: https://clinicaltrials.gov/study/NCT04045613

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Clinical Trial Results:
An open-label multi-cohort Phase 1b/2 study of derazantinib and atezolizumab in patients with urothelial cancer expressing activating molecular FGFR aberrations (FIDES-02)

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Baseline characteristics

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Primary: Objective Response Rate (ORR) Based on RECIST 1.1 (Substudies 1,3,4 and 5)

Primary: Objective Response Rate (ORR) Based on RECIST 1.1 (Substudies 1,3,4 and 5)

Primary: Recommended Phase 2 Dose (RP2D) of Derazantinib-atezolizumab in Combination Based on DLT Criteria, Safety and Efficacy Data (Substudy 2)

Primary: Recommended Phase 2 Dose (RP2D) of Derazantinib-atezolizumab in Combination Based on DLT Criteria, Safety and Efficacy Data (Substudy 2)

Primary: Number of Patients With Dose-limiting Toxicities (DLTs) in Substudy 2

Primary: Number of Patients With Dose-limiting Toxicities (DLTs) in Substudy 2

Secondary: ORR Based on RECIST 1.1 (Substudy 2)

Secondary: ORR Based on RECIST 1.1 (Substudy 2)

Secondary: Progression-free Survival (PFS) by RECIST

Secondary: Progression-free Survival (PFS) by RECIST

Secondary: Number of Patients With at Least Grade 3 Adverse Events (AEs)

Secondary: Number of Patients With at Least Grade 3 Adverse Events (AEs)

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Clinical trials

Clinical Trial Results: An open-label multi-cohort Phase 1b/2 study of derazantinib and atezolizumab in patients with urothelial cancer expressing activating molecular FGFR aberrations (FIDES-02)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Objective Response Rate (ORR) Based on RECIST 1.1 (Substudies 1,3,4 and 5)

Primary: Objective Response Rate (ORR) Based on RECIST 1.1 (Substudies 1,3,4 and 5)

Primary: Recommended Phase 2 Dose (RP2D) of Derazantinib-atezolizumab in Combination Based on DLT Criteria, Safety and Efficacy Data (Substudy 2)

Primary: Recommended Phase 2 Dose (RP2D) of Derazantinib-atezolizumab in Combination Based on DLT Criteria, Safety and Efficacy Data (Substudy 2)

Primary: Number of Patients With Dose-limiting Toxicities (DLTs) in Substudy 2

Primary: Number of Patients With Dose-limiting Toxicities (DLTs) in Substudy 2

Secondary: ORR Based on RECIST 1.1 (Substudy 2)

Secondary: ORR Based on RECIST 1.1 (Substudy 2)

Secondary: Progression-free Survival (PFS) by RECIST

Secondary: Progression-free Survival (PFS) by RECIST

Secondary: Number of Patients With at Least Grade 3 Adverse Events (AEs)

Secondary: Number of Patients With at Least Grade 3 Adverse Events (AEs)

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Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
An open-label multi-cohort Phase 1b/2 study of derazantinib and atezolizumab in patients with urothelial cancer expressing activating molecular FGFR aberrations (FIDES-02)