Conditions: Malignant Melanoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
This open-label, multicenter study will evaluate the pharmacokinetics, safety and efficacy of vemurafenib in Chinese participants with BRAF V600 mutation-positive unresectable or metastatic melanoma. Participants will receive vemurafenib 960 milligrams (mg) orally twice daily until disease progression or unacceptable toxicity occurs.

Detailed description:

Arms:
arm 1: Participants will receive vemurafenib orally as 960 mg twice daily on Days 1 to 21 (morning dose only on Day 21), with a drug holiday from Days 22 to 27, and from Day 28 until progression, unacceptable toxicity, consent withdrawal, decision by the investigator or Sponsor, or protocol/eligibility violation. arm 2: Participants will receive vemurafenib orally as 960 mg twice daily from Day 1 until progression, unacceptable toxicity, consent withdrawal, decision by the investigator or Sponsor, or protocol/eligibility violation.

Interventions: intervention 1: Vemurafenib
Intervention descriptions: intervention 1: Participants will receive vemurafenib at a dose of 960 mg twice daily orally.

Protocol document:
Prot_SAP_000.pdf: 
Official Title: 
A PHASE I OPEN-LABEL, MULTICENTER, MULTIPLE-DOSE
STUDY TO INVESTIGATE THE PHARMACOKINETICS, SAFETY,
AND EFFICACY OF VEMURAFENIB IN CHINESE PATIENTS
WITH BRAFV600 MUTATION-POSITIVE UNRESECTABLE OR
METASTATIC MELANOMA 
NCT Number: 
NCT01910181 
Document Date: 
PROTOCOL AND STATISTICAL ANALYSIS PLAN 
Version 1: 22 May 2012
Version 2: 24 April 2013
Version 3: 18 September 2013
Version 4: 23 July 2014
Version 5: 20 April 2015




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PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol YO28390 has been amended for the following reasons: 
• 
Safety information for vemurafenib (Zelboraf®) has been updated to include: 
New risk of progression of a preexisting RAS-mutated pancreatic 
adenocarcinoma (see Section 1.5.3.9.1) 
Information on pancreatitis reported with vemurafenib use (see 
Section 1.5.3.9.5), as well as recommended assessment for any suspected 
case of pancreatitis during study (see Section 4.5.1.7) 
Information on potentiation of radiation treatment toxicity reported with 
Vemurafenib use (see Section 1.5.3.9.6) 
Some other safety information updates according to IB version 12 (see 
Section 1.5.3.2) 
• 
To improve clarity, sequence of subheadings have been adjusted (see 
Section 1.5.3.2), and some new subheadings have been added as appropriate (see 
Sections 1.5.3.4, 1.5.3.6, and 1.5.3.9). 
• 
References have been updated as appropriate (Section 10). 
 
Additional minor changes have been made to improve the clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 
 


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PROTOCOL AMENDMENT, VERSION 5: 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
Section 1.5.3.8 (Deaths and Serious Adverse Events) was moved to Section 1.5.3.2 and 
subsequent sections were renumbered accordingly. 
SECTION 1.5.3.2:  Deaths and Serious Adverse Events 
Deaths 
Across all studies, the majority of deaths were attributed to progressive disease (PD).  In 
the pivotal, Phase III Study NO25026, 19% of patients died in the vemurafenib group 
and 34% in the DTIC group.  No patient died after crossing over from the DTIC group to 
the vemurafenib group.  In Studies Study NP22657, and NP25163, 39% and 25% of 
patients had died as of the 31 January 2011 clinical cutoff date.  In Study NP25163, 
48% (n = 25) of patients died as of the end of the study. 
Serious Adverse Events 
In Study NP22657, 53% of patients experienced one or more serious adverse events, 
and 37% experienced one or more treatment-related serious adverse events.  The most 
common treatment-related serious adverse events included SCC of the skin (23%), BCC 
(7%), KA (3%), elevated liver function tests (2%), rash (2%), pyrexia (2%), and arthralgia 
(2%).  In Study NP25163, 4033% of patients experienced one or more serious adverse 
events, and 293% experienced one or more treatment-related serious adverse events.  
The most common treatment-related SAE was cuSCC (139%). 
For a more detailed summary of deaths and serious adverse events, see the 
Vemurafenib IB, Section 5.5.4 and 5.5.55.1.3. 
SECTION 1.5.3.4:  New Primary Melanomas 
Eight skin lesions in 7 of 337 vemurafenib-treated patients were reported as new primary 
malignant melanomas in Study NO25026. No cases were reported in 338 287 patients 
treated with DTIC.  Cases were managed with excision and without sequelae, and 
patients continued treatment without dose adjustment. 
SECTION 1.5.3.5:  Non-Cutaneous Squamous Cell Carcinoma 
Two cases of SCC of the head and neck have been reported in 2 patients treated with 
vemurafenib in excess of 300 days while enrolled in a clinical trial.  Pathology exam of 
both tumors (one a primary tonsillar tumor, the other a primary tongue tumor) revealed 
the presence of invasive SCC.  Of note, the first patient’s medical history was significant 
for risk factors for head and neck cancer and the tumor tissue tested positive for human 
papilloma virus (HPV).  The second patient does not appear to possess any risk factors 
for head and neck cancer, and the preliminary examination of the tumor tissue did not 
reveal the presence of HPV genome.  Full details are provided in the current IB. 


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Five cases of adenomatous colonic polyps have been reported in patients who received 
vemurafenib for more than 2 years while enrolled in a clinical trial (Chapman et al. 2012).  
The first patient developed an upper gastrointestinal bleed, and on work up was found to 
have duodenal ulceration (non malignant), hyperplastic gastric polyps, and five colonic 
polyps (three of which were adenomatous).  A previous colonoscopy in 2008, at the time 
of a jejunal resection for recurrent melanoma, documented no prior evidence of colonic 
polyps.  All polyps were resected, and the patient subsequently resumed vemurafenib 
therapy.  The second patient was found, on elective colonoscopy, to have seven colonic 
polyps (five of which were adenomatous), and all were detected and removed.  This 
patient had not undergone a previous colonoscopy.  The patient has discontinued 
treatment with vemurafenib.  The third patient had, on elective colonoscopy, 10 colonic 
polyps (seven of which were adenomatous).  This patient had a previous colonoscopy 
7 years prior to starting vemurafenib.  The fourth patient had, on elective colonoscopy, 
one adenomatous colonic polyp.  The fifth patient had, on elective colonoscopy, three 
adenomatous colonic polyps.  The latter two patients had histories of no prior 
colonoscopy.  In addition, a patient on the Expanded Access Program had one colonic 
adenoma discovered after being on vemurafenib 0.57 years.  This patient had a 
colonoscopy 1.3 years prior to starting vemurafenib, and a polyp was found and 
resected at that time.   
SECTION 1.5.3.6:  Adenomatous Colonic Polyps 
Five cases of adenomatous colonic polyps have been reported in patients who received 
vemurafenib for more than 2 years while enrolled in a clinical trial 
(Chapman et al. 2012).  The first patient developed an upper gastrointestinal bleed, and 
on work-up was found to have duodenal ulceration (non-malignant), hyperplastic 
gastric polyps, and five colonic polyps (three of which were adenomatous).  A previous 
colonoscopy in 2008, at the time of a jejunal resection for recurrent melanoma, 
documented no prior evidence of colonic polyps.  All polyps were resected, and the 
patient subsequently resumed vemurafenib therapy.  The second patient was found, on 
elective colonoscopy, to have seven colonic polyps (five of which were adenomatous), 
and all were detected and removed.  This patient had not undergone a previous 
colonoscopy.  The patient has discontinued treatment with vemurafenib.  The third 
patient had, on elective colonoscopy, 10 colonic polyps (seven of which were 
adenomatous).  This patient had a previous colonoscopy 7 years prior to starting 
vemurafenib.  The fourth patient had, on elective colonoscopy, one adenomatous colonic 
polyp.  The fifth patient had, on elective colonoscopy, three adenomatous colonic polyps.  
The latter two patients had histories of no prior colonoscopy.  In addition, a patient on 
the Expanded Access Program had one colonic adenoma discovered after being on 
vemurafenib 0.57 years.  This patient had a colonoscopy 1.3 years prior to starting 
vemurafenib, and a polyp was found and resected at that time. 


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SECTION 1.5.3.9:  Post-Approval Safety Update 
1.5.3.9.1 
Progression of Existing Malignancy 
One case of progression of NRAS-mutated chronic myelomonocytic leukemia (CMML) 
occurred in a male patient with metastatic melanoma treated with vemurafenib for less 
than 2 weeks (Callahan et al. 2012).  After the first dose of vemurafenib, laboratory 
results showed a marked leucoytosis and monocytosis and vemurafenib treatment was 
subsequently held.  There was a temporal relationship between vemurafenib treatment 
and increase in WBC and absolute monocyte counts, through multiple cycles of 
dechallenge and rechallenge.  In vitro studies demonstrated proliferation of the leukemic 
cell population upon stimulation with a BRAF inhibitor, an effect that was reversed upon 
addition of a MEK inhibitor.  Further, the cells exhibited dose-dependent and reversible 
activation of ERK in the NRAS-mutated leukemic clone.  A second case of progression of 
a preexisting RAS-mutated malignancy (pancreatic adenocarcinoma with KRAS 
mutation) was reported with vemurafenib in 2014.  On the basis of its mechanism of 
action, vemurafenib may cause progression of cancers associated with RAS mutations.  
Vemurafenib should be used with caution in patients with a prior or concurrent cancer 
associated with RAS mutation.  Full details are provided in the current Vemurafenib IB. 
1.5.3.9.2 
Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) 
As of 31 March 2013, 12 cases of drug reaction with eosinophilia and systemic 
symptoms (DRESS) syndrome have been observed with vemurafenib treatment.  No 
fatal cases have been reported.  The time to onset was 7 to 25 days.  In the majority of 
patients (n = 7), vemurafenib was discontinued.  Some patients (n = 5) were treated with 
systemic steroids with corresponding improvement or resolution of symptoms.  In 
addition, 2 patients who were treated with vemurafenib after ipilimumab presented with 
Grade 3 rash and had biopsies that showed pathology consistent with drug 
hypersensitivity reaction (Harding et al. 2012).  Full details are provided in the current 
Vemurafenib IB. 
1.5.3.9.3 
Liver Injury 
An analysis of liver−related adverse events reported with vemurafenib use showed that 
63 cases (out of an estimated exposure of approximately 20,000 patients) of medically 
confirmed serious adverse events were consistent with drug−induced liver injury (DILI) 
based on clinical chemistry criteria from the DILI Expert Working Group 
(Aithal et al. 2011).  Of the 63 cases, two were assessed as severe, both reported as 
hepatic failure. There were no reported deaths among the 63 cases of liver injury; the 
outcome of both cases of severe liver injury was reported as completely resolved with 
vemurafenib discontinuation.  The median time to onset of the adverse events was 44 
days after initial dose.  The median ALT to ALP ratio was calculated as 1.5, which 
suggested a trend toward a cholestatic pattern of liver injury.  The analysis did not reveal 
any risk factors or populations at risk. 


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1.5.39.4 
Neutropenia 
A review of the Roche safety database found neutropenia to be an uncommon (6 cases 
per 1000 person-years, 0.6%) adverse drug reaction associated with the use of 
vemurafenib, typically occurring during the first 6−12 weeks of treatment.  It appeared to 
be reversible usually within 2 weeks, with either temporary interruption, dose reduction 
or discontinuation of vemurafenib, and in some cases was managed with granulocyte 
colony-stimulating factors (G-CSF). 
1.5.3.9.5 
Pancreatitis 
As of Q2 2014, an adverse drug reaction of pancreatitis has been identified in patients 
being treated with vemurafenib.  Seventeen cases of pancreatitis with no strong risk 
factors or alternative explanations were reported.  Eight of the 17 cases were assessed as 
likely associated with vemurafenib use based on event onset latency and 
re-challenge/de-challenge information.  The clinical presentation, including mild to 
moderate severity, was consistent with the clinical picture of drug-induced pancreatitis 
(Lankisch et al. 1995). 
1.5.3.9.6 
Risk of Radiation Recall and Radiation Sensitization  
As of Q4 2014, an adverse drug reaction of potentiation of radiation treatment toxicity 
has been identified in patients treated with radiation either prior, during, or subsequent 
to vemurafenib treatment.  This is based on 20 cases of radiation injuries, adjudicated 
as radiation recall (n = 8) and radiation sensitization (n = 12).  The nature and severity 
of the events in all 20 cases were evaluated as worse than expected for the normal tissue 
tolerance to therapeutic radiation with fatal outcome in 3 cases.  The reaction was seen 
in the skin, esophagus, lung, liver, rectum, and urinary bladder.  Vemurafenib should 
be used with caution when given concomitantly or sequentially with radiation 
treatment.  Full details are provided in the current Vemurafenib IB. 
1.5.3.9.7 
Safety in Combination with Ipilimumab 
In a Phase I trial (CA 184161, sponsored by Bristol-Myers Squibb), asymptomatic 
Grade 3 increases in transaminases and bilirubin occurred with concurrent 
administration of ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) 
(Ribas et al. 2012).  All liver laboratory abnormalities were asymptomatic and reversible 
with permanent discontinuation of the study drugs or, in some cases, administration of 
corticosteroids.  Based on these data, concurrent administration of ipilimumab and 
vemurafenib is not recommended outside of a clinical trial.  Full details are provided in 
the current Vemurafenib IB.  
SECTION 4.5.1.7:  Laboratory Assessments 
The Sponsor (Roche) recommends that workup of any suspected case of pancreatitis 
should include serum amylase and lipase testing in addition to other appropriate 
testing (e.g., CT abdomen). 


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TABLE 5:  Dose Interruption/Modification Criteria for Vemurafenib 
“No dose reduction” was changed to “N/A” for Dose adjustments for resumption of 
treatment for Grade 1 and tolerable Grade 2 toxicities. 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 
 
 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14 
PROTOCOL SYNOPSIS .................................................................................... 15 
1. 
BACKGROUND .......................................................................................... 24 
1.1 
Background on Metastatic Melanoma ................................... 24 
1.2 
Background on Role of Oncogenic BRAF Kinase 
in Melanoma.......................................................................... 25 
1.3 
Vemurafenib .......................................................................... 25 
1.4 
Nonclinical Development Program ........................................ 26 
1.4.1 
Nonclinical Pharmacology ..................................................... 26 
1.4.2 
Nonclinical Metabolism and Pharmacokinetics...................... 27 
1.4.3 
Nonclinical Toxicology and Safety Pharmacology ................. 27 
1.5 
Clinical Development Program .............................................. 30 
1.5.1 
Description of Clinical Studies ............................................... 30 
1.5.1.1 
Phase I Dose-Finding Study (PLX 06-02) and 
other Phase I Studies ............................................................ 30 
1.5.1.2 
Two Phase I Extension Cohorts ............................................ 30 
1.5.1.3 
Phase II Single-Arm Study (NP22657/BRIM-2) ..................... 30 
1.5.1.4 
Phase III Randomized Controlled Study 
(NO25026/BRIM-3)................................................................ 31 
1.5.2 
Clinical Pharmacokinetics of Vemurafenib............................. 31 
1.5.3 
Safety .................................................................................... 33 
1.5.3.1 
Dose-Limiting Toxicities......................................................... 36 
1.5.3.2 
Deaths and Serious Adverse Events ..................................... 36 
1.5.3.3 
Cutaneous Squamous Cell Carcinoma.................................. 38 
1.5.3.4 
New Primary Melanomas....................................................... 38 
1.5.3.5 
Non-Cutaneous Squamous Cell Carcinoma.......................... 38 
1.5.3.6 
Adenomatous Colonic Polyps................................................ 38 
1.5.3.7 
Hypersensitivity Reactions..................................................... 39 
1.5.3.8 
ECG Analysis ........................................................................ 39 
1.5.3.9 
Post-Approval Safety Update ................................................ 40 
1.5.4 
Clinical Efficacy ..................................................................... 42 
1.6 
Study Rationale and Benefit–Risk Assessment..................... 43 


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2. 
OBJECTIVES.............................................................................................. 44 
2.1 
Primary Objective .................................................................. 44 
2.2 
Secondary Objectives............................................................ 44 
3. 
STUDY DESIGN ......................................................................................... 45 
3.1 
Description of Study .............................................................. 45 
3.1.1 
Overview................................................................................ 45 
3.1.1.1 
Pharmacokinetic Cohort ........................................................ 45 
3.1.1.2 
Expansion Cohort .................................................................. 46 
3.2 
End of Study.......................................................................... 46 
3.3 
Rationale for Study Design.................................................... 46 
3.3.1 
Rationale for Test Product Dosage........................................ 47 
3.3.2 
Rationale for Patient Population ............................................ 47 
3.4 
Outcome Measures ............................................................... 48 
3.4.1 
Pharmacokinetic Outcome Measures.................................... 48 
3.4.2 
Efficacy Outcome Measures.................................................. 48 
3.4.3 
Safety Outcome Measures .................................................... 48 
4. 
MATERIALS AND METHODS .................................................................... 48 
4.1 
Patients.................................................................................. 48 
4.1.1 
Inclusion Criteria.................................................................... 49 
4.1.2 
Exclusion Criteria................................................................... 50 
4.2 
Method of Treatment Assignment and Blinding..................... 51 
4.3 
Study Treatment.................................................................... 51 
4.3.1 
Formulation, Packaging, and Handling.................................. 51 
4.3.2 
Dosage, Administration, and Compliance.............................. 51 
4.3.3 
Investigational Medicinal Product Accountability ................... 52 
4.3.4 
Post-Trial Access to Vemurafenib ......................................... 53 
4.4 
Concomitant Therapy ............................................................ 53 
4.4.1 
Permitted Therapy ................................................................. 53 
4.4.2 
Prohibited Therapy ................................................................ 54 
4.4.3 
Medication Precautions in case of Drug–Drug 
Interactions............................................................................ 54 
4.4.3.1 
Medications that Affect the QT Interval.................................. 55 
4.5 
Study Assessments ............................................................... 55 


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4.5.1 
Description of Study Assessments ........................................ 55 
4.5.1.1 
Medical History and Demographic Data ................................ 55 
4.5.1.2 
Vital Signs.............................................................................. 55 
4.5.1.3 
Physical Examinations........................................................... 55 
4.5.1.4 
Pharmacokinetic Assessments.............................................. 56 
4.5.1.5 
Performance Status............................................................... 57 
4.5.1.6 
Tumor and Response Evaluations......................................... 57 
4.5.1.7 
Laboratory Assessments ....................................................... 58 
4.5.1.8 
Electrocardiograms................................................................ 59 
4.5.1.9 
Dermatological Evaluations and Additional 
Assessments for SCC Surveillance ....................................... 60 
4.5.1.10 
Mandatory Samples for Determination of Patient 
Eligibility................................................................................. 61 
4.5.2 
Timing of Study Assessments ............................................... 61 
4.5.2.1 
Screening and Pretreatment Assessments............................ 61 
4.5.2.2 
Assessments during Treatment............................................. 62 
4.5.2.3 
Assessments at Study Completion/Early 
Termination Visit.................................................................... 62 
4.5.2.4 
Follow-Up Assessments ........................................................ 62 
4.5.2.5 
Assessments at Unplanned Visits ......................................... 63 
4.6 
Patient, Study, and Site Discontinuation................................ 63 
4.6.1 
Patient Discontinuation.......................................................... 63 
4.6.1.1 
Discontinuation from Study Drug........................................... 63 
4.6.1.2 
Withdrawal from Study........................................................... 64 
4.6.2 
Study and Site Discontinuation.............................................. 64 
5. 
ASSESSMENT OF SAFETY....................................................................... 64 
5.1 
Safety Plan ............................................................................ 64 
5.1.1 
Dose Delays and Modifications ............................................. 65 
5.2 
Safety Parameters and Definitions ........................................ 67 
5.2.1 
Adverse Events ..................................................................... 67 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 68 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 69 


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5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 69 
5.3.1 
Adverse Event Reporting Period ........................................... 69 
5.3.2 
Eliciting Adverse Event Information ....................................... 70 
5.3.3 
Assessment of Severity of Adverse Events ........................... 70 
5.3.4 
Assessment of Causality of Adverse Events ......................... 70 
5.3.5 
Procedures for Recording Adverse Events............................ 71 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 71 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................... 71 
5.3.5.3 
Persistent or Recurrent Adverse Events................................ 72 
5.3.5.4 
Abnormal Laboratory Values ................................................. 72 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 73 
5.3.5.6 
Abnormal Liver Function Tests.............................................. 73 
5.3.5.7 
Deaths ................................................................................... 74 
5.3.5.8 
Preexisting Medical Conditions.............................................. 74 
5.3.5.9 
Lack of Efficacy or Worsening of Primary 
Disease.................................................................................. 74 
5.3.5.10 
Hospitalization or Prolonged Hospitalization.......................... 75 
5.3.5.11 
Overdoses ............................................................................. 75 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 75 
5.4.1 
Emergency Medical Contacts................................................ 76 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest...................................................................... 76 
5.4.3 
Reporting Requirements for Pregnancies.............................. 77 
5.4.3.1 
Pregnancies in Female Patients............................................ 77 
5.4.3.2 
Pregnancies in Female Partners of Male Patients................. 77 
5.4.3.3 
Abortions ............................................................................... 78 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 78 
5.5 
Follow-Up of Patients after Adverse Events .......................... 78 
5.5.1 
Investigator Follow-Up........................................................... 78 
5.5.2 
Sponsor Follow-Up ................................................................ 78 
5.6 
Post-Study Adverse Events................................................... 78 


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5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 79 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 79 
6.1 
Determination of Sample Size ............................................... 80 
6.2 
Summaries of Conduct of Study............................................ 80 
6.3 
Summaries of Demographic and baseline 
characteristics........................................................................ 80 
6.4 
Pharmacokinetic Analyses..................................................... 80 
6.5 
Efficacy Analyses .................................................................. 81 
6.6 
Safety Analyses..................................................................... 82 
6.7 
Exploratory Analyses............................................................. 82 
6.8 
Interim Analyses .................................................................... 83 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 83 
7.1 
Data Quality Assurance......................................................... 83 
7.2 
Electronic Case Report Forms............................................... 83 
7.3 
Source Data Documentation.................................................. 84 
7.4 
Use of Computerized Systems .............................................. 84 
7.5 
Retention of Records............................................................. 84 
8. 
ETHICAL CONSIDERATIONS.................................................................... 85 
8.1 
Compliance with Laws and Regulations ................................ 85 
8.2 
Informed Consent .................................................................. 85 
8.3 
Institutional Review Board or Ethics Committee.................... 86 
8.4 
Confidentiality........................................................................ 86 
8.5 
Financial Disclosure .............................................................. 87 
9. 
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION............................................................................. 87 
9.1 
Study Documentation ............................................................ 87 
9.2 
Site Inspections ..................................................................... 87 
9.3 
Administrative Structure......................................................... 87 
9.4 
Publication of Data and Protection of 
Trade Secrets........................................................................ 87 
9.5 
Protocol Amendments ........................................................... 88 


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10. REFERENCES ........................................................................................... 89 
 
 
LIST OF TABLES 
Table 1 
IC50 Values (nM) of Vemurafenib against Selected Kinases....... 26 
Table 2 
Inhibition of Proliferation:  IC50 Values of Vemurafenib in a 
Variety of Cell Lines .................................................................... 26 
Table 3 
Summary of ADRs1 Occurring in ≥ 10% of Patients in the 
Vemurafenib Treatment Arm....................................................... 34 
Table 4 
Study Design Scheme for PK Cohort.......................................... 45 
Table 5 
Dose Interruption/Modification Criteria for Vemurafenib ............. 67 
Table 6 
Adverse Event Severity Grading Scale ....................................... 70 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments........................................................... 92 
Appendix 2 
Schedule of Pharmacokinetic Assessments ............................... 98 
Appendix 3 
New Response Evaluation Criteria in Solid Tumors Quick 
Reference – Version 1.1 ............................................................. 99 
Appendix 4 
American Joint Committee on Cancer TNM Staging for 
Melanoma ................................................................................. 111 
Appendix 5 
ECOG Performance Status....................................................... 112 
Appendix 6 
Alternative and Preferred Methods for Patients Unable to 
Tolerate Radiological Contrast Agents...................................... 113 
Appendix 7 
Impact of Vemurafenib on Concomitant Medications................ 114 
Appendix 8 
Medications that Affect the QT Interval ..................................... 117 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE I OPEN-LABEL, MULTICENTER, MULTIPLE-DOSE STUDY TO 
INVESTIGATE THE PHARMACOKINETICS, SAFETY, AND EFFICACY OF 
VEMURAFENIB IN CHINESE PATIENTS WITH BRAFV600 
MUTATION-POSITIVE UNRESECTABLE OR METASTATIC MELANOMA 
PROTOCOL NUMBER: 
YO28390 
VERSION NUMBER: 
5 
TEST PRODUCT: 
Vemurafenib (RO5185426) 
MEDICAL MONITOR: 
 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of the form to your local study monitor.  Please retain the original 
for your study files.


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PROTOCOL SYNOPSIS 
TITLE: 
A PHASE I OPEN-LABEL, MULTICENTER, MULTIPLE-DOSE STUDY TO 
INVESTIGATE THE PHARMACOKINETICS, SAFETY, AND EFFICACY OF 
VEMURAFENIB IN CHINESE PATIENTS WITH BRAFV600 MUTATION-POSITIVE 
UNRESECTABLE OR METASTATIC MELANOMA 
PROTOCOL NUMBER: 
YO28390 
VERSION NUMBER: 
5 
TEST PRODUCT: 
Vemurafenib (RO5185426) 
PHASE: 
I 
INDICATION: 
BRAFV600 mutation-positive unresectable or metastatic melanoma 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Primary Objective 
The pharmacokinetic (PK) objective for this study is to evaluate the pharmacokinetics of 
vemurafenib following 960 mg twice daily (BID) oral administration (PO) in Chinese patients with 
BRAFV600 mutation–positive unresectable or metastatic melanoma. 
This is the primary objective of this study. 
 
Secondary Objectives 
The efficacy objective for this study is to describe the efficacy of vemurafenib by using best 
overall response rate (BORR; confirmed), duration of response, progression-free survival (PFS), 
and overall survival (OS) in Chinese patients with BRAFV600 mutation-positive unresectable or 
metastatic melanoma. 
The safety objective for this study is to investigate the safety and tolerability of vemurafenib in 
Chinese patients with BRAFV600 mutation-positive unresectable or metastatic melanoma. 
 
Study Design 
Description of Study 
This is an open-label, multicenter, Phase I study with a PK cohort and an expansion cohort.  
Only patients who test positive for the BRAFV600 mutation as determined by the cobas® 
4800 BRAFV600 Mutation Test will be allowed to participate in this study.   
Approximately 20 patients will be enrolled in the PK cohort.  The dosing regimens in different 
periods are described as follows:           
• 
Period A:  Following a screening period of up to 28 days, approximately 20 patients will be 
enrolled into the study for PK assessment.  Patients will receive 960 mg BID PO on 
Days 1 to 20, and on Day 21, patients will only receive their morning dose.  All patients will 
provide blood samples on Days 1, 15, 19, and 21 for PK analysis as described in 
Appendix 2. 
• 
Period B:  Begins with Day 22 and lasts until Day 27.  Study drug will be held for the 
purpose of characterizing the elimination profile of vemurafenib.  All patients will provide 
blood samples on Days 22 and 24 for PK analysis as described in Appendix 2. 
• 
Period C:  After a pre-dose PK sample collection, starting on Day 28, all patients may 
resume vemurafenib 960 mg BID until the development of progressive disease (PD), 
unacceptable toxicity, withdrawal of consent, or other any criteria as listed in Section 4.6.  


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• 
Follow-up period:  All adverse events (related and unrelated to study drug) occurring at 
any time during Periods A, B, or C up to 28 days after the last dose of study medication in 
Period C must be reported; drug-related adverse events must be followed until resolution.  
All patients who received at least one dose of vemurafenib will be followed for squamous 
cell carcinoma (SCC) and any new primary malignancy evaluation until 6 months after 
discontinuation of study treatment or death, withdrawal of consent, or loss to follow up, 
whichever is earlier. 
 
After recruitment of the PK cohort is complete, approximately 25 additional Chinese patients 
with BRAFV600 mutation-positive unresectable or metastatic melanoma will be recruited into the 
expansion cohort.  
Following a screening period of up to 28 days, all eligible patients will complete the 
assessments on Day 1 (see Appendix 1) as their baseline and will receive vemurafenib 960 mg 
BID until the development of PD, unacceptable toxicity, withdrawal of consent, or any other 
criteria as listed in Section 4.6.  
The follow-up procedures for patients in the expansion cohort are the same as for those in the 
PK cohort. 
 
Number of Patients 
Approximately 45 Chinese patients will be recruited into this study.   
 
Target Population 
Patients must meet the following criteria for study entry: 
• 
Chinese male or female patients ≥ 18 years of age 
• 
Histologically confirmed metastatic melanoma (surgically unresectable Stage IIIc or 
Stage IV, American Joint Committee on Cancer).  Unresectable Stage IIIc disease must 
have confirmation from a surgical oncologist. 
• 
Patients are either treatment-naïve or had received prior systemic treatments for 
metastatic melanoma. 
• 
Positive BRAFV600 mutation result determined by a designated laboratory using the cobas 
4800 BRAFV600 Mutation Test prior to administration of vemurafenib. 
• 
Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 prior 
to the administration of vemurafenib 
• 
Previous allowed chemotherapy, immunotherapy, or radiation therapy must have been 
completed at least 2 weeks prior to study drug administration, and all associated toxicity 
must be resolved (to ≤ Grade 1 or baseline) prior to study drug administration. 
• 
Recovery from effects of any major surgery (excluding tumor biopsy at baseline) 
or significant traumatic injury at least 14 days before the first dose of study treatment 
• 
Adequate hematologic, renal, and liver function as defined by laboratory values performed 
within 28 days prior to initiation of dosing. 
• 
Absolute neutrophil count ≥ 1.5 x 109/L 
• 
Platelet count ≥ 100 × 109/L 
• 
Hemoglobin ≥ 9 g/dL 
• 
Serum creatinine ≤ 1.5 × the upper limit of normal (ULN) or creatinine 
clearance > 60 mL/min by Cockroft-Gault formula 
• 
AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN for patients with concurrent liver metastases) 
• 
Bilirubin ≤ 1.5 × ULN (for patients with Gilbert’s Syndrome, bilirubin ≤ 3 × ULN) 
• 
Alkaline phosphatase ≤ 2.5 × ULN (≤ 5 × ULN for patients with concurrent 
liver metastases) 
• 
Albumin ≥ 3 g/dL 


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• 
Negative serum or urine pregnancy test within 7 days prior to commencement of dosing in 
pre-menopausal women.  Women of non-childbearing potential may be included if they are 
either surgically sterile or have been postmenopausal for ≥ 1 year. 
• 
Fertile men and women must use an effective method of contraception during treatment 
and for at least 6 months after completion of treatment as directed by their physician 
(in accordance with local requirements). 
• 
Absence of any psychological, familial, sociological, or geographical condition potentially 
hampering compliance with the study protocol and follow-up schedule; those conditions 
should be discussed with the patient before trial entry. 
• 
Eastern Clinical Oncology Group Performance Status of 0 or 1 
• 
Life expectancy > 3 months 
• 
Be able to swallow pills 
 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with active CNS lesions are excluded (i.e., those with radiographically unstable, 
symptomatic lesions).  Note:  Patients treated with stereotactic therapy or surgery are 
eligible if they remain without evidence of disease progression in brain for ≥ 3 months.  They 
must also be off corticosteroid and anticonvulsant therapy for ≥ 3 weeks.  Whole brain 
radiotherapy is not allowed with the exception of patients who have had definitive resection 
or stereotactic therapy of all radiologically detectable parenchymal lesions. 
• 
History of or known spinal cord compression or carcinomatous meningitis 
• 
Anticipated or ongoing administration of anti-cancer therapies other than those 
administered in this study 
• 
Active SCC that has not been excised or has not yet adequately healed post excision 
• 
Pregnant or lactating women 
• 
Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant small 
bowel resection that would preclude adequate vemurafenib absorption 
• 
QTc interval ≥ 450 ms at screening ECG or history of congenital long QT syndrome 
• 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
v4.0 Grade 3 hemorrhage within 28 days of starting the study treatment 
• 
Any of the following within the 6 months prior to study drug administration: myocardial 
infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled 
hypertension, cerebrovascular accident or transient ischemic attack, or symptomatic 
pulmonary embolism. 
• 
Known clinically significant active infection 
• 
History of allogeneic bone marrow transplantation or organ transplantation 
• 
Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or study drug administration, 
or may interfere with the interpretation of study results, which in the judgment of the 
investigator would make the patient inappropriate for entry into this study 
• 
Patients with previous malignancy within the past 5 years are excluded other than 
adequately treated patients with basal cell carcinoma or SCC of the skin, melanoma in-situ, 
and carcinoma in-situ of the cervix and/or curatively treated cancer, from which the patient 
is currently disease-free, or any malignancy from which the patient has been continuously 
disease-free for at least 5 years.  Isolated elevation in prostate-specific antigen in the 
absence of radiographic evidence of metastatic prostate cancer is allowed. 
• 
Patients who have been previously treated with a BRAF inhibitor (sorafenib allowed) 
or MEK inhibitor 
• 
Patients who have had at least one dose of study drug (vemurafenib) in a previous clinical 
trial that includes vemurafenib 


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• 
Known HIV positivity or AIDS-related illness, or hepatitis B virus or hepatitis C virus carriers 
(hepatitis B surface antigen positive, HCV antibody positive) 
• 
Received any investigational treatment within 4 weeks of study drug start 
 
Length of Study 
Patient recruitment is estimated to require approximately 22 months.  The data cutoff for 
updated analysis will occur when all patients included in the PK and expansion cohorts have 
completed at least 6 months of treatment (or discontinued treatment) or when > 70% of treated 
patients have experienced disease progression by RECIST v1.1 or death, whichever occurs 
later.  It is expected to occur about 12 months after the first patient is enrolled.  
 
End of Study 
Patients still receiving vemurafenib at the time of updated analysis will be allowed to continue 
treatment until PD, unacceptable toxicity, death, loss to follow-up, or withdrawal of consent.  
The study will end when the last patient has permanently discontinued treatment with 
vemurafenib and has completed the 6-month follow-up period for safety assessment. 
 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Maximum plasma concentration (Cmax) on Days 1 and 21 
• 
Time to maximal plasma concentration (Tmax) on Days 1 and 21 
• 
Area under the plasma − concentration time curve (AUC) from time 0 to 8 hours (AUC0-8h) 
on Days 1 and 21 
• 
AUC from time 0 to 12 hours (AUC0-12h or AUCτ) on Days 1 and 21 
• 
AUC from time 0 to 168 hours (AUC0-168h) beginning on Day 21 
• 
Minimum plasma concentration (Cmin) on Days 15, 19, and 21 
• 
Accumulation ratio (the AUC ratio on Day 21/Day 1) 
• 
Elimination rate constant (Kel) 
• 
Half-life (t1/2) 
 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
BORR (confirmed) 
• 
Duration of response 
• 
PFS 
• 
OS 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, nature, and intensity (severity) of adverse events and serious adverse events, 
graded according to NCI CTCAE v4.0 
• 
Changes in vital signs 
• 
Changes in clinical laboratory test results 
• 
ECG assessments 
• 
Dermatology evaluations for cutaneous SCC (cuSCC) surveillance 
• 
Head, neck, anus, anal canal, and  pelvic (for female patients) evaluations and computed 
tomography scans for non-cuSCC surveillance 
 


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Investigational Medicinal Products 
Test Product 
Each box of study medication contains a total of 56 film-coated tablets in aluminum blisters that 
are 240 mg each.   
Vemurafenib tablets should be swallowed whole with a glass of water (approximately 240 mL).  
Vemurafenib tablets should not be chewed or crushed. 
PK cohort:  In Period A, patients will receive 960 mg BID PO for Days 1–20, and on Day 21, 
patients will receive only the morning dose.  Patients will discontinue vemurafenib starting with 
the evening dose on Day 21. 
Vemurafenib may be taken either 1 hour before or 2 hours after a meal, except on Days 1 
and 21.  On Days 1 and 21, patients should fast overnight for at least 8 hours before the 
morning dose, and continue to fast for an additional 4 hours post-dose.  Patients should plan on 
a standard meal at 4 hours post-dose, but are allowed to have light snacks (i.e., crackers, toast, 
juice, and water) within the 4-hour period. 
There is no study drug administration in Period B. 
In Period C starting on Day 28, all patients will receive the study drug at 960 mg BID until the 
development of PD, unacceptable toxicity, withdrawal of consent or any other criteria as listed in 
Section 4.6.  
Expansion cohort:  All patients will receive vemurafenib 960 mg BID until the development of 
PD, unacceptable toxicity, withdrawal of consent, or any other criterion as listed in Section 4.6.  
On the days of BID dosing (except Day 1 in the PK cohort), patients should be instructed to take 
4 tablets in the morning and 4 tablets in the evening (total daily dose of 1920 mg [960 mg BID]) 
approximately 12 hours later.  Both doses should be taken either 1 hour before or 2 hours after 
a meal.   
Patients will be given a dosing diary to record the time and date of study drug administration.  
Administration dates and times will be recorded in the electronic Case Report Form (eCRF) by 
the study coordinators.  
A cycle is defined as 4 weeks (28 days).  A 4-week supply (Cycles 1–10) or 8-week supply 
(starting from Cycle 11) of study drug can be given to the patient on Day 1 of each or every 
other cycle.  Patients will be instructed not to open a new box until the previous box has been 
finished and to bring their study drug and used boxes back to all clinic visits for reconciliation. 
 
Non-Investigational Medicinal Products 
Female patients of child-bearing potential who are using oral contraceptives, hormone 
replacement therapy, or other maintenance therapy will be asked to continue their use. 
Patients taking prescribed therapies for intercurrent illnesses, or consistently dosed nutritional 
or herbal medicines (other than anti-cancer treatments) at the time of study entry should 
continue to take their medicines unless asked by the Investigator to discontinue or modify them. 
Anti-emetics and anti-diarrheal medications should not be administered prophylactically before 
initial treatment with study drug.  At the discretion of the Investigator, prophylactic anti-emetic 
and anti-diarrheal medication(s) may be used per standard clinical practice before subsequent 
doses of study drug.  Hematopoietic growth factors (e.g., erythropoietin and granulocyte 
colony-stimulating factors) and pain medications as dictated by standard practice are 
acceptable while the patient is enrolled in the study.  However, growth factors should not be 
administered prophylactically before initial treatment with study drug. 
Patients who experience adverse events during the study may be treated symptomatically by 
the investigator as clinically indicated. 
Additionally, any diagnostic, therapeutic, or surgical procedure performed during the study 
period should be recorded on eCRF including the date, indication, description of the 
procedure(s), and any clinical findings.   
 


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Statistical Methods 
Primary Analysis 
The primary objective of the study is to evaluate the pharmacokinetics of vemurafenib following 
960 mg BID oral administration in Chinese patients with BRAFV600 mutation–positive 
unresectable or metastatic melanoma. 
For the purposes of statistical analysis, the PK population will include all patients evaluable for 
PK analysis, i.e., patients who provided sufficient PK data to obtain at least one of the primary 
PK variables.  Patients will be excluded from the PK analysis if they significantly violate the 
inclusion or exclusion criteria, deviate significantly from sampling times or other provisions of 
the protocol, or if data are unavailable which may influence the analysis. 
Plasma concentration on Day 1 and steady state will be listed and graphically displayed for 
vemurafenib. 
Non-compartmental analysis using WinNonlin software will be used to obtain PK parameters of 
vemurafenib.  All PK parameters for vemurafenib will be presented by listings and descriptive 
summary statistics (arithmetic mean, geometric mean, standard deviation, coefficient of 
variation, minimum, maximum and number of observations).  Rate of elimination may be 
estimated using data from PK samples collected during the drug holiday period.    
The following PK parameters will be reported: 
• 
Cmax on Days 1 and 21 
• 
Tmax on Days 1 and 21 
• 
AUC0-8h on Days 1 and 21 
• 
AUC0-12h on Days 1 and 21 
• 
AUC0-168h beginning on Day 21 
• 
Cmin on Days 15, 19, and 21 
• 
Accumulation Ratio 
• 
Kel 
• 
t1/2 
 
Determination of Sample Size   
No formal sample size calculation was performed for this study.  The sample size of 20 PK 
patients is chosen to allow acceptable variability of the PK data.  Together with extra 25 patients 
in the expansion cohort, it would give a Clopper-Pearson 95% CI of 26%−56% for BORR 
assuming the target BORR (confirmed) is 40%.  


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
AUC 
area under the plasma concentration–time curve 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate transaminase 
BCC 
basal cell carcinoma 
BID 
twice daily 
BML 
below measurable limit 
BORR 
best overall response rate 
CFDA 
China Food and Drug Administration 
CHF 
congestive heart failure 
CI 
confidence interval 
Cmax 
maximal plasma concentration 
Cmin 
minimal plasma concentration 
CMML 
chronic myelomonocytic leukemia 
CRC 
colorectal cancer 
CT 
computerized tomography 
cuSCC 
cutaneous squamous cell carcinoma 
CV% 
coefficient of variation 
DILI 
drug−induced liver injury 
DLT 
dose-limiting toxicity 
DRESS 
drug reaction with eosinophilia and systemic symptoms 
DTIC 
dacarbazine 
EC 
Ethics Committee 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factors 
GLP 
Good Laboratory Practice  
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein cholesterol 


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Abbreviation 
Definition 
hERG 
human ether-a-go-go gene 
HIV 
human immunodeficiency virus 
HPV 
human papillomavirus 
HR 
hazard ratio 
IB  
Investigator’s Brochure 
IC50 
half-maximal inhibitory concentration 
ICH 
International Conference on Harmonization 
ILS 
increase in lifespan 
IMP 
Investigational Medicinal Product 
IND 
Investigational new drug 
IRC 
Institutional Review Committee 
IV 
intravenous 
KA 
keratoacanthomas 
KM 
Kaplan Meier 
Kel 
elimination rate constant 
LDH 
lactate dehydrogenase 
LDL-C 
low density lipoprotein cholesterol 
MBP 
micro-precipitated bulk powder 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events  
NOAEL 
no-observed-adverse-effect level   
OS 
overall survival 
PD 
progressive disease 
P-gp 
P-glycoprotein 
PFS 
progression-free survival 
PK 
pharmacokinetic 
QTc 
corrected QT interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SCC 
squamous cell carcinoma 
SJS 
Stevens-Johnson syndrome  
TEN 
toxic epidermal necrolysis 
TGI 
tumor growth inhibition 
TK 
toxicokinetic 
tmax 
time to maximal plasma concentration 


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Abbreviation 
Definition 
t½  
elimination half-life 
ULN 
upper limit of normal 


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1. 
BACKGROUND 
1.1 
BACKGROUND ON METASTATIC MELANOMA  
Metastatic melanoma is one of the most deadly cancers, with a 5-year survival rate of 
15% and a median overall survival (OS) of around 8 months.  Approximately 
160,000 new cases of melanoma are diagnosed globally each year; it is more frequent in 
males and Caucasians (Ries et al. 2003).  According to a World Health Organization 
report, approximately 48,000 melanoma-related deaths occur worldwide per year 
(Lucas 2006).  The highest rates of melanoma occur in Australia and New Zealand, 
where the annual incidence is more than double the highest rates recorded in Europe.  
Currently, the lifetime risk for development of melanoma in Australia is 1 in 25 for men 
and 1 in 34 for women (SUNSMART 2007, Department of Health and Ageing 2008).  
In Europe, approximately 26,100 males and 33,300 females are diagnosed with 
melanoma annually, and approximately 8300 males and 7600 females die from the 
disease every year (European Network of Cancer Registries 2003).  In the United States 
in 2007, more than 58,000 people (over 33,000 men and over 25,000 women) were 
diagnosed with melanoma and over 8400 (more than 5500 men and almost 
3000 women) died of the disease (U.S. Centers for Disease Control and Prevention 
2010).  Over the past several decades, a significant increase in the incidence of 
melanoma has been observed.  The annual increase in the incidence rate varies 
between regions throughout the world, but in general the increase in the Caucasian 
population has been approximately 3% − 7% per year.  The number of deaths due to 
malignant melanoma has also increased in most fair-skinned populations throughout the 
world in the past few decades (Diepgen and Mahler 2002). 
Malignant melanoma demonstrates a clear demographic and ethnic disparity.  In China, 
the incidence of melanoma is relatively lower (0.52 per 100,000 patients) than in the 
west (varies from 3−5 per 100,000 patients in Mediterranean countries to 40−60 per 
100,000 patients in Australia and New Zealand) (Zhao et al. 2006, Garbe et al. 2009, 
Dummer et al. 2012); Stage III and IV patients comprise 25.1% and 12.8%, respectively 
(China Melanoma Guide 2011).  For patients with Stage IV disease, median survival 
time was 1.42 years, and the 5-year survival rate was 4.6% (China Melanoma Guide 
2011). 
Many agents tested in advanced melanoma patients have shown little or no clinical 
benefit over the last 3 decades since the approval of recombinant human 
interleukin-2 and dacarbazine (DTIC).  In China, DTIC is still considered the standard 
first-line treatment, despite the lack of any evidence for improving OS.  Metastatic 
melanoma continues to challenge investigators as a disease with a high-unmet medical 
need.  Hence, the use of investigational agents as either a first-line or second-line 
treatment is an accepted modality of treatment in the metastatic melanoma setting.  


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1.2 
BACKGROUND ON ROLE OF ONCOGENIC BRAF KINASE 
IN MELANOMA 
Recent advances in the understanding of the biology of melanoma have resulted in 
identifying the role of BRAF kinase in melanoma.  Mutated BRAF dimers constitutively 
activate the RAF-MEK pathway leading to the generation of transcriptional signaling 
that promotes tumor growth.  BRAF mutations in melanoma have been identified in 
50%−68% of metastatic melanomas, specifically melanomas that arise from 
intermittent sun-exposed skin (e.g., in superficial spreading and nodular melanomas) 
(Beeram et al. 2005, Maldonado et al. 2003, Lang and Mackie 2005, Curtin et al. 2005).  
BRAF mutations are uncommon in acral, mucosal, and uveal melanomas.  At the 
same time, BRAF mutations are common in benign nevi, suggesting that BRAF 
mutations are an early event and may drive melanoma oncogenesis.  About 90% of 
the BRAF mutations seen in metastatic melanoma occur in codon V600 and over 
90% of the V600 mutations are V600E (1799 T>A) (Sanger Institute).  Other 
uncommon variants, such as V600K, V600R, and V600D (in order of decreasing 
frequency), have also been identified, primarily in melanoma. 
Nonclinical data indicate that these variant mutations, like V600E, result in constitutive 
activation of the BRAF kinase.  Most of the transforming activity of the BRAFV600E is 
thought to result through the constitutive activation of the mitogen-activated protein 
kinase pathway (Gray-Schopfer et al. 2007).  The therapeutic relevance of BRAF is 
supported by the demonstration that depletion of mRNA for oncogenic BRAF by siRNA 
leads to growth inhibition of melanoma cell lines in vitro (Hingorani et al. 2003, 
Sumimoto et al. 2004).  This has led to the development of agents that can inhibit BRAF 
kinase and tests to identify mutations (Smalley et al. 2007, Ascierto et al. 2010, 
Flaherty et al. 2010). 
The cobas® BRAFV600 mutation assay and Sanger Sequencing techniques have been 
utilized to identify BRAFV600 mutation status in clinical trials. 
1.3 
VEMURAFENIB 
Vemurafenib is a low molecular weight, orally available inhibitor of oncogenic BRAF 
kinase.  The high level of selectivity of vemurafenib for the BRAFV600 mutation as 
demonstrated in biochemical, cell-based, and in vivo assays is outlined in the 
sections below.   
In August 2011, vemurafenib was approved in the United States for the treatment of 
patients with unresectable or metastatic melanoma with BRAFV600E mutation; in 
October 2011 and February 2012, vemurafenib was approved in Switzerland and the 
European Union, respectively, for the treatment of adult patients with BRAFV600 
mutation-positive unresectable or metastatic melanoma. 
See the Vemurafenib Investigator's Brochure (IB) for details on nonclinical and clinical 
studies. 


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1.4 
NONCLINICAL DEVELOPMENT PROGRAM 
1.4.1 
Nonclinical Pharmacology 
In vitro biochemical and cell-based assays show that vemurafenib displays selectivity 
against a broad range of kinases, including the V600E oncogenic BRAF kinase 
(see Table 1). 
Table 1 
IC50 Values (nM) of Vemurafenib against Selected Kinases 
Kinase 
V600E BRAF 
WT BRAF 
RAF1 
PTK6 
KIT 
KDR 
Vemurafenib (nM) 
44 
110 
44 
240 
610 
5300 
IC50 = half-maximal inhibitory concentration. 
 
As shown in Table 2, cell lines bearing BRAF mutations are selectively sensitive to 
inhibition by vemurafenib. 
Table 2 
Inhibition of Proliferation:  IC50 Values of Vemurafenib in a Variety 
of Cell Lines 
Cell Line: 
A375 
WM2664 
COLO829 
COLO205 
SKMel2 
SW620 
H1299 
Tumor:  
Melanoma 
Melanoma 
Melanoma 
Colorectal 
Melanoma 
Colorectal 
NSCLC 
Oncogene: 
BRAFV600E 
BRAFV600D 
BRAFV600E 
BRAFV600E 
NRAS 
KRAS 
KRAS 
IC50 (µM): 
0.55 
0.42 
0.08 
0.04 
9.2 
6.5 
13 
IC50 = half-maximal inhibitory concentration; NSCLC = non-small cell lung cancer. 
  
In vivo activity for vemurafenib was assessed in a mouse xenograft study in which 
HT29 cells were implanted into the right lateral flank of female athymic NCr nu/nu mice.  
Treatment with vemurafenib demonstrated dose-dependent tumor growth inhibition (TGI) 
at doses of 25 mg/kg, 50 mg/kg, and 75 mg/kg twice daily (BID), and the TGI of 
vemurafenib at doses of 75 mg/kg and 100 mg/kg BID was equivalent.  Similarly, there 
was a dose-dependent increase in life span (ILS) with vemurafenib at doses of 25 mg/kg, 
50 mg/kg, and 75 mg/kg BID, with an equivalent ILS at doses of 75 mg/kg and 
100 mg/kg BID.  Vemurafenib at all doses significantly improved survival versus vehicle.  
This benefit was biologically significant according to National Cancer Institute (NCI) 
criteria (> 25% ILS).  Pharmacokinetic (PK) measurements at the end of the dosing 
period indicated that the dose-response relationship in efficacy correlates with the drug 
exposures, and the efficacy observed with the lowest dose of 25 mg/kg BID of 
vemurafenib occurs at an area under the plasma − concentration time curve (AUC) 
of 1250 μM • h (Data Package 2006).  
Please refer to the Vemurafenib IB for a detailed description of the nonclinical 
pharmacology data. 


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1.4.2 
Nonclinical Metabolism and Pharmacokinetics 
A series of in vitro and in vivo studies have been conducted with vemurafenib to assess 
nonclinical pharmacokinetics and metabolism (Flaherty et al. 2010, Kopetz et al. 2010).  
The single-dose pharmacokinetics of vemurafenib were evaluated in the mouse, rat, dog, 
and monkey.  Multiple-dose pharmacokinetics were assessed during general toxicity and 
toxicokinetic (TK) studies in rats and beagle dogs.  The metabolic disposition and 
drug−drug interaction potential of vemurafenib were investigated in various in vitro 
systems. 
The volume of distribution was modest and clearance was low in both rats and dogs 
following intravenous (IV) injection (Flaherty et al. 2010, Kopetz et al. 2010).  
Vemurafenib was absorbed and widely distributed to tissues, and mainly eliminated via 
biliary excretion in rats.  Drug levels in the rat CNS were undetectable following a single 
oral dose of 100 mg/kg of vemurafenib.   
Data demonstrate that in vitro protein binding of vemurafenib is high (> 99%).  In vitro 
evaluation using hepatocytes from multiple species suggested minimal metabolism of 
vemurafenib by human, dog, and monkey hepatocytes.  Vemurafenib is not an inhibitor 
and/or an irreversible inactivator of CYP3A4/5 in vitro.  Inhibition of CYP2C9 is observed 
in vitro (half-maximal inhibitory concentration [IC50] ~6 μM), indicating a potential for 
interactions with drugs mainly eliminated by the enzyme.  CYP enzyme activity is not 
induced in the in vitro human hepatocyte induction assay.  Vemurafenib is a weak 
substrate of P-glycoprotein (P-gp) and is a P-gp inhibitor.  Thus, vemurafenib may have 
potential for P-gp mediated drug − drug interactions when co-administered with other 
P-gp substrates.  
1.4.3 
Nonclinical Toxicology and Safety Pharmacology 
The toxicology of vemurafenib was evaluated in single-dose and a series of repeat-dose 
toxicity and TK studies for up to 26 weeks in Sprague-Dawley rats and 13 weeks in 
beagle dogs (oral gavage administration once daily).  A corn oil formulation of 
vemurafenib was used for single-dose toxicology, 28-day repeat-dose toxicology, 
and safety pharmacology studies.  Due to limited systemic exposures with the corn oil 
formulation, a new formulation developed for nonclinical and clinical studies, hereafter 
referred to as micro-precipitated bulk powder (MBP) formulation, achieved higher 
systemic exposures for the 13- and 26-week repeat-dose toxicology studies, the in vivo 
micronucleus assay, and reproductive and developmental toxicology studies.  Refer to 
the Vemurafenib IB for a more detailed description of the nonclinical toxicology and 
safety pharmacology studies.  
Repeat-Dose Toxicity: 
In rats given vemurafenib in the corn oil formulation for 28 days, higher cholesterol levels 
and slightly higher heart weights were observed in the 1000 mg/kg/day group, and 
minimal to moderate microscopic lymphangiectasis (dilated lymphatic vessels) in the 


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jejunum was seen in the 100 mg/kg/day and 1000 mg/kg/day groups.  These findings 
were not considered adverse, as there was no overall impact on animal health.  
Importantly, the ame findings were not observed in rats that received vemurafenib in the 
MBP formulation for 26 weeks.  Systemic exposures achieved in rats were greater with 
the MBP formulation than the corn oil formulation.  The no observed adverse effect level 
(NOAEL) for rats was 450 mg/kg/day (MBP formulation) for 26 weeks (AUC0–24h = 2602 
µM • h), the highest dose levels examined.  
In dogs, once daily vemurafenib doses up to 450 mg/kg/day in the MBP formulation for 
13 weeks were well tolerated with no treatment-related adverse findings up to the 
NOAEL of 450 mg/kg/day, which was the highest dose level tested.  However, 
the systemic vemurafenib exposures achieved in dogs at the highest dose level 
(mean UC0-24h = 825 μM • h) were below the mean steady-state exposure in patients 
receiving 960 mg BID in the ongoing Phase I study (mean AUC0-24h = 1795 μM • h).  
A 39-week chronic toxicity study was initiated using the same MBP formulation with 
increased dosing frequency (BID) to aid in establishing the maximum tolerated dose 
(MTD) and to characterize potential target organ toxicity in dogs at exposures 
approaching those achieved in patients in the ongoing Phase I clinical trial.  This 
39-week toxicity study was prematurely terminated because the dogs were not able to 
tolerate the highest vemurafenib dose levels (300 mg/kg and 450 mg/kg BID or 
600 mg/kg/day and 900 mg/kg/day).  The exposures achieved at these dose levels 
(mean AUC0-24h = 1195 and 1295 μM • h for 600 mg/kg/day and 900 mg/kg/day, 
respectively) were still below the steady-state exposures observed in patients given 
960 mg BID (mean AUC0-24h = 1795 μM • h).  Two moribund dogs (1 male and 1 female) 
in the high-dose group were euthanized due to intolerable clinical signs (emesis, 
significant reduction in food intake, body weight loss, hypoactivity, elevated body 
temperature, and dehydration) even after study drug interruption and preventive 
measures (i.e., canned food and subcutaneous fluid) failed to produce improvement.  
Histopathologic examination of tissues from the two euthanized dogs revealed 
treatment-related adverse findings of hepatotoxicity (2 dogs), which correlated with 
elevations in liver enzymes, and focal bone marrow necrosis only in the sternum but not 
in the femur or in the spleen (1 dog) without hematological changes.  No changes in 
cartilages or growth plates in bones were observed.  No treatment-related adverse 
findings were observed in the rest of the tissues in these two moribund euthanized dogs.  
Overall, these findings suggest that dogs are more sensitive to the adverse effects of 
vemurafenib than humans.  A new 13-week repeat-dose BID toxicology and TK study in 
dogs with a 4-week interim necropsy and a 4-week recovery period has been initiated to 
investigate the extent, progression, and the reversibility of the observed findings 
(Vemurafenib IB).  


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Genotoxicity: 
No signs of genotoxicity were identified in a standard battery of tests (in vitro Ames, 
chromosome aberration, and in vivo micronucleus assays) conducted with vemurafenib. 
Reproductive and Developmental Toxicity: 
In rats, no adverse effects were observed in maternal or fetal generations treated with 
vemurafenib doses up to 250 mg/kg/day.  The NOAEL for embryo/fetal development 
toxicity in rats was 250 mg/kg/day (AUC0-24h = 3245 μM • h), the highest dose examined 
(Roche Reference No. 10482 2008). 
In rabbits, maternal toxicities (reduced food consumption and decreased body weight 
gain) were observed at 450 mg/kg/day, but there was no evidence of embryofetal toxicity, 
or any evidence of teratogenicity.  The NOAEL for embryo-fetal development toxicity in 
rabbits was 450 mg/kg/day (AUC0-24h = 1376 μM • hr), the highest dose examined 
(Roche Reference No. 10483 2008).  
Safety Pharmacology: 
A series of in vitro and in vivo experiments have been performed to evaluate potential 
effects of vemurafenib on the cardiovascular system.  The results of these studies can 
be summarized as follows: 
• 
Vemurafenib did not inhibit the human ether-a-go-go-related gene (hERG) (IKr) 
channel in a rubidium flux hERG screen up to the maximum soluble concentration of 
25 µM and was inactive against the hERG (IKr) channel in the 63 panel receptor 
screen at 10 µM. 
• 
In a Good Laboratory Practice (GLP) patch clamp assay, the IC50 for inhibition of the 
hERG channel in serum-free conditions was 1.24 µM.  This value is approximately 
120-fold higher than the IC50 for the target inhibition (pERK). 
• 
A GLP Purkinje cell assay was negative, with no effects on conduction at 
vemurafenib concentrations up to 8 µM. 
 
In an ECG radiotelemetry study in dogs, a single oral administration of vemurafenib at 
doses up to 1000 mg/kg (estimated Cmax = 42 µM, ≤ 1-fold to efficacious maximal plasma 
concentration [Cmax; 85 µM] in patients) resulted in no significant effects on heart rate, 
arterial blood pressure, body temperature, or ECG parameters.  Furthermore, all ECGs 
were qualitatively and quantitatively within normal limits in dogs given up to 
450 mg/kg/day (maximum feasible dose in the MBP formulation) in the 13-week 
repeat-dose toxicity study (up to steady-state Cmax = 91 µM). 
No adverse effects were observed after single oral dose administration of vemurafenib 
up to 1000 mg/kg (estimated Cmax = 160 µM, 2-fold to efficacious Cmax in patients treated 
720 mg to 960 mg BID) in rats in the CNS and respiratory safety pharmacology studies.  


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Phototoxicity: 
Vemurafenib absorbs ultraviolet (UV) light significantly between 240 nm and 450 nm.  
Therefore, vemurafenib was assessed for possible phototoxic potential in vitro by the 
3T3 fibroblast Neutral Red uptake assay.  Vemurafenib was shown to be phototoxic 
in vitro on cultured murine fibroblasts after UVA irradiation.  However, vemurafenib did 
not induce phototoxic skin reaction in an in vivo 7-day phototoxicity study in female 
hairless rats at dose levels up to 450 mg/kg (maximum feasible dose; predicted 
exposure ~1500 µM • h). 
1.5 
CLINICAL DEVELOPMENT PROGRAM 
1.5.1 
Description of Clinical Studies 
1.5.1.1 
Phase I Dose-Finding Study (PLX 06-02) and other 
Phase I Studies 
The dose of vemurafenib was established in a multicenter, Phase I dose escalation 
study with a total of 55 patients, of whom 49 had a diagnosis of melanoma 
(Flaherty et al. 2010; Vemurafenib IB). 
The pharmacokinetics of the marketed formulation has been evaluated in Phase I clinical 
pharmacology studies including a drug interaction study (Study NP22676; n = 20), 
a study to evaluate the pharmacokinetics of vemurafenib at 240 mg to 960 BID doses 
using the 240 mg MPB tablets (Study NP25163; n = 50), and a mass balance study 
(Study NP25158; n = 6). 
1.5.1.2 
Two Phase I Extension Cohorts  
Once the recommended Phase II dose of 960 mg BID had been identified, a cohort of 
32 additional patients with metastatic melanoma and prospectively identified BRAFV600 
mutations were enrolled in the extension phase of this study (Flaherty et al. 2010).  
A different cohort of 21 patients with metastatic colorectal cancer (CRC) and identified 
BRAFV600 mutations were treated in the extension phase with the established dose of 
960 mg BID (Kopetz et al. 2010).  The primary objective of these extension cohorts was 
to determine clinical response rate.  Secondary objectives were safety and additional PK 
and pharmacodynamic evaluations.  
1.5.1.3 
Phase II Single-Arm Study (NP22657/BRIM-2)  
In this open-label, multicenter Phase II study, 132 patients were enrolled and treated 
with oral vemurafenib 960 mg BID, without scheduled dose interruption, until either 
progression of disease, unacceptable toxicity, withdrawal of consent, or any other 
reason as specified in the protocol (Sosman et al. 2012; Vemurafenib IB).  
The primary objective of this study was to evaluate the efficacy of vemurafenib in 
previously treated metastatic melanoma patients with BRAFV600E mutation-positive status 
by the companion diagnostic using best overall response rate (BORR), as assessed by 
an independent review committee (IRC) using the Response Evaluation Criteria in Solid 
Tumors (RECIST, v1.1) guidelines for metastatic melanoma.  Secondary objectives 


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included BORR assessed by the Investigator, duration of response, progression-free 
survival (PFS), OS, safety/toxicity, effect on QT interval, quality of life using Functional 
Assessment of Cancer Therapy-Melanoma (v4), validation of the cobas 4800 BRAFV600 
mutation test, and additional PK and pharmacodynamic parameters.  
1.5.1.4 
Phase III Randomized Controlled Study (NO25026/BRIM-3)  
This randomized, open-label, multicenter Phase III study planned to enroll approximately 
680 patients with treatment-naïve metastatic melanoma confirmed by histopathology 
(unresectable Stage IIIC or Stage IV) and identified BRAFV600E mutation by the 
companion diagnostic (Chapman et al. 2011; Vemurafenib IB).  Patients were randomly 
assigned to be treated with either vemurafenib 960 mg orally (PO) BID every day or IV 
DTIC 1000 mg/m2 on Day 1 every 3 weeks. OS and PFS were defined as co-primary 
endpoints (Study NO25026, protocol version C).  The Data Safety and Monitoring Board 
Charter provided guidance outlining the statistical criteria that could enable crossover of 
patients from the DTIC arm to the vemurafenib arm based on the 50% OS interim 
analysis.  Major secondary study objectives included comparisons of BORR, time to 
response, duration of response, time to treatment failure, and tolerability/safety.  Further 
assessments of the PK profile of vemurafenib, validation of the cobas 4800 BRAFV600 
mutation test, evaluation of quality of life, and additional pharmacodynamic analyses 
were planned.  See the Vemurafenib IB for more detailed information. 
1.5.2 
Clinical Pharmacokinetics of Vemurafenib  
The pharmacokinetics of vemurafenib was first evaluated in study PLX06-02, 
the first-in-human dose ranging study that led to the selection of 960 mg orally 
administered BID dose as the recommended dose for further clinical development.  
During the course of PLX06-02 development, several vemurafenib formulations and 
dose strengths were evaluated.  The 240-mg film-coated tablet of vemurafenib was 
subsequently selected as commercial formulation based on its pharmacokinetic 
properties, which were characterized in Study NP25163 at dose range of 240−960 mg 
BID in patients with BRAFV600 mutation–positive metastatic melanoma.   
Studies NP25163, NP22657, NP22676, and NO25026 were conducted to characterize 
the pharmacokinetics of the 240 mg vemurafenib tablets at 960 mg BID, including 
marked accumulation after multiple doses and relative constant exposure throughout the 
dose interval at steady state.  The time to steady state was formally evaluated in 
Study NP25163 using the individual based statistical approach, where 5 of 12 patients 
(41.6%) in the 960 mg BID cohort achieved steady state on Day 15, while the remaining 
patients reached 60%−80% of the projected steady-state exposure.   
At steady state, daily fluctuations in the concentration–time profiles were small, with Cmax 
values approximately 1.2-fold higher than pre-dose values.  Minimum plasma 
concentration (Cmin) vemurafenib concentrations averaged 53–60 μg/mL across studies 
and remained constant for patients continuing on the treatment regimen.  
In Study NP22676, vemurafenib mean steady-state AUC0-24h exposure was 


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approximately 1200 μg • h/mL (~2400 μM • h), which is in the range of exposure required 
for tumor regression in the less sensitive xenograft model, HT29.  In Study NP25163, 
vemurafenib was shown to be dose proportional over the dose range of 240, 480, 
720, and 960 mg BID, with an overlap in the ranges of individual exposures between 
doses.  A population PK analysis utilizing 458 patients from Studies NO25026, NP22657, 
and NP25163 estimated the half-life to be approximately 57 hours. 
In all clinical studies and at all dose levels evaluated, vemurafenib exhibits relatively high 
inter-patient variability (coefficient of variation [CV%]) and wide range between minimum 
and maximum individual values (approximately 15- to 27-fold for AUC0-8h and 12- to 
14-fold for Cmax). 
In Studies NP25163 and NP22657, the inter-patient variability (CV%) for both AUC and 
Cmax was generally higher after the first dose (Day 1; range, 57.6%−69.9%) than after 
multiple doses (Day 15; range, 27.9%−38.4%).  The reason for these differences is not 
known.  The CV% values for trough (range, 32%−49%) and post-dose (range, 34%−43%) 
are consistent across studies.  Vemurafenib trough and post-dose values in individual 
patients depend on dose modification throughout the course of the treatment.  However, 
the inter-patient variability (CV%) and the width of the range of individual values are 
independent of dose reduction or treatment interruption.  These results suggest that 
dose modification alone cannot explain the inter-patient variability in trough values 
observed in these studies.  The impact of food intake at the time of measurement may 
have an impact on the variability of trough and post-dose measurements as food intake 
was not strictly controlled across all studies, particularly the Phase II and 
Phase III studies.  At this time, no clear explanation is available to explain the 
inter-patient variability. 
The relative proportions of vemurafenib and its metabolites were characterized in a 
mass balance study (NP25158) following oral administration of a single dose of 
14C-vemurafenib to melanoma patients.  In this study, the majority of the parent molecule 
and metabolites were eliminated in the feces, accounting for an average of 94% of the 
input radioactivity (renal elimination accounted for < 1% of the input radioactive dose, 
constituting a negligible elimination path for vemurafenib).  The parent compound was 
the predominant component in all analyzed plasma samples with metabolites 
representing < 5% of the total chromatographic radioactivity. 
Over the first 96 hours, each metabolite accounted for < 0.5% of the total administered 
dose in urine and ≤ 6% of the total administered dose in feces.  In the absence of 
absolute bioavailability, the fraction absorbed of the oral dose cannot be reliably 
estimated.  Based on mass spectrometry, no new metabolites have been detected in 
plasma and feces in this study that have not been observed in in vitro studies with rat 
and human hepatocytes and in vivo studies in rats and dogs.  The chemical structures of 
metabolites have not been identified. 


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For drug-drug interaction results, please see Section 4.4.3. 
1.5.3 
Safety  
Vemurafenib has a manageable safety profile based on the adverse events (AE) 
observed across clinical trials.  Treatment-related adverse events were noted to emerge 
within the first 1−2 months of initiation of treatment.  Adverse events leading to dose 
modifications (interruption and/or dose reduction) occur in almost 40% of patients 
treated at 960 mg BID; however, the majority of these events are successfully managed 
by a treatment interruption interval of 1 week and/or a dose reduction to 720 mg BID.  
It was reported in the pivotal Phase III study NO25026 that 7% of adverse events 
reported resulted in treatment discontinuation. 
The most frequently reported adverse events in vemurafenib-treated patients 
(≥ 30% patients) in the pivotal Phase III NO25026 study and pooled safety population 
(Phase I PLX06-02 and Phase II NP22657 studies and post approval safety study 
MO25515) were (preferred terms) arthralgia, rash, alopecia, fatigue, nausea, pruritus, 
diarrhea, skin papilloma, hyperkeratosis, and photosensitivity.  The majority of these 
events were mild or moderate in intensity.  Table 3 summarizes adverse drug reactions 
(ADRs) that occurred in at least 10% of patients treated with vemurafenib in either the 
Phase III NO25026 or Phase 2 NP22657 study.  These events were considered ADRs 
based on their consistent occurrence across trials; differences in treatment duration 
and/or patient populations may be contributing factors to differences in the incidence of 
ADRs between studies.  


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Table 3 
Summary of ADRs1 Occurring in ≥ 10% of Patients in the 
Vemurafenib Treatment Arm 
ADRs 
Phase III Study: Treatment-Naive Patients 
Phase II Study: 
Patients who Failed 
at least One Prior 
Systemic Therapy 
 
 
Vemurafenib 
n=336 
Dacarbazine 
n=287 
Vemurafenib 
n=132 
 
 
All 
Grades
(%) 
Grade 
3 
(%) 
Grade 
4 
(%) 
All 
Grades
(%) 
Grade 
3 
(%) 
Grade 
4 
(%) 
All 
Grades 
(%) 
Grade 
3 
(%) 
Grade 
4 
(%) 
Skin and subcutaneous 
tissue disorders 
 
 
 
 
 
 
 
 
 
Rash 
37 
8 
- 
2 
- 
- 
54 
7 
- 
Photosensitivity reaction 
33 
3 
- 
4 
- 
- 
52 
3 
- 
Alopecia 
45 
<1 
- 
2 
- 
- 
38 
- 
- 
Pruritis 
23 
1 
- 
1 
- 
- 
32 
2 
- 
Hyperkeratosis 
24 
1 
- 
<1 
- 
- 
30 
- 
- 
Rash maculo-papular 
9 
2 
- 
<1 
- 
- 
21 
6 
- 
Actinic keratosis 
8 
- 
- 
3 
- 
- 
17 
- 
- 
Dry skin 
19 
- 
- 
1 
- 
- 
19 
- 
- 
Rash papular 
5 
<1 
- 
- 
- 
- 
13 
- 
- 
Erythema 
Palmar-plantar 
erythrodysaesthesia 
síndrome 
14 
8 
- 
<1 
- 
- 
2 
1 
- 
- 
- 
- 
10 
10 
- 
2 
- 
- 
Musculoskeletal and 
connective tissue 
disorders 
 
 
 
 
 
 
 
 
 
Arthralgia 
53 
3 
- 
3 
<1 
- 
68 
8 
- 
Myalgia 
13 
- 
- 
1 
- 
- 
24 
<1 
- 
Pain in extremity 
18 
<1 
- 
6 
2 
- 
10 
- 
- 
Musculoskeletal pain 
8 
<1 
- 
4 
<1 
- 
12 
- 
- 
Back pain 
Arthritis 
8 
2 
- 
<1 
- 
- 
5 
- 
<1 
- 
- 
- 
11 
10 
<1 
2 
- 
- 
General disorders and 
administration site 
conditions 
 
 
 
 
 
 
 
 
 
Fatigue 
38 
2 
- 
33 
2 
- 
57 
4 
- 
Oedema peripheral 
17 
<1 
- 
5 
- 
- 
23 
- 
- 
Pyrexia 
Asthenia 
19 
11 
<1 
<1 
- 
- 
9 
9 
<1 
<1 
- 
- 
19 
2 
2 
- 
- 
- 


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Table 3 
Summary of ADRs1 Occurring in ≥ 10% of Patients in the 
Vemurafenib Treatment Arm (cont.) 
ADRs 
Phase III Study: Treatment-Naive Patients 
Phase II Study: 
Patients who Failed 
at least One Prior 
Systemic Therapy 
 
 
Vemurafenib 
n=336 
Dacarbazine 
n=287 
Vemurafenib 
n=132 
 
 
All 
Grades
(%) 
Grade 
3 
(%) 
Grade 
4 
(%) 
All 
Grades
(%) 
Grade 
3 
(%) 
Grade 
4 
(%) 
All 
Grades 
(%) 
Grade 
3 
(%) 
Grade 
4 
(%) 
Gastrointestinal disorders  
 
 
 
 
 
 
 
 
Nausea  
35 
2 
- 
43 
2 
- 
42 
3 
- 
Diarrhoea 
28 
<1 
- 
13 
<1 
- 
32 
<1 
- 
Vomiting 
18 
1 
- 
26 
1 
- 
28 
2 
- 
Constipation 
12 
<1 
- 
24 
- 
- 
17 
- 
- 
Nervous system disorders  
 
 
 
 
 
 
 
 
Headache 
23 
<1 
- 
10 
- 
- 
29 
- 
- 
Dysgeusia 
Neuropathy peripheral 
14 
2 
- 
- 
- 
- 
3 
<1 
- 
- 
- 
- 
11 
11 
- 
<1 
- 
- 
Neoplasms benign, 
malignant and unspecified 
(incl. cysts and polyps) 
 
 
 
 
 
 
 
 
 
Skin papilloma 
21 
<1 
- 
- 
- 
- 
31 
- 
- 
SCC of skin2 
24 
22 
- 
<1 
<1 
- 
23 
23 
- 
Seborrhoeic keratosis 
10 
<1 
- 
1 
- 
- 
14 
- 
- 
Investigations 
 
 
 
 
 
 
 
 
 
γ-glutamyltransferase 
increased 
Weight decreased 
5 
 
8 
3 
 
<1 
<1 
 
- 
1 
 
2 
- 
 
- 
- 
 
- 
15 
 
10 
6 
 
<1 
4 
 
- 
Metabolism and nutrition 
disorders 
 
 
 
 
 
 
 
 
 
Decreased appetite 
18 
- 
- 
8 
<1 
- 
23 
- 
- 
Respiratory, thoracic and 
mediastinal disorders 
 
 
 
 
 
 
 
 
 
Cough 
8 
- 
- 
7 
- 
- 
15 
- 
- 
Injury, poisoning and 
procedural complications 
 
 
 
 
 
 
 
 
 
Sunburn 
10 
- 
- 
- 
- 
- 
14 
- 
- 


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Table 3 
Summary of ADRs1 Occurring in ≥ 10% of Patients in the 
Vemurafenib Treatment Arm (cont.) 
ADR = adverse drug reaction; incl. = including; NCI CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events; SCC = squamous cell carcinoma. 
1 ADRs reported using MedDRA and graded using NCI-CTCAE v 4.0 for assessment of toxicity. 
2 All cases of cutaneous SCC were to be reported as Grade 3 per instructions to study 
investigators, and no dose modification or interruption was required. 
 
The following clinically relevant ADRs were reported in < 10% of patients in the 
vemurafenib-treated group in the Phase III and Phase II studies: 
• 
Skin and subcutaneous tissue disorders: keratosis pilaris, panniculitis, erythema 
nodosum, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) 
• 
Nervous system disorders: dizziness, VIIth nerve paralysis 
• 
Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal 
cell carcinoma (BCC) 
• 
Infections and infestations: folliculitis 
• 
Eye disorders: retinal vein occlusion, uveitis 
• 
Vascular disorders: vasculitis 
 
Refer to the Vemurafenib IB for updated safety information. 
1.5.3.1 
Dose-Limiting Toxicities 
Five patients experienced dose-limiting toxicities (DLTs) in Study PLX06-02 (1 patient at 
720 mg BID; 4 patients at 1120 mg BID).  One DLT, Grade 4 pancytopenia, was 
observed at 720 mg BID.  Upon resolution of the pancytopenia after 9 days of study drug 
interruption, the patient was rechallenged with vemurafenib at a lower dose of 360 mg 
BID without recurrence of the pancytopenia.  In the 1120 mg BID cohort, 4 of 6 patients 
developed protocol-defined, non–life-threatening DLTs (including Grade 3 rash with 
pruritus, fatigue, and/or arthralgia) that resolved with temporary drug interruption.  
All 4 patients were rechallenged at a lower dose of 720 mg BID and continued in the 
study.  No occurrence of pancytopenia was observed in the 1120 mg BID dose cohort.   
Approximately 40% of patients who received the MBP formulation had their vemurafenib 
dose interrupted and/or reduced because of an AE. 
The majority of adverse events that led to dose interruption and/or reduction were of 
Grade 3 severity and included a broad range of events, most of which resolved with no 
sequelae. 
1.5.3.2 
Deaths and Serious Adverse Events 
Deaths 
Across all studies, the majority of deaths were attributed to progressive disease (PD).  In 
the pivotal, Phase III Study NO25026, 19% of patients died in the vemurafenib group 


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and 34% in the DTIC group.  No patient died after crossing over from the DTIC group to 
the vemurafenib group.  In Study NP22657, 39% of patients had died as of the 31 
January 2011 clinical cutoff date.  In Study NP25163, 48% (n = 25) of patients died as 
of the end of the study.  
Serious Adverse Events 
Across all three studies (NO25026, NP22657, and NP25163), the most commonly 
reported vemurafenib-related serious adverse event (SAE) was cuSCC.  In 
Study NO25026, 42% and 18% of patients in the vemurafenib and DTIC groups, 
respectively, experienced one or more serious adverse event.  Thirty-one percent and 
5% of patients in the vemurafenib and DTIC groups, respectively, experienced one or 
more treatment-related serious adverse event. 
The most common treatment-related serious adverse events in the vemurafenib group 
were cuSCC (17%) and KA (9%).  All occurrences of cuSCC/KA were required to be 
reported as Grade 3 and serious.  No other treatment-related serious adverse events 
occurred in > 1% of patients in either treatment group.  Severe dermatologic reactions 
have been reported in patients receiving vemurafenib, including rare cases of Stevens-
Johnson syndrome and toxic epidermal necrolysis.  One notable treatment-related 
serious adverse events occurred in a vemurafenib-treated patient after the 1 March 2011 
clinical cutoff date for safety.  This patient developed toxic epidermal necrolysis.  The 
event improved slightly after the patient was given treatment, but was not resolved at 
last report.  The patient was discharged from the hospital and permanently discontinued 
treatment with vemurafenib. 
Four of 37 DTIC patients (11%) who crossed over to receive vemurafenib experienced 
serious adverse events after the start of vemurafenib.  These events included pyrexia, 
anemia, convulsion, lower respiratory tract infection, and cellulitis; only the episode of 
pyrexia was judged by the Investigator to be related to treatment.  
The serious adverse events data at the 1 February 2012 cutoff date were generally 
consistent with data reported with the 1 March 2011 cutoff in study NO25026.  
Forty-seven percent (47%) of patients experienced serious adverse events in the 
vemurafenib group versus 18% of patients in the DTIC group, compared with 42% and 
18%, respectively, at the 1 March 2011 cutoff.  Although there were some increases in 
the incidence of serious adverse events that were reported, similar to the increases 
described for Grade ≥ 3 adverse events, there was no overall change in the types of 
adverse events that were reported.   
In Study NP22657, 53% of patients experienced one or more serious adverse events, 
and 37% experienced one or more treatment-related serious adverse events.  The most 
common treatment-related serious adverse events included SCC of the skin (23%), BCC 
(7%), KA (3%), elevated liver function tests (2%), rash (2%), pyrexia (2%), and arthralgia 
(2%).  In Study NP25163, 40% of patients experienced one or more serious adverse 


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events, and 29% experienced one or more treatment-related serious adverse events.  
The most common treatment-related SAE was cuSCC (13%). 
For a more detailed summary of deaths and serious adverse events, see the 
Vemurafenib IB, Section 5.5.4 and 5.5.5. 
1.5.3.3 
Cutaneous Squamous Cell Carcinoma 
As of cutoff date for safety data of September 2, 2011, in Studies NO25026, NP22657, 
and NP25163, 79 (23.5%), 34 (25.8%), and 10 (19.2%) patients, respectively, developed 
cutaneous squamous cell carcinomas (SCC) and keratoacanthomas (cuSCC/KA).  Most 
cuSCC cases were KAs:  58/79 (73.4%), 30/34 (88.2%), and 10/10 (100%) in 
Studies NO25026, NP22657, and NP25163, respectively. 
1.5.3.4 
New Primary Melanomas 
Eight skin lesions in 7 of 337 vemurafenib-treated patients were reported as new primary 
malignant melanomas in Study NO25026. No cases were reported in 287 patients 
treated with DTIC.  Cases were managed with excision and without sequelae, and 
patients continued treatment without dose adjustment. 
1.5.3.5 
Non-Cutaneous Squamous Cell Carcinoma 
Two cases of SCC of the head and neck have been reported in 2 patients treated with 
vemurafenib in excess of 300 days while enrolled in a clinical trial.  Pathology exam of 
both tumors (one a primary tonsillar tumor, the other a primary tongue tumor) revealed 
the presence of invasive SCC.  Of note, the first patient’s medical history was significant 
for risk factors for head and neck cancer and the tumor tissue tested positive for human 
papilloma virus (HPV).  The second patient does not appear to possess any risk factors 
for head and neck cancer, and the preliminary examination of the tumor tissue did not 
reveal the presence of HPV genome.  Full details are provided in the current IB. 
Surveillance measures, including regular dermatologic and head and neck examinations 
and chest computed tomography (CT) scans, has been established to monitor for and 
treat SCC (both cutaneous and non-cutaneous) in patients receiving vemurafenib in 
clinical trials (see Section 4.5.1.9). 
1.5.3.6 
Adenomatous Colonic Polyps 
Five cases of adenomatous colonic polyps have been reported in patients who received 
vemurafenib for more than 2 years while enrolled in a clinical trial 
(Chapman et al. 2012).  The first patient developed an upper gastrointestinal bleed, and 
on work-up was found to have duodenal ulceration (non-malignant), hyperplastic 
gastric polyps, and five colonic polyps (three of which were adenomatous).  A previous 
colonoscopy in 2008, at the time of a jejunal resection for recurrent melanoma, 
documented no prior evidence of colonic polyps.  All polyps were resected, and the 
patient subsequently resumed vemurafenib therapy.  The second patient was found, on 
elective colonoscopy, to have seven colonic polyps (five of which were adenomatous), 


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and all were detected and removed.  This patient had not undergone a previous 
colonoscopy.  The patient has discontinued treatment with vemurafenib.  The third 
patient had, on elective colonoscopy, 10 colonic polyps (seven of which were 
adenomatous).  This patient had a previous colonoscopy 7 years prior to starting 
vemurafenib.  The fourth patient had, on elective colonoscopy, one adenomatous colonic 
polyp.  The fifth patient had, on elective colonoscopy, three adenomatous colonic polyps.  
The latter two patients had histories of no prior colonoscopy.  In addition, a patient on 
the Expanded Access Program had one colonic adenoma discovered after being on 
vemurafenib 0.57 years.  This patient had a colonoscopy 1.3 years prior to starting 
vemurafenib, and a polyp was found and resected at that time. 
1.5.3.7 
Hypersensitivity Reactions 
A case of hypersensitivity reaction with rash, fever, rigors, and hypotension 8 days after 
starting vemurafenib 960 mg BID was reported in a clinical trial.  Similar symptoms were 
observed upon re-initiation of treatment with a single dose of 240 mg vemurafenib.  The 
patient discontinued vemurafenib permanently and recovered without sequelae. 
1.5.3.8 
ECG Analysis 
In the nonclinical GLP patch clamp in vitro assay, the IC50 for inhibition of the hERG 
channel in serum-free conditions was 1.24 μM.  The mean Cmax at steady state attained 
in melanoma patients with vemurafenib 960 mg BID has exceeded the IC50 for hERG 
blockade in vitro, albeit with a high degree of protein binding in humans. 
However, QTc prolongation was observed in the ECG substudy of NP22657.  The 
effects of single and multiple doses of vemurafenib (960 mg BID) on ECG 
measurements, including the QT interval, were evaluated in 132 adult patients with 
metastatic melanoma in the Phase II Study NP22657.  
Ninety-one patients (68.9%) exhibited either normal ECG values throughout the study 
(n = 25) or developed new abnormal but clinically insignificant ECG changes (n = 66).  
However, 41 patients (31.1%) exhibited new ECG changes considered to be abnormal 
and potentially significant.  No patients developed new abnormal U waves, but 
19 patients (14.4%) had new abnormal T-waves.  Vemurafenib did not cause a 
meaningful change from the time-matched baseline ECG in either the QRS or the PR 
(PQ) interval. 
Two patients (1.5%) developed treatment-emergent QTcP values > 500 ms 
(NCI Common Terminology Criteria for Adverse Events [CTCAE] Grade 3), while 
49 (37.1%) and 6 (4.5%) of patients exhibited treatment-emergent, QTcP 
values > 450 ms and > 480 ms, respectively.  No patients had treatment-emergent 
uncorrected QT values > 500 ms. Treatment-emergent, individual QTcP changes > 30 ms 
from baseline were observed in 58 (43.9%) patients, but only 1 patient (0.8%) exhibited 
a QTcP change > 60 ms from baseline. 


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The pattern of increasing vemurafenib concentration from Days 1 to 15 of vemurafenib 
treatment appeared to correlate with the increased mean QTcP change observed from 
Days 1 to 15 and the constant vemurafenib exposures observed in later cycles appeared 
to correlate with the maintenance of the effect on QTc interval. 
None of the QT prolongation events were serious or led to premature withdrawal from 
treatment or dose modification/interruption; none were clearly associated with 
prolongation of cardiac repolarization, arrhythmia, or any other cardiac function disorder.  
Refer to the Vemurafenib IB for additional details. 
1.5.3.9 
Post-Approval Safety Update 
1.5.3.9.1 
Progression of Existing Malignancy 
One case of progression of NRAS-mutated chronic myelomonocytic leukemia (CMML) 
occurred in a male patient with metastatic melanoma treated with vemurafenib for less 
than 2 weeks (Callahan et al. 2012).  After the first dose of vemurafenib, laboratory 
results showed a marked leucoytosis and monocytosis and vemurafenib treatment was 
subsequently held.  There was a temporal relationship between vemurafenib treatment 
and increase in WBC and absolute monocyte counts, through multiple cycles of 
dechallenge and rechallenge.  In vitro studies demonstrated proliferation of the leukemic 
cell population upon stimulation with a BRAF inhibitor, an effect that was reversed upon 
addition of a MEK inhibitor.  Further, the cells exhibited dose-dependent and reversible 
activation of ERK in the NRAS-mutated leukemic clone.  A second case of progression of 
a preexisting RAS-mutated malignancy (pancreatic adenocarcinoma with KRAS 
mutation) was reported with vemurafenib in 2014.  On the basis of its mechanism of 
action, vemurafenib may cause progression of cancers associated with RAS mutations.  
Vemurafenib should be used with caution in patients with a prior or concurrent cancer 
associated with RAS mutation.  Full details are provided in the current Vemurafenib IB. 
1.5.3.9.2 
Drug Reaction with Eosinophilia and Systemic Symptom 
(DRESS) 
As of 31 March 2013, 12 cases of drug reaction with eosinophilia and systemic 
symptoms (DRESS) syndrome have been observed with vemurafenib treatment.  No 
fatal cases have been reported.  The time to onset was 7 to 25 days.  In the majority of 
patients (n = 7), vemurafenib was discontinued.  Some patients (n = 5) were treated with 
systemic steroids with corresponding improvement or resolution of symptoms.  In 
addition, 2 patients who were treated with vemurafenib after ipilimumab presented with 
Grade 3 rash and had biopsies that showed pathology consistent with drug 
hypersensitivity reaction (Harding et al. 2012).  Full details are provided in the current 
Vemurafenib IB. 
1.5.3.9.3 
Liver Injury 
An analysis of liver−related adverse events reported with vemurafenib use showed that 
63 cases (out of an estimated exposure of approximately 20,000 patients) of medically 
confirmed serious adverse events were consistent with drug−induced liver injury (DILI) 


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based on clinical chemistry criteria from the DILI Expert Working Group 
(Aithal et al. 2011).  Of the 63 cases, two were assessed as severe, both reported as 
hepatic failure. There were no reported deaths among the 63 cases of liver injury; the 
outcome of both cases of severe liver injury was reported as completely resolved with 
vemurafenib discontinuation.  The median time to onset of the adverse events was 44 
days after initial dose.  The median ALT to ALP ratio was calculated as 1.5, which 
suggested a trend toward a cholestatic pattern of liver injury.  The analysis did not reveal 
any risk factors or populations at risk. 
1.5.3.9.4 
Neutropenia 
A review of the Roche safety database found neutropenia to be an uncommon (6 cases 
per 1000 person-years, 0.6%) adverse drug reaction associated with the use of 
vemurafenib, typically occurring during the first 6−12 weeks of treatment.  It appeared to 
be reversible usually within 2 weeks, with either temporary interruption, dose reduction 
or discontinuation of vemurafenib, and in some cases was managed with granulocyte 
colony-stimulating factors (G-CSF). 
1.5.3.9.5 
Pancreatitis 
As of Q2 2014, an adverse drug reaction of pancreatitis has been identified in patients 
being treated with vemurafenib.  Seventeen cases of pancreatitis with no strong risk 
factors or alternative explanations were reported.  Eight of the 17 cases were assessed as 
likely associated with vemurafenib use based on event onset latency and 
re-challenge/de-challenge information.  The clinical presentation, including mild to 
moderate severity, was consistent with the clinical picture of drug-induced pancreatitis 
(Lankisch et al. 1995). 
1.5.3.9.6 
Risk of Radiation Recall and Radiation Sensitization  
As of Q4 2014, an adverse drug reaction of potentiation of radiation treatment toxicity 
has been identified in patients treated with radiation either prior, during, or subsequent 
to vemurafenib treatment.  This is based on 20 cases of radiation injuries, adjudicated 
as radiation recall (n = 8) and radiation sensitization (n = 12).  The nature and severity 
of the events in all 20 cases were evaluated as worse than expected for the normal tissue 
tolerance to therapeutic radiation with fatal outcome in 3 cases.  The reaction was seen 
in the skin, esophagus, lung, liver, rectum, and urinary bladder.  Vemurafenib should 
be used with caution when given concomitantly or sequentially with radiation 
treatment.  Full details are provided in the current Vemurafenib IB. 
1.5.3.9.7 
Safety in Combination with Ipilimumab 
In a Phase I trial (CA 184161, sponsored by Bristol-Myers Squibb), asymptomatic 
Grade 3 increases in transaminases and bilirubin occurred with concurrent 
administration of ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID) 
(Ribas et al. 2012).  All liver laboratory abnormalities were asymptomatic and reversible 
with permanent discontinuation of the study drugs or, in some cases, administration of 
corticosteroids.  Based on these data, concurrent administration of ipilimumab and 


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vemurafenib is not recommended outside of a clinical trial.  Full details are provided in 
the current Vemurafenib IB.  
1.5.4 
Clinical Efficacy 
Clinical efficacy data to support the use of vemurafenib for the treatment of patients with 
BRAFV600 mutation-positive unresectable or metastatic melanoma is primarily based on 
results from three studies (NO25026, NP22657, and PLX06- 02). All three studies were 
multicenter, international, and open label.  
• 
NO25026, Phase 3: clinical cutoff:  31 March 2011; vemurafenib n = 337; 
DTIC n = 338.  Updated analyses are also provided based on a clinical cutoff date of 
1 February 2012. 
• 
NP22657, Phase 2:  clinical cutoff: 31 January 2011; n = 132. Updated analyses are 
also provided based on a clinical cutoff date of 1 February 2012. 
• 
PLX06-02, Phase 1:  clinical cutoff: 3 June 2010.  Dose escalation phase: 
(patients with solid tumors); vemurafenib original formulation, n = 26, vemurafenib 
MBP formulation, n = 30.  Treatment extension phase:  metastatic melanoma 
patients, n = 32, metastatic CRC patients, n = 21. Updated analyses for the 
melanoma extension cohort patients are provided based on a clinical cutoff date of 
17 July 2012. 
 
In all three studies (NO25026, NP22657, and PLX06-02) in which vemurafenib was used 
to treat previously untreated or previously treated patients with BRAFV600 
mutation-positive metastatic melanoma, consistent, robust, and clinically meaningful 
benefits were observed. 
In the Phase 3 Study (NO25026), as of the 31 March 2011 cutoff date, after a median 
5.19 months of follow-up in the vemurafenib arm, the Kaplan-Meier (KM) estimate of 
median survival among patients randomized to vemurafenib was not reached 
(95% CI:  9.59 months, not reached). Among patients randomized to DTIC, after a 
median 4.46 months of follow-up, the KM estimate of median survival was 7.89 months 
(95% CI:  7.26 months, 9.63 months).  The KM estimate of the 6-month survival rate 
among patients randomized to vemurafenib was 83% (95% CI: 79%, 87%) and 
63% (95% CI:  57%, 69%) among patients randomized to DTIC.  The hazard ratio (HR) 
for death was 0.44 (95% CI: 0.33, 0.59) in favor of vemurafenib.  Treatment with 
vemurafenib demonstrated a clinically meaningful and statistically significant 
improvement in PFS compared with dacarbazine treatment (p < 0.0001).  There was a 
statistically significant improvement in BORR (confirmed) as assessed by the 
investigator with vemurafenib (48.4%; 95% CI:  41.6%, 55.2%) compared with DTIC 
(5.5%; 95% CI:  2.8%, 9.3%, p < 0.0001). 
In updated analyses (1 February 2012 cutoff date), the survival benefit of vemurafenib 
treatment compared with DTIC treatment was again observed.  With a median of 
12.5 months of follow up for vemurafenib patients, updated OS analyses showed that 


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vemurafenib treatment is associated with a nearly 4 month improvement in median 
survival compared with DTIC (13.6 months vs. 9.7 months, respectively).  The HR for 
death in this analysis was 0.70 (95% CI: 0.57, 0.87) in favor of vemurafenib.  Updated 
PFS analyses showed that vemurafenib treatment was associated with an approximately 
5-month improvement in median PFS compared with DTIC (6.9 months vs. 1.6 months, 
respectively); the PFS HR was 0.38 (95% CI: 0.32, 0.46) in favor of vemurafenib.  In 
these analyses, data were censored as specified in the Statistical Analysis Plan at the 
time of crossover for DTIC patients who crossed over to receive vemurafenib treatment. 
In the Phase 2 Study NP22657, with a 31 January 2011 clinical cutoff date, after a 
median duration of follow-up of 10.4 months, the primary endpoint of BORR (confirmed) 
as assessed by the IRC was 53% (95% CI:  44.2%, 61.8%).  Secondary endpoints that 
were supportive of antitumor activity as assessed by the IRC included median response 
duration and OS.  The median response duration was 6.7 months (95% CI:  5.6 months, 
8.6 months), and the median OS had not been reached (95% CI: 11.2 months, not 
reached).  Median PFS was 6.1 months (95% CI: 5.5 months, 6.9 months). 
In updated analyses, with a 1 February 2012 clinical cutoff date, with a median follow-up 
of 13.4 months, BORR, duration of response, and PFS were similar to the prior analysis.  
The KM estimate of median OS was 15.9 months (95% CI: 11.2 months, 19.3 months), 
and the estimate of median PFS was 6.8 months (95% CI: 5.5–7.9 months). 
In the Phase 1 Study (PLX06-02), a BORR  (confirmed) of 56% was observed (duration 
of follow-up not available) with a median duration of response of 227 days (7.6 months), 
median PFS of 233 days (7.8 months), and a 1-year survival rate of 57%. 
In updated analyses of survival (using a 17 July 2012 cutoff date), the median OS in the 
melanoma cohort was 13.8 months, and the 2-year survival rate was 38%. 
Consistent with in vitro evidence demonstrating strong inhibition of vemurafenib across 
cell lines expressing variant BRAFV600 mutations, improvement in OS, PFS, and BORR 
was also observed in patients with BRAFV600K mutations identified by Sanger sequencing 
in the NO25026 study, and in BORR in the NP22657 study. 
While acknowledging the limited number of patients in these analyses, these data 
support the clinical activity of vemurafenib in metastatic melanomas harboring less 
common activating BRAFV600 mutations. 
For updated efficacy information, refer to the Vemurafenib IB. 
1.6 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
Metastatic melanoma represents a major clinical challenge, as it is an essentially 
incurable disease with few satisfactory treatment options.  Current first-line treatment 
options have yielded low response rates and, although ipilumumab has demonstrated an 


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OS advantage, it is associated with significant toxicities (Robert et al. 2011).  
Furthermore, no biomarkers for patient selection or reliably predicting development of 
severe immune-related toxicity are known for ipilimumab. 
Vemurafenib is a highly selective inhibitor of the oncogenic BRAF kinase, which has 
been identified in a large number of malignant melanomas.  Results from Phase I, II, 
and III studies in the West have shown that vemurafenib was associated with consistent, 
robust, and clinically meaningful benefits as measured by all primary and secondary 
efficacy endpoints, in treatment-naïve or previously treated patients with BRAFV600 
mutation-positive metastatic melanoma.  To date, no other first- or second-line treatment 
options for metastatic melanoma have shown consistent improvement in all three 
efficacy parameters (OS, PFS, and BORR) in this population with high unmet medical 
need.  These data indicate that vemurafenib is an effective treatment option in this 
patient population.   
As there is very limited information on vemurafenib in the treatment of Asian patients 
(only 4 Asian patients were treated with vemurafenib, 1 in the Phase 1 study PLX06-02, 
3 in an ongoing safety Study MO25515), and to safely apply clinical information obtained 
in Caucasians to support usage of vemurafenib to treat Chinese melanoma patients, 
the Study YO28390 is planned to investigate the pharmacokinetics, safety, and efficacy 
of vemurafenib in Chinese patients with BRAFV600 mutation–positive unresectable or 
metastatic melanoma.  This study will comply with the International Conference on 
Harmonisation (ICH) Guidance E5 (Ethnic Factors in the Acceptability of Foreign Clinical 
Data) and regulatory requirements of the People’s Republic of China. 
2. 
OBJECTIVES 
2.1 
PRIMARY OBJECTIVE  
The PK objective for this study is to evaluate the pharmacokinetics of vemurafenib 
following 960 mg BID oral administration in Chinese patients with BRAFV600 
mutation-positive unresectable or metastatic melanoma. 
This is the primary objective of this study. 
2.2 
SECONDARY OBJECTIVES 
The efficacy objective for this study is to describe the efficacy of vemurafenib by using 
BORR (confirmed), duration of response, PFS, and OS in Chinese patients with 
BRAFV600 mutation-positive unresectable or metastatic melanoma. 
The safety objective for this study is to investigate the safety and tolerability of 
vemurafenib in Chinese patients with BRAFV600 mutation–positive unresectable or 
metastatic melanoma. 


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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview 
This is an open-label, multicenter, Phase I study with a PK cohort and an expansion 
cohort.  Only patients who test positive for the BRAFV600 mutation as determined by the 
cobas 4800 BRAFV600 Mutation Test will be allowed to participate in this study.  
Approximately 45 Chinese patients will be recruited into this study.  Patient recruitment 
is estimated to require approximately 22 months. 
3.1.1.1 
Pharmacokinetic Cohort 
Approximately 20 patients will be enrolled in the PK cohort.  The study design scheme 
for the PK cohort is in Table 4.  
Table 4 
Study Design Scheme for PK Cohort 
Screening 
Period A 
Period B 
Period C 
(extension phase) 
Follow-up 
Days –28 to –1 
Days 1–21 
Days 22–27 
Day 28 and 
beyond 
After completion 
of study treatment 
No 
vemurafenib 
administration 
Vemurafenib 
960 mg BID 
Vemurafenib 
holiday 
Vemurafenib 
960 mg BID 
No vemurafenib 
administration 
BID = twice daily. 
 
The dosing regimens in different periods are described as follows: 
• 
Period A:  Following a screening period of up to 28 days, approximately 20 patients 
will be enrolled into the study for PK assessment.  Patients will receive 960 mg BID 
PO on Days 1 to 20, and on Day 21, patients will only receive their morning dose.  
All patients will provide blood samples on Days 1, 15, 19, and 21 for PK analysis as 
described in Appendix 2. 
• 
Period B:  Begins with Day 22 and lasts until Day 27.  Study drug will be held for 
the purpose of characterizing the elimination profile of vemurafenib.  All patients will 
provide blood samples on Days 22 and 24 for PK analysis as described in 
Appendix 2. 
• 
Period C:  After a pre-dose PK sample collection, starting on Day 28, all patients 
may resume vemurafenib 960 mg BID until the development of PD, unacceptable 
toxicity, withdrawal of consent, or any other criterion as listed in Section 4.6.  
• 
Follow-up period:  All adverse events (related and unrelated to study drug) 
occurring at any time during Periods A, B, or C up to 28 days after the last dose of 
study medication in Period C must be reported; drug-related events must be 
followed until resolution.  All patients who received at least one dose of vemurafenib 
will be followed for SCC evaluation until 6 months after discontinuation of study 
treatment or death, withdrawal of consent, or loss to follow-up, whichever is earlier. 


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3.1.1.2 
Expansion Cohort 
After recruitment of the PK cohort is complete, approximately 25 additional Chinese 
patients with BRAFV600 mutation-positive unresectable or metastatic melanoma will be 
recruited into the expansion cohort.  
Following a screening period of up to 28 days, all eligible patients will complete the 
assessments on Day 1 (see Appendix 1) as their baseline and will receive vemurafenib 
960 mg BID until the development of PD, unacceptable toxicity, withdrawal of consent, 
or any other criterion as listed in Section 4.6.  
The follow-up procedures for patients in the expansion cohort are the same as for those 
in the PK cohort. 
For detailed information on the safety and efficacy evaluations for both cohorts, please 
refer to the Schedule of Assessments (see Appendix 1).  PK samples will be obtained 
according to the schedule outlined in Appendix 2. 
3.2 
END OF STUDY 
Patients still receiving vemurafenib at the time of updated analysis will be allowed to 
continue treatment until PD, unacceptable toxicity, death, loss to follow-up, or withdrawal 
of consent.  
The study will end when the last patient has permanently discontinued treatment with 
vemurafenib and has completed the 6-month follow-up period for safety assessment.  
3.3 
RATIONALE FOR STUDY DESIGN 
This is a Phase I, open-label, multicenter, multiple-dose study.  The purpose of the study 
is to investigate the pharmacokinetics, safety, and efficacy of vemurafenib in Chinese 
patients with BRAFV600 mutation-positive unresectable or metastatic melanoma. 
In the PK portion of the study (Periods A and B), the PK profile after the first dose (Day 1) 
and at steady-state will be evaluated to determine the accumulation ratio of vemurafenib 
in Chinese patients.  To achieve the complete steady-state in plasma in all patients, the 
21-day continuous BID dosing (Days 1−21) in Period A will be employed.  This is based 
on the results from the PK dose ranging Study NP25163, which demonstrated that more 
than 14 days of continuous dosing may be required to complete the approach to steady 
state in plasma in certain patients.  The 6-day “drug holiday” in Period B (Days 22−27) is 
used for assessing the elimination phase of vemurafenib at steady state 
because > 95% of plasma clearance of drug occurred within 7 days in Study NP25163. 
Since 10 evaluable patients had been sufficient for solid PK data in NP 25163, total 
20 patients will be recruited for the PK cohort and at least 10 patients are expected to 
complete the PK portion of the study.   


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After recruitment of the PK cohort is complete, an additional 25 patients will be enrolled 
into the expansion cohort for efficacy and safety assessments.  All patients will receive 
vemurafenib 960 mg BID until the development of PD, unacceptable toxicity, consent 
withdrawal, or any other criterion as listed in Section 4.6.  The purpose of the expansion 
cohort is to collect additional safety and efficacy results in Chinese patients. 
3.3.1 
Rationale for Test Product Dosage 
A regimen of 960 mg BID has been chosen in this study to characterize the 
pharmacokinetics of vemurafenib and collect additional safety and efficacy results in 
Chinese patients.  This is the regulatory authority-approved starting dose for 
vemurafenib to treat mutation-positive unresectable or metastatic melanoma in the 
United States, Switzerland, and European Union, and was also the MTD determined in a 
first-in-human study conducted in Caucasian patients (Study PLX 06-02). 
In global registration studies, a high incidence of at least one temporary interruption 
and/or dose reduction (approximately 40%−50%) due to treatment-emergent adverse 
events at the MTD of 960 mg BID was observed; however, permanent discontinuation of 
study drug for toxicity was rare. 
A risk management plan specific for this study in Chinese patients based largely on the 
global studies risk management plan (see Section 5.1) and dose reduction guidelines 
will be used to manage symptomatic adverse events and possible QTc prolongation in 
this bridging study. 
3.3.2 
Rationale for Patient Population 
The mechanism of action of vemurafenib and existing nonclinical and clinical data all 
suggest that the activity of the drug is limited to patients whose tumors are positive for 
the V600 mutation(s) of the BRAF gene.  Patients whose tumors are not positive for the 
mutation will not be treated with vemurafenib. 
The global clinical trial program included treatment-naïve and previously treated patients 
with BRAFV600 mutation–positive unresectable or metastatic melanoma.  Results from 
global Phase II and III studies have shown that vemurafenib demonstrates high 
response rates and improves the OS and PFS in patients with metastatic melanoma who 
carry the BRAFV600 mutation. 
Therefore, the BRAFV600 mutation status for eligible patients must have been 
determined using the cobas 4800 BRAFV600 Mutation Test.  This includes previously 
untreated patients or those previously treated but without prior exposure to any BRAF 
(sorafenib allowed) or MEK inhibitor therapy, having locally advanced and unresectable 
or metastatic melanoma, are eligible. 


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3.4 
OUTCOME MEASURES  
3.4.1 
Pharmacokinetic Outcome Measures  
The PK outcome measures for this study are as follows: 
• 
Cmax on Days 1 and 21 
• 
Time to maximal plasma concentration (Tmax) on Days 1 and 21 
• 
AUC from time 0 to 8 hours (AUC0-8h) on Days 1 and 21 
• 
AUC from time 0 to 12 hours (AUC0-12h or AUCτ) on Days 1 and 21 
• 
AUC from time 0 to 168 hours (AUC0-168h) beginning on Day 21 
• 
Cmin on Days 15, 19, and 21 
• 
Accumulation ratio (the AUC ratio on Day 21/Day 1) 
• 
Elimination rate constant (Kel) 
• 
Half-life (t1/2) 
 
3.4.2 
Efficacy Outcome Measures 
The efficacy outcome measures for this study are as follows: 
• 
BORR (confirmed) 
• 
Duration of response 
• 
PFS 
• 
OS 
  
3.4.3 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, nature, and intensity (severity) of adverse events and serious adverse 
events, graded according to NCI CTCAE v4.0 
• 
Changes in vital signs 
• 
Changes in clinical laboratory test results 
• 
ECG assessments 
• 
Dermatology evaluations for cuSCC surveillance 
• 
Head, neck, anus, anal canal, and pelvic (for female patients) evaluations and CT 
scans for non-cuSCC surveillance 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
This study will enroll Chinese patients ≥18 years of age who are BRAFV600 mutation 
positive and have histologically confirmed metastatic melanoma (unresectable Stage IIIC 
or Stage IV).  Patients may be either treatment-naïve or have received prior systemic 
treatments for metastatic melanoma.  Written informed consent must be obtained from 
patients prior to performing any study-related procedures.  


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4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Chinese male or female patients ≥ 18 years of age. 
• 
Histologically confirmed metastatic melanoma (surgically unresectable Stage IIIc or 
Stage IV, American Joint Committee on Cancer).  Unresectable Stage IIIc disease 
must have confirmation from a surgical oncologist. 
• 
Patients are either treatment-naïve or had received prior systemic treatments for 
metastatic melanoma. 
• 
Positive BRAFV600 mutation result determined by a designated laboratory using the 
cobas 4800 BRAFV600 Mutation Test prior to administration of vemurafenib. 
• 
Measurable disease by RECIST v1.1 prior to the administration of vemurafenib. 
• 
Previous allowed chemotherapy, immunotherapy, or radiation therapy must have 
been completed at least 2 weeks prior to study drug administration, and all 
associated toxicity must be resolved (to ≤ Grade 1 or baseline) prior to study 
drug administration. 
• 
Recovery from effects of any major surgery (excluding tumor biopsy at baseline) 
or significant traumatic injury at least 14 days before the first dose of 
study treatment. 
• 
Adequate hematologic, renal, and liver function as defined by laboratory values 
performed within 28 days prior to initiation of dosing. 
• 
Absolute neutrophil count ≥ 1.5 x 109/L 
• 
Platelet count ≥ 100 × 109/L 
• 
Hemoglobin ≥ 9 g/dL 
• 
Serum creatinine ≤ 1.5 × the upper limit of normal (ULN) or creatinine 
clearance > 60 mL/min by Cockroft-Gault formula 
• 
AST and ALT ≤ 2.5 × ULN (≤ 5 × ULN for patients with concurrent 
liver metastases) 
• 
Bilirubin ≤ 1.5 × ULN (for patients with Gilbert’s Syndrome, bilirubin ≤ 3 × ULN) 
• 
Alkaline phosphatase ≤ 2.5 × ULN (≤ 5 × ULN for patients with concurrent liver 
metastases) 
• 
Albumin ≥ 3 g/dL 
• 
Negative serum or urine pregnancy test within 7 days prior to commencement of 
dosing in pre-menopausal women.  Women of non-childbearing potential may be 
included if they are either surgically sterile or have been postmenopausal 
for ≥ 1 year. 
• 
Fertile men and women must use an effective method of contraception during 
treatment and for at least 6 months after completion of treatment as directed by their 
physician (in accordance with local requirements). 


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• 
Absence of any psychological, familial, sociological, or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule; 
those conditions should be discussed with the patient before trial entry. 
• 
ECOG PS of 0 or 1. 
• 
Life expectancy > 3 months. 
• 
Be able to swallow pills. 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Patients with active CNS lesions are excluded (i.e., those with radiographically 
unstable, symptomatic lesions).  Note:  Patients treated with stereotactic therapy or 
surgery are eligible if they remain without evidence of disease progression in brain 
for ≥ 3 months.  They must also be off corticosteroid and anticonvulsant therapy 
for ≥ 3 weeks.  Whole brain radiotherapy is not allowed with the exception of patients 
who have had definitive resection or stereotactic therapy of all radiologically 
detectable parenchymal lesions. 
• 
History of or known spinal cord compression or carcinomatous meningitis. 
• 
Anticipated or ongoing administration of anti-cancer therapies other than those 
administered in this study. 
• 
Active SCC that has not been excised or has not yet adequately healed 
post excision. 
• 
Pregnant or lactating women. 
• 
Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant 
small bowel resection that would preclude adequate vemurafenib absorption. 
• 
QTc interval ≥ 450 ms at screening ECG or history of congenital long QT syndrome. 
• 
NCI CTCAE v4.0 Grade 3 hemorrhage within 28 days of starting the 
study treatment. 
• 
Any of the following within the 6 months prior to study drug administration: 
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure (CHF), serious cardiac arrhythmia 
requiring medication, uncontrolled hypertension, cerebrovascular accident or 
transient ischemic attack, or symptomatic pulmonary embolism. 
• 
Known clinically significant active infection. 
• 
History of allogeneic bone marrow transplantation or organ transplantation. 
• 
Other severe, acute, or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
drug administration, or may interfere with the interpretation of study results, which in 
the judgment of the investigator would make the patient inappropriate for entry into 
this study. 


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• 
Patients with previous malignancy within the past 5 years are excluded other than 
adequately treated patients with BCC or SCC of the skin, melanoma in-situ, 
and carcinoma in-situ of the cervix and/or curatively treated cancer, from which the 
patient is currently disease-free, or any malignancy from which the patient has been 
continuously disease-free for at least 5 years.  Isolated elevation in prostate-specific 
antigen in the absence of radiographic evidence of metastatic prostate cancer is 
allowed. 
• 
Patients who have been previously treated with a BRAF inhibitor (sorafenib allowed) 
or MEK inhibitor. 
• 
Patients who have had at least one dose of study drug (vemurafenib) in a previous 
clinical trial that includes vemurafenib. 
• 
Known HIV positivity or AIDS-related illness, or hepatitis B virus or hepatitis C virus 
(HCV) carriers (hepatitis B surface antigen positive, HCV antibody positive). 
• 
Received any investigational treatment within 4 weeks of study drug start. 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is a single-arm Phase I, open-label, multicenter, multiple-dose study.   
Twenty patients will be enrolled into the PK cohort, and after the recruitment of PK 
cohort is complete, an additional 25 patients will be enrolled into the expansion cohort 
for efficacy and safety assessments.  
4.3 
STUDY TREATMENT  
4.3.1 
Formulation, Packaging, and Handling 
Vemurafenib is supplied in 240-mg film-coated tablets packed in aluminium blisters for 
oral administration.  For additional information for vemurafenib film-coated tablets, 
please refer to IB.  
Vemurafenib will be stored at the clinical site under recommended storage conditions as 
indicated on the study drug label.  Patients will be requested to store vemurafenib at the 
recommended storage conditions noted on the label out of the reach of children or other 
cohabitants. 
Vemurafenib will be labeled in compliance with Good Manufacturing Procedures.  The 
drug label will include the contents, protocol number, batch number, and storage 
conditions, as well as any other required information mandated by local health 
authorities (e.g., “For Investigational Use Only”). 
4.3.2 
Dosage, Administration, and Compliance 
Each box of study medication contains a total of 56 film-coated tablets in aluminum 
blisters that are 240 mg each.   


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Vemurafenib tablets should be swallowed whole with a glass of water 
(approximately 240 mL).  Vemurafenib tablets should not be chewed or crushed. 
PK cohort:   
In Period A, patients will receive 960 mg BID PO for Days 1–20, and on Day 21, patients 
will receive only the morning dose.  Patients will discontinue vemurafenib starting with 
the evening dose on Day 21. 
Vemurafenib may be taken either 1 hour before or 2 hours after a meal, except on 
Days 1 and 21.  On Days 1 and 21, patients should fast overnight for at least 8 hours 
before the morning dose, and continue to fast for an additional 4 hours post-dose.  
Patients should plan on a standard meal at 4 hours post-dose, but are allowed to have 
light snacks (i.e., crackers, toast, juice, and water) within the 4-hour period. 
There is no study drug administration in Period B. 
In Period C starting on Day 28, all patients will receive the study drug at 960 mg BID 
until the development of PD, unacceptable toxicity, withdrawal of consent, or any other 
criterion as listed in Section 4.6.  
Expansion Cohort: 
All patients will receive vemurafenib 960 mg BID until the development of PD, 
unacceptable toxicity, withdrawal of consent, or any other criterion as listed in 
Section 4.6.  
On the days of BID dosing (except Day 1 in the PK cohort), patients in both cohorts 
should be instructed to take 4 tablets in the morning and 4 tablets in the evening 
(total daily dose of 1920 mg [960 mg BID]) approximately 12 hours later.  Both doses 
should be taken either 1 hour before or 2 hours after a meal.  Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 5.1.1. 
Patients will be given a dosing diary to record the time and date of study drug 
administration.  Administration dates and times will be recorded in the eCRF by the 
study coordinators.  
A cycle is defined as 4 weeks (28 days).  A 4-week supply (Cycles 1–10) or 8-week 
supply (starting from Cycle 11) of study drug can be given to the patient on Day 1 of 
each or every other cycle.  Patients will be instructed not to open a new box until the 
previous box has been finished and to bring their study drug and used boxes back to all 
clinic visits for reconciliation.   
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study 
(vemurafenib) will be provided by the Sponsor.  The investigational site will acknowledge 


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receipt of IMPs, and confirm the shipment condition and content.  Any damaged 
shipments will be replaced.  
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed upon by the 
Sponsor.  The site must obtain written authorization from the Sponsor before any IMP is 
destroyed, and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log. 
4.3.4 
Post-Trial Access to Vemurafenib  
The Sponsor does not intend to provide vemurafenib or other study interventions to 
patients after conclusion of the study or any earlier patient withdrawal.   
4.4 
CONCOMITANT THERAPY 
4.4.1 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to screening to the study completion/early termination visit.  All concomitant 
medications should be reported to the Investigator and recorded on the Concomitant 
Medications eCRF.  
Female patients of child-bearing potential who are using oral contraceptives, hormone 
replacement therapy, or other maintenance therapy will be asked to continue their use. 
Patients taking prescribed therapies for intercurrent illnesses, or consistently dosed 
nutritional or herbal medicines (other than anti-cancer treatments) at the time of study 
entry should continue to take their medicines unless asked by the Investigator to 
discontinue or modify them. 
Anti-emetics and anti-diarrheal medications should not be administered prophylactically 
before initial treatment with study drug.  At the discretion of the Investigator, prophylactic 
anti-emetic and anti-diarrheal medication(s) may be used per standard clinical practice 
before subsequent doses of study drug.  Hematopoietic growth factors 
(e.g., erythropoietin and G-CSF) and pain medications as dictated by standard practice 
are acceptable while the patient is enrolled in the study.  However, growth factors should 
not be administered prophylactically before initial treatment with study drug. 
Patients who experience adverse events during the study may be treated 
symptomatically by the investigator as clinically indicated. 


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Additionally, any diagnostic, therapeutic, or surgical procedure performed during the 
study period should be recorded on eCRF including the date, indication, description of 
the procedure(s), and any clinical findings.   
4.4.2 
Prohibited Therapy 
All concomitant medication or treatment required by the patient will be at the discretion 
of the treating physician.  The following medications and treatments are not allowed 
while the patient is on study:  
• 
St. John’s wort or hyperforin. 
• 
Any concomitant therapy intended for the treatment of melanoma, either approved 
by health authorities or experimental, including chemotherapy, radiation therapy, 
immunotherapy, hormonal therapy, biologic therapy, investigational agents, 
or herbal therapy. 
• 
Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, 
atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, 
voriconazole) and inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentine, phenobarbital) are not allowed 30 days prior to the first dose of study 
drug and during the study for the patients in PK cohort.  
• 
Radiotherapy for the treatment of disease during study, except limited field 
radiotherapy for palliative bone pain due to preexisting bone metastasis if not 
considered a target lesion for RECIST assessments. 
 
Patients who require the use of any of these agents will be discontinued from study 
treatment.  
4.4.3 
Medication Precautions in case of Drug–Drug Interactions 
Results from an in vivo drug−drug interaction study in patients with cancer demonstrated 
that vemurafenib is a moderate CYP1A2 inhibitor, a weak CYP2D6 inhibitor and a 
CYP3A4 inducer. 
The results from this clinical study demonstrate that co-administration of vemurafenib 
increased the AUC of caffeine (CYP1A2 substrate) 2.6-fold and increased the AUC of 
dextromethorphan (CYP2D6 substrate) by 47%, while it decreased the AUC of 
midazolam (CYP3A4 substrate) by 39%, suggesting vemurafenib may inhibit CYP1A2 
and CYP2D6 activity and induce CYP3A4 activity.  Concomitant use of vemurafenib with 
agents with narrow therapeutic windows that are metabolized by CYP1A2, CYP2D6, and 
CYP3A4 is not recommended as vemurafenib may alter their concentrations.  If 
co-administration cannot be avoided, exercise caution and consider a dose reduction of 
the concomitant CYP1A2 and CYP2D6 substrate drug. 
Co-administration of vemurafenib resulted in an 18% increase in AUC of S-warfarin 
(CYP2C9 substrate). Exercise caution and consider additional INR monitoring when 
vemurafenib is used concomitantly with warfarin. 


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Based on in vitro data, vemurafenib is a substrate of CYP3A4, and therefore, 
concomitant administration of strong CYP3A4 inhibitors or inducers may alter 
vemurafenib concentrations.  Thus, strong CYP3A4 inhibitors (e.g., ketoconazole, 
itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, 
indinavir, nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, phenobarbital) are not allowed for the patients in PK 
cohort.  For the patients in the expansion cohort, these strong CYP3A4 inhibitors or 
inducers should be used with caution when co-administered with vemurafenib. 
A more extensive list of medications whose metabolism might be affected by 
vemurafenib can be found in Appendix 7 , which includes a non-exhaustive list of 
CYP1A2, CYP3A4, and CYP2C9 substrates.  For further information 
see Vemurafenib IB.  
4.4.3.1 
Medications that Affect the QT Interval 
Certain medications could affect the QT interval on ECG measurements required in this 
study.  Specifically, anti-emetics other than those belonging to the 5-HT3 receptor 
antagonist class (i.e., granisetron, ondansetron, dolasetron, palonosetron) are preferred 
since the latter have the potential to prolong the QT interval.  Investigators are advised 
to avoid or take precautions in closely monitoring patients who are on medications or 
herbal and vitamin supplements that may increase the QT interval.  Alternative treatment 
options for medications known to affect the QT interval should be discussed with each 
patient prior to his or her inclusion into this study.  A list of medications that may cause 
QT interval prolongation is provided in Appendix 8. Please refer to http://www.azcert.org/ 
for additional information and references. 
4.5 
STUDY ASSESSMENTS  
4.5.1 
Description of Study Assessments 
4.5.1.1 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), smoking history, and all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, 
nutritional supplements) used by the patient within 7 days prior to the screening visit. 
Demographic data will include age, gender, and self-reported race/ethnicity. 
4.5.1.2 
Vital Signs 
Vital signs will include measurements of pulse rate, systolic and diastolic blood pressure 
while the patient is in a seated position, and body temperature. 
4.5.1.3 
Physical Examinations 
A complete physical examination will include evaluation of the head, eyes, ears, nose, 
and throat; heart and vascular system; lungs and respiratory system; abdomen and 
abdominal organs; gastrointestinal system; skin and musculoskeletal system; and 


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neurological system.  Changes from normal or from baseline abnormalities should be 
recorded at each subsequent examination.  New or worsened abnormalities should be 
recorded as adverse events, if appropriate. 
As part of tumor assessments, physical examination should include evaluation of the 
presence and degree of enlarged lymph nodes, hepatomegaly, splenomegaly, 
and skin metastases. 
4.5.1.4 
Pharmacokinetic Assessments 
Blood samples will be collected to evaluate the pharmacokinetics as specified in 
Appendix 2 for the PK cohort.  At each PK assessment timepoint, venous blood samples 
(2 mL) will be collected to measure concentrations of vemurafenib. 
PK plasma samples will be obtained on Day 1 to characterize the single dose PK profile 
of vemurafenib, on Days 15 and 19 for Cmin during the treatment, and as noted in 
Appendix 2 on Days 21–28 to characterize the PK profile of vemurafenib after achieving 
steady state.  
The total volume blood loss for PK assessments will be approximately 58 mL during this 
study.  
The procedures for the collection, handling, and shipping of the PK laboratory samples 
are specified in a separate laboratory manual.   
Fasting Requirements  
Vemurafenib may be taken either 1 hour before or 2 hours after a meal with or without 
food, except on Days 1 and 21 of PK sampling in Period A.  
On Days 1 and 21 in Period A, patients should fast overnight for at least 8 hours before 
the morning dose, and continue to fast for an additional 4 hours post-dose.  Patients 
should plan on a standard meal at 4 hours post-dose on Days 1 and 21 of PK sampling, 
and are allowed to have light snacks (i.e., crackers, toast, juice, and water) within the 
4-hour period.   
Period A 
PK plasma samples for vemurafenib will be obtained on Days 1, 15, 19, and 21.  
PK sampling will be obtained pre-dose, and at 1, 2, 4, 5, 8, and 12 hours post-dose on 
Days 1 and 21.  PK sampling will be obtained pre-dose on Days 15 and 19.  
The pre-dose PK samples can be taken up to 1 hour before the dose.  The pre-dose PK 
sample CANNOT be taken after the dose.  Post-dose PK samples have a window of 
15 minutes.  


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Period B 
Two PK samples will be taken approximately 4 hours apart on Days 22 (i.e., at 24 hours 
[±15 minutes] and 28 hours [±1 hour] after the morning dose on Day 21).  Two PK 
samples will be taken approximately 4 hours apart on Day 24:  at 72 hours (±15 minutes) 
and 76 hours (± 1 hour) after the morning dose on Day 21.  The 24- and 72-hour 
post-dose PK samples (after the morning dose on Day 21) have a window of 
± 15 minutes.  The 28- and 76-hour post-dose PK samples (after the morning dose on 
Day 21) have a window of ± 1 hour.  
Period C 
On Day 28, one PK sample will be taken pre-dose (morning).  The pre-dose PK samples 
can be taken up to 1 hour before the dose.  The pre-dose PK sample CANNOT be taken 
after the dose.  
One PK sample will be taken at the time of all RECIST/BORR assessments for all 
patients, including the PK cohort and expansion cohort. 
Unscheduled PK Sampling  
One unscheduled PK sample should be taken as close as possible to the time of onset 
of an AE/SAE leading to dose adjustment or treatment interruption, and as close as 
possible to the time of first (unconfirmed) diagnosis of disease progression.  
4.5.1.5 
Performance Status 
PS will be measured using the ECOG PS Scale (see Appendix 5).  It is recommended 
that, where possible, a patient’s PS be assessed by the same person throughout the 
study.  Refer to Appendix 1 for details on when ECOG PS is collected.  All patients will 
be evaluated continually throughout trial to see if performance status score changes. 
4.5.1.6 
Tumor and Response Evaluations 
The activity of vemurafenib will be determined by the assessment of tumor responses in 
patients with measurable disease according to RECIST (v1.1). 
Tumor assessments are to be performed as scheduled according to the calendar days 
regardless of treatment delays.  On-study tumor assessments are to be performed every 
8 weeks (2 cycles) from the date of first dose of study drug until the development of PD, 
or withdrawal of consent.  The date of first dose of study drug should always be used as 
the baseline when calculating when the next tumor assessment is due.  Because in this 
study disease progression must be documented by CT or MRI scan, CT or MRI scan 
should also be performed whenever disease progression is suspected 
(e.g., symptomatic deterioration).  The determination of anti-tumor efficacy will be based 
on tumor assessments made according to the RECIST v1.1 (Appendix 3).  An objective 
response should be confirmed by repeat assessments ≥ 4 weeks after initial 
documentation or at the next scheduled tumor assessment if it is to occur > 4 weeks after 


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the initial response.  The CT scans should be performed with contrast agents unless 
contraindicated for medical reasons.  The same imaging modality should be used 
throughout the study to measure disease.  Tumor evaluation by positron emission 
tomography scan or by ultrasound cannot be a substitute for CT or MRI scans.  CT or 
MRI scans will include chest, brain, abdomen, and pelvis at screening.  Brain must be 
included in subsequent tumor assessments if a patient has brain metastases; otherwise 
brain will only be evaluated when clinically indicated.  A bone scan is required at 
screening.  Repeat bone scans are required every 16 weeks only if bone metastases are 
present at baseline; otherwise a repeat bone scan is required only if new bone 
metastases are suspected.  A bone scan is also required at the time of determination of 
response for patients who have bone metastases. 
Measurable lesions that have been previously irradiated will not be considered target 
lesions unless increase in size has been observed following completion of radiation 
therapy. 
If a patient inadvertently misses a prescribed tumor evaluation or a technical error 
prevents the evaluation, the patient may continue treatment until the next scheduled 
assessment.  If at any time during treatment phase there is suspicion of disease 
progression based on clinical or laboratory findings before the next scheduled 
assessment, an unscheduled tumor assessment should be performed. 
All scans will be evaluated locally at each center by designated radiologist (separate 
from the principal investigator), who will read and evaluate all scans for the subjects 
enrolled in this study at his own center. 
4.5.1.7 
Laboratory Assessments 
All laboratory assessment will be evaluated locally at each center.  Normal ranges for 
the study laboratory parameters must be supplied.  Laboratory safety tests shall be 
collected at timepoints specified in Appendix 1, Schedule of Assessments.  
Hematology, serum biochemistry, viral serology/detection, and urinalysis will be done as 
part of regular safety assessments. 
• 
Hematology:  hemoglobin, hematocrit, white blood cells, absolute neutrophil count, 
and platelet count 
• 
Biochemistry:  urea (BUN), ALT, AST, bilirubin, alkaline phosphatase, amylase, 
creatinine, albumin, phosphorus, serum electrolytes (sodium, potassium, 
magnesium, chloride, bicarbonate), glucose, total protein, total calcium, 
γ-glutamyltransferase, total cholesterol, triglyceride, LDL-C, HDL-C, and LDH (LDH 
will be obtained only at screening and baseline (Day 1 pre-dose). 
Note:  total cholesterol, triglyceride, LDL-C, and HDL-C will be collected from 
patients who have fasted overnight (for at least 8 hours) 


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• 
Viral serology/detection:  hepatitis B (hepatitis B surface antigen) and HCV antibody 
and anti-HIV antibody. 
• 
Urinalysis:  urinalysis must include a determination of glucose, protein, hemoglobin 
(blood), bilirubin, ketones, pH, and specific gravity.  A microscopic exam should be 
performed for 2 + or higher hemoglobin or protein levels (must include sediment, 
RBC, WBC, casts, crystals, epithelial cells, bacteria). 
• 
Serum for the pregnancy test at screening if a urine test was not used 
The Sponsor (Roche) recommends that workup of any suspected case of pancreatitis 
should include serum amylase and lipase testing in addition to other appropriate 
testing (e.g., CT abdomen). 
4.5.1.8 
Electrocardiograms 
For the PK cohort, a triplicate 12-lead ECG assessment will be performed at screening, 
Cycle 1 Day 1 (pre-dose and 2 and 4 hours post-dose), Cycle 1 Day 15 (pre-dose), 
Day 21 (pre-dose and 2, 4, and 24 hours post-dose), Day 28 - the first day of Period C 
(pre-dose), and pre-dose on Cycle 3 Day 1.  After Cycle 3, ECG assessments will be 
performed at the beginning of every other treatment cycle (i.e., Day 1 of Cycles 5, 7, 9, 
etc.) and at the end of Study Completion/Early Termination visit.  All ECGs will be taken 
at least 15 minutes before the scheduled PK sampling or any other type of blood draw. 
For the expansion Cohort, 12-lead ECG assessment will be performed at screening, 
Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, and Cycle 3 Day 1.  After Cycle 3, ECG 
assessments will be performed at the beginning of every other treatment cycle 
(i.e., Day 1 of Cycles 5, 7, 9, etc.) and at the end of study treatment visit.  ECGs should 
be performed at least 15 minutes prior to the first daily administration of study drug and 
drawing of any blood samples.  
Machine-read automated ECG intervals will be captured on the eCRF including, heart 
rate, RR, QRS, QT, QTc interval (using Fredericia correction formula), and any clinically 
significant ECG abnormalities, including U wave and T wave abnormalities. 
Triplicate ECGs will be obtained as three 10-second recordings in close succession and 
not more than 2 minutes apart.  Patients must be in a supine position for 5 minutes prior 
to the ECG.  The ECGs should be reviewed promptly by a qualified physician and any 
clinically important finding recorded on the appropriate eCRF.  The investigator is 
responsible for providing the interpretation of all ECGs. 
All ECG recordings must be performed using a standard high-quality, high-fidelity 
electrocardiograph machine equipped with computer-based interval measurements.  
Digital ECG recording is recommended. 


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4.5.1.9 
Dermatological Evaluations and Additional Assessments for 
SCC Surveillance 
Dermatological evaluations and additional assessments will be completed to monitor for 
and treat SCC.  The SCC surveillance plan includes thorough skin examinations by a 
dermatologist or other qualified physician, a head, neck, anus, anal canal, and pelvic (for 
female patients) exam by the treating physician, and a CT scan of the chest. 
A complete dermatological history of prior medications and cuSCC risk factors 
(i.e., radiation therapy, sun exposure, immunosuppression, prior SCC, use of tanning 
beds, precursor lesions, and photochemotherapy for psoriasis) must be collected.  
In patients who develop cuSCC or any suspicious skin lesions during the trial, the patient 
may choose to continue or discontinue from the trial in consultation with the investigator. 
If the patient elects to continue in the trial, definitive treatment (i.e., surgical excision) 
of any SCC/KA or other suspicious lesion(s) is required.  
Schedule of Dermatology Evaluations  
• 
At screening (any time up to 28 days prior to Day 1), Cycle 2 Day 1, and Cycle 3 
Day 1.  After Cycle 3, these assessments will be performed at the beginning of 
every other treatment cycle (i.e., Day 1 of Cycles 5, 7, 9, etc.) and at the Study 
Completion/Early Termination visit.  These assessments will be repeated at 
Months 3 and 6 after the last study treatment or until death, withdrawal of consent, 
or loss to follow-up, whichever is earlier:  
• 
A window of + 21 days applies to the schedule of study visits for purposes of 
dermatology evaluation (with exception of screening). 
• 
Patients should consult their treating physician as needed for any new skin 
lesion while on study drug. 
• 
The occurrence of any other skin changes, including rash and photosensitivity, 
should be reported to the study investigator, and patients will be referred to a 
dermatologist for further evaluation as required. 
• 
Non-cuSCC:  risk management (treating physician) 
• 
A thorough head and neck examination to monitor for non-cutaneous SCC, 
consisting (at a minimum) of a visual inspection of the oral mucosa and lymph 
node palpation, must be performed by the treating physician for all patients 
enrolled in this clinical trial.  A head and neck exam will be performed at 
screening, Cycle 2 Day 1, and Cycle 3 Day 1.  After Cycle 3, these 
assessments will be performed every other treatment cycle (Day 1 of Cycle 5, 
7, 9, etc.) and at the end of study treatment visit.  These assessments will be 
repeated at Months 3 and 6 after the study treatment or until death, withdrawal 
of consent, or loss to follow-up, whichever is earlier.  


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• 
All patients will undergo digital and visual examination of the anus and anal 
canal at baseline and at the end of study treatment (28 days after the last dose 
of study treatment) and female patients must also have a visual pelvic 
examination (including evaluation of the uterine cervix) at baseline and at the 
end of study treatment (28 days after the last dose of study treatment) as 
additional measures to monitor for the occurrence of SCC of the anus, anal 
canal, and cervix, respectively. 
 
Chest CT Scans 
• 
Chest CT scans must be done at baseline (i.e., up to 28 days prior to the start of 
treatment), every 6 months while on study treatment, and 6 months after 
discontinuation of study treatment or until death, withdrawal of consent, or loss to 
follow-up, whichever occurs earlier.  A window of ± 21 days of scheduled study visit 
is allowed for collection of the chest CT scan (with exception of screening). The 
routinely scheduled CT scan of the chest for assessment of response and 
progression of the underlying malignancy can be used for the assessment of SCC 
risk while the patient is on study drug. 
 
4.5.1.10 
Mandatory Samples for Determination of Patient Eligibility 
The following mandatory samples will be collected for determination of patient eligibility: 
A sample of formalin-fixed paraffin-embedded tumor will be submitted for all patients 
being considered for this trial.  This sample will consist of five serially cut unstained 
sections of 5 microns in thickness.  The sample can also be one formalin-fixed, 
paraffin-embedded block.  If archived tumor tissue is not available, a biopsy will be taken.  
Tumor samples will be submitted to a designated testing site where DNA will be isolated 
and tested using the cobas 4800 BRAFV600 Mutation Test.   
DNA samples will be retained from the tumor specimens for subsequent re-testing, if 
necessary.  These samples will be stored in the central reference laboratory until the 
New Drug Application has been reviewed and approved by the China Food and Drug 
Administration (CFDA). 
4.5.2 
Timing of Study Assessments 
4.5.2.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.   
All screening and baseline assessments are outlined in Schedule of Assessments in 
Appendix 1.  Consent must be obtained within 42 days of study treatment start (Day 1).  
An original signed consent form will be retained by the investigator and the patient will 
receive a copy to take home. 


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A screening assessment should be performed between –28 and –1 days before the start 
of the study treatment (Day 1).  Submission of tumor tissue for BRAF mutation status 
can occur prior to Day –28 but must occur after consent has been obtained.  If a new 
biopsy (separate from the one used to make the diagnosis of melanoma) is necessary to 
obtain tumor tissue for BRAF mutation status, the biopsy must occur after consent has 
been obtained.  All screening assessments are outlined in the Schedule of Assessments 
(see Appendix 1).  Patients must fulfill all entry criteria to be accepted into the study. 
An Eligibility Screening Form documenting the investigator’s assessment of each 
screened patient with regard to the protocol’s inclusion and exclusion criteria is to be 
completed and signed by the Investigator (or designee). 
A screen failure log must be maintained by the investigator.  See Appendix 1 for the 
schedule of screening and pretreatment assessments. 
4.5.2.2 
Assessments during Treatment 
All treatment assessments must be performed within ± 3 days of the scheduled visit 
dates except where indicated otherwise (see Appendix 1).  Assessments should be 
performed prior to administration of study treatment, unless otherwise noted in the 
schedule of assessments. 
In the PK cohort, all assessments must be performed on the day of the specified visit in 
Periods A and B (please refer to Appendix 2 for the time window for PK sampling); 
beginning from Period C (Cycle 2), a  ± 3 day window is permitted for completion of the 
scheduled visit in order to accommodate holidays, travel delays, site closures, or for 
other reasons (see Appendix 1).  Assessments of tumor response and progression 
should be performed according to RECIST v1.1 (see Appendix 3). 
See Appendix 1 for the schedule of assessments performed during the treatment period. 
4.5.2.3 
Assessments at Study Completion/Early Termination Visit 
Patients who complete the study treatment or discontinue early from the study will be 
asked to return to the clinic within 28 days after their last dose of vemurafenib for a 
Study Completion/Early Termination visit.  
See Appendix 1 for the schedule of assessments performed at the Study 
Completion/Early Termination visit. 
4.5.2.4 
Follow-Up Assessments 
After the Study Completion/Early Termination visit, the following data will be collected 
until either death, withdrawal of consent, or the patient is lost to follow up: 
• 
Survival status 
• 
All adverse events (with exception of SCC) will be collected until 28 days after the 
last dose of study treatment.  


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• 
Dermatological evaluation until 6 months after the last dose of study drug  
• 
Non-cutaneous SCC evaluation until 6 months after the last dose of study drug 
• 
Chest CT at 6 months after study treatment completion 
 
Patients who discontinue study treatment for reasons other than disease progression or 
death should continue to collect scheduled tumor assessments every 2 cycles until 
patient death or progressive disease. Adverse events should be followed as outlined in 
Section 5.5 and 5.6  
Please see Appendix 1 for the schedule of follow-up assessments. 
4.5.2.5 
Assessments at Unplanned Visits 
CT or MRI scan should be performed whenever disease progression is suspected 
(e.g., symptomatic deterioration).  The results should be recorded in corresponding 
pages of eCRF. 
4.6 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
The investigator may discontinue a patient from study drug or withdraw a patient from 
the study at any time.  In addition, patients may voluntarily discontinue study drug or 
withdraw from the study at any time for any reason.  Reasons for discontinuation of 
study drug or withdrawal from the study may include, but are not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Disease progression (defined using RECIST v1.1 methodology; see Appendix 3) 
• 
Change in patient eligibility 
• 
Noncompliance with protocol requirements 
 
4.6.1.1 
Discontinuation from Study Drug 
Patients must discontinue study drug if they experience any of the following: 
• 
Pregnancy 
• 
Disease progression 
• 
Unacceptable toxicity 
 
In the follow-up portion of the study, patients who stop study treatment due to disease 
progression will also be followed for survival every 3 months until death, withdrawal of 
consent, or loss to follow-up.  All patients who received at least one dose of vemurafenib 
will be followed for SCC evaluation until 6 months after discontinuation of study drug or 
until death, withdrawal of consent, or loss to follow-up, whichever is earlier.  


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See Appendix 1 for assessments done at the Study Completion/Early Termination Visit. 
Patients who discontinue study drug prematurely will be asked to return to the clinic for a 
Study Completion/Early Termination visit (see Section 4.5.2.3) and may undergo 
follow-up assessments (see Section 4.5.2.4).  The primary reason for premature study 
drug discontinuation should be documented on the appropriate eCRF.  Patients who 
discontinue study drug prematurely will not be replaced. 
4.6.1.2 
Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the Investigator if the study is placed on hold, or if the Sponsor 
decides to discontinue the study or development program.   
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the ICH guideline for Good Clinical Practice (GCP) or local 
regulations 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Real-time safety monitoring will occur on an ongoing basis for all patients enrolled in this 
study, using the NCI CTCAE v4.0.  Complete details of the safety evaluation to be 
performed in this study are provided below, including expedited reporting of SAEs to the 
study Sponsor.   
The most common AEs in vemurafenib-treated patients (≥ 30% patients) in the pivotal 
Phase III NO25026 study and pooled safety population (Phase I PLX06-02 and Phase II 
NP22657 studies and post-approval safety study MO25515) were (preferred terms) 


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arthralgia, rash, alopecia, fatigue, nausea, pruritus, diarrhea, skin papilloma, 
hyperkeratosis, and photosensitivity.  The majority of these events were mild or 
moderate in intensity. 
The inclusion and exclusion criteria for this study (see Section 4.1) and safety monitoring 
plan are designed to minimize the risk of toxicity to patients. 
Each safety assessment will include pertinent patient history since the previous 
assessment, physical examination, and clinical laboratory tests. 
All AEs will be considered treatment related unless clearly attributed to disease 
progression or to another clear etiology identified by the investigator.   
5.1.1 
Dose Delays and Modifications 
Missed or delayed doses (> 4 hours after normal administration time) should be skipped 
and not administered as a double dose at the next administration.  Missed doses should 
be recorded in the patient diary. 
Management of symptomatic adverse drug reactions (e.g., arthralgia, fatigue, rash) other 
than cuSCC adverse reactions may require temporary interruption and/or dose reduction 
of vemurafenib treatment.  If dose reduction is needed, dose reduction in 240-mg BID 
decrements is recommended based on individual safety and tolerability.  Dose 
escalation after dose reduction is generally not recommended unless under special 
circumstances—i.e., increased likelihood of clinical benefit for the dose increase and no 
safety concerns.  This should only be done after discussion with the Sponsor. Dose 
increases above 960 mg BID will NOT be allowed.  
For Grade 1 and tolerable Grade 2 toxicities, patients may continue full dose.  
For intolerable Grade 2 toxicities or Grade 3 toxicities, dosing will be interrupted until 
resolution to Grade 1 or less and dose reductions in 240-mg BID decrements are 
required for the first (i.e., to 720 mg BID) and second (i.e., to 480 mg BID) occurrence.  
On the third appearance of intolerable Grade 2 or Grade 3 toxicity despite two dose 
reductions, it is recommended that patients discontinue vemurafenib.  Dose reduction 
below 480 mg BID will NOT be allowed during the study. 
For Grade 4 toxicities, patients should discontinue study treatment or, based on 
investigator judgment, interrupt until resolution to Grade 1 or less with dose reduction of 
50% upon restarting study drug.  Patients should permanently discontinue vemurafenib 
for a second occurrence of any Grade 4 toxicities. 
For all patients receiving vemurafenib treatment, if QTc (using Fredericia’s correction 
formula) increases to > 500 msec or if a change from baseline of ≥ 60 msec is observed 
on study, vemurafenib treatment should be temporarily interrupted and QTc interval 


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should be monitored weekly until it is < 500 msec or returns to baseline before 
reinstituting therapy at a reduced dose.   
Appropriate electrolyte evaluation (potassium, magnesium, and calcium levels) should 
be monitored and any electrolyte abnormalities, especially hypokalemia, should be 
corrected prior to reinstitution of therapy.  Other cardiac risk factors (hypertension, CHF, 
bradyarrhythmias, diabetes, etc.) should be corrected per standard of care. 
If the QTc interval does not improve within 28 days after interruption of vemurafenib 
dosing, permanently discontinue vemurafenib. 
Upon re-initiation of vemurafenib treatment, patients should have their dose reduced by 
one dose level (see Section 5.1.1, Table 5).  ECG and electrolytes should be monitored 
at the following intervals: 
• 
Pre-dose on morning of study drug resumption (time 0 hour) 
• 
2 and 4 weeks after resuming study drug 
• 
Once a cycle for 3 consecutive cycles after study drug resumption 
• 
Every 2 cycles thereafter 
 
Vemurafenib treatment should be permanently discontinued if QTc increases to >500 ms 
AND changes from baseline exceed 60 ms. 
Vemurafenib treatment should be permanently discontinued if patients experience SJS, 
TEN, or DRESS. 
More than 28 days interruption of dosing for whatever reason is considered permanent 
discontinuation from the study treatment 
Exceptions will be granted for reversible laboratory abnormalities with no clinical 
sequelae and/or clinical significance in the opinion of the investigator and Sponsor (see 
Table 5). 


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Table 5 
Dose Interruption/Modification Criteria for Vemurafenib 
Dose Modifications 
Toxicity Grade 
(CTCAE) a 
Vemurafenib dose changes during 
current treatment period 
Dose adjustments for 
resumption of treatment 
Grade 1 and tolerable Grade 2 toxicities 
 
No dose reduction 
N/A 
Grade 2 (intolerable toxicities) or Grade 3 
1st Appearance 
Interrupt until resolved (Grade 0-1) 
Reduce by 240 mg twice daily 
2nd Appearance 
Interrupt until resolved (Grade 0-1) 
Reduce by 240 mg twice daily 
3rd Appearance 
Discontinue permanently 
 
Grade 4 
1st Appearance 
Discontinue permanently or interrupt 
until resolved (Grade 0-1) 
Reduce to 480 mg twice daily 
(50% of starting dose) 
2nd Appearance 
Discontinue permanently 
 
CTCAE = Common Terminology Criteria for Adverse Events. 
a The intensity of clinical AEs graded by the CTCAE v4.0. 
 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, SAEs and non-serious 
AEs of special interest (AESIs); measurement of protocol-specified safety laboratory 
assessments; measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for GCP, an AE is any untoward medical occurrence in a 
clinical investigation subject administered a pharmaceutical product, regardless of 
causal attribution.  An AE can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 


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• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug 
• 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to 
the Sponsor) 
An SAE is any AE that meets any of the following criteria: 
• 
Fatal (i.e., the AE actually causes or leads to death) 
• 
Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death).  This does not include any AE that had it occurred in a 
more severe form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10) 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Significant medical event in the Investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
A new primary malignancy (other than cuSCC or new primary melanoma) or 
progression or recurrence of a prior malignancy (other than the disease under study) 
will be categorized as a serious adverse event. 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (rated as mild, moderate, or severe, or according to NCI CTCAE criteria; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor immediately (within 
24 hours) after learning of the event (see Section 5.4.2 for reporting instructions). 


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5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious AESIs are required to be reported by the investigator to the Sponsor 
immediately (within 24 hours) after learning of the event (see Section 5.4.2 for reporting 
instructions).  AESIs for this study include the following: 
• 
Grade 3 or greater photosensitivity  
• 
Grade 4 elevations of AST, ALT, serum bilirubin, OR cases of elevated ALT or AST 
in combination with either an elevated serum bilirubin value or clinical jaundice 
(see Section 5.3.5.6) 
• 
cuSCC 
• 
Grade 3 or greater QT interval prolongation  
• 
Suspected transmission of infectious agents via a medical product 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Section 5.4−5.6. 
For each AE recorded on the Adverse Event eCRF, the Investigator will assess 
seriousness (see Section 5.2.2 for seriousness criteria), severity (see Section 5.3.3), and 
causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only SAEs 
caused by a protocol-mandated intervention should be reported (e.g., SAEs related to 
invasive procedures such as biopsies). 
After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
reported until 28 days after the last dose of study drug.  After this period, investigators 
should report any deaths, SAEs, or other AEs of concern that are believed to be related 
to prior treatment with study drug (see Section 5.6). 


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5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
• 
“How have you felt since your last clinic visit?” 
• 
“Have you had any new or changed health problems since you were last here?” 
  
5.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v4.0) will be used for assessing AE 
severity.  Table 6 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE. 
Table 6 
Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
or limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to AE d 
AE = adverse event; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
Note:  Based on the NCI CTCAE (v4.0), which can be found at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as an SAE 
(see Section 5.4.2 for reporting instructions), per the definition of SAE in Section 5 2 2  
d Grades 4 and 5 events must be reported as SAEs (see Section 5.4.2 for reporting 
instructions), per the definition of SAE in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an AE is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 


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• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported AEs based on 
signs and symptoms should be nullified and replaced by one AE report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first 
symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  However, medically significant AEs occurring secondary to 
an initiating event that are separated in time should be recorded as independent events 
on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 


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• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by a mild, non-serious infection, only neutropenia 
should be reported on the eCRF. 
• 
If neutropenia is accompanied by a severe or serious infection, both events should 
be reported separately on the eCRF. 
 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity of the event should be recorded, and the severity should be 
updated to reflect the most extreme severity any time the event worsens.  If the event 
becomes serious, the Adverse Event eCRF should be updated to reflect this. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result should be 
reported as an AE if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Clinically significant in the Investigator’s judgment  
 
The Investigator must review all laboratory findings.  Medical and scientific judgment 
should be exercised in deciding whether an isolated laboratory abnormality should be 
classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholecystitis), only the 
diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 


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characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result should be reported 
as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the Investigator’s judgment  
 
The Investigator must review all vital sign findings.  Medical and scientific judgment 
should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST (> 3 × baseline value) in combination with either 
an elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with total 
bilirubin > 2 × ULN (of which ≥ 35% is direct bilirubin) 
• 
Treatment-emergent ALT or AST > 3 × baseline value in combination with 
clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 


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and reported to the Sponsor immediately (within 24 hours) after learning of the event, 
either as an SAE or a non-serious AESI (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified AE reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of metastatic melanoma should be recorded only on 
the Study Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless 
of relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term “sudden death” should only be used for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 hours after the patient was last seen alive and 
stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. 
During post-study survival follow-up, deaths attributed to progression of metastatic 
melanoma should be recorded only on the Study Completion/Early 
Discontinuation eCRF. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
5.3.5.9 
Lack of Efficacy or Worsening of Primary Disease 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs.  These data will be captured as 
efficacy assessment data only.  Because in this study the expected pattern of disease 
progression will be solely based on RECIST v1.1.  CT or MRI scan should also be 
performed whenever disease progression is suspected (e.g., symptomatic deterioration).  


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If there is any uncertainty as to whether an event is due to disease progression, it should 
be reported as an AE. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE (per the definition of SAE in Section 5.2.2), except as outlined 
below.   
The following hospitalization scenarios are not considered to be SAEs: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or PK sampling) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
• 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
• 
The patient has not suffered an AE 
• 
Hospitalization due solely to progression of the underlying cancer 
 
5.3.5.11 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an AE unless it results in untoward medical effects.   
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.  
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated AE fulfills serious criteria, the 
event should be reported to the Sponsor immediately (within 24 hours) after learning of 
the event (see Section 5.4.2). 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
The investigator must report the following events to the Sponsor immediately (within 
24 hours) after learning of the event, regardless of relationship to study drug: 
• 
SAEs 
• 
Non-serious AESIs 
• 
Pregnancies 
 


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The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (within 24 hours) after becoming aware of the information.  New 
significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting SAEs to the local 
health authority and Ethics Committee (EC). 
5.4.1 
Emergency Medical Contacts 
MEDICAL MONITOR (ROCHE MEDICAL RESPONSIBLE) CONTACT 
INFORMATION  
Primary Contact 
Medical Monitor: 
 
Telephone No.: 
 
Mobile Telephone No.: 
 
Secondary Contact 
Medical Monitor: 
 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the Investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk and 
Medical Monitor contact information will be distributed to all Investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of SAEs and non-serious AESIs, investigators should record all case details 
that can be gathered immediately (within 24 hours) on the Adverse Event eCRF and 
submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
If the EDC system is unavailable, a paper Serious Adverse Event/Non-Serious Adverse 
Event of Special Interest CRF and Fax Coversheet should be completed and faxed to 


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Roche Safety Risk Management or its designee immediately (within 24 hours) after 
learning of the event, using the fax numbers provided to Investigators (see "Protocol 
Administrative and Contact Information & List of Investigators").  Once the EDC system 
is available, all information will need to be entered and submitted via the EDC system.   
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 12 days after the last 
dose of study drug.  A Pregnancy Report eCRF should be completed by the Investigator 
immediately (within 24 hours) after learning of the pregnancy and submitted via the EDC 
system.  A pregnancy report will automatically be generated and sent to Roche Safety 
Risk Management.  Pregnancy should not be recorded on the Adverse Event eCRF.  
The investigator should discontinue study drug and counsel the patient, discussing the 
risks of the pregnancy and the possible effects on the fetus.  Monitoring of the patient 
should continue until conclusion of the pregnancy. 
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and 
Pregnancy Fax Coversheet should be completed and faxed to Roche Safety Risk 
Management or its designee immediately (within 24 hours) after learning of the 
pregnancy, using the fax numbers provided to Investigators (see "Protocol 
Administrative and Contact Information & List of Investigators"). 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the Investigator if their partner becomes pregnant during the study or within 
86 days after the last dose of study drug.  A Pregnancy Report eCRF should be 
completed by the Investigator immediately (within 24 hours) after learning of the 
pregnancy and submitted via the EDC system.  Attempts should be made to collect and 
report details of the course and outcome of any pregnancy in the partner of a male 
patient exposed to study drug.  The pregnant partner will need to sign an Authorization 
for Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy.  Once the authorization has been signed, the Investigator will update the 
Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy.  An investigator who is contacted by the male patient or his pregnant partner 
may provide information on the risks of the pregnancy and the possible effects on the 
fetus, to support an informed decision in cooperation with the treating physician 
and/or obstetrician. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 


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5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (within 24 hours) after learning of 
the event (see Section 5.4.2).   
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner 
of a male patient exposed to study drug should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (within 
24 hours) after learning of the event (see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the patient is lost to follow up, 
or the patient withdraws consent.  Every effort should be made to follow all SAEs 
considered to be related to study drug or trial-related procedures until a final outcome 
can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For SAEs, non-serious AESIs, and pregnancies, the Sponsor or a designee may 
follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional 
case details and outcome information (e.g., from hospital discharge summaries, 
consultant reports, autopsy reports) in order to perform an independent medical 
assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the Study Completion/Early Termination visit, the investigator should instruct each 
patient to report to the investigator any subsequent AEs that the patient’s personal 
physician believes could be related to prior study drug treatment or study procedures.   
The Investigator should notify the Sponsor of any death, SAE, or other AE of concern 
occurring at any time after a patient has discontinued study participation if the event is 
believed to be related to prior study drug treatment or study procedures.  The Sponsor 


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should also be notified if the investigator becomes aware of the development of cancer 
or a congenital anomaly/birth defect in a subsequently conceived offspring of a patient 
that participated in this study. 
The investigator should report these events to Roche Safety Risk Management on the 
Adverse Event eCRF.  If the Adverse Event eCRF is no longer available, the investigator 
should report the event directly to Roche Safety Risk Management via telephone 
(see "Protocol Administrative and Contact Information & List of Investigators"). 
During post-study survival follow-up, deaths attributed to progression of melanoma 
should be recorded only on the Study Completion/Early Discontinuation eCRF}. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
• 
Vemurafenib IB  
• 
Vemurafenib Core Data Sheet 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
For the purpose of the primary objective analysis, PK (primary) analysis will include only 
PK cohort patients and will be conducted when the last patient in PK cohort completes 
the PK blood draw on Day 28.  A primary Clinical Study Report that describes these PK 
results as well as appropriate efficacy and safety for patients will be generated for filing 
purposes. 
The data cutoff for updated analysis will occur when all patients included in the PK and 
expansion cohorts have completed at least 6 months of treatment (or discontinued 
treatment) or when > 70% of treated patients have experienced disease progression by 
RECIST v1.1 or death, whichever occurs later.  It is expected to occur about 12 months 
after the first patient is enrolled.  
The final analysis will occur after the last patient has permanently discontinued treatment 
with vemurafenib. 


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6.1 
DETERMINATION OF SAMPLE SIZE 
No formal sample size calculation was performed for this study.  The sample size of 
20 PK patients is chosen to allow acceptable variability of the PK data.  Together with 
extra 25 patients in the expansion cohort, it would give a Clopper-Pearson 95% CI of 
26%−56% for BORR assuming the target BORR (confirmed) is 40%.  
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, study treatment administration, major protocol violations, and 
discontinuations from the study will be summarized descriptively for the treated 
population.  The incidence of treatment discontinuation will be tabulated.  Major protocol 
violations, including violations of inclusion/exclusion criteria, will be summarized for the 
treated population. 
6.3 
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics such as age, sex, race, weight, ECOG PS, 
and baseline disease characteristics such as histologic subtype and primary location of 
disease will be summarized for the treated population.  Descriptive baseline summaries 
of continuous data will present mean, standard deviation, median, minimum, and 
maximum.  Descriptive summaries of discrete data will present the category counts as 
frequencies and percentages. 
6.4 
PHARMACOKINETIC ANALYSES 
The primary objective of the study is to evaluate the pharmacokinetics of vemurafenib 
following 960 mg BID oral administration in Chinese patients with BRAFV600 
mutation-positive unresectable or metastatic melanoma. 
For the purposes of statistical analysis, the PK population will include all patients 
evaluable for PK analysis, i.e., patients who provided sufficient PK data to obtain at least 
one of the primary PK variables.  Patients will be excluded from the PK analysis if they 
significantly violate the inclusion or exclusion criteria, deviate significantly from sampling 
times or other provisions of the protocol, or if data are unavailable which may influence 
the analysis. 
Plasma concentration on Day 1 and steady state will be listed and graphically displayed 
for vemurafenib. 
Non-compartmental analysis using WinNonlin software will be used to obtain PK 
parameters  of vemurafenib.  All PK parameters for vemurafenib will be presented by 
listings and descriptive summary statistics (arithmetic mean, geometric mean, standard 
deviation, coefficient of variation, minimum, maximum, and number of observations).  
Rate of elimination may be estimated using data from PK samples collected during the 
drug holiday period.    


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The following PK parameters will be reported: 
• 
Cmax on Days 1 and 21 
• 
Tmax on Days 1 and 21 
• 
AUC0-8h on Days 1 and 21 
• 
AUC0-12h on Days 1 and 21 
• 
AUC0-168h beginning on Day 21 
• 
Cmin on Days 15, 19, and 21 
• 
Accumulation Ratio 
• 
Kel 
• 
t1/2 
 
6.5 
EFFICACY ANALYSES 
Efficacy endpoints include BORR (confirmed), PFS, and OS.  BORR, PFS, and OS 
analyses will include all patients who received at least one dose of vemurafenib.  All 
efficacy data will be summarized using descriptive statistics. 
The BORR is defined as the number of patients whose confirmed objective response is 
complete response or partial response divided by the total number of treated patients. 
PR/CR must be confirmed by repeated assessment that should be performed no less 
than 4 weeks after the criteria for response are first met.  Patients without a 
post-baseline tumor assessment will be considered as non-responders. 
An estimate of BORR (confirmed) and its 95% CI will be calculated using 
Clopper-Pearson method.   
Duration of response (DOR) is defined as the time from the initial response to disease 
progression or death among patients who have experienced a CR or PR during study.  
At the time of analysis, patients who have not progressed or have died after achieving a 
response will be censored at the last tumor assessment date.  DOR will be estimated 
using Kaplan-Meier methodology. 
PFS is defined as the time between date of first treatment and the date of first 
documented disease progression or death, whichever occurs first.  Disease progression 
will be determined based on investigator assessment with use of RECIST v1.1.  Patients 
who have not experienced disease progression or death at the time of analysis will be 
censored at the time of the last tumor assessment.  Patients with no post-baseline tumor 
assessment will be censored at the first treatment date.   
KM methodology will be used to estimate median PFS and 6-month PFS rate and the 
KM curve will be constructed to provide a visual description.  The 95% CI for median 
PFS will be calculated using the Brookmeyer and Crowley method. 


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OS is defined as the time from the date of first treatment to the date of death, regardless 
of the cause of death.  Data for patients who are not reported as having died at the time 
of analysis will be censored at the date when they were last known to be alive.   
KM methodology will be used to estimate median OS and 6-month survival rate and the 
KM curve will be constructed to provide a visual description.  The 95% CI for median OS 
will be calculated using the Brookmeyer and Crowley method. 
6.6 
SAFETY ANALYSES 
Safety analyses will include all patients who receive at least one dose of study treatment 
(the safety population). 
Drug exposure will be summarized to include treatment duration, dosage, and dose 
intensity. 
Verbatim description of AEs will be mapped to MedDRA thesaurus terms and graded 
according to NCI CTCAE v4.0.  All AEs occurring during or after the first study treatment 
will be summarized by NCI CTCAE grade.  In addition, SAEs, severe AEs (Grade 3 and 
above), and AEs leading to discontinuation or interruption of study treatment will be 
summarized accordingly.  Multiple occurrences of the same event will be counted once 
at the maximum severity.  In addition, the following events:  cuSCC, photosensitivity, 
liver laboratory abnormalities, and events potentially related to QT interval prolongation 
will be summarized separately, including incidence, time to first onset of the event, and 
the total number of episodes.  
Laboratory data with values outside of the normal ranges will be identified.  In addition, 
select laboratory data will be summarized by grade.  
Changes in vital signs will be summarized. 
All deaths and causes of death will be summarized.  
Concentration−QTc effect relationship will be explored with various QT-RR correction 
methods (i.e., Bazett, Fridericia, population (study-specific), and if warranted by the 
changes in the heart rate, individual correction will be made).  Vemurafenib 
concentration−QTc effect relationships may be explored and this concentration−QTc 
data may be pooled with corresponding data from other studies to enhance the analysis 
of the concentration−QTc effect relationship.  The concentration−QTc analysis may use 
linear and nonlinear mixed effect modeling techniques. 
6.7 
EXPLORATORY ANALYSES  
Exploratory analyses include the following: 
Descriptive tables with side-by-side PK parameters in Chinese and Caucasian patients 
will be presented, with exploratory statistical comparison for descriptive purposes only. 


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Statistical output will be 2-sided 90% CI of the geometric mean ratio (test/reference) for 
steady-state AUC and Cmax. Test = Chinese (current study); reference = Caucasian 
(dose-specific PK data from eCTD).  Acceptance criterion for CI width will not be 
pre-specified for purposes of this analysis. 
Final conclusion on PK comparability will be determined in the context of the benefit−risk 
ratio for vemurafenib in patients with life-threatening melanoma where no comparably 
efficacious therapy exists in China. 
 
6.8 
INTERIM ANALYSES 
Not applicable. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC using eCRFs.  
Sites will be responsible for data entry into the EDC system.  In the event of discrepant 
data, the Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data 
(vemurafenib concentration−time data) will be sent directly to the Sponsor, using the 
Sponsor’s standard procedures to handle and process the electronic transfer of these 
data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using a Sponsor-designated EDC system.  Sites will receive 
training and will have access to a manual for appropriate eCRF completion.  eCRFs will 
be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the Investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 


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7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and EC review.  The investigational site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with health authority requirements pertaining to computerized systems used 
in clinical research.  An acceptable computerized data collection system allows 
preservation of the original entry of data.  If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for at least 15 years 
after completion or discontinuation of the study, or for the length of time required by 


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relevant national or local health authorities, whichever is longer.  After that period of time, 
the documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and 
the principles of the Declaration of Helsinki, or the laws and regulations of the country in 
which the research is conducted, whichever affords the greater protection to the 
individual.  The study will comply with the requirements of the ICH E2A guideline 
(Clinical Safety Data Management:  Definitions and Standards for Expedited Reporting).   
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or Caregiver's Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the “Consent Forms”) before EC submission.  
The final EC-approved Consent Forms must be provided to the Sponsor for health 
authority submission purposes according to local requirements.  
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised EC-approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
EC policy) during their participation in the study.  For any updated or revised Consent 
Forms, the case history or clinical records for each patient shall document the informed 
consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study. 


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A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the EC by the Principal 
Investigator and reviewed and approved by the EC before the study is initiated.  In 
addition, any patient recruitment materials must be approved by the EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the EC.  Investigators are also responsible for 
promptly informing the EC of any protocol amendments (see Section 9.5). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
Investigators must comply with requirements for reporting serious adverse events to the 
local health authority and EC.  Investigators may receive written IND safety reports or 
other safety-related communications from the Sponsor.  Investigators are responsible for 
ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their EC, and 
archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may only be 
disclosed to third parties as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the CFDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the EC for each study site, as 
appropriate. 


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8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., last patient last visit). 
9. 
STUDY DOCUMENTATION, MONITORING, 
AND ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of EC and governmental 
approval.  In addition, at the end of the study, the Investigator will receive the patient 
data, which includes an audit trail containing a complete record of all changes to data. 
9.2 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The Investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the ECs to inspect facilities and records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
This study is sponsored by Roche.  Approximately two to three study centers in China 
will participate in this study, enrolling a total of approximately 45 patients.  Roche will 
provide clinical operations oversight, data management support, and medical monitoring.  
Tumor tissue from consenting patients will be sent to a central laboratory for analysis of 
BRAFV600 mutation status.  Blood samples for pharmacokinetics will be sent to a central 
laboratory for analysis.  Sample analysis will be performed by an external vendor or 
Roche.  
9.4 
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS 
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
prior to submission.  This allows the Sponsor to protect proprietary information and to 
provide comments based on information from other studies that may not yet be available 
to the Investigator. 
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally 


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support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  The Sponsor is responsible 
for promptly informing the EC of any amendments to the protocol.  Approval must be 
obtained from the EC before implementation of any changes, except for changes 
necessary to eliminate an immediate hazard to patients or changes that involve logistical 
or administrative aspects only (e.g., change in Medical Monitor or contact information). 


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10. 
REFERENCES 
Aithal GP, Watkins PB, Andrade RJ, et al.  Case definition and phenotype 
standardization in drug-induced liver injury.  Clin Pharmacol Ther. 2011;89:806-15. 
Ascierto P, Streicher HZ, Sznol M. Melanoma: A model for testing new agents in 
combination therapies. J Translational Med 2010;8:38. 
Australian Government Dept. of Health and Ageing. 2008. 
http://www.skincancer.gov.au/internet/skincancer/publishing.nsf/Content/fact-2. 
Accessed 23 April 2012. 
Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development 
against Cancer. J Clin Oncol 2005;23:6771-6790. 
Callahan MK, Rampal R, Harding JJ, et al. Progression of RAS-mutant leukemia during 
RAF inhibitor treatment. N Engl J Med 2012;367:2316-21. 
Chapman PB, Hauschild A, Robert C, et al; BRIM-3 Study Group. Improved survival with 
vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 
2011;364:2507-16. 
Chapman PB, Metz D, Supelveda AR, et al. Development of colonic adenomas and 
gastric polyps in BRAF mutant melanoma patients treated with vemurafenib. 
Pigment Cell Melanoma Res [abstract]. 2012;25:847. 
China Melonoma Guideline, 2011. 
Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in 
melanoma. N Engl J Med 2005;353:2135-2147. 
Diepgen TL, Mahler V. The epidemiology of skin cancer. Br J Dermatol 
2002;146(Suppl.61):1-6. 
Dummer R, Keilholz U, Pentheroudakis G, et al. Cutaneous melanoma: ESMO Clinical 
Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012 
Oct;23 Suppl 7:vii86-91. 
European Network of Cancer Registries No. 4, November 2003. 
Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in 
metastatic melanoma. N Engl J Med 2010;363:809-819. 
Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol 27:3-9, 2009. 
Gray-Schopfer V, Wellbrock C, Marais R. Melanoma biology and new targeted therapy. 
Nature 2007;445:851-857. 
Harding JJ, Lacouture ME, Pulitzer M, et al. Hypersensitivity skin reactions in melanoma 
patients treated with vemurafenib after ipilimumab therapy J Clin Oncol 2012;30(S; 
abstract 8515). 


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Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA. Integrating 
BRAF/MEK inhibitors in combination therapy for melanoma. Cancer Research 
2003;63:5198-5202. 
Investigator’s Brochure RO5185426: [Please refer to current version, including any 
addendums].   
Kopetz S, Desai J, Chan E, et al. PLX4032 in metastatic colorectal cancer patients with 
mutant BRAF tumors. J Clin Oncol 2010;28:3534. 
Lang J, Mackie RM. Prevalence of exon 15 BRAF mutations in primary melanoma of the 
superficial spreading, nodular, acral, and lentigo maligna subtypes. J Invest 
Dermatol. 2005;125:575-579. 
Lankisch PG, Droge M, Gottesleben F. Drug induced acute pancreatitis: incidence and 
severity. Gut 1995;37:565-567 
Lucas R. Global Burden of Disease of Solar Ultraviolet Radiation, Environmental Burden 
of Disease Series, July 25, 2006; No. 13. News release, World Health 
Organization. 
Maldonado JL, Fridlyand J, Patel H, et al. Determinants of BRAF mutations in primary 
melanomas. J Natl Cancer Inst 2003;95:1878-1890. 
Ribas A, Hodi FS, Callahan M, et al. Correspondence: hepatotoxicity with combination of 
vemurafenib and ipilimumab. N Engl J Med 2012;368:1365-1366 
Ries LAG, et al., eds. SEER Cancer Statistics Review, 1975–2000. Bethesda, MD: 
National Cancer Institute; 2003: Tables XVI-1-9. 
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-2526. 
Epub 2011 Jun 5. 
Sanger. http://www.sanger.ac.uk/genetics/CGP/cosmic/. Accessed 23 April 2012. 
Smalley KSM, Herlyn M, et al. Targeting BRAF/MEK in melanoma: new hope or another 
false dawn? Expert Tev Dermatol 2007;2:179-190. 
Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutated advanced 
melanoma treated with vemurafenib. N Engl J Med 2012;366:707-14. 
Sumimoto H, Miyagishi M, Miyoshi H, et al. Inhibition of growth and invasive ability of 
melanoma by invasion of mutated BRAF with lentivirusmediated RNA interference. 
Oncogene 2004;23:6031-6039. 
SUNSMART Cancer Council Victoria. 2007. http://www.sunsmart.com.au. Accessed 
23 April 2012. 
US Centers for Disease Control and Prevention. Skin Cancer Statistics. Updated 23 
November 2010. http://www.cdc.gov/cancer/skin/statistics/index.htm. Accessed 
13 April 2012.   


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Zhao P, Chen W, et al. Chinese Cancer Registry Annual Report 2009-cancer incidence 
and mortality in Chinese cancer registration areas in 2006 [R]. Beijing: Military 
Medical Science Press 2010;74-79:170-174.  


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Appendix 1 Schedule of Assessments 
Study Treatment 1 28 Day Cycle 
Cycle1 
Cycle2 
Cycle3
+ 
 
Screening 
Period 
(28 Days) 
Period A for 
PK Cohort 
Period B for 
PK Cohort 
Period C for 
PK Cohort 
Day of 
Last 
Study 
Dose 
Completion/ 
Early 
Termination 
Visit 18 
Post-  
Treatment 
Follow-Up 
Protocol Activities 
-42 to 
-28 
-28 to -1 
1 2 
15
19 
21
22 
24 
28 + 
57+ 
 
 
Every 
3 months 
Informed consent 3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Submission of 
tumor tissue for 
BRAF 
mutation status 4 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
and demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 5 
 
X 
(X) 
 
 
 
 
 
X 
X 
 
X 
 
ECOG PS 
 
X  
X 
 
 
 
 
 
X 
X 
 
X 
 
Laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology/ 
biochemistry/ 
urinalysis (PK 
cohort)6 
 
X 
(X) 
 
 
X 
 
 
X 
X 
 
X 
 
Hematology/ 
biochemistry/ 
urinalysis 
(expansion 
cohort)6 
 
X 
(X) 
 
 
 
 
 
X 
X 
 
X 
 
LDH 
 
X 
(X) 
 
 
 
 
 
 
 
 
 
 


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Schedule of Assessments (cont.) 
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Study Treatment 1 28 Day Cycle 
Cycle1 
Cycle2 
Cycle3
+ 
 
Screening 
Period 
(28 Days) 
Period A for 
PK Cohort 
Period B for 
PK Cohort 
Period C for 
PK Cohort 
Day of 
Last 
Study 
Dose 
Completion/ 
Early 
Termination 
Visit 18 
Post-  
Treatment 
Follow-Up 
Protocol Activities 
-42 to 
-28 
-28 to -1 
1 2 
15
19 
21
22 
24 
28 + 
57+ 
 
 
Every 
3 months 
HBsAg and HCV, 
HIV antibody 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(serum or urine) 7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Triplicate 12-lead 
ECG (PK cohort) 8 
 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
Triplicate 12-lead 
ECG (expansion 
cohort) 9 
 
X 
X 
X 
 
 
 
 
X 
X 
 
X 
 
PK blood 
sampling:  PK 
cohort 10 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK blood 
sampling:  
expansion cohort 
11 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
 
Tumor assessment 
12 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Dermatology 
evaluation 13 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
X 


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Schedule of Assessments (cont.) 
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Study Treatment 1 28 Day Cycle 
Cycle1 
Cycle2 
Cycle3
+ 
 
Screening 
Period 
(28 Days) 
Period A for 
PK Cohort 
Period B for 
PK Cohort 
Period C for 
PK Cohort 
Day of 
Last 
Study 
Dose 
Completion/ 
Early 
Termination 
Visit 18 
Post-  
Treatment 
Follow-Up 
Protocol Activities 
-42 to 
-28 
-28 to -1 
1 2 
15
19 
21
22 
24 
28 + 
57+ 
 
 
Every 
3 months 
Non-cuSCC 
Evaluation 13 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
X 
Chest CT scan for 
presence of SCC 
14 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Adverse events 15 
 
 
X 
X 
X 
Concomitant and 
previous 
medications 15 
 
X 
X 
X 
X 
Patient diary for 
study drug 
administration 
 
 
X 
 
 
Survival 
assessment 16 
 
 
 
 
X 
Study treatment:  
administration of 
vemurafenib 17 
 
 
X 
 
 
ECOG PS = Eastern Clinical Oncology Group Performance Status; HBsAG = hepatitis B surface antigen; HCV = hepatitis C virus; 
non-cuSCC = non-cutaneous squamous cell carcinoma; PK = pharmacokinetic. 
( ) - Need not be repeated on Day 1 if tests have been performed within 7 days before Day 1 (start of study treatment). 


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Schedule of Assessments (cont.) 
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Notes:  Clinic visits are completed on Day 1 of every 4 week cycle for Cycles 1–10 (every 4 weeks). Starting from Cycle 11, clinic visits will be 
completed on Day 1 of every other cycle (every 8 weeks). All assessments should be performed within ± 3 day of the scheduled visit, unless 
otherwise specified.  On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
 
1. Study treatment:  All assessments should be performed prior to dosing with study medications unless otherwise indicated.  All cycles are 
28 days in duration. Enough study drugs for treatment will be dispensed at each clinic visit.   
2. Cycle 1/Day 1:  Blood chemistry, hematology, LDH, physical examination and triplicate 12-lead ECG not required if acceptable screening 
assessment is performed within 7 days prior to the start of study treatment. 
3. Informed consent:  Must be obtained prior to undergoing any trial specific procedure. 
4. Submission of tumor tissue for BRAF mutation status:  Tumor tissue must be submitted for BRAFV600 mutation screening (one 
formalin-fixed, paraffin-embedded block or at least 5 serially cut unstained 5 micron sections cut from one block, mounted on slides).  A biopsy 
will be taken if no archived tumor tissue is available.  Submission of tumor tissue for BRAFV600 mutation status can occur prior to the 28-day 
screening period as long as the submission is after informed consent (Informed consent must be obtained within 42 days of the first dose).  
DNA from the tumor tissue will be retained for subsequent re-testing, if necessary. 
5. Physical examination:  Includes an examination of major body systems, height (at screening only), weight, blood pressure, and pulse rate at 
baseline and on Day 1 of each clinical visit. 
6. Hematology, biochemistry, urinalysis:  Obtain at screening, baseline (Day 1), Day 1 of Cycles 2–10, Day 1 of every other cycle starting from 
Cycle 11, and at the completion /early termination visit.  All lipid parameters should be obtained after the patient has fasted overnight (for at 
least 8 hours). For the PK cohort, hematology / biochemistry / urinalysis should also be obtained at Day 21 Cycle 1.  Required tests are listed 
in Section 4.5.1.7.  
7. Pregnancy test:  All female patients of child-bearing potential are required to have a negative pregnancy test at screening within 7 days prior 
to commencement of dosing.   
8. 12-lead ECG (PK cohort): A triplicate 12-lead ECG assessments will be performed at screening, Cycle 1 Day 1 (pre-dose and 2 and 4h 
post-dose), Cycle 1 Day 15(pre-dose), Cycle Day 21 (pre-dose and 2, 4, and 24 hours post-dose), Day 28 - the first day of Period C (pre-dose), 
and pre-dose on Cycle 3 Day 1; after Cycle 3, ECG assessments will be performed every other treatment cycle (Day 1 of Cycle 5, 7, 9 etc.) and 
at the study completion/early termination visit.  All ECGs will be taken at least 15 minutes before the scheduled PK sampling or any other type 
of blood draw. 


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9. 12-lead ECG (expansion cohort): A triplicate 12-lead ECG assessments will be performed at screening, Cycle 1 Day 1 and Day 15, Cycle 2 
Day 1, and Cycle 3 Day 1; after cycle 3, ECG assessments will be performed every other treatment cycle (Day 1 of Cycle 5, 7, 9 etc.) and at 
the study completion/early termination visit.  ECGs should be performed at least 15 minutes prior to the first daily administration of study drug 
and any blood draws. 
10. PK blood sampling (PK cohort):  Schedule of PK sampling, See Appendix 2.  One unscheduled PK sample should be taken at the time of 
onset of AE/SAE leading to dose adjustment/treatment interruption and as close as possible to the time of first (unconfirmed) diagnosis of 
disease progression.  
11. PK blood sampling (Expansion Cohort):  PK sample will be taken at pre-dose on Cycle 1 Day 1, and at the time of all RECIST/BORR 
assessments.  One unscheduled PK sample should be taken at the time of onset of AE/SAE leading to dose adjustment/treatment interruption 
and as close as possible to the time of first (unconfirmed) diagnosis of disease progression. 
12. Tumor assessments:  All patients must have a brain CT and/or MRI at screening to assess for brain metastasis.  After the baseline 
assessment, if no brain metastasis, subsequent brain CT and/or MRI should only be obtained as clinical indicated.  A bone scan is required at 
screening.  Repeat bone scans are required every 16 weeks only if bone metastases are present at baseline.  A bone scan is also required at 
the time of determination of response for patients who have bone metastases.  Radiological tumor assessments (CT and/or MRI scans; bone 
scans only if clinically indicated) of chest, abdomen, pelvis will be obtained to assess extent of disease at the following timepoints:  screening 
(anytime within 28-day period), Cycle 3 Day 1 and every 2 cycles thereafter until documented disease progression.  Tumor assessments can 
be completed within ± 7 days of scheduled visit. If at any time during treatment phase there is suspicion of disease progression based on 
clinical or laboratory findings before the next scheduled assessment, an unscheduled tumor assessment should be performed.  If a bone scan 
is used for progressive disease, then a corresponding CT scan needs to be completed.  All tumor assessment will be performed based on a 
calendar schedule beginning from the date of first dose of study treatment. 
13. Dermatology evaluation and non-cuSCC evaluation:  Dermatology evaluation and non-cuSCC evaluation are required at screening, Cycle 2 
Day 1, and Cycle 3 Day 1; after Cycle 3, these assessments will be performed every other treatment cycle (Day 1 of Cycles 5, 7, 9, etc.) and at 
the study completion/early discontinuation visit.  These assessments will be repeated 3 and 6 months after last study treatment or until death, 
withdrawal of consent, or loss to follow-up, whichever is earlier. A window of + 21 days is acceptable. Refer to section 4.5.1.9 for 
detailed information. 
14. Chest CT scan for presence of SCC: Chest CT scans must be done at baseline (i.e., up to 28 days prior to the start of treatment), an every 
6 months while on study treatment and 6 months after discontinuation of study treatment or until death, withdrawal of consent, or loss to 
follow-up. A window of ± 21 days of scheduled study visit is allowed for collection of the chest CT scan (with exception of screening). 
 


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Schedule of Assessments (cont.) 
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15. Adverse events and concomitant medications/treatments: Assess concomitant medications at baseline and continually report along with 
adverse events throughout study treatment.  Adverse events of special interest and concomitant medications will be followed for up to 28 days 
post last dose of vemurafenib during the follow up period. Drug-related adverse events will be followed until resolution. After this period, collect 
any serious adverse events/adverse events that the investigator considers having a causal relationship with vemurafenib, regardless of time 
elapsed since post last dose of vemurafenib and even if the study has stopped.  
16. Survival follow up:  Patients who discontinue study treatment for reasons other than disease progression or death should continue to collect 
scheduled tumor assessments every 2 cycles until patient death or progressive disease. Post-progressive disease survival status will be 
collected every 3 months.  The study will be closed when all patients enrolled have been followed until progression, death or loss to follow-up. 
Telephone contact is acceptable for survival follow up.  
17. Administration of vemurafenib:  For the PK cohort, in Period A, the study drug is administered twice daily on Days 1 to 20. The study drug is 
administered in the morning (AM) only on Day 21. The patient does NOT take the evening dose on Day 21. Patients in the PK cohort should 
resume twice-daily vemurafenib administration starting from Day 28.  
18. End of treatment visit: Patients who complete study treatment or discontinue study treatment early will be asked to return to the clinic 28 ± 3 
days after the last dose of study drug for an end of treatment visit. 
 
 


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Appendix 2 Schedule of Pharmacokinetic Assessments 
Cycle 1 
Cycle 2+ 
Periods 
Screening 
Period A 
Period B 
Period C 
Follow-up after End 
of Study Treatment 
Day 
Day –28 to –1 
Days 1–21 
Days 22–27 
     Day 28 and Beyond 
Every 3 Months 
Pharmacokinetics:  
PK sampling in PK 
cohort 
N/A 
Days 1 and 21 
Pre-dose and 1, 
2, 4, 5, 8, and 
12 hours 
post-dose 
Days 15 and 19 
Pre-dose 
Day 22 
24 hours (± 15 minutes) 
and 28 hours (± 1 hour) 
after the morning dose on 
Day 21 
Day 24 
72 hours (± 15 minutes) 
and 76 hours (± 1 hour) 
after the morning dose on 
Day 21 
Day 28 
Pre-dose (morning) 
At the time of onset of AE/SAE 
leading to dose 
adjustment/treatment 
interruption;  
As close as possible to the time 
of first (unconfirmed) diagnosis 
of disease progression;  
At the time of all RECIST/BORR 
assessments  
Prior to stopping 
study drug at the 
clinic visit and at the 
final visit (at the time 
of progression or 
withdrawal)  
Pharmacokinetics:  
PK sampling in 
expansion cohort 
N/A 
Day 1:  Pre-dose 
(morning) 
N/A 
At the time of onset of AE/SAE 
leading to dose 
adjustment/treatment 
interruption;  
As close as possible to the time 
of first (unconfirmed) diagnosis 
of disease progression;  
At the time of all RECIST/BORR 
assessments 
Prior to stopping 
study drug at the 
clinic visit and at the 
final visit (at the time 
of progression or 
withdrawal) 
AE = adver e event; BORR = be t overall re pon e rate; N/A = not applicable; PK = pharmacokinetic; RECIST = Re pon e Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event.


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Appendix 3 New Response Evaluation Criteria in Solid Tumors 
Quick Reference – Version 1.1 
Measurability of Tumor at Baseline 
Deﬁnitions  
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows:  
Measurable Tumor Lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of:  
• 
10 mm by CT scan (CT scan slice thickness ≤ 5 mm).  
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable).  
• 
20 mm by chest X-ray.  
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, 
a lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.  See also section below on “Baseline 
documentation of target and non-target lesions” for information on lymph 
node measurement.  
Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inﬂammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, abdominal 
masses/abdominal organomegaly identiﬁed by physical exam that is not measurable by 
reproducible imaging techniques.  


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Special Considerations Regarding Lesion Measurability  
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment:  
Bone lesions: 
• 
Bone scan, PET scan, or plain ﬁlms are not considered adequate imaging 
techniques to measure bone lesions.  However, these techniques can be used to 
conﬁrm the presence or disappearance of bone lesions.  
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identiﬁable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such  
as CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the deﬁnition of measurability described above.  
• 
Blastic bone lesions are non-measurable.  
 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically deﬁned simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) because 
they are, by deﬁnition, simple cysts.  
• 
“Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the deﬁnition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.  
 
Lesions with prior local treatment:  
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  Study protocols should detail the 
conditions under which such lesions would be considered measurable. 
  
Speciﬁcations by Methods of Measurements  
Measurement of Lesions  
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment.  
Method of Assessment  
The same method of assessment and the same technique should be used to 
characterize each identiﬁed and reported lesion at baseline and during follow-up.  
Imaging based evaluation should always be done rather than clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  


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Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superﬁcial and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.  As noted above, when lesions can be 
evaluated by both clinical exam and imaging, imaging evaluation should be undertaken 
because it is more objective and may also be reviewed at the end of the study.  
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are 
clearly deﬁned and surrounded by aerated lung.  Still, non-contrast CT is preferred over 
chest X-ray. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has deﬁned measurability of lesions 
on CT scan based on the assumption that CT slice thickness is ≤ 5 mm.  When CT 
scans have slice thickness > 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations 
(e.g., for body scans). 
If prior to enrolment it is known that a patient is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast 
CT or MRI (with or without IV contrast) will be used to evaluate the patient at baseline 
and follow-up, should be guided by the tumor type under investigation and the anatomic 
location of the disease.  For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI 
(enhanced or non-enhanced) will be performed, should also be based on the tumor type, 
anatomic location of the disease and should be optimized to allow for comparison to the 
prior studies if possible.  Each case should be discussed with the radiologist to 
determine if substitution of these other approaches is possible and, if not, the patient 
should be considered not evaluable from that point forward. 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement.  Ultrasound examinations cannot be reproduced in 
their entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements will be 
taken from one assessment to the next.  If new lesions are identiﬁed by ultrasound in the 
course of the study, conﬁrmation by CT or MRI is advised.  If there is concern about 
radiation exposure at CT, MRI may be used instead of CT in selected instances.  
Cytology, histology:  These techniques can be used to differentiate between PR and CR 
in rare cases if required by protocol (for example, residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain).  When effusions are 
known to be a potential adverse effect of treatment (e.g., with certain taxane compounds 


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or angiogenesis inhibitors), the cytological conﬁrmation of the neoplastic origin of any 
effusion that appears or worsens during treatment can be considered if the measurable 
tumor has met criteria for response or stable disease in order to differentiate between 
response (or stable disease) and progressive disease.  
Tumor Response Evaluation  
Assessment of Overall Tumor Burden and Measurable Disease  
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements.  Only patients with measurable disease at baseline should be included 
in protocols where objective tumor response is the primary endpoint.  Measurable 
disease is deﬁned by the presence of at least one measurable lesion (as detailed above 
in Section 1.1.1).  In studies where the primary endpoint is tumor progression 
(either time to progression or proportion with progression at a ﬁxed date), the protocol 
must specify if entry is restricted to those with measurable disease or whether patients 
having non-measurable disease only are also eligible.  
Baseline Documentation of “Target” and “Non-Target” Lesions  
When more than one measurable lesion is present at baseline all lesions up to a 
maximum of ﬁve lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identiﬁed as target lesions and will be recorded and 
measured at baseline. 
This means in instances where patients have only one or two organ sites involved a 
maximum of two (one site) and four lesions (two sites), respectively, will be recorded.  
Other lesions in that organ will be recorded as non-measurable lesions (even if size is 
greater than 10mm by CT scan) 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, 
on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should 
be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor.  Pathological nodes which are 
deﬁned as measurable and may be identiﬁed as target lesions must meet the criterion of 
a short axis of  ≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute 
to the baseline sum.  The short axis of the node is the diameter normally used by 
radiologists to judge if a node is involved by solid tumor.  Nodal size is normally reported 
as two dimensions in the plane in which the image is obtained (for CT scan this is almost 


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always the axial plane; for MRI the plane of acquisition may be axial, sagittal, or coronal).  
The smaller of these measures is the short axis.  For example, an abdominal node which 
is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualiﬁes as a 
malignant, measurable node.  In this example, 20 mm should be recorded as the node 
measurement.  All other pathological nodes (those with short axis  ≥ 10 mm but <15 mm) 
should be considered non-target lesions.  Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed.  
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.  
All other lesions (or sites of disease) including pathological lymph nodes should be 
identiﬁed as non-target lesions and should also be recorded at baseline. Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”  In addition, it is possible to record multiple non-target 
lesions involving the same organ as a single item on the case report form (e.g., “multiple 
enlarged pelvic lymph nodes” or “multiple liver metastases”).  
Response Criteria  
Deﬁnitions of the criteria used to determine objective tumor response for target lesions 
include the following: 
• 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis 
to <10 mm. 
• 
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.  
• 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
(Note: the appearance of one or more new lesions is also considered progression). 
• 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study.  
 


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Special Notes on the Assessment of Target Lesions 
Lymph nodes:  Lymph nodes identiﬁed as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study.  This means 
that when lymph nodes are included as target lesions, the “sum” of lesions may not be 
zero even if complete response criteria are met, since a normal lymph node is deﬁned as 
having a short axis of < 10 mm.  Case report forms or other data collection methods may 
therefore be designed to have target nodal lesions recorded in a separate section where, 
in order to qualify for CR, each node must achieve a short axis <10 mm.  For PR, 
SD, and PD, the actual short axis measurement of the nodes is to be included in the 
sum of target lesions.  
Target lesions that become “too small to measure”:  while on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being “too small to measure.”  When this occurs 
it is important that a value be recorded on the case report form: 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
If the lesion is believed to be present and is faintly seen but too small to measure, 
a default value of 5 mm should be assigned and below measurable limit (BML) should 
be ticked (Note:  It is less likely that this rule will be used for lymph nodes because they 
usually have a deﬁnable size when normal and are frequently surrounded by fat such as 
in the retroperitoneum; however, if a lymph node is believed to be present and is faintly 
seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well and BML should also be ticked).  
This default value is derived from the 5 mm CT slice thickness (but should not be 
changed with varying CT slice thickness).  The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false 
responses or progressions based upon measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm and in that case BML should not be ticked. 
(BML is equivalent to a less than sign <). 
Lesions that split or coalesce on treatment:  when non-nodal lesions “fragment,” 
the longest diameters of the fragmented portions should be added together to calculate 
the target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 


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maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion.”  
Evaluation of Non-Target Lesions  
This section provides the deﬁnitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the timepoints speciﬁed in the protocol.  
Complete Response (CR):  Disappearance of all non-target lesions and normalization of 
tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD):  Unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression).  
Special Notes on Assessment of Progression of Non-Target Disease  
The concept of progression of non-target disease requires additional explanation 
as follows:  
When the patient also has measurable disease: in this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease in a magnitude that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.  A modest “increase” in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status.  
The designation of overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare.  
When the patient has only non-measurable disease: this circumstance arises in some 
Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantiﬁed (by deﬁnition, if all lesions are truly non-measurable) a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 


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measurable disease:  i.e., an increase in tumor burden representing an additional 
73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from “trace” to 
“large,” an increase in lymphangitic disease from localized to widespread, or may be 
described in protocols as “sufficient to require a change in therapy.”  If “unequivocal 
progression” is seen, the patient should be considered to have had overall PD at that 
point.  While it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so; therefore the 
increase must be substantial.  
New lesions  
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no speciﬁc criteria for 
the identiﬁcation of new radiographic lesions; however, the ﬁnding of a new lesion 
should be unequivocal:  i.e., not attributable to differences in scanning technique, 
change in imaging modality or ﬁndings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or ﬂare of 
preexisting lesions).  
This is particularly important when the patient’s baseline lesions show partial or 
complete response.  For example, necrosis of a liver lesion may be reported on a CT 
scan report as a “new” cystic lesion, which it is not.  
A lesion identiﬁed on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example 
of this is the patient who has visceral disease at baseline and while on study has a brain 
CT or MRI ordered which reveals metastases.  The patient’s brain metastases are 
considered to be evidence of PD even if he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans conﬁrm 
there is deﬁnitely a new lesion, then progression should be declared using the date of 
the initial scan.  
18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) 
While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible “new” disease).  New lesions on the 
basis of FDG-PET imaging can be identiﬁed according to the following algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.  


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No FDG-PET at baseline and a positive FDG-PET at follow-up: 
• 
If the positive FDG-PET at follow-up corresponds to a new site of disease conﬁrmed 
by CT, this is PD. 
• 
If the positive FDG-PET at follow-up is not conﬁrmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly 
progression occurring at that site (if so, the date of PD will be the date of the initial 
abnormal FDG-PET scan). 
• 
If the positive FDG-PET at follow-up corresponds to a preexisting site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD.  
Evaluation of Best Overall Response  
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment taking into account any requirement for conﬁrmation.  
On occasion a response may not be documented until after the end of therapy so 
protocols should be clear if post-treatment assessments are to be considered in 
determination of best overall response.  Protocols must specify how any new therapy 
introduced before progression will affect best response designation.  
The patient’s best overall response assignment will depend on the ﬁndings of both target 
and non-target disease and will also take into consideration the appearance of 
new lesions.  
Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require conﬁrmatory measurement.  Speciﬁcally, in non-randomized trials where 
response is the primary endpoint, conﬁrmation of PR or CR is needed to deem either 
one the “best overall response.”  This is described further below.  
Timepoint Response  
A response assessment is assumed to occur at each protocol-speciﬁed timepoint.   
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline.  
Missing Assessments and Not-Evaluable Designation  
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 
convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response.  This would be most likely to happen 
in the case of PD.  


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For example, if a patient had a baseline sum of 50 mm with three measured lesions and 
at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient 
will have achieved PD status, regardless of the contribution of the missing lesion.  
If one or more target lesions were not assessed either because the scan was not done, 
or could not be assessed because of poor image quality or obstructed view, 
the Response for Target Lesions should be “Unable to Assess” because the patient is 
not evaluable.  Similarly, if one or more non-target lesions are indicated 
as “not assessed,” the response for non-target lesions should be “Unable to Assess” 
(except where there is clear progression).  Overall response would be “Unable to 
Assess” if either the target response or the non-target response is “Unable to Assess” 
(except where this is clear evidence of progression) as this equates with the case being 
not evaluable at that timepoint. 
Best Overall Response:  All Timepoints 
The best overall response will be determined by statistical programming once all the 
data for the patient is known. 
Table 1  
Response Evaluation Criteria in Solid Tumors 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD  
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial 
response; SD = stable disease. 
 


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Appendix 3 New Response Evaluation Criteria in Solid Tumors 
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Table 2:  Best Overall Response when Confirmation of CR and PR Required 
Overall Response 
First Timepoint 
Overall Response 
Subsequent Timepoint 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR a 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
 
NE 
SD provided minimum criteria for SD duration met, 
otherwise NE 
NE 
NE 
NE 
CR = complete response; NE = inevaluable; PD = progressive disease; PR = partial response; 
SD = stable disease. 
a  If a CR is truly met at first timepoint, then any disease seen at a subsequent timepoint, even 
disease meeting PR criteria relative to baseline, makes the disease PD at that point (because 
disease must have reappeared after CR).  Best response would depend on whether minimum 
duration for SD was met.  However, sometimes “CR” may be claimed when subsequent scans 
suggest small lesions were likely still present and in fact the patient had PR, not CR at the first 
timepoint.  Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
 
Special Notes on Response Assessment  
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans.  This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes.  As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the case 
report form (eCRF).  
In trials where conﬁrmation of response is required, repeated “NE” timepoint 
assessments may complicate best response determination.  The analysis plan for the 
trial must address how missing data/assessments will be addressed in determination of 
response and progression.  For example, in most trials it is reasonable to consider a 
patient with timepoint responses of PR-NE-PR as a conﬁrmed response.  


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Appendix 3 New Response Evaluation Criteria in Solid Tumors 
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Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document objective 
progression even after discontinuation of treatment. Symptomatic deterioration is not a 
descriptor of an objective response:  it is a reason for stopping study therapy.  
The objective response status of such patients is to be determined by evaluation of 
target and non-target disease as shown in Tables 1 and 2.  
Conditions that deﬁne “early progression, early death, and non-evaluability” are study 
speciﬁc and should be clearly described in each protocol (depending on treatment 
duration, treatment periodicity).  
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (ﬁne needle aspirate/biopsy) 
before assigning a status of complete response.  FDG-PET may be used to upgrade a 
response to a CR in a manner similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent ﬁbrosis or scarring.  The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by 
disease speciﬁc medical literature for the indication.  However, it must be acknowledged 
that both approaches may lead to false-positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity.  
For equivocal ﬁndings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment, progression is conﬁrmed, the date of 
progression should be the earlier date when progression was suspected. 
Reference:  Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation 
criteria in solid tumours: revised  RECIST guideline (version 1.1). Eur J Cancer. 
2009 Jan;45(2):228-47. 


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Appendix 4 American Joint Committee on Cancer TNM Staging 
for Melanoma 
Clinical stage grouping for Stage IV melanoma is defined as any T, any N, and any M1 
Tumor (T) classification 
TX Primary tumor cannot be assessed (e.g., shave biopsy, regressed primary) 
Tis Melanoma in situ 
< or = 1.0 mm 
a: without ulceration and level II/III* 
T1 
b: with ulceration or level IV or V* 
1.01-2.0 mm 
a: without ulceration 
T2 
b: with ulceration 
2.01-4.0 mm 
a: without ulceration 
T3 
b: with ulceration 
>4.0 mm 
a: without ulceration 
T4 
b: with ulceration 
Node (N) classification 
One lymph node 
a: micrometastases (clinically occult) 
N1 
b: macrometastases (clinically apparent) 
2-3 lymph nodes 
a: micrometastases 
b: macrometastases 
N2 
c: in-transit met(s)/satellite(s) without metastatic lymph nodes 
N3 4 or more metastatic lymph nodes, or matted lymph nodes, or in-transit 
met(s)/satellite(s) with metastatic lymph node(s) 
Metastasis (M) classification 
M1a Distant skin, subcutaneous, or lymph node metastases, normal LDH 
M1b Lung metastases, normal LDH 
M1c All other visceral metastases, normal LDH 
Any distant metastases, elevated LDH 
* Clark's levels: level II: invades the papillary dermis; level III: invades to the papillary-reticular 
dermal interface; level IV: invades the reticular dermis; level V: invades subcutaneous tissue. 
 Micrometastases are diagnosed after elective or sentinel lymphadenectomy. 
 Macrometastases are defined as clinically detectable lymph node metastases confirmed by 
therapeutic lymphadenectomy or when any lymph node metastasis exhibits gross 
extracapsular extension. 
 


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Appendix 5 ECOG Performance Status 
Patients will be graded according to the ECOG Performance Status scale and criteria as 
described below: 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light housework, office work.  
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50 % of waking 
hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead 
*  As published in Am J Clin Oncol:  Oken MM, Creech RH, Tormey DC, et al.:  Toxicity and 
Response Criteria of the Eastern Cooperative Oncology Group.  Am J Clin Oncol 
1982;5:649-655. 
 


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Appendix 6 Alternative and Preferred Methods for Patients 
Unable to Tolerate Radiological Contrast Agents 
For patients who cannot tolerate radiological contrast agents, the following methods are 
preferred and should be used as alternative means for collecting radiological 
assessments in these patients.  
• 
For CT contrast contraindication:  unenhanced CT of the chest, enhanced MRI of 
the abdomen/pelvis 
• 
For MRI contrast contraindication:  CT of the chest, unenhanced MRI of the 
abdomen/pelvis, and MRI of the thorax on systems that can acquire the entire data 
set in a single breath-hold or are gated in place of the chest CT  
 


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Appendix 7 Impact of Vemurafenib on Concomitant 
Medications 
 
 
 


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Appendix 7  
Impact of Vemurafenib on Concomitant Medications (cont.) 
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Appendix 7  
Impact of Vemurafenib on Concomitant Medications (cont.) 
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Appendix 8 Medications that Affect the QT Interval 
Albuterol  
Doxepin  
Lithium  
Quinidine  
Alfuzosin  
Droperidol  
Mesoridazine  
Ranolazine  
Amantadine  
Ephedrine  
Metaproterenol  
Risperidone  
Amiodarone  
Epinephrine  
Methadone  
Ritodrine  
Amitriptyline  
Erythromycin  
Methylphenidate  
Roxithromycin  
Amphetamine  
Felbamate  
Mexiletine  
Salmeterol  
Arsenic trioxide  
Fenfluramine  
Midodrine  
Sertindole  
Astemizole  
Flecainide 
Moexipril  
Sertraline  
Atazanavir  
Fluconazole  
Moxifloxacin  
Sibutramine  
Atomoxetine  
Fluoxetine  
Nicardipine  
Sibutramine  
Azithromycin  
Foscarnet  
Nilotinib  
Solifenacin  
Bepridil  
Fosphenytoin  
Norepinephrine  
Sotalol  
Chloral hydrate  
Galantamine  
Nortriptyline  
Sparfloxacin  
Chloroquine  
Gatifloxacin  
Octreotide  
Sunitinib  
Chlorpromazine  
Gemifloxacin  
Ofloxacin  
Tacrolimus  
Ciprofloxacin  
Granisetron  
Ondansetron  
Tamoxifen  
Cisapride  
Halofantrine 
Oxytocin  
Telithromycin  
Citalopram  
Haloperidol  
Paliperidone  
Terbutaline  
Clarithromycin  
Ibutilide 
Paroxetine  
Terfenadine  
Clomipramine  
Imipramine 
Pentamidine  
Thioridazine  
Clozapine  
Indapamide  
Perflutren lipid 
microspheres  
Tizanidine  
Cocaine  
Isoproterenol  
Phentermine  
Tolterodine  
Desipramine  
Isradipine  
Phenylephrine  
Trimethoprim-Sulfa 
Dexmethylphenidate  Itraconazole 
Phenylpropanolamine  
Trimipramine  
Disopyramide  
Ketoconazole 
Pimozide  
Vardenafil  
Dobutamine  
Lapatinib  
Probucol  
Venlafaxine  
Dofetilide  
Levafloxacin  
Procainamide  
Voriconazole  
Dolasetron  
Levalbuterol  
Protriptyline  
Ziprasidone  
Domperidone  
Levomethadyl  
Pseudoephedrine  
 
Dopamine  
Lisdexamfetamine Quetiapine