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Clinical Trial Results:
A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab with a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients with BRAF V600E-mutant Metastatic Colorectal Cancer

Summary
EudraCT number	2015-005805-35
Trial protocol	GB HU BE AT NL CZ DK ES NO DE IT
Global end of trial date	10 Nov 2022

Results information
Results version number	v1(current)
This version publication date	13 Nov 2023
First version publication date	13 Nov 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

C4221009

ISRCTN number

US NCT number

NCT02928224

WHO universal trial number (UTN)

Other trial identifiers

ARRAY-818-302: BEACON CRC

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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

06 Dec 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Nov 2022

Was the trial ended prematurely?

Main objective of the trial

Safety Lead-in- - Assess the safety/tolerability of the combination of encorafenib + binimetinib + cetuximab in subjects with B-RAF proto-oncogene, serine/threonine kinase (BRAF) V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC). Randomised Phase 3- In subjects with BRAFV600E mCRC: - Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or 5- fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI)/cetuximab (Control Arm) as measured by overall survival (OS) - Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) as measured by Objective Response Rate (ORR) per Blinded Independent Central Review (BICR).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Oct 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

6 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 7

Country: Number of subjects enrolled

Australia: 36

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Belgium: 45

Country: Number of subjects enrolled

Brazil: 20

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

Czechia: 10

Country: Number of subjects enrolled

Denmark: 10

Country: Number of subjects enrolled

France: 25

Country: Number of subjects enrolled

Germany: 29

Country: Number of subjects enrolled

Hungary: 6

Country: Number of subjects enrolled

Israel: 8

Country: Number of subjects enrolled

Italy: 85

Country: Number of subjects enrolled

Japan: 27

Country: Number of subjects enrolled

Mexico: 2

Country: Number of subjects enrolled

Netherlands: 39

Country: Number of subjects enrolled

Norway: 15

Country: Number of subjects enrolled

Poland: 11

Country: Number of subjects enrolled

Russian Federation: 27

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 41

Country: Number of subjects enrolled

Spain: 102

Country: Number of subjects enrolled

Taiwan: 17

Country: Number of subjects enrolled

Turkey: 7

Country: Number of subjects enrolled

Ukraine: 4

Country: Number of subjects enrolled

United Kingdom: 31

Country: Number of subjects enrolled

United States: 85

Worldwide total number of subjects

702

EEA total number of subjects

383

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)

450

From 65 to 84 years

252

85 years and over

Subject disposition

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Recruitment details

Screening details

Subjects were at least 18 years of age with confirmed metastatic colorectal cancer (CRC) whose disease had progressed after 1 or 2 prior regimens in the metastatic setting and whose tumor tissue was BRAF V600E-mutant as previously determined by a local assay at any time prior to screening.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Combined Safety Lead-in

Arm description

Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

300 milligrams (mg), once daily.

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

400 mg/meter square initial dose (120-minute infusion), then 250 mg/meter square (60-minute infusion) thereafter, once weekly.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

45 mg, twice daily

Phase 3: Triplet Arm

Arm description

Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Encorafenib: 300 mg, once daily.

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

400 mg/meter square initial dose (120-minute infusion), then 250 mg/meter square (60-minute infusion) thereafter, once weekly.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

45 mg, twice daily

Phase 3: Doublet Arm

Arm description

Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.

Arm type

Experimental

Investigational medicinal product name

Cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

400 mg/meter square initial dose (120-minute infusion), then 250 mg/meter square (60-minute infusion) thereafter, once weekly.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

300 mg, once daily.

Phase 3:Control Arm

Arm description

Investigator’s choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible subjects could crossover to receive either triplet or doublet regimen.

Arm type

Active comparator

Investigational medicinal product name

Irinotecan/cetuximab or FOLFIRI/cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care.

Number of subjects in period 1	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Started	37	224	220	221
Crossover participants	0	0	0	3
Completed	0	0	0	0
Not completed	37	224	220	221
Consent withdrawn by subject	-	3	7	20
Death	30	209	193	198
Study participation terminated by sponsor	3	8	12	3
Unspecified	3	3	5	-
Lost to follow-up	1	1	3	-

Baseline characteristics

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Reporting group title

Combined Safety Lead-in

Reporting group description

Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.

Reporting group title

Phase 3: Triplet Arm

Reporting group description

Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.

Reporting group title

Phase 3: Doublet Arm

Reporting group description

Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.

Reporting group title

Phase 3:Control Arm

Reporting group description

Reporting group values	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm	Total
Number of subjects	37	224	220	221	702
Age Categorical
Units: Subjects
<=18 years	0	0	0	0	0
Between 18 and 65 years	23	141	137	149	450
>=65 years	14	83	83	72	252
Age Continuous
Units: years
arithmetic mean (standard deviation)	58.3 ( 10.34 )	59.5 ( 11.65 )	60.2 ( 11.65 )	58.4 ( 12.07 )	-
Sex: Female, Male
Units: Subjects
Female	22	119	106	127	374
Male	15	105	114	94	328
Race
Units: Subjects
American Indian or Alaska Native	0	0	1	0	1
Asian	7	20	25	39	91
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	1	2	0	0	3
White	29	195	183	172	579
More than one race	0	0	0	0	0
Unknown or Not Reported	0	7	11	10	28
Region
Units: Subjects
North America	5	30	28	29	92
Europe	25	150	145	125	445
Rest of World	7	44	47	67	165
Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Baseline
ECOG PS was used to assess the physical health of subjects, and ranges from 0 to 5 where 0: fully active, 1: restricted in physically strenuous activity, 2: ambulatory and capable of self-care but unable to work, 3: capable only of limited self-care, 4: completely disabled; cannot carry on any self-care; totally confined to bed or chair, 5: dead.
Units: Subjects
0-Fully active	22	116	112	108	358
1-Restircted in physically strenuous activity	15	108	104	113	340
2-Ambulatory and capable of all self-care	0	0	4	0	4
Number of Subjects According to Primary Tumor Location
Units: Subjects
Left Colon	11	79	83	68	241
Right Colon	23	126	110	119	378
Left and Right Colon	0	8	11	22	41
Unknown	3	11	16	12	42
Number of Subjects According to Removal of Primary Tumor
Units: Subjects
Completely Resected	20	133	123	122	398
Partially Resected/Unresected	17	91	97	99	304
Number of Subjects According to Number of Organs Involved
Units: Subjects
Greater than or equal to 2	16	114	117	123	370
More than 3	21	110	103	98	332
Ethnicity
Units: Subjects
Hispanic or Latino	0	14	13	6	33
Not Hispanic or Latino	37	203	195	202	637
Unknown or Not Reported	0	7	12	13	32

End points

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Reporting group title

Combined Safety Lead-in

Reporting group description

Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.

Reporting group title

Phase 3: Triplet Arm

Reporting group description

Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.

Reporting group title

Phase 3: Doublet Arm

Reporting group description

Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.

Reporting group title

Phase 3:Control Arm

Reporting group description

Subject analysis set title

Pharmacokinetic Population of Encorafenib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Encorafenib + binimetinib + cetuximab. Encorafenib + cetuximab. Investigator’s choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.

Primary: (Safety Lead-in) Number of Subjects with Adverse Events (AEs)

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End point title

(Safety Lead-in) Number of Subjects with Adverse Events (AEs) ^[1] ^[2]

End point description

An AE is any untoward medical occurrence in a subject or clinical study subject, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of subjects reporting AEs were reported in this endpoint. The Safety Set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received.

End point type

Primary

End point timeframe

Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

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: Only descriptive data was planned to be analysed.
[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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Subjects	37

No statistical analyses for this end point

Primary: (Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to Adverse Events (AEs) - Interim Analysis

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End point title

(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to Adverse Events (AEs) - Interim Analysis ^[3] ^[4]

End point description

An AE is any untoward medical occurrence in a subject or clinical study subject, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of subjects with dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this endpoint. The Safety Set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received.

End point type

Primary

End point timeframe

Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

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: Only descriptive data was planned to be analysed.
[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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Subjects	26

No statistical analyses for this end point

Primary: (Safety Lead-in) Number of Subjects with Dose-Limiting Toxicities (DLTs)

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End point title

(Safety Lead-in) Number of Subjects with Dose-Limiting Toxicities (DLTs) ^[5] ^[6]

End point description

The dose-determining set (DDS) consisted of all combined safety lead-in (CSLI) subjects from the safety set who either completed a minimum exposure requirement (received >= 75% dose intensity of the planned dose for each binimetinib, encorafenib and cetuximab) and had sufficient safety evaluations or experienced a dose-limiting toxicity (DLT).

End point type

Primary

End point timeframe

Cycle 1 (up to 28 days)

Notes
[5] - 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: Only descriptive data was planned to be analysed.
[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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Subjects	5

No statistical analyses for this end point

Primary: (Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to Adverse Events (AEs) - Final Analysis

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End point title

(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to Adverse Events (AEs) - Final Analysis ^[7] ^[8]

End point description

An AE is any untoward medical occurrence in a subject or clinical study subject, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of subjects according to incidence of dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this endpoint. The Safety Set consisted of all subjects who received at least 1 dose of study drug and had at least 1 posttreatment assessment, which may have included death. Subjects were analysed according to treatment received.

End point type

Primary

End point timeframe

From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)

Notes
[7] - 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: Only descriptive data was planned to be analysed.
[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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Subjects
Dose interruptions	30
Dose modifications	16
Discontinuation due to AEs	8

No statistical analyses for this end point

Primary: (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Interim Analysis

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End point title

(Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Interim Analysis ^[9]

End point description

OS was defined as the time from randomisation to death due to any cause. The Full Analysis Set (FAS) for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.

End point type

Primary

End point timeframe

From randomisation to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.1 weeks for triplet arm and 52.4 weeks for control arm)

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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3:Control Arm
Number of subjects analysed	224	221
Units: Months
median (confidence interval 95%)	9.03 (8.02 to 11.43)	5.42 (4.76 to 6.57)

Triplet Arm vs. Control Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3:Control Arm

Number of subjects included in analysis

445

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Stratified Log-rank

Confidence interval

Primary: (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Final Analysis

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End point title

(Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Final Analysis ^[10]

End point description

OS was defined as the time from randomisation to death due to any cause. The Full Analysis Set (FAS) for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.

End point type

Primary

End point timeframe

From randomisation to death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Notes
[10] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3:Control Arm
Number of subjects analysed	224	221
Units: Months
median (confidence interval 95%)	9.82 (8.34 to 11.73)	5.88 (5.09 to 7.16)

Triplet vs Control Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3:Control Arm

Number of subjects included in analysis

445

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Stratified Log-rank

Confidence interval

Primary: (Phase 3) Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm

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End point title

(Phase 3) Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm ^[11]

End point description

ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of complete response (CR) or partial response (PR) divided by the total number of subjects, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 millimeter [mm] short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Primary

End point timeframe

Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Notes
[11] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3:Control Arm
Number of subjects analysed	111	107
Units: Percentage of subjects
number (confidence interval 95%)	26.1 (18.2 to 35.3)	1.9 (0.2 to 6.6)

Triplet vs Control Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3:Control Arm

Number of subjects included in analysis

218

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Chi-squared

Confidence interval

Secondary: (Safety Lead-in) Objective Response Rate (ORR) by Investigator

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End point title

(Safety Lead-in) Objective Response Rate (ORR) by Investigator ^[12]

End point description

ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. The Safety Lead-in (SLI) Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)

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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	36
Units: Percentage of subjects
number (confidence interval 95%)	52.8 (35.5 to 69.6)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Duration of Response (DOR) by Investigator

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End point title

(Safety Lead-in) Duration of Response (DOR) by Investigator ^[13]

End point description

DOR was defined as the time from first radiographic evidence of response to the earliest documented disease progression (PD) or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From time of response to the earliest documented PD or death due to underlying disease (maximum treatment exposure of 280 weeks)

Notes
[13] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	19
Units: Months
median (confidence interval 95%)	6.47 (4.17 to 11.07)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Objective Response Rate (ORR) by BICR

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End point title

(Safety Lead-in) Objective Response Rate (ORR) by BICR ^[14]

End point description

ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)

Notes
[14] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	36
Units: Percentage of subjects
number (confidence interval 95%)	41.7 (25.5 to 59.2)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Duration of Response (DOR) by BICR

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End point title

(Safety Lead-in) Duration of Response (DOR) by BICR ^[15]

End point description

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint. 99999 indicated data could not be calculated due to insufficient subjects with events.

End point type

Secondary

End point timeframe

From time of response to the earliest documented PD or death due to underlying disease (maximum treatment exposure of 280 weeks)

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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	15
Units: Months
median (confidence interval 95%)	8.15 (2.79 to 99999)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Time to Response by Investigator

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End point title

(Safety Lead-in) Time to Response by Investigator ^[16]

End point description

Time to response was defined as the time from first dose to first radiographic evidence of response. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From first dose to first radiographic evidence of response (maximum treatment exposure of 280 weeks)

Notes
[16] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	36
Units: Months
median (confidence interval 95%)	1.45 (1.38 to 1.64)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Time to Response by BICR

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End point title

(Safety Lead-in) Time to Response by BICR ^[17]

End point description

End point type

Secondary

End point timeframe

From first dose to first radiographic evidence of response (maximum treatment exposure of 280 weeks)

Notes
[17] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	36
Units: Months
median (confidence interval 95%)	1.45 (1.38 to 1.64)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Progression-free Survival (PFS) by Investigator

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End point title

(Safety Lead-in) Progression-free Survival (PFS) by Investigator ^[18]

End point description

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The SLI Efficacy Set consisted of all CSLI subjects in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 280 weeks)

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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	36
Units: Months
median (confidence interval 95%)	8.08 (5.59 to 9.3)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Progression-free Survival (PFS) by BICR

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End point title

(Safety Lead-in) Progression-free Survival (PFS) by BICR ^[19]

End point description

End point type

Secondary

End point timeframe

From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 280 weeks)

Notes
[19] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	36
Units: Months
median (confidence interval 95%)	5.59 (4.44 to 9.3)

No statistical analyses for this end point

Secondary: (Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm

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End point title

(Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm ^[20]

End point description

OS was defined as the time from randomisation to death due to any cause. The Full Analysis Set (FAS) for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.

End point type

Secondary

End point timeframe

From randomisation to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.7 weeks for doublet arm and 52.4 weeks for control arm)

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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	220	221
Units: Months
median (confidence interval 95%)	9.40 (8.11 to 11.24)	5.88 (5.09 to 7.16)

Doublet vs Control Arm

Comparison groups

Phase 3: Doublet Arm v Phase 3:Control Arm

Number of subjects included in analysis

441

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Stratified Log-rank

Confidence interval

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm per Investigator

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End point title

(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm per Investigator ^[21]

End point description

PFS was defined as the time from first dose to the earliest documented disease progression (PD) or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.

End point type

Secondary

End point timeframe

From first dose to the earliest documented disease progression (PD) or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Notes
[21] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3:Control Arm
Number of subjects analysed	224	221
Units: Months
median (confidence interval 95%)	4.47 (4.24 to 5.36)	1.58 (1.51 to 2.07)

Triplet vs Control Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3:Control Arm

Number of subjects included in analysis

445

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Stratified Log-rank

Confidence interval

Secondary: (Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm

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End point title

(Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm ^[22]

End point description

OS was defined as the time from randomisation to death due to any cause. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 subjects.

End point type

Secondary

End point timeframe

From randomisation to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.7 weeks for doublet arm and 89.1 weeks for triplet arm)

Notes
[22] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Number of subjects analysed	224	220
Units: Months
median (confidence interval 95%)	9.82 (8.34 to 11.73)	9.40 (8.11 to 11.24)

Triplet vs Doublet Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3: Doublet Arm

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5958

Method

Stratified Log-rank

Confidence interval

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm per BICR

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End point title

(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm per BICR ^[23]

End point description

End point type

Secondary

End point timeframe

From first dose to the earliest documented disease progression (PD) or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3:Control Arm
Number of subjects analysed	224	221
Units: Months
median (confidence interval 95%)	4.30 (4.14 to 5.19)	1.51 (1.45 to 1.71)

Triplet vs Control Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3:Control Arm

Number of subjects included in analysis

445

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Stratified Log-rank

Confidence interval

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm per BICR

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End point title

(Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm per BICR ^[24]

End point description

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.

End point type

Secondary

End point timeframe

From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	220	221
Units: Months
median (confidence interval 95%)	4.21 (3.71 to 5.36)	1.51 (1.45 to 1.71)

Doublet vs Control Arm

Comparison groups

Phase 3: Doublet Arm v Phase 3:Control Arm

Number of subjects included in analysis

441

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Stratified Log-rank

Confidence interval

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm per Investigator

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End point title

(Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm per Investigator ^[25]

End point description

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 subjects.

End point type

Secondary

End point timeframe

From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	220	221
Units: Months
median (confidence interval 95%)	4.27 (4.04 to 5.36)	1.58 (1.51 to 2.07)

Doublet vs Control Arm

Comparison groups

Phase 3: Doublet Arm v Phase 3:Control Arm

Number of subjects included in analysis

441

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Stratified Log-rank

Confidence interval

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR

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End point title

(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR ^[26]

End point description

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.

End point type

Secondary

End point timeframe

From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Number of subjects analysed	224	220
Units: Months
median (confidence interval 95%)	4.30 (4.14 to 5.19)	4.21 (3.71 to 5.36)

Triplet vs Doublet Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3: Doublet Arm

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1004

Method

Stratified Log-rank

Confidence interval

Secondary: (Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator

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End point title

(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator ^[27]

End point description

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects.

End point type

Secondary

End point timeframe

From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Notes
[27] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Number of subjects analysed	224	220
Units: Months
median (confidence interval 95%)	4.47 (4.24 to 5.36)	4.27 (4.04 to 5.36)

Triplet vs Doublet Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3: Doublet Arm

Number of subjects included in analysis

444

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.3724

Method

Stratified Log-rank

Confidence interval

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm per Investigator

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End point title

(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm per Investigator ^[28]

End point description

ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Notes
[28] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3:Control Arm
Number of subjects analysed	111	107
Units: Percentage of subjects
number (confidence interval 95%)	26.1 (18.2 to 35.3)	3.7 (1.0 to 9.3)

Triplet vs Control Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3:Control Arm

Number of subjects included in analysis

218

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Chi-squared

Confidence interval

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR

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End point title

(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR ^[29]

End point description

ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Notes
[29] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Number of subjects analysed	111	113
Units: Percentage of subjects
number (confidence interval 95%)	26.1 (18.2 to 35.3)	20.4 (13.4 to 29.0)

Triplet vs Doublet Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3: Doublet Arm

Number of subjects included in analysis

224

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1928

Method

Cochran-Mantel-Haenszel

Confidence interval

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR

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End point title

(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR ^[30]

End point description

ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Notes
[30] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	113	107
Units: Percentage of subjects
number (confidence interval 95%)	20.4 (13.4 to 29.0)	1.9 (0.2 to 6.6)

Doublet vs Control Arm

Comparison groups

Phase 3: Doublet Arm v Phase 3:Control Arm

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Chi-squared

Confidence interval

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator

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End point title

(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator ^[31]

End point description

ORR per RECIST, v1.1, was defined as the percentage of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Notes
[31] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	113	107
Units: Percentage of subjects
number (confidence interval 95%)	15.9 (9.7 to 24.0)	3.7 (1.0 to 9.3)

Doublet vs Control Arm

Comparison groups

Phase 3: Doublet Arm v Phase 3:Control Arm

Number of subjects included in analysis

220

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001

Method

Chi-squared

Confidence interval

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator

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End point title

(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator ^[32]

End point description

ORR per RECIST, v1.1, was defined as the number of subjects achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalisation of tumor marker level, all lymph nodes must be non-pathological in size(<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Notes
[32] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Number of subjects analysed	111	113
Units: Percentage of subjects
number (confidence interval 95%)	26.1 (18.2 to 35.3)	15.9 (9.7 to 24.0)

Triplet vs Doublet Arm

Comparison groups

Phase 3: Triplet Arm v Phase 3: Doublet Arm

Number of subjects included in analysis

224

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.0357

Method

Cochran-Mantel-Haenszel

Confidence interval

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm per Investigator

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End point title

(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm per Investigator ^[33]

End point description

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint. 99999 indicated data could not be calculated due to insufficient subjects with events.

End point type

Secondary

End point timeframe

From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Notes
[33] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3:Control Arm
Number of subjects analysed	111	107
Units: Months
median (confidence interval 95%)	4.80 (3.29 to 6.57)	5.75 (2.56 to 99999)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm per BICR

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End point title

(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm per BICR ^[34]

End point description

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint. 99999 indicated data could not be calculated due to insufficient subjects with events.

End point type

Secondary

End point timeframe

From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Notes
[34] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3:Control Arm
Number of subjects analysed	111	107
Units: Months
median (confidence interval 95%)	4.80 (2.96 to 9.69)	99999 (2.56 to 99999)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR

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End point title

(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR ^[35]

End point description

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Notes
[35] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Number of subjects analysed	111	113
Units: Months
median (confidence interval 95%)	4.80 (2.96 to 9.69)	6.06 (4.07 to 8.28)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm per Investigator

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End point title

(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm per Investigator ^[36]

End point description

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint. 99999 indicated data could not be calculated due to insufficient subjects with events.

End point type

Secondary

End point timeframe

From time of response to PD or death due to underlying disease (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Notes
[36] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	113	107
Units: Months
median (confidence interval 95%)	5.70 (3.65 to 6.74)	5.75 (2.56 to 99999)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm per BICR

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End point title

(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm per BICR ^[37]

End point description

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint. 99999 indicated data could not be calculated due to insufficient subjects with events.

End point type

Secondary

End point timeframe

From time of response to PD or death due to underlying disease (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Notes
[37] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	113	107
Units: Months
median (confidence interval 95%)	6.06 (4.07 to 8.28)	99999 (2.56 to 99999)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm per Investigator

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End point title

(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm per Investigator ^[38]

End point description

Time to response defined as the time from first dose to first radiographic evidence of response. The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Notes
[38] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3:Control Arm
Number of subjects analysed	49	7
Units: Months
median (confidence interval 95%)	1.48 (1.41 to 1.51)	2.63 (1.45 to 2.79)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm per BICR

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End point title

(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm per BICR ^[39]

End point description

End point type

Secondary

End point timeframe

From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Notes
[39] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3:Control Arm
Number of subjects analysed	50	3
Units: Months
median (confidence interval 95%)	1.43 (1.41 to 1.51)	1.45 (1.41 to 2.63)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by Investigator

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End point title

(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by Investigator ^[40]

End point description

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated. The Phase 3 Response Efficacy Set consisted of the first 330 subjects randomised into the Phase 3 portion of the study and any additional subjects randomised on the same day as the 330th randomised subject. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Notes
[40] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Number of subjects analysed	111	113
Units: Months
median (confidence interval 95%)	4.80 (3.29 to 6.57)	5.70 (3.65 to 6.74)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm per Investigator

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End point title

(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm per Investigator ^[41]

End point description

End point type

Secondary

End point timeframe

From first dose to first radiographic evidence of response (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Notes
[41] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	31	7
Units: Months
median (confidence interval 95%)	1.48 (1.41 to 1.54)	2.63 (1.45 to 2.79)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per BICR

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End point title

(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per BICR ^[42]

End point description

End point type

Secondary

End point timeframe

From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Notes
[42] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Number of subjects analysed	50	36
Units: Months
median (confidence interval 95%)	1.43 (1.41 to 1.51)	1.48 (1.41 to 1.58)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per Investigator

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End point title

(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per Investigator ^[43]

End point description

End point type

Secondary

End point timeframe

From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Notes
[43] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Number of subjects analysed	49	31
Units: Months
median (confidence interval 95%)	1.48 (1.41 to 1.51)	1.48 (1.41 to 1.54)

No statistical analyses for this end point

Secondary: (Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm per BICR

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End point title

(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm per BICR ^[44]

End point description

End point type

Secondary

End point timeframe

From first dose to first radiographic evidence of response (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Notes
[44] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	36	3
Units: Months
median (confidence interval 95%)	1.48 (1.41 to 1.58)	1.45 (1.41 to 2.63)

No statistical analyses for this end point

Secondary: (Phase 3) Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Subjects (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet

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End point title

(Phase 3) Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Subjects (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet ^[45]

End point description

The EORTC QLQ-C30 questionnaire consisted of 30 questions generating 5 functional scores (physical, role, cognitive, emotional,& social); a global health (GH) status/global quality of life scale score; 3 symptom scale scores (fatigue, pain, & nausea & vomiting); & 6 standalone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, & diarrhea) & perceived financial burden. All items were graded by severity experienced during previous week & used 4-point-scale (1: not at all, 2: a little, 3: quite a bit, 4: very much). The scores were converted to health-related quality of life (HRQoL) scale ranging from 0-100. Higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity). The FAS for Phase 3 portion of study consisted of all randomised Phase 3 subjects. Here, ‘n’=subjects evaluable for the specified timepoints. 99999 indicated data could not be calculated due to insufficient subjects with events.

End point type

Secondary

End point timeframe

Baseline, Cycle(C)1 Day(D)1 , C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Notes
[45] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	224	220	221
Units: Units on a scale
arithmetic mean (standard deviation)
Change at Cycle 1 Day 1, n= 138, 120, 133	-2.4 ( 13.44 )	-4.3 ( 16.27 )	-3.4 ( 15.60 )
Change at Cycle 2 Day 1, n= 181,123, 180	-1.6 ( 19.06 )	3.8 ( 18.46 )	-1.9 ( 22.45 )
Change at Cycle 3 Day 1, n= 148, 51, 142	0.7 ( 18.86 )	3.5 ( 19.96 )	-0.2 ( 24.07 )
Change at Cycle 4 Day 1, n= 119, 37, 105	0.2 ( 15.63 )	4.2 ( 22.17 )	1.4 ( 21.65 )
Change at Cycle 5 Day 1, n= 99, 26, 81	-1.1 ( 18.66 )	4.3 ( 22.09 )	-2.2 ( 22.06 )
Change at Cycle 6 Day 1, n= 68, 13, 60	-4.0 ( 16.76 )	5.6 ( 23.25 )	-4.5 ( 19.43 )
Change at Cycle 7 Day 1, n= 47, 10, 50	-2.5 ( 16.01 )	4.3 ( 21.77 )	1.7 ( 12.30 )
Change at Cycle 8 Day 1, n= 39, 7, 40	-2.6 ( 14.83 )	4.2 ( 16.98 )	0.0 ( 27.64 )
Change at Cycle 9 Day 1, n= 33, 7, 31	-5.8 ( 17.74 )	-5.6 ( 16.44 )	-4.8 ( 12.60 )
Change at Cycle 10 Day 1, n= 23, 4, 24	-3.3 ( 17.90 )	-2.8 ( 16.97 )	2.1 ( 20.83 )
Change at Cycle 11 Day 1, n= 16, 1, 19	-5.2 ( 20.38 )	3.9 ( 15.31 )	33.3 ( 99999 )
Change at Cycle 12 Day 1, n= 14, 2, 18	0.0 ( 22.41 )	-4.6 ( 13.77 )	4.2 ( 53.03 )
Change at Cycle 13 Day 1, n= 9, 1, 13	0.0 ( 20.41 )	-3.2 ( 14.25 )	0.0 ( 99999 )
Change at Cycle 14 Day 1, n= 7, 0, 7	-1.2 ( 24.26 )	-6.0 ( 15.00 )	99999 ( 99999 )
Change at Cycle 15 Day 1, n= 7, 0, 6	3.6 ( 33.63 )	2.8 ( 8.61 )	99999 ( 99999 )
Change at Cycle 16 Day 1, n= 5, 0, 3	-16.7 ( 42.08 )	-5.6 ( 9.62 )	99999 ( 99999 )
Change at Cycle 17 Day 1, n= 3, 0, 3	-27.8 ( 20.97 )	-2.8 ( 12.73 )	99999 ( 99999 )
Change at Cycle 18 Day 1, n= 1, 0, 3	-16.7 ( 99999 )	-8.3 ( 8.33 )	99999 ( 99999 )
Change at Cycle 19 Day 1, n= 1, 0, 2	0.0 ( 99999 )	-8.3 ( 11.79 )	99999 ( 99999 )
Change at Cycle 20 Day 1, n= 1, 0, 1	-25 ( 99999 )	-8 ( 99999 )	99999 ( 99999 )
Change at Cycle 21 Day 1, n= 1, 0, 1	0.0 ( 99999 )	-16.7 ( 99999 )	99999 ( 99999 )
Change at Cycle 22 Day 1, n= 0, 0, 1	99999 ( 99999 )	-16.7 ( 99999 )	99999 ( 99999 )
Change at Cycle 23 Day 1, n= 0, 0, 1	99999 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )
Change at End of Treatment, n= 74, 79, 72	-14.1 ( 22.66 )	-13.1 ( 21.61 )	-15.5 ( 27.04 )
Change at 30 Day Follow Up, n= 24, 21, 16	-17.4 ( 22.51 )	-10.4 ( 15.96 )	-24.6 ( 24.08 )
Baseline, n= 209, 200, 201	62.8 ( 22.18 )	60.7 ( 21.33 )	62.8 ( 21.82 )

No statistical analyses for this end point

Secondary: (Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet

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End point title

(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet ^[46]

End point description

FACT-C=Functional Assessment of Chronic Illness Therapy (FACIT) ,which assessed HRQoL of cancer subjects & subjects with other chronic illnesses. It consists of total 36 items (27 items of general version of FACT-C and disease-specific subscale containing 9 CRC-specific items), summarised to 5 subscales: physical well-being (7 items),functional well-being (7 items), social/family well-being (7 items);all 3 subscales range:0-28, emotional well-being (6 items)range:0-24, colorectal cancer subscale (9 items) range:0-36; higher subscale score=better QoL. All single-item measures range:0='Not at all' to 4='Very much'. Table summarises functional well-being subscale, individual questions are linearly scaled & combined to form functional well-being subscale score (range 0-28). High score represents better QoL.FAS for Phase 3 portion=all randomised Phase 3 subjects. Here, ‘n’=subjects evaluable for specified timepoints. 99999=data could not be calculated due to insufficient subjects.

End point type

Secondary

End point timeframe

Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Notes
[46] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	224	220	221
Units: Units on a scale
arithmetic mean (standard deviation)
Change at Cycle 1 Day 1, n= 142, 117, 130	-0.2 ( 3.36 )	-0.9 ( 4.06 )	-1.4 ( 3.32 )
Change at Cycle 2 Day 1, n= 183, 123, 176	-0.3 ( 4.28 )	-0.6 ( 5.08 )	-0.9 ( 4.48 )
Change at Cycle 3 Day 1, n= 148, 50, 137	-0.2 ( 5.15 )	-0.2 ( 5.23 )	-0.7 ( 5.03 )
Change at Cycle 4 Day 1, n= 119, 37, 105	0.4 ( 4.53 )	-0.1 ( 4.66 )	-1.8 ( 6.48 )
Change at Cycle 5 Day 1, n= 100, 26, 81	0.7 ( 6.4 )	-0.2 ( 4.5 )	-1.6 ( 4.58 )
Change at Cycle 6 Day 1, n= 68, 13, 58	0.7 ( 6.05 )	0.6 ( 4.56 )	-1.9 ( 5.3 )
Change at Cycle 7 Day 1, n= 47, 10, 49	0.5 ( 5.85 )	-0.1 ( 4.70 )	-0.5 ( 5.41 )
Change at Cycle 8 Day 1, n= 40, 8, 39	0.9 ( 6.35 )	0.2 ( 4.24 )	-2.1 ( 4.97 )
Change at Cycle 9 Day 1, n= 32, 7, 30	-1.9 ( 4.32 )	-0.8 ( 3.74 )	-2.6 ( 2.30 )
Change at Cycle 10 Day 1, n= 22, 4, 24	-1.7 ( 4.76 )	-1.3 ( 3.59 )	0.5 ( 4.36 )
Change at Cycle 11 Day 1, n= 17, 2, 19	-1.5 ( 4.47 )	-0.5 ( 4.65 )	-4.5 ( 7.78 )
Change at Cycle 12 Day 1, n= 14, 2, 18	-1.5 ( 4.93 )	-1.1 ( 4.61 )	-4.5 ( 9.19 )
Change at Cycle 13 Day 1, n= 9, 1, 13	-2.0 ( 6.76 )	-3.2 ( 5.34 )	-8.0 ( 99999 )
Change at Cycle 14 Day 1, n= 7, 0, 7	-2.4 ( 5.22 )	-4.0 ( 5.74 )	99999 ( 99999 )
Change at Cycle 15 Day 1, n= 7, 0, 6	-2.3 ( 6.85 )	-1.5 ( 4.72 )	99999 ( 99999 )
Change at Cycle 16 Day 1, n= 5, 0, 3	-4.2 ( 4.02 )	-0.7 ( 0.58 )	99999 ( 99999 )
Change at Cycle 17 Day 1, n= 3, 0, 3	-6.7 ( 5.51 )	-0.7 ( 4.51 )	99999 ( 99999 )
Change at Cycle 18 Day 1, n= 1, 0, 3	-5.0 ( 99999 )	-3.0 ( 4.36 )	99999 ( 99999 )
Change at Cycle 19 Day 1, n= 1, 0, 2	-7.0 ( 99999 )	-6.0 ( 0.00 )	99999 ( 99999 )
Change at Cycle 20 Day 1, n= 1, 0, 1	-6.0 ( 99999 )	-5.0 ( 99999 )	99999 ( 99999 )
Change at Cycle 21 Day 1, n= 1, 0, 1	-9.0 ( 99999 )	-5.0 ( 99999 )	99999 ( 99999 )
Change at Cycle 22 Day 1, n= 0, 0, 1	99999 ( 99999 )	-12.0 ( 99999 )	99999 ( 99999 )
Change at Cycle 23 Day 1, n= 0, 0, 1	99999 ( 99999 )	-9.0 ( 99999 )	99999 ( 99999 )
Change at End of Treatment, n= 74, 79, 73	-2.4 ( 4.84 )	-2.2 ( 5.14 )	-3.1 ( 6.06 )
Change at 30 Day Follow Up, n= 24, 21, 16	-3.5 ( 6.44 )	-0.8 ( 5.42 )	-4.2 ( 6.41 )
Baseline, n= 211, 200, 199	16.3 ( 6.22 )	16.2 ( 5.9 )	16.8 ( 6.07 )

No statistical analyses for this end point

Secondary: (Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet

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End point title

(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet ^[47]

End point description

The EQ-5D-5L contains 1 item for each of 5 dimensions of health-related QoL (i.e., mobility, self-care, usual activities, pain or discomfort and anxiety or depression). Response options for each item varied from having no problems to moderate problems or extreme problems. The EQ-5D-5L (v4.0) is a standardised measure of health utility that provides a single index value for one’s health status. The EQ-5D-5L is frequently used for economic evaluations of health care and has been recognised as a valid and reliable instrument for this purpose. The EQ visual analog scale (VAS) is a score that is directly reported by the subject and ranges from 0 to 100 (higher is better quality health). The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, 'n' signifies subjects evaluable for the specified timepoints. 99999 indicated data could not be calculated due to insufficient subjects.

End point type

Secondary

End point timeframe

Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Notes
[47] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	224	220	221
Units: Units on a scale
arithmetic mean (standard deviation)
Change at Cycle 1 Day 1, n= 141, 120, 135	0.8 ( 10.89 )	-0.9 ( 14.09 )	-2.1 ( 15.02 )
Change at Cycle 2 Day 1, n= 183, 124, 181	1.4 ( 14.74 )	1.9 ( 14.81 )	-2.4 ( 17.20 )
Change at Cycle 3 Day 1, n= 150, 52, 141	3.0 ( 13.94 )	4.2 ( 17.32 )	-1.4 ( 17.40 )
Change at Cycle 4 Day 1, n= 118, 37, 105	4.0 ( 13.06 )	5.6 ( 14.87 )	-0.4 ( 15.14 )
Change at Cycle 5 Day 1, n= 99, 26, 80	3.3 ( 14.66 )	5.1 ( 15.11 )	2.5 ( 11.17 )
Change at Cycle 6 Day 1, n= 66, 13, 58	1.3 ( 13.33 )	2.9 ( 16.84 )	-3.6 ( 13.26 )
Change at Cycle 7 Day 1, n= 46, 10, 47	1.4 ( 13.64 )	3.6 ( 16.71 )	2.4 ( 7.44 )
Change at Cycle 8 Day 1, n= 39, 8, 39	4.1 ( 10.77 )	2.0 ( 16.11 )	-2.8 ( 12.95 )
Change at Cycle 9 Day 1, n= 33, 7, 30	0.3 ( 15.16 )	-4.0 ( 12.99 )	-8.1 ( 8.80 )
Change at Cycle 10 Day 1, n= 23, 4, 23	0.2 ( 13.34 )	-8.1 ( 13.68 )	-1.8 ( 2.36 )
Change at Cycle 11 Day 1, n= 17, 2, 18	0.2 ( 13.87 )	-0.1 ( 10.15 )	4.0 ( 8.49 )
Change at Cycle 12 Day 1, n= 13, 2, 17	-4.0 ( 20.11 )	-0.6 ( 11.67 )	1.5 ( 12.02 )
Change at Cycle 13 Day 1, n= 9, 1, 12	-3.0 ( 17.17 )	-4.1 ( 14.41 )	-2.0 ( 99999 )
Change at Cycle 14 Day 1, n= 7, 0, 7	-4.0 ( 18.06 )	-0.4 ( 13.99 )	99999 ( 99999 )
Change at Cycle 15 Day 1, n= 7, 0, 6	-3.4 ( 14.67 )	4.2 ( 7.36 )	99999 ( 99999 )
Change at Cycle 16 Day 1, n= 5, 0, 3	-10.4 ( 24.87 )	3.3 ( 2.89 )	99999 ( 99999 )
Change at Cycle 17 Day 1, n= 3, 0, 3	-18.3 ( 20.21 )	1.7 ( 5.77 )	99999 ( 99999 )
Change at Cycle 18 Day 1, n= 1, 0, 3	7.0 ( 99999 )	-3.3 ( 2.89 )	99999 ( 99999 )
Change at Cycle 19 Day 1, n= 1, 0, 2	8.0 ( 99999 )	-5.5 ( 13.44 )	99999 ( 99999 )
Change at Cycle 20 Day 1, n= 1, 0, 1	8.0 ( 99999 )	2.0 ( 99999 )	99999 ( 99999 )
Change at Cycle 21 Day 1, n= 1, 0, 1	8.0 ( 99999 )	-5.0 ( 99999 )	99999 ( 99999 )
Change at Cycle 22 Day 1, n= 0, 0, 1	99999 ( 99999 )	-5.0 ( 99999 )	99999 ( 99999 )
Change at Cycle 23 Day 1, n= 0, 0, 1	99999 ( 99999 )	-5.0 ( 99999 )	99999 ( 99999 )
Change at End of Treatment, n= 75, 80, 72	-8.5 ( 17.40 )	-8.0 ( 18.99 )	-12.7 ( 21.34 )
Change at 30 Day Follow Up, n= 24, 21, 16	-11.1 ( 20.23 )	-5.9 ( 20.18 )	-11.0 ( 17.51 )
Baseline, n= 210, 199, 203	69.0 ( 19.03 )	66.5 ( 19.51 )	68.3 ( 19.71 )

No statistical analyses for this end point

Secondary: (Phase 3) Change From Baseline in the Subject Global Impression of Change (PGIC) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet

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End point title

(Phase 3) Change From Baseline in the Subject Global Impression of Change (PGIC) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet ^[48]

End point description

The PGIC is a measure of subject's perceptions of change in their symptoms over time that can be used as an anchoring method to determine the minimal clinically important difference for other subject reported outcome (PROs). For this assessment, subjects answered the following question: “Since starting treatment, my colorectal cancer symptoms are: (1) very much improved, (2) much improved, (3) minimally improved, (4) no change, (5) minimally worse, (6) much worse or (7) very much worse.” The FAS for the Phase 3 portion of the study consisted of all randomised Phase 3 subjects. Here, 'n' signifies subjects evaluable for the specified timepoints. 99999 indicated data could not be calculated due to insufficient subjects.

End point type

Secondary

End point timeframe

Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Notes
[48] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	224	220	221
Units: Units on a scale
arithmetic mean (standard deviation)
Change at Cycle 1 Day 1, n= 91, 83, 92	-0.1 ( 0.93 )	0.1 ( 1.21 )	0.0 ( 0.90 )
Change at Cycle 2 Day 1, n= 127, 90, 130	-0.7 ( 1.44 )	-0.8 ( 1.60 )	-0.3 ( 1.52 )
Change at Cycle 3 Day 1, n= 101, 37, 105	-0.9 ( 1.44 )	-1.2 ( 1.53 )	-0.5 ( 1.56 )
Change at Cycle 4 Day 1, n= 80, 28, 79	-0.9 ( 1.49 )	-1.1 ( 1.68 )	-0.5 ( 1.35 )
Change at Cycle 5 Day 1, n= 66, 19, 59	-0.9 ( 1.61 )	-1.1 ( 1.69 )	-0.7 ( 1.41 )
Change at Cycle 6 Day 1, n= 45, 9, 40	-0.8 ( 1.31 )	-1.2 ( 1.70 )	-0.8 ( 1.39 )
Change at Cycle 7 Day 1, n= 30, 7, 36	-1.1 ( 1.44 )	-1.0 ( 1.61 )	-1.1 ( 1.07 )
Change at Cycle 8 Day 1, n= 23, 5, 27	-1.2 ( 1.56 )	-1.1 ( 1.58 )	-1.0 ( 0.71 )
Change at Cycle 9 Day 1, n= 21, 5, 21	-0.8 ( 1.26 )	-0.9 ( 1.37 )	-1.0 ( 0.71 )
Change at Cycle 10 Day 1, n= 15, 3, 17	-0.5 ( 1.51 )	-0.6 ( 1.28 )	-0.3 ( 0.58 )
Change at Cycle 11 Day 1, n= 13, 2, 13	-0.9 ( 1.38 )	-1.1 ( 1.38 )	0.0 ( 0.00 )
Change at Cycle 12 Day 1, n= 11, 2, 12	-0.9 ( 1.45 )	-0.8 ( 1.36 )	-0.5 ( 0.71 )
Change at Cycle 13 Day 1, n= 8, 1, 10	-1.3 ( 1.39 )	-0.9 ( 1.52 )	-1.0 ( 99999 )
Change at Cycle 14 Day 1, n= 7, 0, 6	-1.1 ( 1.46 )	-1.5 ( 1.05 )	99999 ( 99999 )
Change at Cycle 15 Day 1, n= 6, 0, 5	-1.2 ( 1.47 )	-1.6 ( 0.89 )	99999 ( 99999 )
Change at Cycle 16 Day 1, n= 4, 0, 3	-2.0 ( 0.82 )	-0.7 ( 1.53 )	99999 ( 99999 )
Change at Cycle 17 Day 1, n= 3, 0, 3	-1.3 ( 1.53 )	-1.0 ( 1.00 )	99999 ( 99999 )
Change at Cycle 18 Day 1, n= 1, 0, 3	-2.0 ( 99999 )	-1.0 ( 1.00 )	99999 ( 99999 )
Change at Cycle 19 Day 1, n= 1, 0, 2	-3.0 ( 99999 )	-0.5 ( 2.12 )	99999 ( 99999 )
Change at Cycle 20 Day 1, n= 1, 0, 1	-3.0 ( 99999 )	-2.0 ( 99999 )	99999 ( 99999 )
Change at Cycle 21 Day 1, n= 1, 0, 1	-3.0 ( 99999 )	-2.0 ( 99999 )	99999 ( 99999 )
Change at Cycle 22 Day 1, n= 0, 0, 1	99999 ( 99999 )	-2.0 ( 99999 )	99999 ( 99999 )
Change at Cycle 23 Day 1, n= 0, 0, 1	99999 ( 99999 )	-2.0 ( 99999 )	99999 ( 99999 )
Change at End of Treatment, n= 52, 63, 54	0.3 ( 1.85 )	0.1 ( 1.82 )	0.4 ( 1.58 )
Change at 30 Day Follow Up, n= 18, 19, 10	-0.1 ( 2.08 )	0.5 ( 1.43 )	0.7 ( 1.34 )
Baseline, n= 153, 149, 152	3.8 ( 1.30 )	3.8 ( 1.30 )	3.9 ( 1.28 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Cetuximab

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End point title

(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Cetuximab ^[49]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[49] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter *hour
geometric mean (geometric coefficient of variation)
Cycle 1; n=34	841000 ( 22.2 )
Cycle 2; n=32	970000 ( 20.6 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Encorafenib

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End point title

(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Encorafenib ^[50]

End point description

The pharmacokinetics (PK) set included all subjects in the safety set who had at least 1 post‑dose blood collection for PK with associated bioanalytical results. Subjects were analysed according to the actual treatment and dose received. All subjects reported under 'Number of Subjects Analysed' contributed data to the table but may not have evaluable data for every row. Here, "Number Analysed (n)" signifies subjects evaluable for specified rows.

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[50] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter *hour
geometric mean (geometric coefficient of variation)
Cycle 1; n=34	11300 ( 61.5 )
Cycle 2; n=29	6660 ( 61.7 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Metabolite of Binimetinib (AR00426032)

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End point title

(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Metabolite of Binimetinib (AR00426032) ^[51]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[51] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter *hour
geometric mean (geometric coefficient of variation)
Cycle 1; n=35	206 ( 46.7 )
Cycle 2; n=26	70.0 ( 95.5 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Binimetinib

Top of page

End point title

(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Binimetinib ^[52]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[52] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter *hour
geometric mean (geometric coefficient of variation)
Cycle 1, n=34	1960 ( 43.6 )
Cycle 2, n=29	1540 ( 44.7 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Encorafenib

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End point title

(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Encorafenib ^[53]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[53] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter
geometric mean (geometric coefficient of variation)
Cycle 1; n=34	3360 ( 65.1 )
Cycle 2; n=29	2490 ( 75.6 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Binimetinib

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End point title

(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Binimetinib ^[54]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[54] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter
geometric mean (geometric coefficient of variation)
Cycle 1; n=35	654 ( 50.8 )
Cycle 2; n=26	524 ( 70.1 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Cetuximab

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End point title

(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Cetuximab ^[55]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[55] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter
geometric mean (geometric coefficient of variation)
Cycle 1; n=34	195000 ( 22.2 )
Cycle 2; n=32	199000 ( 26.8 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Cetuximab

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End point title

(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Cetuximab ^[56]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[56] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Hours
median (full range (min-max))
Cycle 1; n=34	3.77 (1.83 to 6.05)
Cycle 2; n=32	3.05 (1.00 to 6.17)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Encorafenib

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End point title

(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Encorafenib ^[57]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[57] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Hours
median (full range (min-max))
Cycle 1; n=34	2.00 (0.883 to 6.25)
Cycle 2; n=29	2.00 (0.950 to 5.73)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Metabolite of Binimetinib (AR00426032)

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End point title

(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Metabolite of Binimetinib (AR00426032) ^[58]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[58] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter
geometric mean (geometric coefficient of variation)
Cycle 1; n=35	59.9 ( 50.8 )
Cycle 2; n=26	20.5 ( 119 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Binimetinib

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End point title

(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Binimetinib ^[59]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[59] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter
geometric mean (geometric coefficient of variation)	55.3 ( 61.5 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Encorafenib

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End point title

(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Encorafenib ^[60]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[60] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter
geometric mean (geometric coefficient of variation)	18.9 ( 191 )

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Metabolite of Binimetinib (AR00426032)

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End point title

(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Metabolite of Binimetinib (AR00426032) ^[61]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[61] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Hours
median (full range (min-max))
Cycle 1; n=35	2.00 (0.833 to 5.78)
Cycle 2; n=26	1.58 (0.933 to 6.52)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Binimetinib

Top of page

End point title

(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Binimetinib ^[62]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[62] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Hours
median (full range (min-max))
Cycle 1; n=35	1.98 (0.883 to 5.67)
Cycle 2; n=26	1.04 (0.900 to 4.00)

No statistical analyses for this end point

Secondary: (Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Encorafenib

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End point title

(Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Encorafenib

End point description

The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from subjects enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register. The analysis set included all subjects in the PK set with measurable plasma concentrations of the test drug plus concentrations from subjects from 4 additional clinical studies. Subjects were analysed according to the actual treatment and dose received.

End point type

Secondary

End point timeframe

2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)

End point values	Pharmacokinetic Population of Encorafenib
Number of subjects analysed	394
Units: Liter/hour
geometric mean (confidence interval 95%)	16.4 (14.9 to 17.5)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for a Metabolite of Binimetinib

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End point title

(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for a Metabolite of Binimetinib ^[63]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[63] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter
geometric mean (geometric coefficient of variation)	3.41 ( 68.5 )

No statistical analyses for this end point

Secondary: (Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Binimetinib

Top of page

End point title

(Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Binimetinib

End point description

End point type

Secondary

End point timeframe

2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)

End point values	Pharmacokinetic Population of Encorafenib
Number of subjects analysed	181
Units: Liter/hour
geometric mean (confidence interval 95%)	19.0 (17.7 to 20.6)

No statistical analyses for this end point

Secondary: (Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Cetuximab

Top of page

End point title

(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Cetuximab ^[64]

End point description

End point type

Secondary

End point timeframe

Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Notes
[64] - 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: Only descriptive data was planned to be analysed.

End point values	Combined Safety Lead-in
Number of subjects analysed	37
Units: Nanogram/milliliter
geometric mean (geometric coefficient of variation)	55400 ( 54.8 )

No statistical analyses for this end point

Secondary: (Phase 3) Evaluation of the Model-Based Clearance (CL) for Cetuximab

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End point title

(Phase 3) Evaluation of the Model-Based Clearance (CL) for Cetuximab

End point description

End point type

Secondary

End point timeframe

2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)

End point values	Pharmacokinetic Population of Encorafenib
Number of subjects analysed	261
Units: Liter/hour
geometric mean (confidence interval 95%)	0.0154 (0.0114 to 0.0225)

No statistical analyses for this end point

Secondary: Phase 3: Number of Subjects With Clinically Notable Shifts in Hematology and Coagulation Laboratory Parameters

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End point title

Phase 3: Number of Subjects With Clinically Notable Shifts in Hematology and Coagulation Laboratory Parameters ^[65]

End point description

Clinically notable shifts was defined as worsening by at least 2 grades or to more than or equal to (>=) Grade 3 based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Notes
[65] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	222	216	193
Units: Subjects
Activated Partial Thromboplastin Time - Hyper	9	9	4
Hemoglobin - Hyper	0	0	0
Hemoglobin - Hypo	97	30	17
Leukocytes - Hyper	0	0	0
Leukocytes - Hypo	2	9	51
Lymphocytes - Hyper	12	3	4
Lymphocytes - Hypo	25	47	57
Neutrophils - Hypo	4	8	65
Platelets - Hypo	1	5	4
Prothrombin Intl. Normalised Ratio - Hyper	3	2	2

No statistical analyses for this end point

Secondary: Phase 3: Number of Subjects With Clinically Notable Shifts in Serum Chemistry Laboratory Parameters

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End point title

Phase 3: Number of Subjects With Clinically Notable Shifts in Serum Chemistry Laboratory Parameters ^[66]

End point description

Clinically notable shifts was defined as worsening by at least 2 grades or to >= Grade 3 based on CTCAE version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Notes
[66] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	222	216	193
Units: Subjects
Alanine Aminotransferase - Hyper	11	7	10
Albumin - Hypo	50	16	17
Alkaline Phosphatase - Hyper	13	12	18
Aspartate Aminotransferase - Hyper	11	7	9
Bilirubin - Hyper	11	13	12
Calcium - Hyper	1	0	0
Calcium - Hypo	15	8	7
Creatine Kinase - Hyper	18	1	3
Creatinine - Hyper	45	11	6
Glucose - Hyper	8	16	4
Glucose - Hypo	4	0	1
Magnesium - Hyper	0	1	2
Magnesium - Hypo	11	4	9
Potassium - Hyper	14	10	5
Potassium - Hypo	5	7	9
Sodium - Hyper	1	1	2
Sodium - Hypo	10	4	5
Troponin I - Hyper	0	0	0
Urate - Hyper	4	2	1

No statistical analyses for this end point

Secondary: Phase 3: Number of Subjects With Clinically Notable Shifts in Urinalysis Laboratory Parameters

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End point title

Phase 3: Number of Subjects With Clinically Notable Shifts in Urinalysis Laboratory Parameters ^[67]

End point description

End point type

Secondary

End point timeframe

Notes
[67] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	222	216	193
Units: Subjects	8	8	5

No statistical analyses for this end point

Secondary: Phase 3: Number of Subjects With Newly Occurring Clinically Notable Vital Sign Abnormalities

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End point title

Phase 3: Number of Subjects With Newly Occurring Clinically Notable Vital Sign Abnormalities ^[68]

End point description

Newly occurring clinically notable changes was defined as subjects not meeting the criterion at baseline and meeting criterion post-baseline. The criterion included: low/high systolic blood pressure (SBP): <= 90 millimeters of mercury(mmHg) with decrease from baseline of >= 20mmHg or >= 160mmHg with increase from baseline of >= 20mmHg, low/high diastolic blood pressure (DBP): <= 50mmHg with decrease from baseline of >= 15mmHg or >= 100mmHg with increase from baseline of >= 15mmHg, low/high pulse: <= 50 beats/min with decrease from baseline of >= 15 beats/min or >= 120 beats/min with increase from baseline of >= 15 beats/min, low/high temperature: <= 36 degree Celsius (deg C) or >= 37.5 deg C. Safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Notes
[68] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	222	216	193
Units: Subjects
Diastolic Blood Pressure - High	8	6	7
Diastolic Blood Pressure - Low	21	27	5
Pulse Rate - High	23	14	20
Pulse Rate - Low	3	4	3
Systolic Blood Pressure - High	19	13	5
Systolic Blood Pressure - Low	37	28	10
Temperature - High	33	23	25
Temperature - Low	93	84	55

No statistical analyses for this end point

Secondary: Phase 3: Number of Subjects With Newly Occurring Clinically Notable Electrocardiogram (ECG) Values

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End point title

Phase 3: Number of Subjects With Newly Occurring Clinically Notable Electrocardiogram (ECG) Values ^[69]

End point description

Newly occurring clinically notable changes was defined as subjects not meeting the criterion at baseline and meeting criterion post-baseline. The criterion included: heart rate- decrease from baseline > 25% and to a value < 50 and increase from baseline > 25% and to a value > 100. QT interval- new > 450 (millisecond) msec, new > 480 msec, new > 500 msec, increase from baseline > 30 msec and increase from baseline > 60 msec. QTcF- new > 450 msec, new > 480 msec, new > 500 msec, increase from baseline > 30 msec and increase from baseline > 60 msec. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Notes
[69] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	222	216	193
Units: Subjects
Heart Rate-Decrease from baseline > 25% & to < 50	1	4	0
Heart Rate-Increase from baseline > 25% & to > 100	27	24	28
QT Interval - New > 450 millisecond (msec)	17	30	7
QT Interval - New > 480 msec	4	7	2
QT Interval - New > 500 msec	3	5	0
QT Interval - increase from baseline > 30 msec	97	99	32
QT Interval - increase from baseline > 60 msec	22	21	10
QTcF - New > 450 msec	39	51	23
QTcF - New > 480 msec	9	18	5
QTcF - New > 500 msec	1	6	2
QTcF - increase from baseline > 30 msec	59	75	24
QTcF - increase from baseline > 60 msec	12	20	5

No statistical analyses for this end point

Secondary: Phase 3: Number of Subjects With Shift From Baseline to Worst Change from Baseline in Visual Acuity Logarithm of the Minimum Angle of Resolution (LogMAR) Score

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End point title

Phase 3: Number of Subjects With Shift From Baseline to Worst Change from Baseline in Visual Acuity Logarithm of the Minimum Angle of Resolution (LogMAR) Score ^[70]

End point description

Visual acuity was measured using the Snellen visual acuity conversion chart. This was determined by establishing the smallest optotypes that could be identified correctly by the subject at a given observation distance. Snellen visual acuity was reported as a Snellen fraction (m/M) in which the numerator (m) indicated the test distance and the denominator (M) indicated the distance at which the gap of the equivalent Landolt ring subtends 1 minute of arc. The LogMAR score was calculated as – log(m/M). The maximum increase in score of <= 0, 0 to < 0.1, 0.1 to < 0.2, 0.2 to < 0.3 and >=0.3 relative to baseline in LogMAR were reported in this endpoint. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received.Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Notes
[70] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	222	216	193
Units: Subjects
Baseline <=0 to >0-<0.1 post-baseline	33	8	0
Baseline <=0 to 0.1-<0.2 post-baseline	15	3	0
Baseline <=0 to 0.2-<0.3 post-baseline	4	0	0
Baseline <=0 to >=0.3 post-baseline	6	1	0
Baseline <=0 to missing score post-baseline	9	86	129
Baseline >0-<0.1 to <=0 post-baseline	17	6	0
Baseline >0-<0.1 to 0.1-<0.2 post-baseline	7	2	0
Baseline >0-<0.1 to 0.2-<0.3 post-baseline	4	1	0
Baseline >0-<0.1 to >=0.3 post-baseline	3	0	0
Baseline >0-<0.1 to missing score post-baseline	3	25	30
Baseline 0.1-<0.2 to <=0 post-baseline	5	1	0
Baseline 0.1-<0.2 to >0-<0.1 post-baseline	1	0	0
Baseline 0.2-<0.3 to <=0 post-baseline	1	0	0
Baseline 0.2-<0.3 to >0-<0.1 post-baseline	3	0	0
Baseline 0.2-<0.3 to 0.1-<0.2 post-baseline	3	1	0
Baseline 0.2-<0.3 to missing score post-baseline	1	4	5
Baseline >=0.3 to <=0 post-baseline	9	2	0
Baseline >=0.3 to >0-<0.1 post-baseline	4	0	0
Baseline >=0.3 to 0.1-<0.2 post-baseline	1	1	0
Baseline >=0.3 to 0.2-<0.3 post-baseline	2	0	0
Baseline >=0.3 to missing score post-baseline	1	19	13
Baseline 0.1-<0.2 to 0.2-<0.3 post-baseline	0	3	0
Baseline 0.1-<0.2 to missing score post-baseline	0	9	7

No statistical analyses for this end point

Secondary: Phase 3: Number of Subjects With Shifts in Left Ventricular Ejection Fraction (LVEF) From Baseline to Maximum Grade On-treatment

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End point title

Phase 3: Number of Subjects With Shifts in Left Ventricular Ejection Fraction (LVEF) From Baseline to Maximum Grade On-treatment ^[71]

End point description

Left ventricular ejection fraction (LVEF) abnormalities were defined according to CTCAE version 4.03 where Grade 0: Non-missing value below Grade 2, Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and < -20%, Grade 3: LVEF between 20% and 39% or absolute change from baseline <= -20%, Grade 4: LVEF lower than 20%. Categories with at least 1 non-zero data values showing any shift in Grade from baseline to 1 day after dose 1 (post-baseline) were reported. Subjects whose grade category was unchanged (e.g. Grade 0 to Grade 0) were not reported. The safety set consisted of all subjects who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Subjects were analysed according to treatment received. Here, "Number of Subjects Analysed" signifies subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)

Notes
[71] - 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: Only descriptive data was planned to be analysed.

End point values	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	222	216	193
Units: Subjects
Baseline Grade 0 to Grade 2 post baseline	27	0	0
Baseline Grade 0 to Grade 3 post baseline	1	1	0
Baseline Grade 0 to missing grade	17	205	186
Baseline Grade 2 to missing grade	0	3	2
Baseline missing grade to Grade 0 post baseline	1	0	0

No statistical analyses for this end point

Other pre-specified: Site of Metastases

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End point title

Site of Metastases

End point description

Number of subjects with different sites of metastases were reported in this outcome measure. One subject may have more than one site of metastases. For CSLI: all subjects who received at least 1 dose of study drug and had at least 1 post treatment assessment, which may include death. For the randomised Phase 3 portion of the study: consisted of all randomised subjects.

End point type

Other pre-specified

End point timeframe

At baseline

End point values	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Number of subjects analysed	37	224	220	221
Units: Sites
Liver	24	145	134	128
Lung	10	86	83	86
Lymph Node	17	86	82	88
Peritoneum/Omentum	17	77	97	93

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs = from initiation of study drug through 30 days after last dose of study drug. CSLI: maximum treatment exposure (MTE) of 280 weeks; Phase 3-Triplet: MTE of 277.4 Weeks; Phase 3- Doublet: MTE of 268 Weeks; Phase 3- Control: MTE of 108 Weeks

Adverse event reporting additional description

An AE is defined as the appearance of (or worsening of any pre-existing) undesirable signs,symptoms, or medical conditions that occur after subject's signed informed consent has been obtained. The safety set consisted of all subjects who received at least 1 dose of study drug & had at least 1 post-treatment assessment,which may have included death.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Combined Safety Lead-in

Reporting group description

Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.

Reporting group title

Phase 3: Triplet Arm

Reporting group description

Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.

Reporting group title

Phase 3: Doublet Arm

Reporting group description

Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.

Reporting group title

Phase 3:Control Arm

Reporting group description

Investigator’s choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.

Serious adverse events	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Total subjects affected by serious adverse events
subjects affected / exposed	22 / 37 (59.46%)	118 / 222 (53.15%)	91 / 216 (42.13%)	78 / 193 (40.41%)
number of deaths (all causes)	5	31	38	29
number of deaths resulting from adverse events	0	11	8	8
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	5 / 216 (2.31%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	3 / 216 (1.39%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3	0 / 0
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%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Transitional cell carcinoma
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Tumour associated fever
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumor haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Peripheral artery stenosis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Analgesic therapy
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	3 / 193 (1.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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 / 1	0 / 0	0 / 0
Catheter site thrombosis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	2 / 216 (0.93%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 37 (5.41%)	5 / 222 (2.25%)	2 / 216 (0.93%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 3	3 / 7	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
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%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
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%)	1 / 222 (0.45%)	1 / 216 (0.46%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perforation
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Drug hypersensitivity
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	2 / 216 (0.93%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Female genital tract fistula
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic pain
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	3 / 193 (1.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Aspiration
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	2 / 216 (0.93%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Dyspnoea
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 37 (5.41%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 37 (2.70%)	8 / 222 (3.60%)	3 / 216 (1.39%)	5 / 193 (2.59%)
occurrences causally related to treatment / all	1 / 1	2 / 8	0 / 3	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumomediastinum
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device occlusion
subjects affected / exposed	1 / 37 (2.70%)	1 / 222 (0.45%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	2 / 37 (5.41%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	2 / 216 (0.93%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Body temperature increased
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Rib fracture
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radiation inflammation
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	3 / 37 (8.11%)	1 / 222 (0.45%)	3 / 216 (1.39%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	4 / 4	1 / 1	3 / 3	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anastomotic ulcer
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anastomotic haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Toxicity to various agents
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Cardiac disorders
Cardio-respiratory arrest
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
Cardiac arrest
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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 / 1	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	3 / 216 (1.39%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Pericarditis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral ischaemia
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Epilepsy
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	1 / 193 (0.52%)
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
Ischaemic stroke
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	1 / 193 (0.52%)
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
Hepatic encephalopathy
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Cognitive disorder
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	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%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haematoma
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Lethargy
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 37 (2.70%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 37 (2.70%)	6 / 222 (2.70%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	5 / 8	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	5 / 193 (2.59%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	1 / 37 (2.70%)	10 / 222 (4.50%)	0 / 216 (0.00%)	10 / 193 (5.18%)
occurrences causally related to treatment / all	1 / 1	9 / 10	0 / 0	9 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 37 (5.41%)	6 / 222 (2.70%)	2 / 216 (0.93%)	4 / 193 (2.07%)
occurrences causally related to treatment / all	0 / 2	3 / 6	2 / 2	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal perforation
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	1 / 193 (0.52%)
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 / 0
Ileus
subjects affected / exposed	0 / 37 (0.00%)	5 / 222 (2.25%)	4 / 216 (1.85%)	4 / 193 (2.07%)
occurrences causally related to treatment / all	0 / 0	0 / 8	2 / 6	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	2 / 216 (0.93%)	4 / 193 (2.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 7	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	2 / 216 (0.93%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 37 (2.70%)	3 / 222 (1.35%)	2 / 216 (0.93%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 1	1 / 3	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 37 (0.00%)	11 / 222 (4.95%)	12 / 216 (5.56%)	7 / 193 (3.63%)
occurrences causally related to treatment / all	0 / 0	0 / 12	0 / 13	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
Abdominal pain
subjects affected / exposed	0 / 37 (0.00%)	7 / 222 (3.15%)	5 / 216 (2.31%)	4 / 193 (2.07%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 6	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal obstruction
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (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
Dyspepsia
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Gastritis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 37 (0.00%)	6 / 222 (2.70%)	4 / 216 (1.85%)	4 / 193 (2.07%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 37 (2.70%)	2 / 222 (0.90%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	4 / 216 (1.85%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
intestinal perforation
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2	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%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Pancreatitis relapsing
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Rectal stenosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Melaena
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Proctalgia
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine ulcer
subjects affected / exposed	1 / 37 (2.70%)	2 / 222 (0.90%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Large intestinal ulcer hemorrhage
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Anal fistula
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Abdominal pain upper
subjects affected / exposed	1 / 37 (2.70%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal hemorrhage
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Esophageal ulcer hemorrhage
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 37 (2.70%)	7 / 222 (3.15%)	3 / 216 (1.39%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	7 / 8	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mallory-Weiss syndrome
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Malabsorption
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Proctitis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal hemorrhage
subjects affected / exposed	1 / 37 (2.70%)	4 / 222 (1.80%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 4	0 / 0	0 / 0
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 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Upper gastrointestinal hemorrhage
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	37 / 193 (19.17%)
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
Gastrointestinal ulcer haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Gastrointestinal obstruction
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenal perforation
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Oesophageal ulcer haemorrhage
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	0 / 37 (0.00%)	3 / 222 (1.35%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	3 / 216 (1.39%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stenosis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	1 / 193 (0.52%)
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
Biliary dilatation
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pruritus generalised
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 37 (2.70%)	8 / 222 (3.60%)	4 / 216 (1.85%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	5 / 8	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephritis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 37 (2.70%)	2 / 222 (0.90%)	0 / 216 (0.00%)	1 / 193 (0.52%)
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
Haematuria
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Renal failure
subjects affected / exposed	2 / 37 (5.41%)	2 / 222 (0.90%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (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
Prerenal failure
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 37 (2.70%)	4 / 222 (1.80%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Chondrocalcinosis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 37 (2.70%)	1 / 222 (0.45%)	2 / 216 (0.93%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fistula
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Muscle tightness
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periostitis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Peritonitis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Sepsis
subjects affected / exposed	1 / 37 (2.70%)	5 / 222 (2.25%)	3 / 216 (1.39%)	3 / 193 (1.55%)
occurrences causally related to treatment / all	0 / 1	0 / 7	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Bacteraemia
subjects affected / exposed	0 / 37 (0.00%)	4 / 222 (1.80%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 5	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%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrintestinal infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Erysipelas
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Cholangitis infective
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Biliary tract infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (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
Abdominal wall abscess
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	2 / 216 (0.93%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound abscess
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Campylobacter gastroenteritis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal abscess
subjects affected / exposed	1 / 37 (2.70%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 37 (0.00%)	4 / 222 (1.80%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Clostridial infection
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis infectious
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal infection
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ophthalmic herpes zoster
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Lung infection
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	1 / 193 (0.52%)
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 / 1
Kidney infection
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infectious colitis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	2 / 37 (5.41%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Herpes simplex
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Septic shock
subjects affected / exposed	0 / 37 (0.00%)	3 / 222 (1.35%)	1 / 216 (0.46%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Pyelonephritis
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	3 / 216 (1.39%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 2	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 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Streptococcal infection
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	4 / 37 (10.81%)	5 / 222 (2.25%)	6 / 216 (2.78%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 5	0 / 7	0 / 7	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%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 37 (2.70%)	2 / 222 (0.90%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	1 / 2	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	1 / 216 (0.46%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	2 / 216 (0.93%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cachexia
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (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
Electrolyte imbalance
subjects affected / exposed	0 / 37 (0.00%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 37 (0.00%)	0 / 222 (0.00%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
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	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Total subjects affected by non serious adverse events
subjects affected / exposed	36 / 37 (97.30%)	218 / 222 (98.20%)	212 / 216 (98.15%)	187 / 193 (96.89%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus
subjects affected / exposed	1 / 37 (2.70%)	1 / 222 (0.45%)	34 / 216 (15.74%)	0 / 193 (0.00%)
occurrences all number	1	2	39	0
Tumour Pain
subjects affected / exposed	4 / 37 (10.81%)	3 / 222 (1.35%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences all number	4	3	2	1
Skin papilloma
subjects affected / exposed	1 / 37 (2.70%)	0 / 222 (0.00%)	15 / 216 (6.94%)	0 / 193 (0.00%)
occurrences all number	11	0	17	0
Vascular disorders
Hypertension
subjects affected / exposed	4 / 37 (10.81%)	8 / 222 (3.60%)	8 / 216 (3.70%)	6 / 193 (3.11%)
occurrences all number	7	11	12	10
Hypotension
subjects affected / exposed	3 / 37 (8.11%)	9 / 222 (4.05%)	9 / 216 (4.17%)	3 / 193 (1.55%)
occurrences all number	3	11	9	3
General disorders and administration site conditions
Fatigue
subjects affected / exposed	20 / 37 (54.05%)	74 / 222 (33.33%)	74 / 216 (34.26%)	54 / 193 (27.98%)
occurrences all number	57	142	152	85
Pyrexia
subjects affected / exposed	16 / 37 (43.24%)	53 / 222 (23.87%)	43 / 216 (19.91%)	30 / 193 (15.54%)
occurrences all number	30	103	52	42
Asthenia
subjects affected / exposed	6 / 37 (16.22%)	63 / 222 (28.38%)	51 / 216 (23.61%)	52 / 193 (26.94%)
occurrences all number	16	163	92	128
Malaise
subjects affected / exposed	7 / 37 (18.92%)	5 / 222 (2.25%)	6 / 216 (2.78%)	11 / 193 (5.70%)
occurrences all number	18	8	7	16
Chills
subjects affected / exposed	6 / 37 (16.22%)	15 / 222 (6.76%)	6 / 216 (2.78%)	3 / 193 (1.55%)
occurrences all number	12	19	8	3
Oedema peripheral
subjects affected / exposed	6 / 37 (16.22%)	30 / 222 (13.51%)	24 / 216 (11.11%)	14 / 193 (7.25%)
occurrences all number	8	36	30	16
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	13 / 37 (35.14%)	22 / 222 (9.91%)	30 / 216 (13.89%)	20 / 193 (10.36%)
occurrences all number	17	26	44	30
Cough
subjects affected / exposed	5 / 37 (13.51%)	26 / 222 (11.71%)	22 / 216 (10.19%)	12 / 193 (6.22%)
occurrences all number	8	31	29	16
Pulmonary embolism
subjects affected / exposed	2 / 37 (5.41%)	4 / 222 (1.80%)	1 / 216 (0.46%)	5 / 193 (2.59%)
occurrences all number	2	4	1	5
Epistaxis
subjects affected / exposed	1 / 37 (2.70%)	8 / 222 (3.60%)	16 / 216 (7.41%)	8 / 193 (4.15%)
occurrences all number	1	9	19	10
Dysphonia
subjects affected / exposed	2 / 37 (5.41%)	5 / 222 (2.25%)	12 / 216 (5.56%)	3 / 193 (1.55%)
occurrences all number	2	5	12	3
Rhinnorrhoea
subjects affected / exposed	3 / 37 (8.11%)	5 / 222 (2.25%)	6 / 216 (2.78%)	1 / 193 (0.52%)
occurrences all number	3	5	9	1
Rhinitis allergic
subjects affected / exposed	3 / 37 (8.11%)	1 / 222 (0.45%)	3 / 216 (1.39%)	1 / 193 (0.52%)
occurrences all number	3	1	3	1
Pleural effusion
subjects affected / exposed	2 / 37 (5.41%)	1 / 222 (0.45%)	3 / 216 (1.39%)	2 / 193 (1.04%)
occurrences all number	2	1	3	3
Psychiatric disorders
Insomnia
subjects affected / exposed	2 / 37 (5.41%)	15 / 222 (6.76%)	25 / 216 (11.57%)	13 / 193 (6.74%)
occurrences all number	2	16	29	13
Depression
subjects affected / exposed	2 / 37 (5.41%)	5 / 222 (2.25%)	5 / 216 (2.31%)	1 / 193 (0.52%)
occurrences all number	2	5	5	1
Investigations
Weight decreased
subjects affected / exposed	3 / 37 (8.11%)	25 / 222 (11.26%)	26 / 216 (12.04%)	12 / 193 (6.22%)
occurrences all number	4	29	26	14
Neutrophil count decreased
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	1 / 216 (0.46%)	21 / 193 (10.88%)
occurrences all number	0	2	3	36
Blood creatine phosphokinase increased
subjects affected / exposed	13 / 37 (35.14%)	26 / 222 (11.71%)	3 / 216 (1.39%)	4 / 193 (2.07%)
occurrences all number	56	81	4	6
Blood creatine increased
subjects affected / exposed	11 / 37 (29.73%)	25 / 222 (11.26%)	6 / 216 (2.78%)	1 / 193 (0.52%)
occurrences all number	57	52	15	3
Alanine aminotransferase increased
subjects affected / exposed	6 / 37 (16.22%)	16 / 222 (7.21%)	15 / 216 (6.94%)	14 / 193 (7.25%)
occurrences all number	9	22	21	18
Aspartate aminotransferase increased
subjects affected / exposed	7 / 37 (18.92%)	14 / 222 (6.31%)	7 / 216 (3.24%)	14 / 193 (7.25%)
occurrences all number	9	22	11	20
Ejection fraction decreased
subjects affected / exposed	5 / 37 (13.51%)	8 / 222 (3.60%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences all number	5	11	0	0
Blood bilirubin increased
subjects affected / exposed	3 / 37 (8.11%)	5 / 222 (2.25%)	9 / 216 (4.17%)	8 / 193 (4.15%)
occurrences all number	3	10	12	10
White blood cell count decrease
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	2 / 216 (0.93%)	14 / 193 (7.25%)
occurrences all number	0	3	3	22
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 37 (0.00%)	6 / 222 (2.70%)	7 / 216 (3.24%)	10 / 193 (5.18%)
occurrences all number	0	11	10	14
Injury, poisoning and procedural complications
Wound
subjects affected / exposed	2 / 37 (5.41%)	1 / 222 (0.45%)	1 / 216 (0.46%)	1 / 193 (0.52%)
occurrences all number	2	1	1	1
Infusion related reaction
subjects affected / exposed	1 / 37 (2.70%)	5 / 222 (2.25%)	18 / 216 (8.33%)	13 / 193 (6.74%)
occurrences all number	1	5	21	13
Cardiac disorders
Palpitations
subjects affected / exposed	2 / 37 (5.41%)	3 / 222 (1.35%)	4 / 216 (1.85%)	1 / 193 (0.52%)
occurrences all number	3	3	4	1
Nervous system disorders
Headache
subjects affected / exposed	7 / 37 (18.92%)	21 / 222 (9.46%)	43 / 216 (19.91%)	5 / 193 (2.59%)
occurrences all number	12	45	51	6
Dizziness
subjects affected / exposed	8 / 37 (21.62%)	16 / 222 (7.21%)	16 / 216 (7.41%)	16 / 193 (8.29%)
occurrences all number	8	21	17	19
Neuropathy peripheral
subjects affected / exposed	1 / 37 (2.70%)	13 / 222 (5.86%)	11 / 216 (5.09%)	5 / 193 (2.59%)
occurrences all number	1	15	22	5
Dysgeusia
subjects affected / exposed	6 / 37 (16.22%)	11 / 222 (4.95%)	10 / 216 (4.63%)	8 / 193 (4.15%)
occurrences all number	7	12	12	8
Peripheral sensory neuropathy
subjects affected / exposed	6 / 37 (16.22%)	7 / 222 (3.15%)	5 / 216 (2.31%)	4 / 193 (2.07%)
occurrences all number	11	10	8	4
Nervous system disorder
subjects affected / exposed	2 / 37 (5.41%)	0 / 222 (0.00%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences all number	2	0	0	0
Restless legs syndrome
subjects affected / exposed	2 / 37 (5.41%)	1 / 222 (0.45%)	10 / 216 (4.63%)	1 / 193 (0.52%)
occurrences all number	3	1	11	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	16 / 37 (43.24%)	105 / 222 (47.30%)	44 / 216 (20.37%)	37 / 193 (19.17%)
occurrences all number	49	376	126	109
Neutropenia
subjects affected / exposed	1 / 37 (2.70%)	3 / 222 (1.35%)	4 / 216 (1.85%)	36 / 193 (18.65%)
occurrences all number	1	5	8	87
Eye disorders
Vision blurred
subjects affected / exposed	12 / 37 (32.43%)	27 / 222 (12.16%)	10 / 216 (4.63%)	1 / 193 (0.52%)
occurrences all number	16	33	14	1
Dry eye
subjects affected / exposed	5 / 37 (13.51%)	9 / 222 (4.05%)	11 / 216 (5.09%)	3 / 193 (1.55%)
occurrences all number	6	11	13	3
Retinal detachment
subjects affected / exposed	2 / 37 (5.41%)	6 / 222 (2.70%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences all number	5	7	1	0
Vitreous floaters
subjects affected / exposed	4 / 37 (10.81%)	3 / 222 (1.35%)	4 / 216 (1.85%)	0 / 193 (0.00%)
occurrences all number	4	3	4	0
Visual impairment
subjects affected / exposed	3 / 37 (8.11%)	4 / 222 (1.80%)	5 / 216 (2.31%)	0 / 193 (0.00%)
occurrences all number	3	7	5	0
Trichomegaly
subjects affected / exposed	2 / 37 (5.41%)	6 / 222 (2.70%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences all number	2	6	1	0
Trichiasis
subjects affected / exposed	4 / 37 (10.81%)	1 / 222 (0.45%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences all number	4	1	0	0
Chorioretinopathy
subjects affected / exposed	2 / 37 (5.41%)	3 / 222 (1.35%)	0 / 216 (0.00%)	0 / 193 (0.00%)
occurrences all number	3	4	0	0
Macular oedema
subjects affected / exposed	3 / 37 (8.11%)	1 / 222 (0.45%)	1 / 216 (0.46%)	0 / 193 (0.00%)
occurrences all number	4	1	1	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	14 / 37 (37.84%)	64 / 222 (28.83%)	39 / 216 (18.06%)	39 / 193 (20.21%)
occurrences all number	22	99	52	48
Abdominal pain
subjects affected / exposed	14 / 37 (37.84%)	74 / 222 (33.33%)	60 / 216 (27.78%)	54 / 193 (27.98%)
occurrences all number	27	130	111	101
Vomiting
subjects affected / exposed	19 / 37 (51.35%)	99 / 222 (44.59%)	58 / 216 (26.85%)	59 / 193 (30.57%)
occurrences all number	33	198	100	91
Nausea
subjects affected / exposed	22 / 37 (59.46%)	107 / 222 (48.20%)	80 / 216 (37.04%)	84 / 193 (43.52%)
occurrences all number	57	227	113	162
Diarrhoea
subjects affected / exposed	29 / 37 (78.38%)	150 / 222 (67.57%)	85 / 216 (39.35%)	96 / 193 (49.74%)
occurrences all number	91	399	158	252
Flatulence
subjects affected / exposed	0 / 37 (0.00%)	15 / 222 (6.76%)	6 / 216 (2.78%)	3 / 193 (1.55%)
occurrences all number	0	17	7	3
Dyspepsia
subjects affected / exposed	4 / 37 (10.81%)	18 / 222 (8.11%)	9 / 216 (4.17%)	7 / 193 (3.63%)
occurrences all number	6	24	9	7
Abdominal pain upper
subjects affected / exposed	5 / 37 (13.51%)	24 / 222 (10.81%)	22 / 216 (10.19%)	15 / 193 (7.77%)
occurrences all number	6	26	27	15
Rectal haemorrhage
subjects affected / exposed	2 / 37 (5.41%)	21 / 222 (9.46%)	6 / 216 (2.78%)	1 / 193 (0.52%)
occurrences all number	3	25	7	1
Gastroesophageal reflux disease
subjects affected / exposed	2 / 37 (5.41%)	10 / 222 (4.50%)	6 / 216 (2.78%)	6 / 193 (3.11%)
occurrences all number	2	10	8	6
Abdominal distension
subjects affected / exposed	2 / 37 (5.41%)	10 / 222 (4.50%)	16 / 216 (7.41%)	8 / 193 (4.15%)
occurrences all number	3	11	17	11
Dry Mouth
subjects affected / exposed	2 / 37 (5.41%)	11 / 222 (4.95%)	10 / 216 (4.63%)	8 / 193 (4.15%)
occurrences all number	2	13	12	8
Anal haemorrhage
subjects affected / exposed	2 / 37 (5.41%)	6 / 222 (2.70%)	1 / 216 (0.46%)	2 / 193 (1.04%)
occurrences all number	2	6	2	2
Ascites
subjects affected / exposed	2 / 37 (5.41%)	5 / 222 (2.25%)	2 / 216 (0.93%)	4 / 193 (2.07%)
occurrences all number	4	6	3	4
Colitis
subjects affected / exposed	2 / 37 (5.41%)	1 / 222 (0.45%)	0 / 216 (0.00%)	1 / 193 (0.52%)
occurrences all number	3	3	0	1
Stomatitis
subjects affected / exposed	6 / 37 (16.22%)	32 / 222 (14.41%)	13 / 216 (6.02%)	45 / 193 (23.32%)
occurrences all number	7	40	15	84
Abdominal pain lower
subjects affected / exposed	2 / 37 (5.41%)	5 / 222 (2.25%)	4 / 216 (1.85%)	2 / 193 (1.04%)
occurrences all number	2	7	5	2
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	25 / 37 (67.57%)	113 / 222 (50.90%)	65 / 216 (30.09%)	77 / 193 (39.90%)
occurrences all number	44	255	116	138
Dry Skin
subjects affected / exposed	19 / 37 (51.35%)	49 / 222 (22.07%)	28 / 216 (12.96%)	17 / 193 (8.81%)
occurrences all number	23	65	36	20
Rash
subjects affected / exposed	3 / 37 (8.11%)	49 / 222 (22.07%)	35 / 216 (16.20%)	28 / 193 (14.51%)
occurrences all number	10	97	54	55
Pruritus
subjects affected / exposed	3 / 37 (8.11%)	35 / 222 (15.77%)	24 / 216 (11.11%)	10 / 193 (5.18%)
occurrences all number	5	47	37	12
Palmar-planar erythrodysaesthesia
subjects affected / exposed	6 / 37 (16.22%)	31 / 222 (13.96%)	11 / 216 (5.09%)	15 / 193 (7.77%)
occurrences all number	7	54	18	21
Rash maculo-papular
subjects affected / exposed	6 / 37 (16.22%)	19 / 222 (8.56%)	19 / 216 (8.80%)	11 / 193 (5.70%)
occurrences all number	8	33	23	14
Skin fissures
subjects affected / exposed	9 / 37 (24.32%)	21 / 222 (9.46%)	9 / 216 (4.17%)	13 / 193 (6.74%)
occurrences all number	12	35	9	16
Erythema
subjects affected / exposed	2 / 37 (5.41%)	9 / 222 (4.05%)	13 / 216 (6.02%)	4 / 193 (2.07%)
occurrences all number	2	13	14	4
Eczema
subjects affected / exposed	2 / 37 (5.41%)	5 / 222 (2.25%)	2 / 216 (0.93%)	1 / 193 (0.52%)
occurrences all number	2	5	2	1
Skin hyperpigmentation
subjects affected / exposed	2 / 37 (5.41%)	1 / 222 (0.45%)	16 / 216 (7.41%)	2 / 193 (1.04%)
occurrences all number	2	1	16	2
Skin lesion
subjects affected / exposed	0 / 37 (0.00%)	2 / 222 (0.90%)	17 / 216 (7.87%)	3 / 193 (1.55%)
occurrences all number	0	2	24	3
Pruritus generalised
subjects affected / exposed	2 / 37 (5.41%)	6 / 222 (2.70%)	12 / 216 (5.56%)	3 / 193 (1.55%)
occurrences all number	2	7	16	5
Alopecia
subjects affected / exposed	1 / 37 (2.70%)	6 / 222 (2.70%)	10 / 216 (4.63%)	21 / 193 (10.88%)
occurrences all number	1	7	11	23
Hyperkeratosis
subjects affected / exposed	1 / 37 (2.70%)	1 / 222 (0.45%)	12 / 216 (5.56%)	0 / 193 (0.00%)
occurrences all number	1	1	17	0
Hypertrichosis
subjects affected / exposed	3 / 37 (8.11%)	4 / 222 (1.80%)	5 / 216 (2.31%)	1 / 193 (0.52%)
occurrences all number	3	5	5	1
Nail disorder
subjects affected / exposed	2 / 37 (5.41%)	4 / 222 (1.80%)	3 / 216 (1.39%)	2 / 193 (1.04%)
occurrences all number	2	4	3	2
Renal and urinary disorders
Haematuria
subjects affected / exposed	2 / 37 (5.41%)	16 / 222 (7.21%)	6 / 216 (2.78%)	4 / 193 (2.07%)
occurrences all number	3	16	8	4
Urinary incontinence
subjects affected / exposed	2 / 37 (5.41%)	1 / 222 (0.45%)	5 / 216 (2.31%)	2 / 193 (1.04%)
occurrences all number	2	1	6	2
Proteinuria
subjects affected / exposed	3 / 37 (8.11%)	5 / 222 (2.25%)	6 / 216 (2.78%)	1 / 193 (0.52%)
occurrences all number	5	5	10	1
Pollakiuria
subjects affected / exposed	4 / 37 (10.81%)	4 / 222 (1.80%)	8 / 216 (3.70%)	0 / 193 (0.00%)
occurrences all number	4	4	8	0
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	8 / 37 (21.62%)	36 / 222 (16.22%)	32 / 216 (14.81%)	27 / 193 (13.99%)
occurrences all number	14	48	46	32
Pain in extremity
subjects affected / exposed	3 / 37 (8.11%)	19 / 222 (8.56%)	26 / 216 (12.04%)	2 / 193 (1.04%)
occurrences all number	4	28	37	3
Myalgia
subjects affected / exposed	9 / 37 (24.32%)	23 / 222 (10.36%)	35 / 216 (16.20%)	4 / 193 (2.07%)
occurrences all number	19	33	45	7
Arthralgia
subjects affected / exposed	9 / 37 (24.32%)	26 / 222 (11.71%)	52 / 216 (24.07%)	3 / 193 (1.55%)
occurrences all number	22	42	84	4
Musculoskeletal pain
subjects affected / exposed	2 / 37 (5.41%)	12 / 222 (5.41%)	32 / 216 (14.81%)	5 / 193 (2.59%)
occurrences all number	2	15	43	5
Muscle spasms
subjects affected / exposed	2 / 37 (5.41%)	22 / 222 (9.91%)	5 / 216 (2.31%)	4 / 193 (2.07%)
occurrences all number	4	40	6	7
Bone pain
subjects affected / exposed	2 / 37 (5.41%)	2 / 222 (0.90%)	3 / 216 (1.39%)	2 / 193 (1.04%)
occurrences all number	3	2	3	5
Flank pain
subjects affected / exposed	3 / 37 (8.11%)	2 / 222 (0.90%)	1 / 216 (0.46%)	3 / 193 (1.55%)
occurrences all number	4	2	1	6
Musculoskeletal chest pain
subjects affected / exposed	2 / 37 (5.41%)	7 / 222 (3.15%)	5 / 216 (2.31%)	2 / 193 (1.04%)
occurrences all number	2	10	16	2
Infections and infestations
Cystitis
subjects affected / exposed	2 / 37 (5.41%)	6 / 222 (2.70%)	2 / 216 (0.93%)	1 / 193 (0.52%)
occurrences all number	2	7	5	1
Conjunctivitis
subjects affected / exposed	2 / 37 (5.41%)	16 / 222 (7.21%)	12 / 216 (5.56%)	3 / 193 (1.55%)
occurrences all number	2	21	18	3
Rash pustular
subjects affected / exposed	6 / 37 (16.22%)	13 / 222 (5.86%)	4 / 216 (1.85%)	4 / 193 (2.07%)
occurrences all number	9	25	5	6
Paronychia
subjects affected / exposed	6 / 37 (16.22%)	21 / 222 (9.46%)	13 / 216 (6.02%)	20 / 193 (10.36%)
occurrences all number	13	39	22	28
Urinary tract infection
subjects affected / exposed	7 / 37 (18.92%)	26 / 222 (11.71%)	16 / 216 (7.41%)	5 / 193 (2.59%)
occurrences all number	11	43	20	6
Nasopharyngitis
subjects affected / exposed	3 / 37 (8.11%)	12 / 222 (5.41%)	15 / 216 (6.94%)	3 / 193 (1.55%)
occurrences all number	3	15	19	3
Upper respiratory tract infection
subjects affected / exposed	1 / 37 (2.70%)	4 / 222 (1.80%)	9 / 216 (4.17%)	10 / 193 (5.18%)
occurrences all number	1	6	12	13
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	15 / 37 (40.54%)	67 / 222 (30.18%)	68 / 216 (31.48%)	56 / 193 (29.02%)
occurrences all number	35	106	96	74
Hypokalaemia
subjects affected / exposed	3 / 37 (8.11%)	16 / 222 (7.21%)	14 / 216 (6.48%)	25 / 193 (12.95%)
occurrences all number	5	21	17	41
Hypomagnesaemia
subjects affected / exposed	6 / 37 (16.22%)	29 / 222 (13.06%)	28 / 216 (12.96%)	19 / 193 (9.84%)
occurrences all number	12	56	34	36
Hypoalbuminaemia
subjects affected / exposed	4 / 37 (10.81%)	20 / 222 (9.01%)	6 / 216 (2.78%)	6 / 193 (3.11%)
occurrences all number	7	29	9	6
Iron deficiency
subjects affected / exposed	3 / 37 (8.11%)	2 / 222 (0.90%)	3 / 216 (1.39%)	1 / 193 (0.52%)
occurrences all number	10	3	4	1
Hypophosphataemia
subjects affected / exposed	2 / 37 (5.41%)	7 / 222 (3.15%)	3 / 216 (1.39%)	4 / 193 (2.07%)
occurrences all number	2	17	5	6
Hypocalcaemia
subjects affected / exposed	2 / 37 (5.41%)	10 / 222 (4.50%)	5 / 216 (2.31%)	9 / 193 (4.66%)
occurrences all number	3	13	5	14

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Were there any global substantial amendments to the protocol? No

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.

Total number of deaths is reported for safety set under Adverse Events section. However, actual number of deaths were, for combined safety lead-in: 30; for Phase 3: Triplet arm: 209; for Phase 3: Doublet arm: 193 and for Phase 3: Control arm: 198.

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IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: (Safety Lead-in) Number of Subjects with Adverse Events (AEs)

Primary: (Safety Lead-in) Number of Subjects with Adverse Events (AEs)

Primary: (Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to Adverse Events (AEs) - Interim Analysis

Primary: (Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to Adverse Events (AEs) - Interim Analysis

Primary: (Safety Lead-in) Number of Subjects with Dose-Limiting Toxicities (DLTs)

Primary: (Safety Lead-in) Number of Subjects with Dose-Limiting Toxicities (DLTs)

Primary: (Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to Adverse Events (AEs) - Final Analysis

Primary: (Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations due to Adverse Events (AEs) - Final Analysis

Primary: (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Interim Analysis

Primary: (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Interim Analysis

Primary: (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Final Analysis

Primary: (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Final Analysis

Primary: (Phase 3) Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm

Primary: (Phase 3) Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm

Secondary: (Safety Lead-in) Objective Response Rate (ORR) by Investigator

Secondary: (Safety Lead-in) Objective Response Rate (ORR) by Investigator

Secondary: (Safety Lead-in) Duration of Response (DOR) by Investigator

Secondary: (Safety Lead-in) Duration of Response (DOR) by Investigator

Secondary: (Safety Lead-in) Objective Response Rate (ORR) by BICR

Secondary: (Safety Lead-in) Objective Response Rate (ORR) by BICR

Secondary: (Safety Lead-in) Duration of Response (DOR) by BICR

Secondary: (Safety Lead-in) Duration of Response (DOR) by BICR

Secondary: (Safety Lead-in) Time to Response by Investigator

Secondary: (Safety Lead-in) Time to Response by Investigator

Secondary: (Safety Lead-in) Time to Response by BICR

Secondary: (Safety Lead-in) Time to Response by BICR

Secondary: (Safety Lead-in) Progression-free Survival (PFS) by Investigator

Secondary: (Safety Lead-in) Progression-free Survival (PFS) by Investigator

Secondary: (Safety Lead-in) Progression-free Survival (PFS) by BICR

Secondary: (Safety Lead-in) Progression-free Survival (PFS) by BICR

Secondary: (Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm

Secondary: (Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm

Secondary: (Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm per BICR

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm per BICR

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm per BICR

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm per BICR

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR

Secondary: (Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR

Secondary: (Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator

Secondary: (Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator

Secondary: (Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm per BICR

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm per BICR

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm per BICR

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm per BICR

Secondary: (Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm per Investigator

Secondary: (Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm per BICR

Secondary: (Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm per BICR

Secondary: (Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by Investigator