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Clinical Trial Results:
An Open-label, Phase II Study of Vemurafenib in Patients with BRAF V600 Mutation-positive Cancers

Summary
EudraCT number	2011-004426-10
Trial protocol	GB ES DE
Global end of trial date	27 Oct 2016

Results information
Results version number	v1
This version publication date	07 Sep 2017
First version publication date	07 Sep 2017
Other versions	v2

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

MO28072

ISRCTN number

US NCT number

NCT01524978

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

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

Scientific contact

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

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

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

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

Analysis stage

Final

Date of interim/final analysis

27 Oct 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

27 Oct 2016

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study is to assess the efficacy of vemurafenib in subjects with BRAF V600 mutation-positive cancers (solid tumors and multiple myeloma, except melanoma and papillary thyroid cancer) and for whom vemurafenib is deemed the best treatment option in the opinion of the investigator.

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

11 Apr 2012

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

1 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 103

Country: Number of subjects enrolled

France: 63

Country: Number of subjects enrolled

Spain: 24

Country: Number of subjects enrolled

Germany: 13

Country: Number of subjects enrolled

United Kingdom: 5

Worldwide total number of subjects

208

EEA total number of subjects

105

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)

134

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

One participant with breast cancer was screened shortly after Cohort 5 (Breast Cancer) had been closed. This participant was allowed to enter the study in Cohort 7: Other BRAF V600-positive tumors. For analysis purposes Cohort 7 was split into sub-cohorts for indications with sufficient participants.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib

Arm description

Subjects with NSCLC were treated with vemurafenib monotherapy.

Arm type

Experimental

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

Cohort 2: Ovarian Cancer - vemurafenib

Arm description

Subjects with ovarian cancer were treated with vemurafenib monotherapy.

Arm type

Experimental

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

Cohort 3a: Colorectal Cancer - vemurafenib

Arm description

Subjects with colorectal cancer were treated with vemurafenib monotherapy.

Arm type

Experimental

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab

Arm description

Subjects with colorectal cancer were treated with vemurafenib and cetuximab combination therapy.

Arm type

Experimental

Investigational medicinal product name

cetuximab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Escalating doses were administered on Day 1 and then once weekly by intravenous infusion. The escalating doses were as follows: Dose Level 1:300 milligrams per square meter (mg/m^2) loading dose of cetuximab and then 200 mg/m^2 weekly; Dose Level 2: 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly; Dose Level 3: 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly.

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Escalating doses were given orally twice a day starting on Day 2 of Cycle 1.The escalating doses were as follows: Dose Level 1: 720 mg of vemurafenib; Dose Level 2: 720 mg of vemurafenib; Dose Level 3: 960 mg of vemurafenib.

Cohort 4: Cholangiocarcinoma - vemurafenib

Arm description

Subjects with cholangiocarcinoma were treated with vemurafenib monotherapy.

Arm type

Experimental

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

Cohort 6: Multiple Myeloma - vemurafenib

Arm description

Subjects with multiple myeloma were treated with vemurafenib monotherapy.

Arm type

Experimental

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

Cohort 7a: ECD/LCH - vemurafenib

Arm description

Subjects with Erdheim-Chester disease (ECD) or Langerhans cell histiocytosis (LCH) were treated with vemurafenib monotherapy.

Arm type

Experimental

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib

Arm description

Subjects with anaplastic thyroid cancer were treated with vemurafenib monotherapy.

Arm type

Experimental

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

Cohort 7c: Advanced Stage Astrocytoma - vemurafenib

Arm description

Subjects with advanced stage astrocytoma were treated with vemurafenib monotherapy.

Arm type

Experimental

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

Cohort 7d: Early Stage Astrocytoma - vemurafenib

Arm description

Subjects with early stage astrocytoma were treated with vemurafenib monotherapy.

Arm type

Experimental

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

Other BRAF V600-positive Tumors - vemurafenib

Arm description

Subjects with other BRAF V600-positive tumors were treated with vemurafenib monotherapy.

Arm type

Experimental

Investigational medicinal product name

vemurafenib

Investigational medicinal product code

Other name

Zelboraf

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

960 milligrams (mg) vemurafenib orally twice a day until disease progression, unacceptable toxicity, or withdrawal of consent.

Number of subjects in period 1	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Started	62	4	10	27	9	9	26	12	12	9	28
Completed	0	0	0	0	0	0	0	0	0	0	0
Not completed	62	4	10	27	9	9	26	12	12	9	28
Adverse event, serious fatal	34	2	5	24	4	4	1	9	5	6	17
Consent withdrawn by subject	12	-	1	1	3	1	6	2	4	-	5
Unspecified	16	2	1	2	1	3	17	1	2	2	5
Lost to follow-up	-	-	3	-	1	1	2	-	1	1	1

Baseline characteristics

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Reporting group title

Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib

Reporting group description

Subjects with NSCLC were treated with vemurafenib monotherapy.

Reporting group title

Cohort 2: Ovarian Cancer - vemurafenib

Reporting group description

Subjects with ovarian cancer were treated with vemurafenib monotherapy.

Reporting group title

Cohort 3a: Colorectal Cancer - vemurafenib

Reporting group description

Subjects with colorectal cancer were treated with vemurafenib monotherapy.

Reporting group title

Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab

Reporting group description

Subjects with colorectal cancer were treated with vemurafenib and cetuximab combination therapy.

Reporting group title

Cohort 4: Cholangiocarcinoma - vemurafenib

Reporting group description

Subjects with cholangiocarcinoma were treated with vemurafenib monotherapy.

Reporting group title

Cohort 6: Multiple Myeloma - vemurafenib

Reporting group description

Subjects with multiple myeloma were treated with vemurafenib monotherapy.

Reporting group title

Cohort 7a: ECD/LCH - vemurafenib

Reporting group description

Subjects with Erdheim-Chester disease (ECD) or Langerhans cell histiocytosis (LCH) were treated with vemurafenib monotherapy.

Reporting group title

Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib

Reporting group description

Subjects with anaplastic thyroid cancer were treated with vemurafenib monotherapy.

Reporting group title

Cohort 7c: Advanced Stage Astrocytoma - vemurafenib

Reporting group description

Subjects with advanced stage astrocytoma were treated with vemurafenib monotherapy.

Reporting group title

Cohort 7d: Early Stage Astrocytoma - vemurafenib

Reporting group description

Subjects with early stage astrocytoma were treated with vemurafenib monotherapy.

Reporting group title

Other BRAF V600-positive Tumors - vemurafenib

Reporting group description

Subjects with other BRAF V600-positive tumors were treated with vemurafenib monotherapy.

Reporting group values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib	Total
Number of subjects	62	4	10	27	9	9	26	12	12	9	28	208
Age categorical
Units: Subjects
Adults (18-64 years)	30	4	10	15	8	7	15	6	12	8	19	134
From 65-84 years	30	0	0	12	1	2	11	6	0	1	8	71
85 years and over	2	0	0	0	0	0	0	0	0	0	1	3
Age Continuous
Units: years
arithmetic mean (standard deviation)	65.4 ± 10.2	45.8 ± 5.3	57.3 ± 5.4	64.3 ± 8.8	53.2 ± 9.7	62.1 ± 4.3	60.8 ± 13.3	66.8 ± 9.2	41.6 ± 12.2	34.3 ± 20.7	53.7 ± 17.5	-
Gender, Male/Female
Units: Subjects
Female	27	4	5	18	5	3	14	3	8	9	15	111
Male	35	0	5	9	4	6	12	9	4	0	13	97

End points

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Reporting group title

Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib

Reporting group description

Subjects with NSCLC were treated with vemurafenib monotherapy.

Reporting group title

Cohort 2: Ovarian Cancer - vemurafenib

Reporting group description

Subjects with ovarian cancer were treated with vemurafenib monotherapy.

Reporting group title

Cohort 3a: Colorectal Cancer - vemurafenib

Reporting group description

Subjects with colorectal cancer were treated with vemurafenib monotherapy.

Reporting group title

Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab

Reporting group description

Subjects with colorectal cancer were treated with vemurafenib and cetuximab combination therapy.

Reporting group title

Cohort 4: Cholangiocarcinoma - vemurafenib

Reporting group description

Subjects with cholangiocarcinoma were treated with vemurafenib monotherapy.

Reporting group title

Cohort 6: Multiple Myeloma - vemurafenib

Reporting group description

Subjects with multiple myeloma were treated with vemurafenib monotherapy.

Reporting group title

Cohort 7a: ECD/LCH - vemurafenib

Reporting group description

Subjects with Erdheim-Chester disease (ECD) or Langerhans cell histiocytosis (LCH) were treated with vemurafenib monotherapy.

Reporting group title

Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib

Reporting group description

Subjects with anaplastic thyroid cancer were treated with vemurafenib monotherapy.

Reporting group title

Cohort 7c: Advanced Stage Astrocytoma - vemurafenib

Reporting group description

Subjects with advanced stage astrocytoma were treated with vemurafenib monotherapy.

Reporting group title

Cohort 7d: Early Stage Astrocytoma - vemurafenib

Reporting group description

Subjects with early stage astrocytoma were treated with vemurafenib monotherapy.

Reporting group title

Other BRAF V600-positive Tumors - vemurafenib

Reporting group description

Subjects with other BRAF V600-positive tumors were treated with vemurafenib monotherapy.

Primary: Confirmed Best Overall Response Rate (BORR)

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End point title

Confirmed Best Overall Response Rate (BORR) ^[1]

End point description

Confirmed BORR: percentage of subjects with an objective response (OR) (complete response [CR], partial response [PR], stringent CR [sCR] or very good PR [VGPR]) on 2 occasions >/= 4 weeks apart as assessed by the Investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. or International Myeloma Working Group (IMWG) criteria. RECIST v1.1: CR: disappearance of all target lesions; PR: >/= 30% decrease in the sum of diameters of target lesions. IMWG: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal free light chain (FLC) ratio and no clonal cells in bone marrow.

End point type

Primary

End point timeframe

Up to approximately 3 years

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Primary efficacy results were summarized by cohort each representing specific cancer types. No statistical analyses were done, since all cohorts received vemurafenib treatment.

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	62 ^[2]	0 ^[3]	10	27	9	9	26	12	12	9	0 ^[4]
Units: percentage of subjects
number (confidence interval 95%)	37.1 (25.16 to 50.31)	( to )	0 (0 to 30.85)	7.4 (0.91 to 24.29)	22.2 (2.81 to 60.01)	22.2 (2.81 to 60.01)	61.5 (40.57 to 79.77)	25 (5.49 to 57.19)	16.7 (2.09 to 48.41)	33.3 (7.49 to 70.07)	( to )

Notes
[2] - Intent-to-Treat (ITT) population included all subjects enrolled in the study.
[3] - Efficacy analysis was not conducted if less than 7 subjects were enrolled.
[4] - Efficacy analysis was not conducted if less than 7 subjects of same cancer type were enrolled.

No statistical analyses for this end point

Secondary: Confirmed Clinical Benefit Rate (CBR)

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End point title

Confirmed Clinical Benefit Rate (CBR)

End point description

Confirmed clinical benefit rate: percentage of participants with confirmed PR or CR or Stable Disease (SD) that have lasted at least 6 months according to RECIST v1.1 or confirmed CR, PR, VGPR, sCR or SD for at least 6 months according to IMWG criteria. RECIST v1.1: PR: >/= 30% decrease in the sum of diameters of target lesions; CR: disappearance of all target lesions; SD: not meeting criteria for CR, PR or progressive disease (PD). IMWG: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal FLC ratio and no clonal cells in bone marrow; SD: not meeting criteria for CR, VGPR, PR or PD.

End point type

Secondary

End point timeframe

Up to approximately 3 years

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	62 ^[5]	0 ^[6]	10	27	9	9	26	12	12	9	0 ^[7]
Units: percentage of subjects
number (confidence interval 95%)	48.4 (35.5 to 61.44)	( to )	0 (-9999 to 9999)	18.5 (6.3 to 38.08)	44.4 (13.7 to 78.8)	22.2 (2.81 to 60.01)	76.9 (56.35 to 91.03)	25 (5.49 to 57.19)	33.3 (9.92 to 65.11)	44.4 (13.7 to 78.8)	( to )

Notes
[5] - ITT population included all subjects enrolled in the study. -9999 or 9999 = not estimable
[6] - Efficacy analysis was not conducted if less than 7 subjects were enrolled.
[7] - Efficacy analysis was not conducted if less than 7 subjects of same cancer type were enrolled.

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR)

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End point title

Overall Response Rate (ORR)

End point description

ORR: percentage of subjects with an objective response (OR) (CR, PR, sCR or VGPR) on 2 occasions >/= 4 weeks apart as assessed by the Investigator using RECIST v1.1. or IMWG criteria. RECIST v1.1: CR: disappearance of all target lesions; PR: >/= 30% decrease in the sum of diameters of target lesions. IMWG: CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to <200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal free light chain (FLC) ratio and no clonal cells in bone marrow. 9999 or -9999=N/A= not applicable

End point type

Secondary

End point timeframe

Up to approximately 3 years

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	62 ^[8]	0 ^[9]	10	27	9	9	26	12	12	9	0 ^[10]
Units: percentage of subjects
number (confidence interval 95%)
CR	0 (0 to 5.78)	( to )	0 (0 to 30.85)	0 (0 to 12.77)	0 (0 to 33.63)	0 (0 to 33.63)	7.7 (0.95 to 25.13)	8.3 (0.21 to 38.48)	8.3 (0.21 to 38.48)	0 (0 to 33.63)	( to )
PR	37.1 (25.16 to 50.31)	( to )	0 (0 to 30.85)	7.4 (0.91 to 24.29)	22.2 (2.81 to 60.01)	11.1 (0.28 to 48.25)	53.8 (33.37 to 73.41)	16.7 (2.09 to 48.41)	8.3 (0.21 to 38.48)	33.3 (7.49 to 70.07)	( to )
VGPR	9999 (-9999 to 9999)	( to )	9999 (-9999 to 9999)	9999 (-9999 to 9999)	9999 (-9999 to 9999)	11.1 (0.28 to 48.25)	9999 (-9999 to 9999)	9999 (-9999 to 9999)	9999 (-9999 to 9999)	9999 (-9999 to 9999)	( to )
sCR	9999 (-9999 to 9999)	( to )	9999 (-9999 to 9999)	9999 (-9999 to 9999)	9999 (-9999 to 9999)	0 (0 to 33.63)	9999 (-9999 to 9999)	9999 (-9999 to 9999)	9999 (-9999 to 9999)	9999 (-9999 to 9999)	( to )

Notes
[8] - ITT population included all subjects enrolled in the study.
[9] - Efficacy analysis was not conducted if less than 7 subjects were enrolled.
[10] - Efficacy analysis was not conducted if less than 7 subjects of same cancer type were enrolled.

No statistical analyses for this end point

Secondary: Duration of Response (DOR)

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End point title

Duration of Response (DOR)

End point description

DOR was defined as the period from the date of initial PR or CR for solid tumors according to RECISTv1.1 and CR, PR, VGPR or sCR for multiple myeloma according to IMWG criteria, until the date of PD or death from any cause. RECIST v1.1: PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. IMWG: PD: increase of >/= 25% from lowest response value in serum or urine M-protein or bone marrow plasma cell percentage or development of new or increase in size of bone lesions or soft tissue plasmacytomas. ITT population included all subjects enrolled in the study irrespective of whether they had received study medication or not. 9999 = not estimable

End point type

Secondary

End point timeframe

Up to approximately 3 years

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	23	0 ^[11]	0 ^[12]	2	2	2	16	3	2	3	0 ^[13]
Units: months
median (confidence interval 95%)	7.16 (5.49 to 18.43)	( to )	( to )	6.54 (5.68 to 7.39)	12.86 (3.58 to 22.14)	9999 (9999 to 9999)	9999 (9999 to 9999)	9.95 (8.31 to 30.98)	9999 (13.08 to 9999)	3.42 (2.4 to 7.49)	( to )

Notes
[11] - Efficacy analysis was not conducted if less than 7 subjects were enrolled.
[12] - None of the subjects had a response and therefore, duration of response could not be determined.
[13] - Efficacy analysis was not conducted if less than 7 subjects of same cancer type were enrolled.

No statistical analyses for this end point

Secondary: Time to Response

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End point title

Time to Response

End point description

Time to response was defined as the time from the first day of study treatment to the date of first CR, or PR for solid tumors according to RECISTv1.1 and CR, PR, VGPR or sCR for multiple myeloma according to IMWG criteria. RECIST v1.1: CR: disappearance of all target lesions; PR: at least a 30% decrease in the sum of diameters of target lesions. IMWG criteria: CR: negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and </= 5% plasma cells in bone marrow; PR: >/= 50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by >/= 90% or to < 200 mg per 24 hours. VGPR: serum and urine M-protein detectable by immunofixation but not on electrophoresis or >/= 90% reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hour; sCR: CR plus normal FLC ratio and no clonal cells in bone marrow. ITT population included all subjects enrolled in the study. -9999 or 9999 = not estimable

End point type

Secondary

End point timeframe

Up to approximately 3 years

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	62	0 ^[14]	10	27	9	9	26	12	12	9	0 ^[15]
Units: months
median (confidence interval 95%)	7.26 (3.68 to 9999)	( to )	9999 (-9999 to 9999)	9999 (-9999 to 9999)	9999 (3.52 to 9999)	5.75 (-9999 to 9999)	5.49 (3.68 to 13.73)	9999 (1.68 to 9999)	9999 (1.74 to 9999)	9999 (2.33 to 9999)	( to )

Notes
[14] - Efficacy analysis was not conducted if less than 7 subjects were enrolled.
[15] - Efficacy analysis was not conducted if less than 7 subjects of same cancer type were enrolled.

No statistical analyses for this end point

Secondary: Time to Tumor Progression (TTP)

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End point title

Time to Tumor Progression (TTP)

End point description

TTP was defined as time from the first day of study treatment to the first occurrence of progressive disease (PD). RECIST v1.1: PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. IMWG: PD: increase of >/= 25% from lowest response value in serum or urine M-protein or bone marrow plasma cell percentage or development of new or increase in size of bone lesions or soft tissue plasmacytomas. ITT population included all subjects enrolled in the study irrespective of whether they had received study medication or not. 9999 = not estimable

End point type

Secondary

End point timeframe

Up to approximately 3 years

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	62	0 ^[16]	10	27	9	9	26	12	12	9	0 ^[17]
Units: months
median (confidence interval 95%)	7.33 (5.29 to 9.66)	( to )	3.88 (1.84 to 5.52)	3.68 (3.45 to 5.39)	3.02 (1.64 to 9)	4.63 (2.89 to 9999)	9999 (9999 to 9999)	2.83 (1.77 to 5.49)	5.62 (1.81 to 14.85)	5.36 (3.02 to 9.1)	( to )

Notes
[16] - Efficacy analysis was not conducted if less than 7 subjects were enrolled.
[17] - Efficacy analysis was not conducted if less than 7 subjects of same cancer type were enrolled.

No statistical analyses for this end point

Secondary: Progression free Survival (PFS)

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End point title

Progression free Survival (PFS)

End point description

PFS was defined as the time from the first day of study treatment, until the first documented PD or death from any cause, whichever occurs first. RECIST v1.1: PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. IMWG criteria: PD: increase of >/= 25% from lowest response value in serum or urine M-protein or bone marrow plasma cell percentage or development of new or increase in size of bone lesions or soft tissue plasmacytomas. ITT population included all subjects enrolled in the study irrespective of whether they had received study medication or not. 9999 = not estimable

End point type

Secondary

End point timeframe

Up to approximately 3 years

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	62	0 ^[18]	10	27	9	9	26	12	12	9	0 ^[19]
Units: months
median (confidence interval 95%)	6.51 (5.16 to 8.97)	( to )	3.88 (1.84 to 5.52)	3.68 (1.81 to 5.39)	3.02 (1.64 to 9)	4.63 (2.89 to 9999)	9999 (9999 to 9999)	2.83 (1.77 to 5.49)	9.59 (1.81 to 14.78)	5.26 (3.02 to 5.72)	( to )

Notes
[18] - Efficacy analysis was not conducted if less than 7 subjects were enrolled.
[19] - Efficacy analysis was not conducted if less than 7 subjects of same cancer type were enrolled.

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS was defined as time between the first day of study treatment and date of death of any cause. ITT population included all subjects enrolled in the study irrespective of whether they had received study medication or not. 9999 = not estimable

End point type

Secondary

End point timeframe

Up to approximately 3 years

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	62	0 ^[20]	10	27	9	9	26	12	12	9	0 ^[21]
Units: months
median (confidence interval 95%)	15.38 (9.56 to 22.77)	( to )	9.3 (7.82 to 12.88)	7.16 (5.49 to 11.73)	17.94 (11.2 to 9999)	24.54 (4.96 to 9999)	9999 (9999 to 9999)	5.88 (2.17 to 16.79)	40.11 (9.59 to 40.11)	12.75 (6.7 to 9999)	( to )

Notes
[20] - Efficacy analysis was not conducted if less than 7 subjects were enrolled.
[21] - Efficacy analysis was not conducted if less than 7 subjects of same cancer type were enrolled.

No statistical analyses for this end point

Secondary: Maximum Tolerated Dose for Vemurafenib in Combination with Cetuximab

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End point title

Maximum Tolerated Dose for Vemurafenib in Combination with Cetuximab

End point description

Cohort 3b included subjects with colorectal cancer treated with escalating doses of vemurafenib and cetuximab. The escalating doses were as follows: Dose Level 1: 720 milligrams (mg) of vemurafenib orally twice daily starting on Day 2 of Cycle 1 and 300 milligrams per square meter (mg/m^2) loading dose of cetuximab by infusion and then 200 mg/m^2 weekly; Dose Level 2: 720 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly; Dose Level 3: 960 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly. Reported here are the maximum tolerated doses for each vemurafenib and cetuximab. The safety population included all subjects who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to approximately 3 years

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	0 ^[22]	0 ^[23]	0 ^[24]	14	0 ^[25]	0 ^[26]	0 ^[27]	0 ^[28]	0 ^[29]	0 ^[30]	0 ^[31]
Units: milligrams (mg)
vemurafenib				960
cetuximab				400

Notes
[22] - Endpoint only applies to combination therapy in cohort 3b.
[23] - Endpoint only applies to combination therapy in cohort 3b.
[24] - Endpoint only applies to combination therapy in cohort 3b.
[25] - Endpoint only applies to combination therapy in cohort 3b.
[26] - Endpoint only applies to combination therapy in cohort 3b.
[27] - Endpoint only applies to combination therapy in cohort 3b.
[28] - Endpoint only applies to combination therapy in cohort 3b.
[29] - Endpoint only applies to combination therapy in cohort 3b.
[30] - Endpoint only applies to combination therapy in cohort 3b.
[31] - Endpoint only applies to combination therapy in cohort 3b.

No statistical analyses for this end point

Secondary: Number of Dose-limiting Toxicities of Vemurafenib in Combination with Cetuximab

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End point title

Number of Dose-limiting Toxicities of Vemurafenib in Combination with Cetuximab

End point description

Cohort 3b included subjects with colorectal cancer treated with escalating doses of vemurafenib and cetuximab. The escalating doses were as follows: Dose Level 1: 720 milligrams (mg) of vemurafenib orally twice daily starting on Day 2 of Cycle 1 and 300 milligrams per square meter (mg/m^2) loading dose of cetuximab by infusion and then 200 mg/m^2 weekly; Dose Level 2: 720 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly; Dose Level 3: 960 mg of vemurafenib twice daily starting on Day 2 of Cycle 1 and 400 mg/m^2 loading dose of cetuximab and then 250 mg/m^2 weekly. Reported here are type and number of dose limited toxicities observed. The safety population included all subjects who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to 28 days

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	0 ^[32]	0 ^[33]	0 ^[34]	14	0 ^[35]	0 ^[36]	0 ^[37]	0 ^[38]	0 ^[39]	0 ^[40]	0 ^[41]
Units: dose-limiting toxicities
Grade 3 amylase increased				1
Grade 4 lipase increased				1

Notes
[32] - Endpoint only applies to combination therapy in cohort 3b.
[33] - Endpoint only applies to combination therapy in cohort 3b.
[34] - Endpoint only applies to combination therapy in cohort 3b.
[35] - Endpoint only applies to combination therapy in cohort 3b.
[36] - Endpoint only applies to combination therapy in cohort 3b.
[37] - Endpoint only applies to combination therapy in cohort 3b.
[38] - Endpoint only applies to combination therapy in cohort 3b.
[39] - Endpoint only applies to combination therapy in cohort 3b.
[40] - Endpoint only applies to combination therapy in cohort 3b.
[41] - Endpoint only applies to combination therapy in cohort 3b.

No statistical analyses for this end point

Secondary: Safety: Percentage of Subjects with Adverse Event

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End point title

Safety: Percentage of Subjects with Adverse Event

End point description

An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. The safety population included all subjects who received at least one dose of study medication.

End point type

Secondary

End point timeframe

Up to approximately 3 years

End point values	Cohort 1: Non-Small Cell Lung Cancer (NSCLC) - vemurafenib	Cohort 2: Ovarian Cancer - vemurafenib	Cohort 3a: Colorectal Cancer - vemurafenib	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Cohort 4: Cholangiocarcinoma - vemurafenib	Cohort 6: Multiple Myeloma - vemurafenib	Cohort 7a: ECD/LCH - vemurafenib	Cohort 7b: Anaplastic Thyroid Cancer - vemurafenib	Cohort 7c: Advanced Stage Astrocytoma - vemurafenib	Cohort 7d: Early Stage Astrocytoma - vemurafenib	Other BRAF V600-positive Tumors - vemurafenib
Number of subjects analysed	62	4	10	27	9	9	26	12	12	9	28
Units: percentage of subjects
number (not applicable)	100	100	100	100	100	100	100	91.7	100	100	100

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From baseline up to approximately 3 years

Adverse event reporting additional description

The safety population included all subjects who received at least one dose of study medication.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab

Reporting group description

Subjects with colorectal cancer were treated with vemurafenib and cetuximab combination therapy.

Reporting group title

Pooled arm - vemurafenib

Reporting group description

Subjects with a variety of cancer types, who were treated with vemurafenib monotherapy, were combined into this arm.

Serious adverse events	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Pooled arm - vemurafenib
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 27 (40.74%)	91 / 181 (50.28%)
number of deaths (all causes)	25	87
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin
subjects affected / exposed	3 / 27 (11.11%)	25 / 181 (13.81%)
occurrences causally related to treatment / all	3 / 3	38 / 39
deaths causally related to treatment / all	0 / 0	0 / 0
Keratoacanthoma
subjects affected / exposed	2 / 27 (7.41%)	18 / 181 (9.94%)
occurrences causally related to treatment / all	2 / 2	28 / 28
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 27 (3.70%)	7 / 181 (3.87%)
occurrences causally related to treatment / all	1 / 1	11 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	1 / 27 (3.70%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	0 / 27 (0.00%)	4 / 181 (2.21%)
occurrences causally related to treatment / all	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic myelomonocytic leukaemia
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Papillary thyroid cancer
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paraganglion neoplasm
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin cancer
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Jugular vein thrombosis
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	1 / 27 (3.70%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 27 (3.70%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 27 (0.00%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	0 / 27 (0.00%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary thrombosis
subjects affected / exposed	1 / 27 (3.70%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 27 (0.00%)	3 / 181 (1.66%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 27 (0.00%)	3 / 181 (1.66%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Respiratory failure
subjects affected / exposed	0 / 27 (0.00%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Laryngeal dyspnoea
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 27 (3.70%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Body temperature increased
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	1 / 27 (3.70%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 27 (0.00%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 27 (0.00%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dressler's syndrome
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral motor neuropathy
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Posterior reversible encephalopathy syndrome
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Pseudolymphoma
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic infarction
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Iridocyclitis
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 27 (3.70%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	1 / 27 (3.70%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal perforation
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	1 / 27 (3.70%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin lesion
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 27 (3.70%)	4 / 181 (2.21%)
occurrences causally related to treatment / all	0 / 2	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder dilatation
subjects affected / exposed	1 / 27 (3.70%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Obstructive uropathy
subjects affected / exposed	1 / 27 (3.70%)	0 / 181 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 27 (0.00%)	5 / 181 (2.76%)
occurrences causally related to treatment / all	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 27 (0.00%)	6 / 181 (3.31%)
occurrences causally related to treatment / all	0 / 0	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 1
Lung infection
subjects affected / exposed	0 / 27 (0.00%)	4 / 181 (2.21%)
occurrences causally related to treatment / all	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 27 (0.00%)	3 / 181 (1.66%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 27 (0.00%)	2 / 181 (1.10%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal abscess
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Furuncle
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Glucose tolerance impaired
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 27 (0.00%)	1 / 181 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 27 (0.00%)	3 / 181 (1.66%)
occurrences causally related to treatment / all	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 3b: Colorectal Cancer - vemurafenib + cetuximab	Pooled arm - vemurafenib
Total subjects affected by non serious adverse events
subjects affected / exposed	26 / 27 (96.30%)	177 / 181 (97.79%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	3	0
Melanocytic naevus
subjects affected / exposed	4 / 27 (14.81%)	41 / 181 (22.65%)
occurrences all number	4	67
Seborrhoeic keratosis
subjects affected / exposed	3 / 27 (11.11%)	36 / 181 (19.89%)
occurrences all number	3	49
Skin papilloma
subjects affected / exposed	7 / 27 (25.93%)	50 / 181 (27.62%)
occurrences all number	8	86
Papilloma
subjects affected / exposed	0 / 27 (0.00%)	17 / 181 (9.39%)
occurrences all number	0	21
Vascular disorders
Hypertension
subjects affected / exposed	3 / 27 (11.11%)	28 / 181 (15.47%)
occurrences all number	3	38
General disorders and administration site conditions
Chest pain
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Asthenia
subjects affected / exposed	10 / 27 (37.04%)	39 / 181 (21.55%)
occurrences all number	13	44
Chills
subjects affected / exposed	2 / 27 (7.41%)	10 / 181 (5.52%)
occurrences all number	2	10
Fatigue
subjects affected / exposed	6 / 27 (22.22%)	60 / 181 (33.15%)
occurrences all number	8	68
Oedema peripheral
subjects affected / exposed	4 / 27 (14.81%)	21 / 181 (11.60%)
occurrences all number	4	25
Pyrexia
subjects affected / exposed	5 / 27 (18.52%)	26 / 181 (14.36%)
occurrences all number	11	30
Cyst
subjects affected / exposed	0 / 27 (0.00%)	21 / 181 (11.60%)
occurrences all number	0	26
Xerosis
subjects affected / exposed	0 / 27 (0.00%)	16 / 181 (8.84%)
occurrences all number	0	18
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 27 (7.41%)	31 / 181 (17.13%)
occurrences all number	4	42
Dysphonia
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Dyspnoea
subjects affected / exposed	5 / 27 (18.52%)	22 / 181 (12.15%)
occurrences all number	7	27
Nasal congestion
subjects affected / exposed	0 / 27 (0.00%)	10 / 181 (5.52%)
occurrences all number	0	11
Psychiatric disorders
Depression
subjects affected / exposed	3 / 27 (11.11%)	10 / 181 (5.52%)
occurrences all number	5	10
Anxiety
subjects affected / exposed	2 / 27 (7.41%)	14 / 181 (7.73%)
occurrences all number	2	14
Insomnia
subjects affected / exposed	0 / 27 (0.00%)	18 / 181 (9.94%)
occurrences all number	0	19
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	2 / 27 (7.41%)	15 / 181 (8.29%)
occurrences all number	2	15
Amylase increased
subjects affected / exposed	6 / 27 (22.22%)	0 / 181 (0.00%)
occurrences all number	6	0
Blood bilirubin increased
subjects affected / exposed	3 / 27 (11.11%)	10 / 181 (5.52%)
occurrences all number	3	14
Electrocardiogram QT prolonged
subjects affected / exposed	4 / 27 (14.81%)	37 / 181 (20.44%)
occurrences all number	4	52
Lipase increased
subjects affected / exposed	9 / 27 (33.33%)	10 / 181 (5.52%)
occurrences all number	10	21
Lymphocyte count decreased
subjects affected / exposed	3 / 27 (11.11%)	0 / 181 (0.00%)
occurrences all number	6	0
Weight decreased
subjects affected / exposed	6 / 27 (22.22%)	20 / 181 (11.05%)
occurrences all number	6	20
Alanine aminotransferase increased
subjects affected / exposed	0 / 27 (0.00%)	15 / 181 (8.29%)
occurrences all number	0	17
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 27 (0.00%)	11 / 181 (6.08%)
occurrences all number	0	12
Blood creatinine increased
subjects affected / exposed	0 / 27 (0.00%)	19 / 181 (10.50%)
occurrences all number	0	26
Injury, poisoning and procedural complications
Sunburn
subjects affected / exposed	4 / 27 (14.81%)	22 / 181 (12.15%)
occurrences all number	4	27
Fall
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	3	0
Nervous system disorders
Headache
subjects affected / exposed	4 / 27 (14.81%)	26 / 181 (14.36%)
occurrences all number	5	30
Dysgeusia
subjects affected / exposed	0 / 27 (0.00%)	24 / 181 (13.26%)
occurrences all number	0	25
Peripheral sensory neuropathy
subjects affected / exposed	0 / 27 (0.00%)	27 / 181 (14.92%)
occurrences all number	0	27
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 27 (11.11%)	30 / 181 (16.57%)
occurrences all number	3	40
Eye disorders
Dry eye
subjects affected / exposed	0 / 27 (0.00%)	11 / 181 (6.08%)
occurrences all number	0	11
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	12 / 27 (44.44%)	12 / 181 (6.63%)
occurrences all number	18	13
Abdominal pain upper
subjects affected / exposed	4 / 27 (14.81%)	0 / 181 (0.00%)
occurrences all number	4	0
Constipation
subjects affected / exposed	5 / 27 (18.52%)	26 / 181 (14.36%)
occurrences all number	6	30
Diarrhoea
subjects affected / exposed	13 / 27 (48.15%)	49 / 181 (27.07%)
occurrences all number	30	67
Dyspepsia
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	3	0
Flatulence
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	5	0
Nausea
subjects affected / exposed	9 / 27 (33.33%)	54 / 181 (29.83%)
occurrences all number	13	80
Rectal haemorrhage
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	3	0
Stomatitis
subjects affected / exposed	4 / 27 (14.81%)	19 / 181 (10.50%)
occurrences all number	5	20
Vomiting
subjects affected / exposed	8 / 27 (29.63%)	41 / 181 (22.65%)
occurrences all number	10	55
Dry mouth
subjects affected / exposed	0 / 27 (0.00%)	12 / 181 (6.63%)
occurrences all number	0	16
Dysphagia
subjects affected / exposed	0 / 27 (0.00%)	14 / 181 (7.73%)
occurrences all number	0	16
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 27 (0.00%)	11 / 181 (6.08%)
occurrences all number	0	14
Skin and subcutaneous tissue disorders
Actinic keratosis
subjects affected / exposed	4 / 27 (14.81%)	28 / 181 (15.47%)
occurrences all number	4	51
Alopecia
subjects affected / exposed	2 / 27 (7.41%)	57 / 181 (31.49%)
occurrences all number	2	58
Dermatitis acneiform
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Dermatitis bullous
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Dry skin
subjects affected / exposed	2 / 27 (7.41%)	39 / 181 (21.55%)
occurrences all number	2	42
Erythema
subjects affected / exposed	7 / 27 (25.93%)	24 / 181 (13.26%)
occurrences all number	11	34
Hyperkeratosis
subjects affected / exposed	4 / 27 (14.81%)	58 / 181 (32.04%)
occurrences all number	9	102
Photosensitivity reaction
subjects affected / exposed	5 / 27 (18.52%)	39 / 181 (21.55%)
occurrences all number	5	44
Pruritus
subjects affected / exposed	5 / 27 (18.52%)	42 / 181 (23.20%)
occurrences all number	5	47
Rash
subjects affected / exposed	10 / 27 (37.04%)	44 / 181 (24.31%)
occurrences all number	16	60
Rash generalised
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Toxic skin eruption
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Skin fissures
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Rash maculo-papular
subjects affected / exposed	3 / 27 (11.11%)	42 / 181 (23.20%)
occurrences all number	5	59
Dermal cyst
subjects affected / exposed	0 / 27 (0.00%)	18 / 181 (9.94%)
occurrences all number	0	24
Dermatitis
subjects affected / exposed	0 / 27 (0.00%)	10 / 181 (5.52%)
occurrences all number	0	10
Keratosis pilaris
subjects affected / exposed	0 / 27 (0.00%)	33 / 181 (18.23%)
occurrences all number	0	33
Milia
subjects affected / exposed	0 / 27 (0.00%)	16 / 181 (8.84%)
occurrences all number	0	18
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 27 (0.00%)	48 / 181 (26.52%)
occurrences all number	0	57
Rash papular
subjects affected / exposed	0 / 27 (0.00%)	21 / 181 (11.60%)
occurrences all number	0	26
Papule
subjects affected / exposed	0 / 27 (0.00%)	13 / 181 (7.18%)
occurrences all number	0	18
Skin lesion
subjects affected / exposed	0 / 27 (0.00%)	11 / 181 (6.08%)
occurrences all number	0	18
Renal and urinary disorders
Haematuria
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	3	0
Micturition urgency
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	14 / 27 (51.85%)	79 / 181 (43.65%)
occurrences all number	21	123
Back pain
subjects affected / exposed	4 / 27 (14.81%)	18 / 181 (9.94%)
occurrences all number	4	21
Pain in extremity
subjects affected / exposed	2 / 27 (7.41%)	13 / 181 (7.18%)
occurrences all number	5	14
Myalgia
subjects affected / exposed	3 / 27 (11.11%)	18 / 181 (9.94%)
occurrences all number	4	23
Muscle spasms
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	3	0
Musculoskeletal pain
subjects affected / exposed	0 / 27 (0.00%)	14 / 181 (7.73%)
occurrences all number	0	15
Infections and infestations
Conjunctivitis
subjects affected / exposed	3 / 27 (11.11%)	0 / 181 (0.00%)
occurrences all number	3	0
Oral candidiasis
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Folliculitis
subjects affected / exposed	3 / 27 (11.11%)	18 / 181 (9.94%)
occurrences all number	3	24
Rash pustular
subjects affected / exposed	3 / 27 (11.11%)	0 / 181 (0.00%)
occurrences all number	3	0
Skin infection
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Urinary tract infection
subjects affected / exposed	3 / 27 (11.11%)	0 / 181 (0.00%)
occurrences all number	6	0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Decreased appetite
subjects affected / exposed	10 / 27 (37.04%)	50 / 181 (27.62%)
occurrences all number	15	56
Hyperglycaemia
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	3	0
Hypoalbuminaemia
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	2	0
Hypokalaemia
subjects affected / exposed	5 / 27 (18.52%)	18 / 181 (9.94%)
occurrences all number	7	20
Hyponatraemia
subjects affected / exposed	2 / 27 (7.41%)	0 / 181 (0.00%)
occurrences all number	4	0

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Were there any global substantial amendments to the protocol? Yes

09 Aug 2012

Cohort 3 was split into two – the pre-existing Cohort 3a - vemurafenib only, and a new Cohort 3b - combination therapy with vemurafenib and cetuximab. The protocol was amended to include rationale for vemurafenib and cetuximab treatment in this cohort.

18 Mar 2014

Additional subjects (up to 70 subjects in total) were allowed to be recruited into a study cohort if a promising response rate was demonstrated in Stage II of that cohort. The exploratory objectives for the study were revised.

16 Jan 2015

The secondary objectives were changed to include the evaluation of tumor assessment scans by an independent review committee (IRC) for Cohort 1 (NSCLC) and other cohorts that demonstrate clinically meaningful efficacy per investigator assessment. The presence of BRAF V600 mutations could be retrospectively confirmed. Inclusion criteria for all subjects were changed to include male or female >/=16 years of age. Inclusion criteria for solid tumors and multiple myeloma were changed so that in order for the subject to be eligible, they must be able to provide a tumor sample (preferably tissue; alternatively DNA) for retrospective confirmation of the BRAF mutation by a central laboratory. IRC assessment of response rates was added a secondary efficacy endpoint focusing on Week 8, Week 16 and BOR for Cohort 1 (NSCLC) and other cohorts that demonstrate clinically meaningful efficacy per investigator assessment.

24 Mar 2016

Prior to the closure of the trial or should the study be closed due to Sponsor decision, it was added that the Sponsor may offer subjects who have completed the protocol-mandated minimum 12-month safety follow-up and who continue to benefit from vemurafenib therapy, the opportunity to receive continued vemurafenib via enrollment in the GO28399 extension trial. The interim analysis was changed to add efficacy analysis at 9 months for expanded cohorts. In case a cohort/indication is expanded up to 70 subjects, the primary analysis for efficacy will occur once all subjects have been followed up for 9 months after last subject had been enrolled in that cohort, or the subject develops progressive disease, withdraws consent, or is lost to follow-up, whichever occurred first.

Were there any global interruptions to the trial? No

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

None reported

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Clinical Trial Results:
An Open-label, Phase II Study of Vemurafenib in Patients with BRAF V600 Mutation-positive Cancers

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Primary: Confirmed Best Overall Response Rate (BORR)

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Clinical trials

Clinical Trial Results: An Open-label, Phase II Study of Vemurafenib in Patients with BRAF V600 Mutation-positive Cancers

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Baseline characteristics

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Primary: Confirmed Best Overall Response Rate (BORR)

Primary: Confirmed Best Overall Response Rate (BORR)

Secondary: Confirmed Clinical Benefit Rate (CBR)

Secondary: Confirmed Clinical Benefit Rate (CBR)

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Secondary: Number of Dose-limiting Toxicities of Vemurafenib in Combination with Cetuximab

Secondary: Safety: Percentage of Subjects with Adverse Event

Secondary: Safety: Percentage of Subjects with Adverse Event

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
An Open-label, Phase II Study of Vemurafenib in Patients with BRAF V600 Mutation-positive Cancers