An Evaluation of the Efficacy Beyond Progression of Vemurafenib Combined With Cobimetinib Associated With Local Treatment Compared to Second-line Treatment in Patients With BRAFV600 Mutation-positive Metastatic Melanoma in Focal Progression With First-line Combined Vemurafenib and Cobimetinib.
Phase: PHASE2
Conditions: Melanoma Metastatic, BRAF V600 Mutation
Sponsor: Intergruppo Melanoma Italiano

Protocol BeyPro2, Version 2.0, November 15, 2017 
 
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Protocol Title:  
An evaluation of the efficacy beyond progression of vemurafenib combined with 
cobimetinib associated with local treatment compared to second-line treatment in 
patients with BRAFV600 mutation-positive metastatic melanoma in focal progression 
with first-line combined vemurafenib and cobimetinib. 
 
Version 2.0, date: November 15, 2017 
 
Abbreviated title: BeyPro2 
EudraCT Number: 2017-003038-98 
Protocol Code: BeyPro2 
Sponsor: IMI – Intergruppo Melanoma Italiano 
Study Coordinator: Dr. Paola Queirolo 
Translational Study Coordinator: Prof. Giuseppe Palmieri 
Design and Statistical analysis: Dott. Paolo Bruzzi1 
 
Scientific Committee:  
Dr. Paola Queirolo1 
Dr. Del Vecchio2 
Dr.ssa Chiarion3 
Prof. Palmieri4 
Dott. Paolo Bruzzi1 
 
1. IRCCS AOU San Martino - IST, Genova 
2. Istituto Nazionale dei Tumori, Milano 
3. Istituto Oncologico Veneto, Padova 
4. ICB-CNR, Sassari 
 
 
 
The trial will be conducted in accordance with the Declaration of Helsinki, the Guideline for Good Clinical Practice of the 
international conference on Harmonization (ICH E6-R2) and all applicable laws and regulations. 
 
 

Protocol BeyPro2, Version 2.0, November 15, 2017 
 
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List of abbreviations 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BORR 
Best Overall Response Rate 
CAP 
Chest Abdomen Pelvis 
CMP 
Clinical Monitoring Plan 
CPK 
Creatine Phosphokinase 
CrCl 
Creatinine Clearance 
CRO 
Contract Research Organization 
cSCC 
Cutaneous Squamous Cell Carcinoma 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
HR 
Hazard Ratio 
IEC 
Independent Ethics Committee 
IWRS 
Interactive Web Response System 
LLN 
Lower Limit of Normal 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical dictionary for regulatory activities 
MUGA 
Multiple Gated Ejection Acquisition  
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PPS 
Per Protocol Set 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RVO 
Retinal Vein Occlusion 
SAE 
Serious Adverse Event 
SCC 
Squamous Cell Carcinoma 
SD 
Stable Disease 
SmPC 
Summary of Product Characteristics 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 
 
 

Protocol BeyPro2, Version 2.0, November 15, 2017 
 
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Synopsis 
Protocol Title: An evaluation of the efficacy beyond progression of vemurafenib combined with cobimetinib 
associated with local treatment compared to second-line treatment in patients with BRAFv600 mutation-positive 
metastatic melanoma in focal progression with first-line combined vemurafenib and cobimetinib 
Country: Italy 
Study Coordinator: Paola Queirolo 
Study Phase: II 
Study Design: This is a randomized, open-label, multicenter, phase II study. All patients will initially be treated 
with first-line vemurafenib + cobimetinib. After focal progression, defined as the appearance or dimensional 
increase of lesions that can be treated with surgery or radiotherapy, patients will be randomized to either continue 
receiving vemurafenib and cobimetinib along with local management (i.e. surgery, radiotherapy), or switch to a 
standard second-line treatment. In the latter patients, local treatment may be provided based on the Investigator’s 
judgment to ensure patient safety and good clinical practice. Patients with non-focal progression of disease will 
not be randomized but will switch to second-line therapy and will be followed up for survival only. Second-line 
treatment consists of immunotherapy with anti-PD-1 antibodies (pembrolizumab or nivolumab). All patients will 
be followed up for 24 months after randomization or last dose of vemurafenib and cobimetinib (for non-
randomized patients). Treatments will continue until the development of progressive disease (non-focal), 
unacceptable toxicity, consent withdrawal, death, reasons deemed appropriate by the treating physician or study 
termination by the Sponsor. 
Primary Objective: The primary objective of the study is to evaluate the efficacy, in terms of overall survival, 
of vemurafenib combined with cobimetinib associated with local treatment compared with second-line therapy in 
patients with BRAFV600 mutation-positive metastatic melanoma in focal progression with first-line combined 
vemurafenib and cobimetinib. 
Treatment: The study treatment is a combination of vemurafenib and cobimetinib. 
Vemurafenib is taken on a 28-day cycle. Each dose consists of four 240 mg (960 mg) tablets twice daily for 28 
consecutive days. The first dose should be taken in the morning and the second dose in the evening approximately 
12 hours later. Each dose can be taken with or without a meal. Vemurafenib tablets should be swallowed whole 
with a glass of water and should not be chewed or crushed. 
Cobimetinib is taken on a 28-day cycle. Each dose consists of three 20 mg tablets (60 mg) and should be taken 
orally, once daily for 21 consecutive days (Days 1 to 21-treatment period), followed by a 7-day break (Days 22 
to 28-treatment break). Each subsequent treatment cycle should start after the 7-day treatment break has elapsed. 
The dose should be taken in the morning. 
Primary Endpoint: The primary endpoint is Overall Survival (OS) for patients with focal progression  
Secondary Endpoints: The secondary endpoints are the following: 
● Progression Free Survival (PFS) for patients with focal progression  
● OS for patients with non-focal progression 
● Prognostic role in terms of OS of focal compared with non-focal progressive disease  
● Safety based on the following variables: 
o Nature, frequency, severity, and timing of adverse events and serious adverse events. 
o Changes in vital signs, physical findings and clinical laboratory results during and following 
vemurafenib + cobimetinib administration. 
Sample Size Justification and Statistics:  
Sample size: The present phase II study is aimed at providing the rationale for a phase III efficacy trial of adequate 

Protocol BeyPro2, Version 2.0, November 15, 2017 
 
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size assessing the efficacy of dual target inhibition beyond focal progression. Consequently, an alfa error rate of 
0.2 (two-sided) will be used. The expected OS of patients with BRAF+ metastatic melanoma after a 1st focal 
progression is difficult to estimate due to the lack of published data on this specific subset of patients. However, 
the survival experience of these patients can be reasonably considered to be intermediate between that of BRAF+ 
patients in first-line treatment with combined BRAF and MEK inhibition and the post-progression survival of the 
same patients, i.e. at approximately 1.5 years of median survival. With 120 patients enrolled over a period of 12 
months, and a total of 60-70 patients randomized into the second-line study in patients with focal progression, at 
least 38 deaths are expected in both groups combined with a 2-year of follow-up after last dose of vemurafenib 
and cobimetinib. With 38 events, the study has 80% power to detect, with an alfa error rate of 0.2 (two-sided), a 
statistical significance difference in favor of the experimental arm corresponding to a Hazard Ratio of 0.5. The 
final analysis will take place after the observation of 38 deaths in the randomized cohorts or after 24 months since 
randomization of the last patient, whichever first. 
Analysis of efficacy: 
● Overall survival of patients with focal progression will be compared between treatment groups using a log-
rank test procedure with a two-sided α =0.2 level. The OS function for each treatment group will be estimated 
using the Kaplan-Meier product-limit method. Median and corresponding two-sided 80% confidence intervals 
will be computed by treatment group. Kaplan-Meier plots of OS will be presented. A Cox proportional hazard 
model for OS with treatment arm as single factor will be used to estimate the hazard ratio of vemurafenib and 
cobimetinib plus local treatment to Standard of Care (SOC) second-line treatment and its corresponding 80% 
confidence interval. 
● Progression free survival will be compared between treatment groups using a log-rank test procedure with a 
two-sided α =0.2 level. The PFS function for each treatment group will be estimated using the Kaplan-Meier 
product-limit method. Median and two-sided 80% confidence intervals (CI) for median PFS will be computed 
by treatment group. Kaplan-Meier plots of PFS will be presented. A Cox proportional hazard model for PFS 
with treatment arm as single factor will be used to estimate the hazard ratio of vemurafenib and cobimetinib 
plus local treatment to SOC second-line treatment and its corresponding 80% confidence interval. 
● Overall survival results of patients with non-focal progression will be descriptively compared with OS results 
of patients with focal progression (i.e. primary efficacy endpoint). No statistical test is foreseen for this 
comparison.  
Analysis of safety 
AEs and laboratory parameters will be assessed according to the Common Terminology Criteria for AEs (CTCAE 
version 4). Other safety data analyzed: ECGs, physical examinations, vital signs and ECOG PS will be listed and 
summarized by treatment arm. 
Main Inclusion Criteria: 
● Patients with histologically confirmed melanoma, either unresectable Stage IIIc or Stage IV metastatic 
melanoma, as defined by the American Joint Committee on Cancer 7th edition. 
● Patients previously untreated for metastatic melanoma. 
● Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue (archival or newly 
obtained tumor samples) by a validated mutational test. 
● Adequate performance status to receive vemurafenib and cobimetinib therapy as determined by treating 
physician.  
Planned Timelines: About 12 centers will enroll a total of 120 patients. The study will have an enrolment period 
of 12 months and a follow-up period of 24 months. The end of the study will occur when all patients have been 
followed up for survival for 24 months after the last patient has been randomized or after the last dose of 
vemurafenib and cobimetinib (for non-randomized patients). 

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Table of contents 
 
Amendment 1 ............................................................................................................................................................................ 7 
1. BACKGROUND AND RATIONALE .................................................................................................................................. 7 
2. STUDY AIMS AND DESIGN ............................................................................................................................................ 12 
2.1 Objectives of the study .................................................................................................................................................. 12 
2.2 Endpoints of the study ................................................................................................................................................... 13 
2.3 Study Design .................................................................................................................................................................. 14 
2.4 Schedule of Assessments and Procedures ...................................................................................................................... 15 
2.4.1 Screening Examination and Eligibility Screening Form ............................................................................................. 15 
2.4.2 Procedures for Enrollment of Eligible Patients ........................................................................................................... 16 
2.4.3 Clinical Assessments and Procedures ......................................................................................................................... 19 
2.4.4 Tumor Response Criteria ............................................................................................................................................ 22 
2.4.5 Clinical Safety Assessments ....................................................................................................................................... 23 
2.4.6 Ancillary biomarker study .......................................................................................................................................... 26 
3. STUDY POPULATION ...................................................................................................................................................... 26 
3.1 Inclusion Criteria ........................................................................................................................................................... 26 
3.2 Exclusion Criteria .......................................................................................................................................................... 27 
3.3 Criteria for Premature Withdrawal ................................................................................................................................ 29 
4. INVESTIGATIONAL MEDICINAL PRODUCTS ............................................................................................................ 29 
4.1 Formulation, appearance, packaging and labeling ......................................................................................................... 29 
4.2 Product storage and stability .......................................................................................................................................... 30 
4.3 Dosing and administration ............................................................................................................................................. 30 
4.4 Dose adjustments/modifications/delays ......................................................................................................................... 31 
4.5 Duration of Therapy....................................................................................................................................................... 35 
4.6 Accountability, assessment of compliance and destruction of the drugs ....................................................................... 35 
5. STATISTICAL CONSIDERATIONS ................................................................................................................................. 36 
5.1 Statistical and analytical plan......................................................................................................................................... 36 
5.2 Statistical hypotheses ..................................................................................................................................................... 36 
5.3 Analysis datasets ............................................................................................................................................................ 37 
5.4 Description of statistical methods .................................................................................................................................. 37 
5.4.1 Analysis of the primary efficacy endpoint .................................................................................................................. 38 
5.4.2 Analysis of the secondary efficacy endpoints ............................................................................................................. 38 
5.4.3 Safety analysis ............................................................................................................................................................ 39 
5.4.4 Baseline descriptive statistics ..................................................................................................................................... 41 
5.4.5 Treatments .................................................................................................................................................................. 41 
5.4.6 Planned interim analyses ............................................................................................................................................ 41 
5.4.7 Exploratory analysis ................................................................................................................................................... 41 
5.5 Sample size .................................................................................................................................................................... 42 
5.6 Enrollment and randomization ....................................................................................................................................... 42 

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6. CLINICAL MONITORING ................................................................................................................................................ 43 
7. SAFETY INSTRUCTIONS AND GUIDANCE ................................................................................................................. 43 
7.1 Warning and precautions ............................................................................................................................................... 43 
7.2 Adverse Events and Laboratory Abnormalities ............................................................................................................. 45 
7.2.1 Adverse Events (AEs) ................................................................................................................................................. 45 
7.2.2 Severity ....................................................................................................................................................................... 45 
7.2.3 Drug AE relationship .................................................................................................................................................. 46 
7.2.4 Serious Adverse Events .............................................................................................................................................. 46 
7.2.5 Progression of Underlying Malignancy ...................................................................................................................... 48 
7.3 Follow-up of AEs (28 days post discontinuation of study drugs and every 12 weeks until 24 months for long term 
follow up) ............................................................................................................................................................................ 48 
7.4 Laboratory Test abnormalities ....................................................................................................................................... 50 
7.4.1 Follow-up of Abnormal Laboratory Test Values ........................................................................................................ 50 
7.5 Handling of Safety Parameters ...................................................................................................................................... 50 
7.5.1 Reporting of AEs ........................................................................................................................................................ 50 
7.5.2 Reporting of SAEs/AESI (immediately reportable).................................................................................................... 50 
7.6 Pregnancy ...................................................................................................................................................................... 51 
8. SOURCE DOCUMENTS AND ACCESS TO DATA/SOURCE DOCUMENTS ............................................................. 51 
9. QUALITY ASSURANCE AND QUALITY CONTROL ................................................................................................... 52 
10. ETHICS ............................................................................................................................................................................. 52 
10.1 Informed consent ......................................................................................................................................................... 53 
10.2 Participant and data confidentiality ............................................................................................................................. 53 
10.3 Research Use of Stored Human Samples, Specimens or Data ..................................................................................... 54 
10.4 Insurance ...................................................................................................................................................................... 54 
11. DATA HANDLING AND RECORD KEEPING.............................................................................................................. 54 
11.1 Data collection and management ................................................................................................................................. 54 
11.2 Study records retention ................................................................................................................................................ 56 
11.3 Protocol deviations ...................................................................................................................................................... 56 
12. PUBLICATION ................................................................................................................................................................. 56 
13. References ......................................................................................................................................................................... 57 
Appendix 1. 
Impact of Vemurafenib on Concomitant Medications ................................................................................... 59 
Appendix 2. 
Translational biomarker study ....................................................................................................................... 62 
 
 
 

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Amendment 1 
This amendment was drawn up to align the protocol with the recommendations of the Ethics Committee 
concerning the definition of second-line therapy. The protocol now states that patients with general 
progression of disease, as well as those with focal progression randomized to second-line treatment, will 
be treated with anti-PD 1 immunotherapy, i.e. nivolumab or pembrolizumab. Both agents are approved 
by the FDA and EMA thanks to their favorable efficacy and toxicity profiles and represent new standard 
of care for the treatment of advanced melanoma. 
The amendment also draws attention to the fact that since all patients are likely to undergo general disease 
progression, the switch to second-line therapy in patients randomized to local treatment plus continuation 
of BRAF+MEK inhibitors will only be delayed, but because of that allow a study of the activity of 
combination treatment beyond local progression. 
Finally, a correction has been made regarding the storing conditions of vemurafenib. 
Changes to the protocol are shown in the track changes version using strike through font for deletions 
and underlined font for insertions. 
1. BACKGROUND AND RATIONALE 
Nearly half of the patients with advanced melanoma harbor a valine to glutamine substitution (V600E) 
in codon 600 of the serine-threonine kinase BRAF (Davies et al 2002). Less common BRAF mutations 
such as lysine (V600K) or arginine substitutions (V600R) have also been reported (Eroglu et al 2016). 
In the past 5 years, two BRAF inhibitors that target these mutations, vemurafenib and dabrafenib, have 
been approved by the US Food and Drug Administration (FDA). These drugs have shown high rates of 
rapid response, with rates ranging from 48% to 59% in phase II and III trials (Chapman et al. 2011; 
Ascierto et al. 2013; Hauschild et al. 2012). Duration of responses is however limited in the majority of 
patients due to the development of acquired resistance, with median progression-free survival (PFS) in 
these patients ranging from 5.1 to 6.8 months (Sosman et al. 2012; Hauschild et al. 2012). 
Mechanisms of resistance to BRAF inhibitor therapy are diverse and include the reactivation of the 
mitogen-activated protein kinase (MAPK) pathway in over two-thirds of tumors, along with promotion 
of parallel signaling networks such as the PI3K–PTEN–AKT pathway (Shi et al. 2014; Rizos et al. 2014; 
Wagle et al. 2011). Sequential therapy with a MEK inhibitor following progression on a BRAF inhibitor 
has not shown benefit, as no responses and a PFS of only 1.8 months was observed in a study of 40 
patients, suggesting that resistance to BRAF inhibitors also confers resistance to MEK inhibitors (Kim et 
al. 2013). Therefore, the premise behind the subsequent clinical trials combining inhibitors of both MEK 

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and mutant BRAF kinase was that they would help to delay resistance and result in higher rates and 
longer duration of responses and reduced toxicity respect to BRAF inhibitor monotherapy (Eroglu et al 
2016). 
Vemurafenib and cobimetinib 
Patients with advanced BRAFV600 mutated melanoma who were either BRAF inhibitor naïve (n = 63) or 
had recently progressed on vemurafenib (n = 66) were included in the phase Ib BRIM7 trial (Ribas et al. 
2014). In the dose escalation phase, patients received vemurafenib 720 or 960 mg BID continuously and 
cobimetinib 60, 80 or 100 mg QD for 14 days on and 14 days off, or 21 days on and 7 days off or 
continuously. The maximum tolerated dose was established as vemurafenib 960 mg BID in combination 
with cobimetinib 60 mg for 21 days on, 7 days off. The Overall Response Rate (ORR) rate was 87% in 
the 63 BRAF inhibitor naïve patients, with a median PFS of 13.7 months (95% CI: 10·1–17·5). ORR 
was 15% in the 66 patients who had already progressed on vemurafenib, with a median PFS of 2.8 months 
(95% CI: 2.6–3.4). The study results were updated with an additional 11 months of follow up; a median 
Overall Survival (OS) of 28.5 months in the vemurafenib-naïve and 8.4 months in the vemurafenib-
progressing patients was reported, with 2-year OS rates of 61.1% and 15.1% respectively (Pavlick et al. 
2015). 
In the coBRIM trial, the addition of cobimetinib (60 mg QD for 21 of 28 days) to vemurafenib (960 mg 
BID) led to an improvement in median PFS of 9.9 in the 247 patients versus 6.2 months in the 248 
patients who received vemurafenib with placebo. Hazard Ratio (HR) for death or disease progression 
was 0.51 (p < 0.001) (Larkin et al. 2014). The ORR was 68% in the combination arm compared to 45% 
in the control arm and was associated with a nonsignificant higher incidence of grade 3 or 4 Adverse 
Events (AE) compared with vemurafenib and placebo (65% versus 59%).There was no significant 
difference in the rate of study drug discontinuation. Toxicities observed more frequently with the 
combination were serous retinopathy, diarrhea, nausea or vomiting, photosensitivity, elevated 
aminotransferase levels and an increased creatine kinase level. As expected, the incidence of secondary 
cutaneous squamous cell cancers decreased with the combination therapy compared with vemurafenib 
alone (down from 11% to 2%). Study results were updated with an 8-months additional follow up, with 
a PFS of 12.3 months for the combination arm compared with 7.3 for monotherapy, HR 0.58, and an 
ORR of 70% versus 50% respectively. Median OS for patients treated with the combination was 22.3 
(Eroglu et al 2016). The overall survival benefit for cobimetinib and vemurafenib observed in the 
coBRIM trial underlines the positive impact that the combination of these two therapies can have on the 

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treatment of advanced BRAFV600 mutation-positive melanoma. The data from these studies confirm the 
clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a 
standard first-line approach to improve survival in patients. 
Although the addition of cobimetinib to vemurafenib is associated with a significant improvement in 
outcomes among patients with BRAF V600-mutated metastatic melanoma, patients treated with the 
combination treatment eventually experience progression of disease. In this setting, the use of anti-PD 1 
immunotherapy with agents such as nivolumab or pembrolizumab has proved to be effective. 
Nivolumab 
Nivolumab is a fully human IgG4 PD-1 immune checkpoint inhibitor antibody approved by the FDA in 
2014 for the treatment of patients with unresectable or metastatic melanoma and disease progression after 
ipilimumab therapy and, if the patient is positive for a BRAF V600 mutation, after treatment with a BRAF 
inhibitor. 
The approval of nivolumab was based on the results of trials Checkmate-037 and Checkmate 066. 
Checkmate 037 was a phase 3 randomized, controlled, open-label study of nivolumab versus 
investigator's choice chemotherapy (ICC) in patients who had unresectable or metastatic melanoma, and 
progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAFV 600 mutation-
positive. Primary endpoints were the proportion of patients who had an objective response and overall 
survival. Objective responses were assessed after 120 patients had been treated with nivolumab and had 
a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. 
A total of 405 patients were randomised to receive either nivolumab (n = 272) or chemotherapy (n = 
133), which consisted of the investigator’s choice of either dacarbazine or carboplatin and paclitaxel. 
Confirmed objective responses were reported in 38 (31.7%, 95% CI 23.5–40.8) of the first 120 patients 
in the nivolumab group versus five (10.6%, 3.5–23.1) of 47 patients in the ICC group. Grade 3–4 adverse 
events related to nivolumab included increased lipase (three [1%]), increased alanine aminotransferase, 
anemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%]), thrombocytopenia 
(six [6%]), and anemia (five [5%]). Grade 3–4 drug-related serious adverse events were noted in 12 (5%) 
nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths 
occurred. 
The study concluded that nivolumab led to a greater proportion of patients achieving an objective 

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response and fewer toxic effects than with alternative available chemotherapy regimens for patients with 
advanced melanoma that had progressed after ipilimumab or ipilimumab and a BRAF inhibitor (Weber 
et al., 2015). 
In an updated analysis (24-month follow-up), ORR was 27.2% (95% CI: 22.0, 32.9) in the nivolumab 
group and 9.8% (95% CI: 5.3, 16.1) in the chemotherapy group. Median durations of response were 31.9 
months (range: 1.4+-31.9) and 12.8 months (range: 1.3+-13.6+), respectively. The PFS HR for 
nivolumab vs. chemotherapy was 1.03 (95% CI: 0.78, 1.36). There was no statistically significant 
difference between nivolumab and chemotherapy in the final OS analysis. The primary OS analysis was 
not adjusted to account for subsequent therapies, with 54 (40.6%) patients in the chemotherapy arm 
subsequently receiving an anti-PD1 treatment. OS may be confounded by dropout, imbalance of 
subsequent therapies and differences in baseline factors. More patients in the nivolumab arm had poor 
prognostic factors (elevated LDH and brain metastases) than in the chemotherapy arm (nivolumab 
Summary of Product Characteristics). 
Checkmate 066 was conducted in patients with previously untreated metastatic melanoma (and without 
BRAF mutations). The results showed a 1-year survival rate of 73% with nivolumab vs 42% with 
dacarbazine, with a hazard ratio of 0.42 (P < .0001). 
The FDA has expanded the frontline melanoma indications for nivolumab as a single agent and in 
combination with ipilimumab (Yervoy) to include patients with BRAF V600 mutations, based on data 
from the phase III Checkmate-067 trial.  
In the pooled dataset of nivolumab 3 mg/kg as monotherapy across tumor types (n = 2227), the most 
frequent adverse reactions (≥ 10%) were fatigue (30%), rash (17%), pruritus (12%), diarrhea (12%), and 
nausea (12%). Most adverse reactions were mild to moderate (Grade 1 or 2) (nivolumab SmPC). 
Pembrolizumab 
Pembrolizumab is another PD-1 immune checkpoint inhibitor antibody approved by the FDA and EMA 
for the treatment of patients with unresectable or metastatic melanoma. Approval was based on results 
of two randomized, open-label, active-controlled clinical trials.  
In the PN-006 trial, patients with unresectable stage III/IV melanoma who had received no more than 
one previous systemic therapy were assigned to receive on a 1:1:1 ratio pembrolizumab at 10 mg/kg 
every 2 weeks, pembrolizumab at 10 mg/kg every 3 weeks, or 4 doses of ipilimumab at 3 mg/kg every 3 

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weeks. Primary end points were PFS and OS. A total of 834 patients were enrolled with 65% treatment 
naïve, and 18% of having received a BRAF inhibitor (representing 50% of patients who had a BRAFV600 
mutation). ORRs were 33.7% for the 2-weekly pembrolizumab group (P < 0.001 vs. ipilimumab), 32.9% 
for the 3-weekly pembrolizumab (P < 0.001), and 11.9% for the ipilimumab group. Rates of CR were 
5.0%, 6.1%, and 1.4% respectively. The estimated 6-month PFS was superior in the pembrolizumab 
groups (2-weekly: 47.3%; 3-weekly: 46.4%) as compared with the ipilimumab group (26.5%) (P < 0.001 
for both pembrolizumab groups versus ipilimumab). Estimated 12-month OS was also superior in the 
pembrolizumab groups (2-weekly: 74.1%, P=0.0005; 3-weekly: 68.4%, P = 0.0036) as compared with 
the ipilimumab group (58.2%). At a median follow-up of 7.9 months, responses were still ongoing in 
89.4%, 96.7%, and 87.9% of patients respectively. Grade 3–5 AEs were lower in the pembrolizumab 
groups (13.3% and 10.1%) than in the ipilimumab group (19.9%) (Robert et al., 2015). 
In the PN-002 trial, patients with confirmed progressive melanoma within 24 weeks of ≥2 ipilimumab 
doses and, if BRAFV600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both, were 
recruited on a 1:1:1 basis to receive pembrolizumab at 2 mg/kg every 3 weeks, pembrolizumab at 10 
mg/kg every 3 weeks, or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, 
carboplatin, dacarbazine, or oral temozolomide). Crossover to pembrolizumab was allowed for patients 
progressing on chemotherapy. A total of 540 patients were enrolled with 48% crossing over to 
pembrolizumab on progression). More than two thirds of patients had ≥2 lines of prior systemic therapy 
including ipilimumab in all patients. About 25% of the patients had BRAF or MEK inhibitors, and about 
50% had chemotherapy. With central review, the response was 21% in the pembrolizumab 2 mg/kg 
group, 25% in the pembrolizumab 10 mg/kg group, and 4% in the chemotherapy group (p < 0.0001 for 
each pembrolizumab dose versus chemotherapy). The primary endpoint of PFS was improved in the 
pembrolizumab 2 mg/kg group (P < 0.0001) and the pembrolizumab 10 mg/kg group (P < 0.0001) 
compared with the chemotherapy group, with 6-month PFS at 34%, 38% and 16% respectively. More 
than 85% of pembrolizumab-induced responses were maintained at the time of PFS analysis. Median 
duration of response had not been reached (Ribas et al., 2015). 
The adverse drug reactions reported for patients being treated with pembrolizumab appear to be mostly 
of low grade and manageable. It was noted that immunological ADRs include skin, gastrointestinal, 
endocrine, hepatic, pulmonary and renal events. These are managed appropriately with the 
recommendations as stated in the SmPC (pembrolizumab SmPC). 
Rationale 

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Patterns of progression with combined therapy are heterogeneous and progressive lesions often represent 
only a small amount of the total tumor burden. In this setting, a local treatment of progressing lesions 
can be provided without modifications of the ongoing systemic treatment. Moreover, even when a local 
treatment cannot be delivered, retrospective evidence in the BRAF monotherapy setting supports 
continuation of therapy in order to maintain partial inhibition of the pathway.  
The activity of treatment beyond progression with combination treatment has never been evaluated in a 
prospective trial. The aim of this trial is to evaluate the impact of combined cobimetinib and vemurafenib 
treatment beyond progression associated with local treatment of progressive lesions in terms of OS 
improvement in patients affected by metastatic melanoma with BRAFV600 mutation treated with 
vemurafenib in combination with cobimetinib who experienced focal progression. 
Patients with focal progression who are randomized to local treatment plus BRAF+MEK inhibitor 
treatment beyond progression will receive second line treatment with an anti-PD-1 agent in case of 
systemic progressive disease. Therefore, the switch to second-line treatment is only postponed until 
systemic progressive disease and all patients will ultimately receive a second line treatment with an anti-
PD-1 agent.  
2. STUDY AIMS AND DESIGN 
2.1 Objectives of the study 
Primary Objective 
The primary objective of the study is to evaluate the efficacy, in terms of overall survival, of vemurafenib 
combined with cobimetinib associated with local treatment compared with second-line therapy, in 
patients with BRAFV600 mutation-positive metastatic melanoma in focal progression with first-line 
combined vemurafenib and cobimetinib. 
Secondary Objectives 
● To compare progression-free survival of patients receiving treatment beyond focal progression vs 
second-line treatment. 
● To compare the adverse event profiles in patients receiving treatment beyond progression vs. second-
line treatment. 
● To evaluate the prognostic role of focal versus non-focal progressive disease 

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Exploratory objective  
A translational study aims to identify positive and negative biomarkers predictive of clinical outcomes 
in paired tumor DNA specimens from the same patients (tumor biopsies and peripheral blood), taken 
before therapy with BRAF+MEK inhibitors and after progression.  
2.2 Endpoints of the study  
Primary Endpoint 
The primary endpoint of the study is OS computed from the day of randomization to the day of death 
from any cause. 
 
 

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Secondary Endpoints 
● PFS computed from the day of randomization to the day of disease progression or death from any 
cause 
● OS for patients with non-focal progression 
● Prognostic role in terms of OS of focal compared with non-focal progressive disease 
● Safety evaluated on the basis of the following variables: 
o Nature, frequency, severity, and timing of adverse events and serious adverse events. 
o Changes in vital signs, physical findings and clinical laboratory results during and following 
vemurafenib + cobimetinib administration 
2.3 Study Design  
This is a randomized, open-label, multicenter, phase II study. The study will enroll approximately 120 
melanoma patients at about 12 sites located in Italy. All patients will initially be treated with first-line 
vemurafenib and cobimetinib. After focal progression, defined as the appearance or dimensional increase 
of lesions that can be treated with surgery or radiotherapy, patients will be randomized to either continue 
receiving vemurafenib and cobimetinib along with local management (i.e. surgery, radiotherapy), or 
switch to a second-line treatment with an anti-PD-1 agent (nivolumab or pembrolizumab). In the latter 
patients, local treatment may be provided based on the Investigator’s judgment to ensure patient safety 
and good clinical practice.  
Patients with non-focal progression of disease will not be randomized but will switch to second-line 
therapy with an anti-PD-1 agent (nivolumab or pembrolizumab), as per local practice, and will be 
followed up for survival only. All patients will be followed up for 24 months after randomization or last 
dose of vemurafenib and cobimetinib (for non-randomized patients). Treatments will continue until the 
development of progressive disease (non-focal), unacceptable toxicity, consent withdrawal, death, 
reasons deemed appropriate by the treating physician or study termination by the Sponsor. 
The study will have an enrolment period of 12 months and a follow-up period of 24 months. The end of 
the study will occur when all patients have been followed up for survival for 24 months after the last 
patient has been randomized, or after the last dose of vemurafenib and cobimetinib (for non-randomized 
patients). 

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* Local treatment may be provided based on the Investigator’s judgment to ensure patient safety and good clinical practice. 
# Patients with non-focal (general) progression after first-line treatment with vemurafenib and cobimetinib will not be randomized and will only 
be followed for survival status. 
* # Second line treatment with an anti-PD-1 agent (nivolumab or pembrolizumab) 
2.4 Schedule of Assessments and Procedures 
The visit and assessment schedule is shown in Table 1. The Table reports assessments to be performed 
on all patients prior to randomization or general progression and on patients with focal progression 
following randomization. Following general progression of disease, both randomized and non-
randomized patients will be followed for survival status only. Most screening/baseline assessments 
must be performed within 28 days prior to the first administration of study drugs on Day 1, with the 
exception of the serum pregnancy test to be done within 7 days and other laboratory exams to be done 
within 14 days. Results of tests or examinations performed as standard of care before obtaining 
informed consent and within the 28 days prior to commencing study drugs may be used. All assessments 
during the study must be performed within a window of -4/+1 days of the day indicated on the 
assessment schedule, except for tumor evaluations, which will have a window of +/- 5 days. Eligibility 
for the study will be determined by the investigator from the screening/baseline assessments according 
to the study inclusion/exclusion criteria. Patients who discontinue study drugs for any reason (e.g. AEs) 
other than disease progression will continue to be followed until disease progression. Follow-up will 
continue for 24 months after randomization or last dose of vemurafenib and cobimetinib (for non-
randomized patients).  
2.4.1 Screening Examination and Eligibility Screening Form 
Written informed consent must be obtained before any study specific assessments or procedures are 
performed. Patients who fulfill all the inclusion and none of the exclusion criteria will be eligible for 
the study. 
* 
# 
Second line 
PD «general» 

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2.4.2 Procedures for Enrollment of Eligible Patients 
A patient who fulfils entry criteria will be given a unique identifying number. A patient number will 
not be reused if the patient leaves the study. Under no circumstances the patients who will be enrolled 
in this study and completed treatment as specified will be permitted to re-enroll in the study. A Patient 
Enrollment and Identification Code List must be maintained by the investigator. 

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Table 1. Schedule of visits and assessments 
Days 
Screening1 
Treatment2: 28-day cycles  
Visit window during the treatment period is -4/+ 1 days 
 
End of 
treatment EOT 
(discontinuation 
of treatment)3 
Post 
treatment 
FU4 
Survival 
follow-
up 
Every 
12 
weeks 19 
 
 
 
-28 to -1 
Day 1 of each 28-day cycle 
 
 
 
Informed consent5 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Inc./Exc. criteria 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
BRAF mutational status 
X 
 
 
 
 
Physical examination, height, weight6 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
 
Performance status (ECOG) 
X 
X 
X 
X 
 
Tumor assessment7 
X 
Every 8 weeks for the first 16 weeks, and then as standard of care with a minimum of 
every 12 weeks 
X 
 
 
Tumor biopsy for ancillary study8 
A fresh biopsy should be obtained at baseline and upon progression if feasible 
 
 
 
Cardiac imaging MUGA/ECHO 
X 
On Day 1 of cycle 2 and every 3 treatment cycles thereafter or as clinically indicated until 
discontinuation 
X 
 
 
ECG9 
X 
As clinically indicated  
X 
 
 
Hematology10 
X 
X 
X 
X 
 
Clinical chemistry10 
X 
X 
X 
X 
 
Blood sample for ancillary study11 
Blood samples are to be taken at baseline and upon progression 
 
 
 
Serum pregnancy test12 
X 
X 
X 
 
 
Dermatological evaluation13 
X 
Every 12 weeks 
X 
X 
X 
Ophthalmological exam 
X 
Every 3 months 
X 
 
 
AEs, SAEs and AESIs14 
X 
Throughout the study 
X 
X 
X 
Concomitant medication15 
X 
Throughout the study 
X 
 
 
Drug dispensing16 
 
X 
 
 
 
Treatment accountability17 
 
X 
X 
 
 
Drug diary18 
 
X 
X 
 
 
Randomization 
 
After “focal” disease progression on treatment with first-line vemurafenib and 
cobimetinib 
 
 
 
Notes: 
Day 1 = first dose of vemurafenib and cobimetinib 
1 All screening/baseline assessments must be performed -28 to -1 days prior to the first administration of study drugs on Day 1. Results of tests or examinations (including tumor assessments) performed before 
obtaining informed consent and within 28 days prior to Day 1 may be used. 
2 All patients will be treated initially with first-line vemurafenib and cobimetinib. Upon disease progression, patients with non-focal progression will switch to second-line therapy with an anti-PD-1 agent (nivolumab 
or pembrolizumab). Patients with focal progression will be randomized to receive either vemurafenib + cobimetinib associated with local management (i.e. surgery, radiotherapy) or second-line treatment with an 
anti-PD-1 agent (nivolumab or pembrolizumab). Patients of both arms will have visits every 28 days. A window of 4 days prior to the scheduled visit date and 1 day after the scheduled visit date (- 4 days / + 1 
days) is allowed for each visit from Cycle 2 onwards. 
3 End of Treatment Visit (EOT) will be performed when the patient discontinues treatments regardless of when it occurs. 
4 Follow up visit is to be performed within 28 days from discontinuation of treatments. 

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5 Informed consent must be obtained prior to any study procedure including screening/baseline assessments. 
6 Height is measured only at screening. 
7 Radiological tumor assessments (CT/MRI chest/abdomen/pelvis along with brain CT/MRI for assessment of brain metastasis will be performed at baseline and every 8 weeks for the first 16 weeks of treatment, 
and then as per institutional standard of care thereafter but at a minimum of every 12 weeks and at the end of study visit. A window of +/- 5 days of scheduled visit is allowed to complete tumor assessments. 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. 
8At baseline, tumor tissues may be obtained from archived samples for patients that cannot be biopsied. 
9 A 12-lead ECG is to be performed at screening, during the study and end of study visit and as clinically indicated. 
10 Hematology and biochemistry assessments do not need to be repeated on Day 1 if performed within 7 days; if the tests need to be repeated, the results must be known before the patient receives treatments to 
ensure that inclusion/exclusion criteria related to these tests are met. 
11 Blood samples are to be obtained before therapy with BRAF+MEK inhibitors and after progression.  
12 Serum pregnancy test to be performed within 7 days prior to Day 1, and on Day 1 of every cycle. 
13 Dermatology evaluation by a dermatologist must be performed at screening every 12 weeks, at the end of study visit if not performed within the previous 12 weeks and at the follow-up visit.  
14 During screening, AEs are not recorded in the eCRF unless they are SAEs related to protocol-mandated procedures. ALL AEs (including SAEs and AESIs) must be recorded from the time of first treatment 
administration. After the last treatment, any new, non-serious AEs that the investigator considers may be related to treatments should be reported up to 28 days after last dose. Any SAEs reported after last dose 
that the investigator considers may be related to treatments should be reported until the end of the study. 
15 All concomitant medications during the study started within 14 days prior to the screening visit and up to the end of study visit must be recorded. 
16 Drug dispensing applies only to patients taking vemurafenib and cobimetinib. Patients randomized to the control arm will be treated with second-line treatment as per clinical practice. 
17 Vemurafenib, cobimetinib and second-line treatment accountability will be performed at every study visit from Cycle 2 onwards and at the End of Study Visit. 
18 Patients will keep a diary to record ONLY those occasions when a dose of vemurafenib and/or cobimetinib was missed (morning or evening, each day of treatment). The patient will bring this diary with him/her 
to each study visit to allow missed doses to be recorded by the investigator. 
19All patients will be followed up for 24 months after randomization or last dose of vemurafenib and cobimetinib (for non-randomized patients). 
 
 

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2.4.3 Clinical Assessments and Procedures 
The following clinical assessments and procedures must be completed for all patients enrolled in this study 
at screening/baseline and/or during study visits. From Cycle 2 onwards, all assessments except for tumor 
evaluations must be performed within a window of 4 days prior to the scheduled visit date to one day after 
the scheduled visit date (- 4 days / + 1 day). A window of +/- 5 days will be applied to tumor evaluations. 
The visit and assessment schedule is shown in Table 1. Patients should be assessed prior to each cycle, 
and as necessary throughout participation in the study. Each treatment cycle has a duration of 28 days. The 
clinical assessments and procedures are outlined below and a schedule of when they are to be performed 
is shown in Table 1. Patients with non-focal progression will be followed for survival status only. 
Screening/Baseline: 
● Informed Consent 
● Medical history (including demographics, relevant medical history, previous and current diseases, 
prior skin cancer history, therapies and procedures, all medications started within 14 days prior to 
screening visit). History should include any visual disturbances or symptoms 
● Physical examination, height and weight 
● Dermatological evaluation for Squamous Cell Carcinoma (SCC) 
● Vital signs (blood pressure, heart rate, temperature, respiratory rate) 
● Eastern Cooperative Oncology Group (ECOG) performance status 
● Hematology and clinical chemistry 
● Serum pregnancy test (within 7 days prior to commencement of dosing) for women of childbearing 
potential 
● Tumor assessments including measurable and non-measurable lesions [baseline brain CT or MRI, 
CT/MRI Chest/Abdomen/Pelvis (CAP), bone scan if clinically indicated] 
● BRAF V600 mutational status (if not already available) with a validated mutational test. 
● 12-lead ECG 
● Cardiac imaging 
● Ophthalmological exam 
● Concomitant therapy 

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● AEs, SAEs and AESIs 
● Tumor tissue and peripheral blood samples for ancillary study (optional). Baseline tumor tissues 
will be obtained from fresh baseline biopsies performed in patients with easily accessible biopsy 
sites. Tumor tissues may be obtained from archived samples for patients that cannot be biopsied. 
Treatment period 
All patients will be treated initially with first-line vemurafenib and cobimetinib. During treatment with 
vemurafenib and cobimetinib, patients should undergo tumor assessments consisting of CT or MRI scans 
of the chest, abdomen, and pelvis. A brain CT/MRI should also be performed for assessment of brain 
metastasis. For patients with palpable/superficial lesions, clinical disease assessments by physical 
examination should be performed. 
Patients with focal progression will be randomized to either continue treatment with vemurafenib and 
cobimetinib in addition to a local treatment (e.gs surgery, radiotherapy) or start treatment with a second-
line treatment with an anti-PD-1 agent (nivolumab or pembrolizumab). Focal Progression is defined as the 
appearance or dimensional increase of new lesions that can be locally treated with surgery or radiotherapy. 
Randomized patients with focal progression will continue to be evaluated as indicated in Table 1. Patients 
with non-focal disease progression will switch to a second-line treatment with an anti-PD-1 agent 
(nivolumab or pembrolizumab) and will be followed-up for survival. 
Patients who discontinue study drugs for any reason (e.g. AEs) other than disease progression will continue 
to be followed until disease progression. Follow-up will continue for 24 months after randomization or 
last dose of vemurafenib and cobimetinib (for non-randomized patients).  
Patients will be given a diary on which to record ONLY those occasions when a dose of vemurafenib 
and/or cobimetinib will be missed (morning or evening, each day of treatment). The patient will bring this 
diary with him/her to each study visit to allow missed doses to be recorded by the investigator. 
The following clinical assessments and procedures will be completed during the treatment periods (first 
line and following focal progression): 
● Physical exam 
● Dermatological evaluation 
● Vital signs (blood pressure, heart rate, temperature, respiratory rate) 
● ECOG PS 

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● Hematology and clinical chemistry 
● Brain CT/MRI for assessment of brain metastasis. Radiological tumor assessments (CT/MRI 
chest/abdomen/pelvis and bone scan if clinically indicated) to assess extent of disease 
● 12-lead ECG 
● Cardiac imaging 
● Ophthalmological exam 
● Concomitant therapy throughout the study 
● AEs, SAEs and AESIs 
● Drug accountability throughout the study 
● Serum pregnancy test 
End of Treatment Visit (when patient discontinues study drugs) 
The End of Study Visit (EOS) will be performed when the patient discontinues treatments regardless of 
when it occurs and the following assessments will be performed: 
● Physical examination 
● Dermatological evaluation 
● Vital signs (blood pressure, heart rate, temperature, respiratory rate) 
● ECOG performance status 
● Hematology and clinical chemistry 
● Serum pregnancy test 
● Tumor assessments if not performed within the previous 8 weeks (CT/MRI CAP, CT/MRI of brain 
as clinically indicated) including assessment of any tumor lesions accessible by physical 
examination 
● 12-lead ECG (if clinically indicated) 
● Cardiac imaging (if not performed within the previous 16 weeks) 
● Ophthalmological evaluation (if not performed within the previous 16 weeks) 
● Concomitant therapy  

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● AEs, SAEs and AESIs 
Follow up visit within 28 days from discontinuation of study drugs 
The following assessments will be performed during the follow up visit: 
● Physical examination 
● Vital signs 
● Hematology and clinical chemistry 
● ECOG performance status 
● Monitoring of AEs and SAEs 
● Dermatological evaluation for evaluation of cutaneous SCC 
● Follow up for disease progression for those patients who have discontinued study drug for any 
reason (i.e. AE) other than disease progression 
● New anti-cancer therapy 
● AEs, SAEs and AESIs 
Survival follow-up 
Patients will be followed up for survival every 12 weeks for up to 24 months after the last patient has been 
randomized. Patients who are not randomized will be followed up for survival every 12 weeks until the 
end of the study (i.e.  24 months after the last dose of vemurafenib and cobimetinib). 
2.4.4 Tumor Response Criteria 
Disease should be assessed at each visit, and until documented non-focal progression ascertained by the 
Investigator. 
Tumor evaluation will be assessed by means of CT or MRI of the chest, abdomen and pelvis (CAP) and 
brain at screening/baseline (between Day -28 and -1), every 8 weeks for the first 16 weeks of treatment, 
and then as per institutional standard of care thereafter but at a minimum of every 12 weeks and at the end 
of study visit. A window of +/- 5 days of scheduled visit is allowed to complete tumor assessments. 
Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue (archival or newly 
obtained tumor samples) must be obtained at screening by means of a validated mutation test. 
Tumor responses will be assessed by the investigator according to Response Evaluation Criteria In Solid 

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Tumors (RECIST) (version 1.1) Criteria. Both measurable and non-measurable lesions will be assessed 
by the investigator. In case of Stable Disease (SD), measurements must indicate SD for at least 6 weeks. 
For assessing response in patients with measurable disease, the preferred radiologic tumor response 
assessment is a CT scan with oral and IV contrast. If IV contrast is contraindicated, a non-contrast chest 
CT will be done with abdominal/pelvic contrast enhanced MRI. If contrast enhanced MRI is 
contraindicated, then non-contrast MRI will suffice. CT/MRI scans of extremities may be done as 
appropriate in individual patients. PET scan, bone scan, and ultrasound are not adequate for RECIST 
response assessment. Patients should be assessed at designated times using a consistent imaging modality. 
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. If more than one method of assessment is used at baseline, 
select the most accurate method according to RECIST when recording data; in addition, this method should 
again be performed in all subsequent evaluations. Tumor measurements should be made by the same 
investigator/radiologist for each patient during the study to the extent that this is feasible. Objective 
responses by RECIST (Version 1.1) should be confirmed by repeat assessments at least 4 weeks after 
initial documentation of response. Clinical lesions will be considered measurable only when they are 
superficial and > 10 mm diameter as assessed using calipers (e.g. skin nodules). For skin lesions, 
documentation by color photography with ruler is required. A CT scan is the preferred modality for skin 
lesions and should be used whenever possible. For patients with palpable/superficial lesions, clinical 
disease assessments by physical examination should be performed throughout study treatment as clinically 
indicated. 
After disease progression during treatment with vemurafenib and cobimetinib, patients will undergo tumor 
assessments: CT or MRI scans of the chest, abdomen, and pelvis should be performed. For patients with 
palpable/superficial lesions, clinical disease assessments by physical examination should be performed. 
Focal Progression will be defined as the appearance or dimensional increase of lesions that can be treated 
locally with surgery or radiotherapy. Patients in focal progression will be randomized to either continue 
with treatment with vemurafenib and cobimetinib in addition to local treatment (e.g. surgery, radiotherapy) 
or start a second-line treatment. 
2.4.5 Clinical Safety Assessments 
Safety evaluations include assessments of Adverse Events (AE), clinical laboratory tests, vital sign 
measurements, physical examination, assessment of Eastern Cooperative Oncology Group (ECOG) 
performance status, dermatology evaluations, cardiac imaging, ECG, ophthalmic examination. The NCI 
CTC-AE (Version 4) will be used to evaluate the clinical safety of the treatments in this study. See Table 

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1 for a schedule of all safety assessments.  
● Adverse events 
Monitoring for adverse events will take place continuously throughout the study, starting from informed 
consent until the end of the study. Patients should be assessed for AEs throughout the study. During 
screening, AEs are not recorded in the eCRF unless they are SAEs related to protocol-mandated 
procedures. 
● Clinical laboratory tests 
Laboratory assessments for safety will be performed at local laboratories and are listed below: 
- 
Hematology: hemoglobin, WBC, ANC, platelet count. 
- 
Biochemistry: glucose, uric acid, creatinine, creatinine-clearance, sodium, potassium, bicarbonate 
(if routinely performed on venous blood samples), total bilirubin with direct and indirect fractions 
(if total bilirubin is elevated), alkaline phosphatase, Aspartate Aminotransferase (AST) [SGOT], 
Alanine Aminotransferase ALT [SGPT]) and LDH. 
- 
Serum Pregnancy Test in women of childbearing potential (within 7 days prior to first administration 
of study drug). 
● Vital signs 
Vital signs consist of body temperature, seated blood pressure and heart rate, and respiratory rate. Blood 
pressure and heart rate should be measured after the subject has been seated quietly for at least 5 minutes 
prior to dosing.  
● Physical examination 
A full physical examination will be performed at screening visit, whereas targeted exams will occur during 
the treatment and post-treatment periods according to the Investigator’s observations and/or subject 
complaints on new or changed conditions. Patients should be asked specifically about skin and vision 
changes. For patients with palpable/superficial lesions, clinical disease assessments by physical 
examination should be performed throughout study treatment as clinically indicated.  
Significant findings that were present prior to the signing of informed consent must be included in the 
Medical History CRF page. Significant new findings that begin or worsen from the time of first treatment 
administration must be recorded on the Adverse Event page of the eCRF. 
● ECOG performance status 

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Eastern Cooperative Oncology Group (ECOG) performance status should be evaluated prior to any study-
related procedures or assessments. 
● Dermatological evaluations 
Dermatological evaluation for Squamous Cell Carcinoma (SCC). Any suspicious lesions should be 
biopsied or resected and sent for pathologic examination. Please refer to vemurafenib Summary of Product 
Characteristics (SmPC) for details on dermatologic monitoring. Evaluations are to be performed at 
screening, every 12 weeks thereafter, at end of treatment and during follow-up. 
● ECG 
As vemurafenib is associated with concentration-dependent QTc prolongation, patients should undergo 
12-lead ECG monitoring at screening/baseline, during the study and end of study as clinically indicated. 
● Cardiac imaging 
Decreases in Left Ventricular Ejection Fraction (LVEF) from baseline have been reported in patients 
receiving cobimetinib, with median time to first onset of events at 4 months (0.7-7 months). All patients 
should therefore undergo evaluation of LVEF, either by echocardiography (ECHO) or multiple gated 
ejection acquisition scan (MUGA) prior to treatment start and around day 1 of cycle 2, and at least every 
3 treatment cycles thereafter or as clinically indicated until treatment discontinuation. Decrease in LVEF 
from baseline can be managed using treatment interruption, dose reduction or with treatment 
discontinuation. 
● Ophthalmological exam 
Serous retinopathy has been reported in patients treated with cobimetinib. Patients should be monitored 
for ocular toxicity every 3 months. Most events observed in clinical trials resolved or improved to 
asymptomatic Grade 1 following dose interruption or reduction. 
Patients with a history of visual disturbances or symptoms at baseline need to undergo ophthalmologic 
examination prior to treatment start to evaluate the presence of retinal pathology, which may exclude these 
patients from this program. Ophthalmologic examination must be performed by a qualified 
ophthalmologist.   
For patients reporting new or worsening visual disturbances during treatment with cobimetinib, an 
ophthalmologic examination is also required. If serous retinopathy is diagnosed, cobimetinib treatment 
should be withheld until visual symptoms improve to Grade ≤ 1. Serous retinopathy can be managed with 
treatment interruption, dose reduction or with treatment discontinuation (see section 5.4). 

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2.4.6 Ancillary biomarker study 
The optional ancillary biomarker study will be performed on tumor tissue biopsies and peripheral blood 
samples. 
● Tumor biopsies: 
Tumor biopsies for this ancillary study will be required at baseline and upon progression when feasible. 
At baseline, tumor tissues will be obtained from fresh baseline biopsies performed in patients with easily 
accessible biopsy sites (subcutaneous and lymph nodes) and from archived samples for patients that cannot 
be biopsied. 
Upon progression, fresh biopsies will be obtained for patients with accessible tumor lesions provided they 
have given their consent to participate in the biomarker study. Accessible lesions are defined as tumor 
lesions that can be easily biopsied i.e. cutaneous, sub-cutaneous and palpable lymph nodes. Failure to 
obtain sufficient tumor sample, after making best efforts, will not be considered a protocol violation. 
Lesions with the biggest change in size, based on interval evaluation, should be excised at time of 
progressive disease. See Appendix 2 for full details. 
● Peripheral blood samples: 
Peripheral blood mononuclear cell samples will be collected for the biomarkers study before therapy with 
BRAF+MEK inhibitors (baseline) and after progression.  
Response/resistance to targeted agents will be measured by mutation analysis on circulating tumor DNA 
to assess new peripheral blood biomarkers. See Appendix 2 for full details. 
3. STUDY POPULATION 
3.1 Inclusion Criteria 
A subject is eligible for the study if all of the following criteria are met: 
Disease-specific inclusion criteria 
1. Patients with histologically confirmed melanoma, either unresectable Stage IIIc or Stage IV metastatic 
melanoma, as defined by the American Joint Committee on Cancer 7th edition. 
2. Patients previously untreated for metastatic melanoma. 
3. Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue (archival or newly 
obtained tumor samples) by a validated mutational test. 

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4. Adequate performance status to receive vemurafenib and cobimetinib therapy as determined by treating 
physician. 
General inclusion criteria 
5. Male or female patient aged ≥18 years  
6. Able to participate and willing to give written informed consent prior to any treatment-related 
procedures and to comply with treatment guidance. 
7. Adequate end-organ function, defined by the following laboratory results obtained within 14 days prior 
to the first dose of program drug treatment: 
a) Bilirubin ≤ 1.5  the upper limit of normal (ULN). 
b) AST, ALT, and alkaline phosphatase ≤ 3  ULN, with the following exceptions: 
● Patients with documented liver metastases: AST and/or ALT ≤5  ULN. 
● Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5  ULN. 
c) Serum creatinine ≤1.5  ULN or creatinine clearance (CrCl) ≥ 40 mL/min based on measured CrCl 
from a 24-hour urine collection or Cockroft-Gault glomerular filtration rate estimation. 
8. Female patients of childbearing potential and male patients with partners of childbearing potential must 
agree to always use two effective forms of contraception during program therapy and for at least 6 
months after completion of program therapy.  
● Please note that potential interactions between vemurafenib and hormonal contraceptives may 
decrease the effectiveness of hormonal contraceptives. 
9. Negative serum pregnancy test prior to commencement of dosing in women of childbearing potential. 
10. Patient should be able to swallow tablets. 
11. Absence of any psychological, familial, sociological, or geographical condition that potentially hampers 
compliance with the treatment regimen; these conditions should be discussed with the patient before 
program entry. 
12. Patient does not currently participate in other clinical trials. 
3.2 Exclusion Criteria 
A subject is excluded from the study if any of the following criteria are met: 

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Cancer-related exclusion criteria 
1. Palliative radiotherapy within 7 days prior to the first dose of program treatment. 
2. Patients with active malignancy (other than BRAF-mutated melanoma) or a previous malignancy within 
the past 3 years except for patients with resected melanoma, resected BCC, resected cutaneous SCC, 
resected melanoma in situ, resected carcinoma in situ of the cervix, and resected carcinoma in situ of 
the breast. 
Exclusion criteria based on organ function 
Ocular 
3. Evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for 
neurosensory retinal detachment / central serous chorioretinopathy (CSCR), retinal vein occlusion 
(RVO), or neovascular macular degeneration.  
4. Systemic risk factor for RVO including uncontrolled glaucoma, uncontrolled hypercholesterolemia, 
hypertriglyceridemia or hyperglycemia. 
Cardiac 
5. History of clinically significant cardiac dysfunction, including the following: 
a) Current unstable angina. 
b) Symptomatic congestive heart failure of New York Heart Association class 2 or higher. 
c) History of congenital long QT syndrome or mean (average of triplicate measurements) QTcF ≥ 450 
msec at baseline; presence of clinically significant ventricular or atrial dysrhythmias ≥ Grade 2. 
d) Uncontrolled hypertension ≥ Grade 2 (patients with a history hypertension controlled with anti-
hypertensives to ≤ Grade 1 are eligible). 
e) Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 
50%, whichever is lower. 
General exclusion criteria 
6. Current severe, uncontrolled systemic disease.  
7. Major surgery or traumatic injury within 14 days prior to first dose of program treatment. 
8. History of malabsorption or other condition that would interfere with absorption of program drugs. 

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9. Hypersensitivity to the active substance or to any of the excipients. 
10. Pregnant or breastfeeding women. 
3.3 Criteria for Premature Withdrawal 
Every patient has the right to discontinue study participation at any time, for any reason. When applicable, 
patients should be informed of the circumstances under which their participation may be terminated by the 
investigator without their consent. The investigator may withdraw patients from the study in the event of 
intercurrent illness, AEs, treatment failure after a prescribed procedure, lack of compliance with the study 
and/or study procedures (e.g., dosing instructions, study visits), or any reason where it is felt by the 
investigator that it is in the best interest of the patient to be discontinued from the study. Any administrative 
or other reasons for withdrawal must be documented and explained to the patient. 
Handling of Participant Withdrawals or Termination 
Patients who discontinue from the study will be asked to return to the clinic within 28 days of the last dose 
of treatment for the follow-up visit and to be contacted every 12 weeks for at least 12 months for survival 
follow-up. If lost to follow-up, the investigator should make every effort to contact the patient by telephone 
or by sending a registered letter to establish as completely as possible the reason for the withdrawal. A 
complete final evaluation at the time of the patient’s withdrawal should be made with an explanation of 
why the patient is withdrawing from the study. 
If the reason for removal of a patient from the study is an AE, the event is to be recorded on the CRF and 
the patient should be followed until the AE has resolved, if possible. All patients will be followed for safety 
for 28 days following the last dose of study medication until the end of the study. 
4. INVESTIGATIONAL MEDICINAL PRODUCTS 
4.1 Formulation, appearance, packaging and labeling 
This is an open-label study and all study treatments, along with their packaging and labelling, have been 
approved by local Health Authorities.  
● Vemurafenib (Zelboraf®) 
Study drug packaging will bear a label with the identification required by local law, the protocol number, 
drug identification and dosage. Vemurafenib is supplied in 240 mg film-coated tablets for oral 
administration packed in blisters contained in boxes. For additional batch-specific instructions and 

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information see the packaging. 
● Cobimetinib (Cotellic®) 
Study drug packaging will bear a label with the identification required by local law, the protocol number, 
drug identification and dosage. Cobimetinib is supplied in 20 mg film-coated tablets for oral administration 
packed in blisters contained in boxes. For additional batch-specific instructions and information see the 
packaging. 
● Control 
Patients randomized to second-line treatment will be treated with an anti-PD-1 agent (nivolumab or 
pembrolizumab).  
4.2 Product storage and stability 
Investigational treatment must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designees have access. 
Upon receipt, all investigational treatment should be stored according to the instructions specified on the 
labels. Clinical supplies are to be dispensed only in accordance with the protocol. Medication labels will be 
in the local language and comply with the legal requirements of each country.  
Vemurafenib is to be stored in a dry place in its original packaging and with the container kept tightly 
closed, 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 vulnerable persons. 
Cobimetinib does not require any particular storage conditions.  
4.3 Dosing and administration 
Vemurafenib 
Vemurafenib is taken on a 28-day cycle. Each dose consists of four 240 mg (960 mg) tablets twice daily 
for 28 consecutive days. The first dose should be taken in the morning and the second dose should be taken 
in the evening approximately 12 hours later. Each dose can be taken with or without a meal. Vemurafenib 
tablets should be swallowed whole with a glass of water and should not be chewed or crushed. 
Missed doses 
If a dose is missed, it can be taken up to 4 hours prior to the next dose to maintain the twice-daily regimen. 
Both doses should not be taken at the same time. 

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Cobimetinib 
Cobimetinib is taken on a 28-day cycle. Each dose consists of three 20 mg tablets (60 mg) and should be 
taken orally, once daily for 21 consecutive days (Days 1 to 21-treatment period), followed by a 7-day break 
(Days 22 to 28-treatment break). Each subsequent treatment cycle should start after the 7-day treatment 
break has elapsed. 
The dose should be taken in the morning with or without meal 
4.4 Dose adjustments/modifications/delays 
● Vemurafenib 
Management of symptomatic adverse drug reactions (e.g. arthralgia, fatigue, rash, etc.) may require 
temporary interruption and/or dose reduction of vemurafenib. When dose reduction is needed, the dose is 
reduced from 960 mg twice daily to 720 mg twice daily initially, and to 480 mg twice daily if additional 
dose reduction is required. Posology adjustments resulting in a dose below 480 mg twice daily are not 
recommended. 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. Dose 
increases above 960 mg twice daily will not be allowed. Dose modification will follow the indications in 
the table below. 
Dose Interruption/Modification Criteria for Vemurafenib for any AEs 
Grade (CTC-AE) (a) 
Recommended dose modification 
Grade 1 or Grade 2 (tolerable)  
Maintain Vemurafenib at a dose of 960 mg twice daily. 
Grade 2 (intolerable) or Grade 3 
 
1st occurrence of any grade 2 or 3 AE 
 
Interrupt treatment until grade 0 – 1. Resume dosing at 720 
mg twice daily (or 480 mg twice daily if the dose has already 
been lowered). 
2nd occurrence of any grade 2 or 3 AE or 
persistence after treatment interruption 
Interrupt treatment until grade 0 – 1. Resume dosing at 480 
mg twice daily (or discontinue permanently if the dose has 
already been lowered to 480 mg twice daily).  
3rd appearance of any grade 2 or 3 AE or 
persistence after 2nd dose reduction 
Discontinue permanently. 
Grade 4 
 
1st occurrence of any grade 4 AE 
Discontinue permanently or interrupt Vemurafenib treatment 
until grade 0 – 1.  
Resume dosing at 480 mg twice daily (or discontinue 
permanently if the dose has already been lowered to 480 mg 
twice daily). 
2nd occurrence of any grade 4 AE or 
persistence of any grade 4 AE after 1st 
dose reduction 
Discontinue permanently. 
a The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v4.0 (CTC-AE). 

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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 decrements are required. On the third appearance of intolerable Grade 2 or Grade 3 
toxicity despite two dose reductions, it is recommended that patients discontinue vemurafenib. 
Exception will be granted for reversible laboratory abnormalities with no clinical sequelae and/or clinical 
significance in the opinion of the Investigator. For Grade 4 toxicities, patients should discontinue study 
treatment or, based on investigator judgement, interrupt until resolution to Grade 1 or less with dose 
reduction of 50% upon restarting study drug. 
Patients who develop cutaneous Squamous Cell Carcinoma (cSCC) or any other skin lesions during the 
trial 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 is required. 
Special consideration must be taken with any patient on study with an increase in QTc > 500 ms or change 
from baseline > 60 ms. If QTc exceeds 500 ms or the change from baseline is greater than 60 ms, 
vemurafenib treatment should be temporarily interrupted. QTc interval should be monitored weekly until it 
is less than 500 ms. Appropriate electrolyte (K+, Mg++, Ca++) evaluation should be performed, with any 
necessary corrections done, and cardiac risk factors (e.g. congestive heart failure, bradyarrhythmias) 
controlled. When QTc decreases to less than 500 ms, re-initiation of treatment may occur at one reduced 
dose level from 960 mg b.i.d. to 720 mg b.i.d. If a subsequent increase in QTc to >500 ms or change from 
baseline greater than 60 ms is observed, vemurafenib may be reduced to 480 mg bid. Permanent 
discontinuation of vemurafenib is recommended if QTc increase meets both criteria of >500 ms and >60 
ms change from pre-treatment values or if QTc > 500 ms or change from baseline > 60 ms is observed on 
2 separate prior occasions. 
If a patient’s dose has been interrupted for > 4 weeks due to an AE, the patient will be considered to have 
discontinued from the study. However, a temporary interruption of study drug of up to 8 weeks is allowed 
in case of tumor surgery or other safety or elective procedures in the best interest of the patient.  
Treatment with vemurafenib must be interrupted prior to tumor surgery, radiotherapy or other procedures. 
● Cobimetinib 
Dose modification of cobimetinib is independent of vemurafenib dose modification. The Table below 
provides general guidance for cobimetinib dose modification. 
 
 

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Recommended cobimetinib dose modifications 
Grade (CTC-AE) 
Recommended cobimetinib dose 
Grade 1 or Grade 2 (tolerable)  
No dose reduction. Maintain dose of 60 mg once daily. 
Grade 2 (intolerable) or Grade 3/4 
 
1st occurrence 
 
Interrupt treatment until grade ≤ 1. Resume treatment at 40 
mg (2 tablets) once daily. 
2nd occurrence 
Interrupt treatment until grade ≤ 1. Resume treatment at 20 
mg (1 tablet) once daily. 
3rd appearance 
Consider permanent discontinuation. 
 
Dose modification advice for left ventricular dysfunction  
Permanent discontinuation of cobimetinib treatment should be considered if cardiac symptoms are 
attributed to the drug and do not improve after temporary interruption. Recommended dose modifications 
in patients with left ventricular ejection fraction (LVEF) decrease from baseline are shown in the table 
below. 
Recommended dose modifications for cobimetinib in patients with (LVEF) decrease from baseline 
Patient 
LEFV value 
Dose 
modification 
LVEF value 
following 
treatment break 
Recommended daily 
dose 
Asymptomatic 
≥ 50% (or 40-49% 
and < 10% absolute 
decrease from 
baseline) 
Continue at 
current dose 
NA 
NA 
< 40% (or 40-49% 
and ≥ 10% absolute 
decrease from 
baseline) 
Interrupt 
treatment for 2 
weeks 
< 10% absolute 
decrease from 
baseline 
1st occurrence: 40 mg 
 
 
 
 
2nd occurrence: 20 mg 
 
 
 
 
3rd occurrence: permanent 
discontinuation 
 
 
 
< 40% (or ≥ 10% 
absolute decrease 
from baseline) 
Permanent 
discontinuation 
Symptomatic 
NA 
Interrupt 
treatment for 4 
weeks 
Asymptomatic 
and < 10% 
absolute decrease 
from baseline 
1st occurrence: 40 mg 
 
 
 
2nd occurrence: 20 mg 

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3rd occurrence: permanent 
discontinuation 
 
 
 
Asymptomatic 
and < 40% (or ≥ 
10% absolute 
decrease from 
baseline) 
Permanent 
discontinuation 
 
 
 
Symptomatic 
regardless of 
LVEF 
Permanent 
discontinuation 
Vemurafenib treatment can be continued when cobimetinib treatment is modified, if clinically indicated. 
● Dose modification advice for cobimetinib when used with vemurafenib  
Liver laboratory abnormalities  
For Grade 1 and 2 liver laboratory abnormalities, cobimetinib and vemurafenib should be continued at the 
prescribed dose.  
Grade 3: Cobimetinib should be continued at the prescribed dose. The dose of vemurafenib may be reduced 
as clinically appropriate. Please refer to the vemurafenib SmPC.  
Grade 4: Cobimetinib treatment and vemurafenib treatment should be interrupted. If liver laboratory 
abnormalities improve to Grade ≤1 within 4 weeks, cobimetinib should be restarted at a dose reduced by 
20 mg and vemurafenib at a clinically appropriate dose, per its SmPC.  
Cobimetinib treatment and vemurafenib treatment should be discontinued if liver laboratory abnormalities 
do not resolve to Grade ≤1 within 4 weeks or if Grade 4 liver laboratory abnormalities recur after initial 
improvement.  
Creatine phosphokinase (CPK) elevations  
Cobimetinib dosing does not need to be modified or interrupted to manage asymptomatic CPK elevations.  
Photosensitivity  
Grade ≤2 (tolerable) photosensitivity should be managed with supportive care. Grade 2 (intolerable) or 
Grade ≥3 photosensitivity: cobimetinib and vemurafenib should be interrupted until resolution to Grade ≤1. 
Treatment can be restarted with no change in cobimetinib dose. Vemurafenib dosing should be reduced as 
clinically appropriate, please refer to its SmPC for further information.  
Rash  
Rash events may occur with either cobimetinib or vemurafenib treatment. The dose of cobimetinib and/or 

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vemurafenib may be either temporarily interrupted and/or reduced as clinically indicated. Additionally, 
Grade ≤2 (tolerable) rash should be managed with supportive care and cobimetinib dosing can be continued 
without modification. Grade 2 (intolerable) or Grade ≥3 acneiform rash: general dose modification 
recommendations in the AE Table above for cobimetinib should be followed. Vemurafenib dosing can be 
continued when cobimetinib treatment is modified (if clinically indicated). Grade 2 (intolerable) or Grade 
≥3 non-acneiform or maculopapular rash: cobimetinib dosing can be continued without modification if 
clinically indicated. Vemurafenib dosing may be either temporarily interrupted and/or reduced, please refer 
to its SmPC for further information.  
QT prolongation 
If during treatment the QTc exceeds 500 msec, please refer to the vemurafenib SmPC (section 4.2) for dose 
modifications for vemurafenib. No dose modification of Cotellic is required when taken in combination 
with vemurafenib. 
See the Summary of Product Characteristics for more details about vemurafenib and cobimetinib. 
4.5 Duration of Therapy 
Treatment with study drug continues until general (non-focal) disease progression or unacceptable toxicity 
(adverse event related to study drug), or the subject meets other criteria for discontinuation of study drug 
outlined in the previous section. 
4.6 Accountability, assessment of compliance and destruction of the drugs  
The investigator is responsible for the control of drugs under investigation. Adequate records for the receipt 
(e.g. Drug Receipt Record) and disposition (e.g. Drug Dispensing Log) of the study drug must be 
maintained. Accountability and patient compliance will be assessed by maintaining adequate “drug 
dispensing” and return records. 
Accurate records must be kept for each study drug provided by Roche. These records must contain the 
following information: 
● Documentation of drug shipments received from Roche (date received, quantity and batch number) 
● Disposition of unused study drug not dispensed to patient 
A Drug Dispensing Log must be kept current and should contain the following information: 
● Identification of the patient to whom the study medication was dispensed 

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● Date(s), quantity and batch number of the study medication dispensed to the patient 
● Date(s), quantity and batch number of the study medication returned by the patient 
All records and drug supplies must be available for verification by the Monitor at every monitoring visit. 
Patients will be asked to return all used and unused drug supply containers at the end of each cycle of 
treatment as a measure of compliance. 
This inventory must be available for verification by the Monitor. Patient compliance will be assessed by 
maintaining adequate study drug dispensing records. The investigator is responsible for ensuring that dosing 
is administered in compliance with the protocol.  
Used and unused investigational product will be destroyed locally/returned to Roche.  
5. STATISTICAL CONSIDERATIONS 
5.1 Statistical and analytical plan 
The final analysis will be performed when randomized patients have been followed up for survival for a 
minimum of 24 months after the last patient has been randomized or after the observation of the 38th death 
in the randomized cohorts, whichever occurs first. 
5.2 Statistical hypotheses 
The primary efficacy endpoint is OS in patients with focal progression. 
The distribution of OS will be estimated using the Kaplan-Meier method. The median OS along with 80% 
confidence intervals will be presented by treatment group. The primary efficacy analysis will be the 
comparison of the distribution of OS between the two treatment groups using a log-rank test at two-sided 
20% level of significance, i.e., 
H0:   
 
SCombo+Local treatment(t) = SSecond Line(t) 
will be tested against the one-sided alternative hypothesis  
Ha1:  
 
SCombo+Local treatment(t) > SSecond Line(t), 
where SCombo+Local treatment(t) is the survival distribution function of OS in the vemurafenib and cobimetinib 
plus local treatment arm and SSecond Line(t) is the survival distribution function of OS in the SOC second line. 
A Cox proportional hazard model will be used to estimate the hazard ratio (HR) of OS, along with 80% 
confidence interval (see Section 6.4.2). 

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5.3 Analysis datasets 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients with focal progression to whom treatment has been 
assigned by randomization. According to the intent to treat principle, patients will be analyzed according to 
the treatment they have been assigned to during the randomization procedure. 
Per Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of patients in the FAS who received at least one dose of the 
randomized treatment and had no major protocol deviation. Protocol deviations leading to exclusion from 
the PPS will be defined in the Statistical Analysis Plan. 
Safety Set 
The Safety Set consists of all patients with focal progression who received at least one dose of study 
treatment or second-line treatment after randomization. Patients who did not take at least one dose of study 
treatment or second-line treatment will not be included in the safety set. Patients will be analyzed according 
to the treatment they actually received. 
Non-focal Progression Set 
The Non-focal Progression set consists of all patients who received at least one dose of vemurafenib + 
cobimetinib treatment in first-line treatment, experienced a non-focal progression and were therefore not 
randomized. 
5.4 Description of statistical methods 
All data collected in this study will be listed and summarized as appropriate as described below. Data from 
all sites will be pooled and summarized. 
Continuous data will be summarized by mean, standard deviation (SD), median, first and third quartiles, 
minimum and maximum. Categorical data will be presented by absolute and relative frequencies (n and %) 
or contingency tables. 
All statistical tables, listings, figures and analyses will be performed by means of SAS® release 9.4 or later 
(SAS Institute, Inc., Cary, NC, USA). 
Two-sided alpha level 0.2 will be considered. No alpha level adjustment will be carried out for primary and 
secondary outcome variables. 

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5.4.1 Analysis of the primary efficacy endpoint 
The efficacy analysis will be performed based on the FAS as primary analysis and on the PPS as supportive 
analysis. 
Overall Survival (OS) 
Overall survival of patients with focal progression is defined as the time, in months, from randomization to 
the date of death from any cause. If a patient is not known to have died, survival time will be censored at 
the date of last contact (“last known date alive”). 
Overall survival will be compared between treatment groups using a log-rank test procedure with a two-
sided α =0.2 level. The OS function for each treatment group will be estimated using the Kaplan-Meier 
product-limit method. Median and corresponding two-sided 80% confidence intervals will be computed by 
treatment group. Kaplan-Meier plots of OS will be presented. 
A Cox proportional hazard model for OS with treatment arm as single factor will be used to estimate the 
hazard ratio of vemurafenib and cobimetinib plus local treatment to second-line SOC and its corresponding 
80% confidence interval. 
5.4.2 Analysis of the secondary efficacy endpoints 
Progression Free Survival (PFS) 
The PFS analysis will be performed on the FAS. 
Progression free survival of patients with focal progression is defined as the time, in months, from 
randomization to the date of the first documented tumor progression or death due to any cause, whichever 
comes first. Clinical deterioration will not be considered progression. For subjects who neither progress nor 
die, time will be censored at the date of their last tumor assessment. For subjects who start a new anti-tumor 
treatment, time will be censored at the date of the start of the new treatment. For a randomized subject who 
does not have any post-randomization tumor assessments and who has not died, time will be censored at the 
randomization date. 
Progression free survival will be compared between treatment groups using a log-rank test procedure with 
a two-sided α =0.2 level. The PFS function for each treatment group will be estimated using the Kaplan-
Meier product-limit method. Median and two-sided 80% confidence intervals (CI) for median PFS will be 
computed by treatment group. Kaplan-Meier plots of PFS will be presented. 
A Cox proportional hazard model for PFS with treatment arm as single factor will be used to estimate the 
hazard ratio of vemurafenib and cobimetinib plus local treatment to second-line SOC and its corresponding 

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80% confidence interval. 
Absolute frequencies and proportions of patients with tumor progression or all-cause death will also be 
provided. 
Overall Survival (OS) of patients with non-focal progression  
The survival analysis of patients with non-focal progression will be performed on the Non-focal Progression 
Set. 
Overall survival of patients with non-focal progression is defined as the time, in months, from date of non-
focal progression to first-line to the date of death from any cause. If a patient is not known to have died, 
survival time will be censored at the date of last contact (“last known date alive”). The OS function will be 
estimated using the Kaplan-Meier product-limit method. Median and corresponding two-sided 80% 
confidence intervals will be computed. A Kaplan-Meier plot of OS will be presented. 
Overall survival results of patients with non-focal progression will be descriptively compared with OS 
results of patients with focal progression (i.e. primary efficacy endpoint). No statistical test will be foreseen 
for this comparison. 
5.4.3 Safety analysis 
Safety analyses will be conducted on the Safety Set and will be reported by actual treatment group and on 
the Non-focal Progression Set. 
Adverse events 
AEs will be assessed according to the Common Terminology Criteria for AEs (CTCAE version 4). 
The incidence of AEs will be tabulated by MedDRA System Organ Class and Preferred Term. The incidence 
of AEs will also be summarized by system organ class, preferred term and severity (based on CTCAE 
grades). The same analysis will be repeated for SAEs regardless of drug relationship, for drug related SAEs, 
AEs with CTCAE grade 3 or 4, AEs of special interest, AEs leading to discontinuation of study treatment 
and for drug related AEs. AEs for which relationship to study drug is not specified will be considered 
treatment-related. Deaths reportable as SAEs will be listed by patient and tabulated by type of AE. 
Laboratory parameters 
Categorization of laboratory values will be assigned programmatically as per NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4 or according to normal ranges for those parameters without 
available CTCAE grading. The calculation of CTCAE grades will be based purely on the observed 

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laboratory values; clinical assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be 
used. For laboratory tests where grades are not defined by CTCAE v4, results will be graded by the 
low/normal/high (low and high) classifications based on laboratory normal ranges. 
The following by-treatment summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests: 
● Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be counted 
only once for the worst grade observed post-baseline. 
● Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 
● Shift tables using the low/normal/high/ (low and high) classification to compare baseline to the worst 
on-treatment value for laboratory tests where CTCAE grades are not defined. 
Listings of all laboratory data with values flagged to show the corresponding CTCAE grades and the 
classifications relative to the laboratory normal ranges will also be generated. 
Other safety data 
ECGs, physical examinations, vital signs and ECOG PS will be listed and summarized by treatment arm. 
ECG 
● Shift table baseline to worst on-treatment result 
● Listing of ECG evaluations for all patients with at least one abnormality 
● Change from baseline QTcF 
Physical examination 
● Shift table baseline to worst on-treatment result 
Vital signs 
● Table with descriptive statistics at baseline, one or several post-baseline time points and change from 
baseline to this/these post-baseline time points 
ECOG PS 
● Shift tables comparing the baseline PS with the worst post-baseline result 

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5.4.4 Baseline descriptive statistics 
All data about patient demographics and baseline characteristics will be summarized, overall and by 
treatment group, by means of descriptive statistics for all patients enrolled in the study (i.e. patients who 
received at least one dose of first-line vemurafenib and cobimetinib treatment). 
A complete description of patient disposition will be provided, overall and by treatment group specifying 
the number of randomized patients, number of patients at each visit, completed and discontinued patients, 
and the reason for the discontinuation. 
The analysis populations will be described and the reasons for excluding the patient from any analysis set 
will be provided with the number of protocol violators per each criterion. 
Medical history data will be presented by MedDRA System Organ Class and Preferred Term. 
5.4.5 Treatments 
The Safety set and the Non-focal progression Set will be used for the following analyses. 
Investigational treatment 
Duration of study treatment, cumulative dose, average daily dose, actual dose intensity and relative dose 
intensity of each of the components of study treatment will be summarized. The number of patients with 
dose changes/interruptions will be presented along with the reasons for the dose change/interruptions. 
Concomitant treatments 
Concomitant medications or procedures and significant non-drug therapies taken concurrently with the 
study treatment will be listed and summarized by WHO Anatomical Therapeutic Chemical (ATC) Class, 
Preferred Term and treatment arm. These summaries will include medications starting on or after the start 
of study treatment or medications starting prior to the start of study treatment and continuing after the start 
of study treatment. Any prior medication or significant non-drug therapy starting and ending prior to the 
start of study treatment will be listed. 
5.4.6 Planned interim analyses 
No formal interim analysis is planned. 
5.4.7 Exploratory analysis 
For sequencing and point mutation calling, coverage and sequencing statistics will be determined using 
Picard CalculateHsMetrics and Picard CalculateInsertSizeMetrics. Non-synonymous mutations will be 
annotated using Oncotator (http://www.broadinstitute.org/oncotator/). Associations with clinical and 

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pathological variables will be evaluated using either Fisher’s exact tests or Freeman–Halton tests. P-values 
less than 0.05 will be considered statistically significant. All the analyses will be carried out using the 
statistical software STATA 12® (StataCorp LP, Texas, USA). 
5.5 Sample size 
The present phase II study is aimed at providing the rationale for a phase III efficacy trial of adequate size 
assessing the efficacy of dual target inhibition beyond focal progression. Consequently, an alfa error rate of 
0.2 (two-sided) will be used. The expected OS of patients with BRAF+ metastatic melanoma after a 1st 
focal progression is difficult to estimate due to the lack of published data on this specific subset of patients. 
However, the survival experience of these patients can be reasonably considered to be intermediate between 
that of BRAF+ patients in 1st line treatment with combined BRAF and MEK inhibition and the post-
progression survival of the same patients, i.e. at approximately 1.5 years of median survival. With 120 
patients enrolled over a period of 12 months, and a total of 60-70 patients randomized into the II line study 
in patients with focal progression, 38 deaths are expected in both groups combined with a 2-year follow-up 
after randomization. With 38 events, the study has 80% power to detect, with an alfa error rate of 0.2 (two-
sided), a statistical significance difference in favor of the experimental arm corresponding to a Hazard Ratio 
of 0.5.  
5.6 Enrollment and randomization 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.) that is assigned by the system 
automatically when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. Once assigned, the Subject No. must not be reused 
for any other subject and the Subject No. for that individual must not be changed. 
Treatment assignment/randomization 
Patients will be assigned, after focal progression, to one of the two treatment arms (i.e. vemurafenib and 
cobimetinib plus local treatment or SOC second line treatment) in a 1:1 ratio. 
The randomization numbers will be generated using procedures that ensure that treatment assignment is 
unbiased. A patient randomization list will be produced using a validated system that automates the random 
assignment of patient numbers to randomization numbers. These randomization numbers are linked to the 
different treatment arms. 
After focal progression, patients will be randomized via an Interactive Web Response System (IWRS) to 

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one of the treatment arms. The IWRS will assign a randomization number to the patient, which will be used 
to link the patient to a treatment arm. The randomization number will be used by the system only to assign 
patients to the treatment arms but will not be communicated to the user. 
6. CLINICAL MONITORING 
Clinical site monitoring will be conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial 
complies with the currently approved protocol, with GCP, and with applicable regulatory requirements.  
Monitoring for this study will be performed by a Contract Research Organization (CRO).  
Details of clinical site monitoring are documented in a Clinical Monitoring Plan (CMP). The CMP describes 
in detail who will conduct the monitoring, at what frequency monitoring will be done, at what level of detail 
monitoring will be performed, and the distribution of monitoring reports.  
Independent audits may be conducted to ensure monitoring practices are performed consistently across all 
participating sites and that monitors are following the CMP.  
7. SAFETY INSTRUCTIONS AND GUIDANCE 
7.1 Warning and precautions  
Investigators and patients should be aware of the risks of photosensitivity reactions and squamous cell 
carcinoma (SCC). 
Mild to severe photosensitivity was reported in several patients in the Phase I study who received doses of 
Vemurafenib that ranged from 240 to 1120 mg b.i.d. All patients should be advised to avoid prolonged sun 
exposure while taking Vemurafenib and for at least 5 days after study drug discontinuation. Patients should 
also be advised to use a broad-spectrum sunscreen of at least SPF >30 to help protect against sunburn. For 
acneiform rash, investigators should consider treatment with minocycline. 
A detailed surveillance plan for SCC is foreseen, which includes a thorough skin evaluation by a 
dermatologist for all patients who participate in the study. A full skin examination is requested at baseline 
and every 12 weeks while on study, when patient discontinues study drug and at the follow-up visit (28 
days after discontinuing study drug and every 12 weeks for 12 months for long-term follow-up). 
Any lesion at baseline or during treatment clinically suspected of representing cutaneous Squamous Cell 
Carcinoma (cSCC), basal cell carcinoma, actinic keratosis, keratoacanthoma or other skin conditions 

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identified by the dermatologist should be treated as per local standard of care. 
Owing to the possible tumor biopsy requirement (for screening or evaluation of suspicious skin lesions) in 
this study, risks such as infection of the surgical site, excessive bleeding, or injury to adjacent tissues, should 
be considered for patients who undergo tumor tissue biopsies. 
Concomitant medications 
Due to the underlying illness and the frequency of co-existent medical conditions in this patient population, 
all concomitant medication or treatment required by the patient will be at the discretion of the treating 
physician. Potential drug–drug interactions during treatment with vemurafenib and/or cobimetinib are 
however possible and are discussed here below. 
● Vemurafenib 
Medications primarily metabolized by CYP450 1A2, 3A4 and 2C9 enzymes, as well as those that strongly 
inhibit or induce the CYP 3A4 enzyme, should be used with caution when co- administered with 
Vemurafenib. 
Appendix 1 includes a non-exhaustive list of typical examples of CYP1A2 and CYP3A4 substrates and 
CYP3A4 inducers and inhibitors. 
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. Coadministration 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%. Concomitant use 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 coadministration cannot be avoided, exercise caution and consider a dose reduction of 
the concomitant CYP1A2 and CYP2D6 substrate drug. 
Coadministration 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. 
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. Strong CYP3A4 inhibitors 
(e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, 
ritonavir, indinavir, nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, rifampin, 

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rifabutin, rifapentine, phenobarbital) should be used with caution when coadministered with vemurafenib. 
● Cobimetinib 
Concurrent use of strong CYP3A inhibitors during treatment with Cobimetinib should be avoided. Caution 
should be exercised if a moderate CYP3A4 inhibitor is co-administered with cobimetinib. If concomitant 
use with a strong or moderate CYP3A inhibitor is unavoidable, patients should be carefully monitored for 
safety and dose modifications applied if clinically indicated. 
7.2 Adverse Events and Laboratory Abnormalities 
7.2.1 Adverse Events (AEs) 
According to the International Conference of Harmonization (ICH), an AE is any untoward medical 
occurrence in a patient or clinical investigation subject (patient) administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign [including an abnormal laboratory finding], symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not considered 
related to the medicinal (investigational) product. Pre-existing conditions which worsen during a study are 
to be reported as AEs. 
7.2.2 Severity 
Severity of all AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events 
v 4.0 (CTCAE v 4.0; most recent sub-version) on a five-point scale (Grade 1 to 5) and reported in detail on 
the CRF. 
CTCAE grades are as follows:  
Grade 1 Mild Discomfort noticed but no disruption of normal daily activity 
Grade 2 Moderate Discomfort sufficient to reduce or affect daily activity. No treatment or medical 
intervention is indicated although this could improve the overall well-being or symptoms of the patient 
Grade 3 Severe Inability to work or perform normal daily activity; treatment or medical intervention is 
indicated in order to improve the overall wellbeing or symptoms; delaying the onset of treatment is not 
putting the survival of the patient at direct risk. 
Grade 4 Life threatening/disabling. An immediate threat to life or leading to a permanent mental or physical 
conditions that prevents work or performing normal daily activities; treatment or medical intervention is 
required in order to maintain survival. 

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Grade 5 Death AE resulting in death. 
7.2.3 Drug AE relationship 
The causality relationship of study drug to the AE will be assessed by the investigator as either:  
Yes or No 
If there is a reasonable suspected causal relationship to the study medication, i.e. there are facts (evidence) 
or arguments to suggest a causal relationship, drug-event relationship should be assessed as Yes. 
The following criteria should be considered in order to assess the relationship as Yes: 
– Reasonable temporal association with drug administration 
– It may or may not have been produced by the patient’s clinical state, environmental or toxic factors, or 
other modes of therapy administered to the patient. 
– Known response pattern to suspected drug 
– Disappears or decreases on cessation or reduction in dose 
– Reappears on re-challenge 
The following criteria should be considered in order to assess the relationship as No: 
– It does not follow a reasonable temporal sequence from administration of the drug. 
– It may readily have been produced by the patient’s clinical state, environmental or toxic factors, or 
other modes of therapy administered to the patient. 
– It does not follow a known pattern of response to the suspected drug. 
– It does not reappear or worsen when the drug is re-administered. 
7.2.4 Serious Adverse Events  
A serious adverse event (SAE) is any experience that suggests a significant hazard, contraindication, side 
effect or precaution. An SAE is any AE that at any dose fulfills at least one of the following criteria: 
– is fatal; (results in death; NOTE: death is an outcome, not an event) 
– is Life-Threatening (NOTE: the term "Life-Threatening" refers to an event in which the patient was at 
immediate risk of death at the time of the event; it does not refer to an event which could hypothetically 
have caused a death had it been more severe). 
– required in-patient hospitalization or prolongation of existing hospitalization; 

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– results in persistent or significant disability/incapacity; 
– is a congenital anomaly/birth defect; 
– is medically significant or requires intervention to prevent one or other of the outcomes listed above 
Note: The term sudden death should be used only when the cause is of a cardiac origin as per standard 
definition. The terms death and sudden death are clearly distinct and must not be used interchangeably.  
Adverse Events of Special Interest (Immediately reportable to the Sponsor) 
The following Adverse Events of Special Interest (AESI) even if assessed as non-serious must be reported 
to Sponsor within 24h of the Investigator becoming aware of the event (expedited reporting as described in 
Section 7.5.2). 
Combined list of cobimetinib plus vemurafenib AESI: 
• 
Grade 1-4 serous retinopathy 
• 
Any Grade retinal vein occlusion 
• 
Grade ≥ 2 Left ventricular dysfunction 
• 
Rhabdomyolysis/Grade ≥3 CPK elevation including elevations of CPK-MM in conjunction with 
other laboratory evidence (aldolase and urine myoglobin), and clinical feature consistent with 
rhabdomyolysis (such as muscle pain, signs of renal failure, dark red or brown urine) 
• 
Grade ≥3 hemorrhage event, or any Grade cerebral hemorrhage 
• 
Grade ≥3 Rash 
• 
Grade ≥3 Diarrhea 
• 
Grade ≥3 Photosensitivity 
• 
Events suggestive of Drug Induced Liver Injury or other Grade ≥3 hepatotoxicity 
• 
AEs potentially associated with prolongation of cardiac repolarization 
• 
Non-cutaneous squamous cell carcinoma 
• 
Skin cancers 
• 
Gastrointestinal polyps 
• 
Any new or worsening malignancy including progression of RAS mutant malignancy, cuSCC, new 
primary melanoma, basal cell carcinoma (with or without radiation sensitization determined per protocol 

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design or inclusion/exclusion) 
• 
Potential drug-induced liver injury as defined by Hy's Law: 
o Treatment-emergent ALT or AST > 3 × baseline value in combination with total bilirubin > 2 × 
ULN (of which ≥ 35% is direct bilirubin) 
o Treatment-emergent ALT or AST > 3 × baseline value in combination with clinical jaundice 
• 
Suspected transmission of an infectious agent by the study treatment, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible spongiform 
encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent. A transmission of an 
infectious agent may be suspected from clinical symptoms or laboratory findings that indicate an infection 
in a patient exposed to a medicinal product. This term applies only when a contamination of study treatment 
is suspected. 
7.2.5 Progression of Underlying Malignancy 
Progression of underlying malignancy is not reported as an AE if it is clearly consistent with the suspected 
progression of the underlying cancer as defined by RECIST criteria, or other criteria as determined by 
protocol. Hospitalization due solely to the progression of underlying malignancy should NOT be reported 
as a SAE. Clinical symptoms of progression may be reported as AEs if the symptom cannot be determined 
as exclusively due to the progression of the underlying malignancy, or does not fit the expected pattern of 
progression for the disease under study. 
Symptomatic deterioration may occur in some patients. In this situation, progression is evident in the 
patient’s clinical symptoms, but is not supported by the tumor measurements, or the disease progression is 
so evident that the investigator may elect not to perform further disease assessments. In such cases, the 
determination of clinical progression is based on symptomatic deterioration. These determinations should 
be a rare exception, as every effort should be made to document the objective progression of underlying 
malignancy. If there is any uncertainty about an AE being due only to the disease under study, it should be 
reported as an AE or SAE 
7.3 Follow-up of AEs (28 days post discontinuation of study drugs and every 12 weeks until 24 
months for long term follow up) 
After 28 days from the last dose of study drugs, continue to follow up AEs as follows:  
Related AEs: Follow until one of the following occurs: 

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– Resolved or improved to baseline 
– Relationship is reassessed as unrelated 
– Death 
– Start of new anti-cancer regimen 
– Investigator confirms that no further improvement can be expected 
– Clinical or safety data is no longer collected, or final database closure 
Unrelated severe or life-threatening AEs: Follow until one of the following occurs: 
– Resolved or improved to baseline 
– Severity improved to Grade 2 
– Death 
– Start of new anti-cancer regimen 
– Investigator confirms that no further improvement can be expected 
– Clinical or safety data is no longer collected, or final database closure 
Unrelated Grade 1 or Grade 2 AEs: follow up until 28 days after last dose of study drugs and every 12 
weeks until 12 months for long-term follow up. The outcome of each AE must be recorded on the CRF. 
Long Term Safety Follow up Visits 
After treatment discontinuation, patients will continue to be followed for the occurrence of second primary 
malignancies and survival status every 12 weeks for 24 months after the last patient is randomized, or until 
the occurrence of one of the following: death, withdrawal of consent, or lost to follow up. 
The following information will be collected in the CRFs every 12 weeks during this follow-up: 
− Date of follow up assessment for a second primary malignancy 
− Type of malignancy 
− Histology of malignancy 
− Date of diagnosis (histologically confirmed locally) 
− Survival status 
This information can be collected during a routine clinic visit, from the patient medical records, or by 

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telephone (call from treating physician (investigator in the study) to the patient and/or other health care 
providers involved in the patient’s care). 
7.4 Laboratory Test abnormalities 
Laboratory test results will be recorded on the laboratory results form of the CRF, or appear on electronically 
produced laboratory reports submitted directly from the central laboratory, if applicable. 
Any laboratory result abnormality fulfilling the criteria for an SAE/AESI should be reported as such, in 
addition to being recorded as an AE in the CRF. 
Any treatment-emergent abnormal laboratory result that is clinically significant, i.e., that meets one or more 
of the following conditions, should be recorded as a single diagnosis on the AE page in the CRF: 
− Accompanied by clinical symptoms 
− Leads to a change in study medication (e.g. dose modification, interruption or permanent 
discontinuation) 
− Requires a change in concomitant therapy (e.g. addition of, interruption of, discontinuation of, or any 
other change in a concomitant medication, therapy or treatment). 
This applies to any protocol and non-protocol specified safety and efficacy laboratory result from tests 
performed after the first dose of study medication, which falls outside the laboratory reference range and 
meets the clinical significance criteria. 
7.4.1 Follow-up of Abnormal Laboratory Test Values 
In the event of medically significant unexplained abnormal laboratory test values, the tests should be 
repeated and followed up until they have returned to the normal range and/or an adequate explanation of the 
abnormality is found. If a clear explanation is established, it should be recorded on the CRF. 
7.5 Handling of Safety Parameters 
7.5.1 Reporting of AEs 
Information about all adverse events, whether volunteered by the patient, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means will be collected on 
the Adverse Event CRF page, documented in the patient’s medical records, and followed as appropriate. 
7.5.2 Reporting of SAEs/AESI (immediately reportable) 
Any SAEs / AESIs (as defined in section above) which occurs during the course of the study from the 

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enrollment visit (start of study screening procedures), including long term follow-up must be reported to the 
sponsor within 24 hours of the investigator becoming aware of the event (expedited reporting). The 
following proviso applies: 
➢ During the screening period, after written informed consent has been signed but prior to initiation of 
study drug, only SAEs related to protocol procedures will be reported.  
➢ From the first administration of vemurafenib and cobimetinib, all SAEs and AESIs must be reported 
until 28 days after the last dose of study drug. Related SAEs must be collected and reported 
regardless of the time elapsed from the last study drugs administration, even if the study has been 
closed.  
The investigator must complete the SAE Reporting Form on the eCRF or, in case of technical issues, 
send it via fax or email to the Pharmacovigilance Officer delegated by Sponsor indicated below within 
24 hours after learning of the event. 
CRO Pharmacovigilance Officer: Dr Riccardo Chisci, OPIS s.r.l. 
 
Email: all_phv@opis.it 
 
Fax: +39 0362 633622 
7.6 Pregnancy 
A female patient must be instructed to stop taking vemurafenib and cobimetinib immediately inform the 
investigator if she becomes pregnant during the study. The investigator should report all pregnancies within 
24 hours using the pregnancy section of the eCRF or, in case of technical issues, by sending it to the 
Pharmacovigilance Officer indicated in Section 7.5.2. The investigator should counsel the patient and 
discuss the risks of continuing with the pregnancy and the possible effects on the fetus. Monitoring of the 
patient should continue until conclusion of the pregnancy.  
Pregnancies occurring up to 6 months after the completion of the study medication must also be reported to 
the Pharmacovigilance Officer. Pregnancy occurring in the partner of a male patient participating in the 
study should be reported to the Pharmacovigilance Officer immediately (no more than 24 hours after 
learning of the pregnancy). The partner should be counseled, the risks of continuing the pregnancy should 
be discussed, as well as the possible effects on the fetus. Monitoring of the pregnant partner should continue 
until conclusion of the pregnancy. 
8. SOURCE DOCUMENTS AND ACCESS TO DATA/SOURCE DOCUMENTS  
Each participating site will maintain appropriate medical and research records for this trial, in compliance 

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with ICH E6 and regulatory and institutional requirements for the protection of confidentiality of 
participants. Each site will permit authorized representatives of Regulatory Agencies to examine (and when 
permitted by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, 
and evaluation of the study safety, progress, and data validity.  
Source data are all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these original 
documents and data records include, but are not limited to, hospital records, clinical and office charts, 
laboratory notes, memoranda, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and participant files and records kept at the 
pharmacy, at the laboratories, and medical-technical departments involved in the clinical trial.  
The eCRF will not be the only record of the patient’s participation in the study in order to ensure that anyone 
who accessed the patient’s medical record would have adequate knowledge that the patient is participating 
in the trial. 
9. QUALITY ASSURANCE AND QUALITY CONTROL 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory 
requirements.  
The investigational site will provide direct access to all trial-related sites, source data/documents, and reports 
for the purpose of monitoring and auditing by the Sponsor, and inspection by local and regulatory 
authorities. 
10. ETHICS 
This clinical study shall be implemented and reported in accordance with the ICH Guidelines for Good 
Clinical Practice, all applicable local regulations and with the ethical principles laid down in the Declaration 
of Helsinki. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the relevant Independent Ethics Committee (IEC) and Competent Authority (CA) for review 
and approval. Approval of both the protocol and the consent form must be obtained before any participant 
is enrolled. Any amendment to the protocol will require review and approval by the IEC and or CA before 

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the changes are implemented to the study. All changes to the consent form will be IEC and/or CA approved; 
a determination will be made regarding whether previously consented participants need to be re-consented. 
10.1 Informed consent  
Consent forms describing in detail the study agent, study procedures, and risks are given to the participant 
and written documentation of informed consent is required prior to enrolment in the trial and before any 
study related procedure takes place.  
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families. Consent forms will be IEC-
approved and the participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. All participants will receive a 
verbal explanation in terms suited to their comprehension of the purposes, procedures, and potential risks 
of the study and of their rights as research participants. Participants will have the opportunity to carefully 
review the written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document prior to any procedures being done specifically for the 
study. The participants may withdraw consent at any time throughout the course of the trial. A copy of the 
informed consent document will be given to the participants for their records. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
10.2 Participant and data confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
Sponsor and their representatives. This confidentiality is extended to cover testing of biological samples 
and genetic tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No information 
concerning the study or the data will be released to any unauthorized third party without prior written 
approval of the Sponsor. 
The study monitor, other authorized representatives of the Sponsor, representatives of the IEC or 
pharmaceutical company supplying study product(s) may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or hospital) and 

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pharmacy records for the participants in this study. The clinical study site will permit access to such records.  
The study participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as long a period 
as dictated by local IEC and Institutional regulations.  
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will not 
include the participant’s contact details or identifying information. Rather, individual participants and their 
research data will be identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites will be secured and password protected. 
10.3 Research Use of Stored Human Samples, Specimens or Data 
Samples and data collected under this protocol may be used to study melanoma, unless otherwise defined 
by the local laws and legislation of the participating countries. 
Samples and data will be stored using codes assigned by the investigators. Data will be kept in password-
protected computers. Only investigators will have access to the samples and data.  
Study participants who request destruction of samples will be notified of compliance with such request and 
all supporting details will be maintained for tracking.  
10.4 Insurance 
Prior to the start of the trial, the Sponsor will ensure that adequate insurance for patients is in place covering 
losses due to death or injury resulting from the trial, in accordance with applicable laws and regulations. In 
addition, the Sponsor will ensure that adequate insurance is in place for both investigator(s) and Sponsor to 
cover liability pertaining to death or injury resulting from the trial. The Investigator(s) will remain 
responsible towards the Sponsor of any fault or misconduct regarding the performance of the Study. 
11. DATA HANDLING AND RECORD KEEPING 
11.1 Data collection and management 
● Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic Case Report 
Form (eCRF) using fully validated software that conforms to 21 CFR Part 11 requirements. Designated 
investigator site staff will not be given access to the Electronic Data Capture (EDC) system until they are 
trained.  

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Web-based software will be used and no installation procedure is needed. Each site-qualified personnel will 
be allowed to access the eCRF by means of a ‘login mask’ requiring Username and Password and may read, 
modify and update only the information reported at his or her site. Each page reports site code and patient 
code. 
On-line validation programs will check for data discrepancies and, by generating appropriate error 
messages, allow the data to be confirmed or corrected before transfer to the CRO working on behalf of the 
Sponsor. The Investigator will certify that the data entered in the eCRF are complete and accurate.  
After database lock, the investigator will receive a CD-ROM of patient data for archiving at the 
investigational site. 
● Database management and quality control 
The CRO working on behalf of the Sponsor will review the data entered in the eCRF by investigational staff 
for completeness and accuracy and instruct site personnel to make any necessary corrections or additions. 
The Data Manager will perform the cleaning session by reviewing the warning messages raised by on-line 
checks and by running post-entry checks by means of validation programs and data listings specific for the 
study. If clarifications are needed, the Data Manager will raise queries by means of data query forms through 
the web application. Designated investigator site staff will be required to respond to queries and the Data 
Manager will make the correction to the database according to the responses. 
Data collection and query flows as well as the on-line and off-line checks are detailed in the Data 
Management Plan and Data Validation documents. 
Concomitant medications and prior medications entered into the database will be coded using the World 
Health Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic Chemical 
(ATC) classification system. Medical history/current medical conditions and adverse events will be coded 
using the Medical dictionary for regulatory activities (MedDRA). 
Randomization codes and data about the study drug are tracked using the eCRF. The system is supplied by 
OPIS, who also manages the database. 
The occurrence of any protocol deviations will be checked and the database will be locked and made 
available for data analysis after these actions have been completed and the database has been declared 
complete and accurate.  

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11.2 Study records retention 
The investigator/institution should maintain the trial documents as specified in Essential Documents for the 
Conduct of a Clinical Trial (ICH E6-R2 Section 8) and as required by applicable regulations and/or 
guidelines. The investigator/institution should take measures to prevent accidental or premature destruction 
of these documents.  
Essential documents (written and electronic) should be retained for a period of not less than twenty five (25) 
years from the completion of the study unless the Sponsor provides written permission to dispose of them 
or, requires their retention for an additional period of time because of applicable laws, regulations and/or 
guidelines. The subjects’ medical files will be archived in accordance with the national laws. 
11.3 Protocol deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or GCP requirements. The 
noncompliance may be on the part of either the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH E6:  
● 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
● 5.1 Quality Assurance and Quality Control, section 5.1.1  
● 5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site to use continuous vigilance to identify and report deviations. All deviations 
must be addressed in study source documents. 
12. PUBLICATION 
This study will ensure that the public has access to the published results of the research.  
The International Committee of Medical Journal Editors (ICMJE) policy requires that all clinical trials be 
registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National Library 
of Medicine. Other biomedical journals are considering adopting similar policies. 
 
 

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13. References 
● Ascierto P., Minor D., Ribas A et al. (2013) Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib 
(GSK2118436) in patients with metastatic melanoma. J Clin Oncol; 31: 3205–3211.  
● Chapman P., Hauschild A., Robert C et al. (2011) Improved survival with vemurafenib in melanoma 
with BRAF V600E mutation. N Engl J Med; 364: 2507–2516  
● Davies H., Bignell G., Cox C. et al. (2002) Mutations of the BRAF gene in human cancer. Nature; 417: 
949–954. 
● Eroglu Z, Ribas A. (2016) Combination therapy with BRAF and MEK inhibitors for melanoma: latest 
evidence and place in therapy. Ther Adv Med Oncol; 8(1): 48–56. 
● Hauschild A., Grob J., Demidov L. et al. (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a 
multicentre, open-label, phase 3 randomised controlled trial. Lancet; 380: 358–365. 
● Kim K., Kefford R., Pavlick A. et al. (2013) Phase II study of the MEK1/MEK2 inhibitor trametinib in 
patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF 
inhibitor. J Clin Oncol; 31: 482–489.  
● Larkin J., Ascierto P., Dreno B. et al. (2014) Combined vemurafenib and cobimetinib in BRAF-mutated 
melanoma. N Engl J Med; 371: 1867–1876. [ 
● Pavlick A., Ribas A., Gonzalez R. et al. (2015) Extended follow-up results of phase Ib study (BRIM7) 
of vemurafenib (VEM) with cobimetinib (COBI) in BRAF-mutant melanoma. J Clin Oncol; 33: 9020. 
● Ribas A., Gonzalez R., Pavlick A. et al. (2014) Combination of vemurafenib and cobimetinib in patients 
with advanced BRAF (V600)-mutated melanoma: a phase 1b study. Lancet Oncol; 15: 954–965. 
● Ribas A., Puzanov I., Dummer R. et al. (2015) Pembrolizumab versus investigator-choice chemotherapy 
for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet 
Oncol; 16(8) 908-18. 
● Rizos H., Menzies A., Pupo G. et al. (2014) BRAF inhibitor resistance mechanisms in metastatic 
melanoma: spectrum and clinical impact. Clin Cancer Res; 20: 1965–1977. 
● Robert C, Schachter J, Long GV et al., (2015) Pembrolizumab versus ipilimumab in advanced 
melanoma. N Engl J Med; 372(26): 2521-32. 
● Shi H., Hugo W., Kong X. et al. (2014) Acquired resistance and clonal evolution in melanoma during 
BRAF inhibitor therapy. Cancer Discov; 4: 80–93.  

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● Sosman J., Kim K., Schuchter L. et al. (2012) Survival in BRAF V600–mutant advanced melanoma 
treated with vemurafenib. N Eng J Med; 366: 707–714.  
● Wagle N., Emery C., Berger M.et al. (2011) Dissecting therapeutic resistance to RAF inhibition in 
melanoma by tumor genomic profiling. J Clin Oncol; 29: 3085–3096. 
● Weber JS, D’angelo SP, Minor D et al. Nivolumab versus chemotherapy in patients with advanced 
melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, 
open-label, phase 3 trial. Lancet Oncol; 2015 (16): 375-384. 
 
 

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Appendix 1. Impact of Vemurafenib on Concomitant Medications 
 
Substrates 
CYP 1A21 
CYP 2C91 
CYP3A42 
Amitriptyline 
caffeine 
clomipramine 
clozapine 
cyclobenzaprine 
estradiol 
fluvoxamine 
haloperidol 
imipramine 
N-DeMe 
mexilletine 
naproxen 
olanzapine 
ondansetron 
phenacetin_ 
acetaminophen 
propranolol riluzole 
ropivacaine tacrine 
theophylline 
tizanidine 
verapamil 
(R)warfarin 
zileuton 
zolmitriptan 
NSAIDs: 
diclofenac 
ibuprofen 
lornoxicam 
meloxicam 
S-naproxen_Nor 
piroxicam suprofen 
 
Oral Hypoglycemic: 
tolbutamide 
glipizide 
Angiotensin 
II 
Blockers: losartan 
irbesartan 
Sulfonylureas: 
glyburide 
glibenclamide 
glipizide 
glimepiride 
tolbutamide 
amitriptyline 
celecoxib 
fluoxetine 
fluvastatin 
glyburide 
nateglinide 
phenytoin-4-OH2 
rosiglitazone 
tamoxifen 
torsemide 
S-warfarin 
Macrolide 
antibiotics: 
clarithromycin 
erythromycin 
telithromycin 
Anti-arrhythmics: 
quinidine_3OH 
 
Benzodiazepines: 
alprazolam 
diazepam_3OH 
midazolam triazolam 
 
Immune Modulators: 
cyclosporine 
tacrolimus 
(FK506) HIV Antivirals: 
indinavir 
nelfinavir 
ritonavir 
saquinavir 
Prokinetic: 
cisapride 
 
Antihistamines: 
astemizole 
chlorpheniramine 
terfenadine 
 
Calcium Channel Blockers: 
amlodipine 
diltiazem felodipine 
lercanidipine 
nifedipine2 
nisoldipine 
nitrendipine 
verapamil 
 
HMG CoA Reductase Inhibitors: 
atorvastatin 
cerivastatin 
 
 
 

Protocol BeyPro2, Version 2.0, November 15, 2017 
 
 
 
 
 
 
      Page 60 of 64 
 
Substrates 
CYP 1A21 
CYP 2C91 
CYP3A42 
 
 
lovastatin 
simvastatin 
Steroid 
6beta-OH: 
estradiol hydrocortisone 
progesterone testosterone 
 
Miscellaneous: 
alfentanyl 
aprepitant 
aripiprazole buspirone 
cafergot 
caffeine 
cilostazol 
cocaine 
codeine-Ndemethylation 
dapsone 
dexamethasone 
dextromethorphan 
docetaxel 
domperidone 
eplerenone fentanyl 
finasteride gleevec 
haloperidol 
irinotecan lidocaine 
methadone 
nateglinide 
ondansetron 
pimozide 
propranolol 
quetiapine quinine 
risperidone 
salmeterol 
sildenafil sirolimus 
tamoxifen 
taxol 
terfenadine 

Protocol BeyPro2, Version 2.0, November 15, 2017 
 
 
 
 
 
 
      Page 61 of 64 
 
 
Trazodone 
vincristine 
 zaleplon 
 ziprasidone 
 zolpidem 
 
• 
1 Exposure of these drugs may be increased following Vemurafenib treatment. 
• 
2 Exposure of these drugs may be decreased following Vemurafenib treatment. 
 
Impact of Concomitant Medications on Vemurafenib3 
CYP 3A4 Inhibitors1 
CYP 3A4 Inducers2 
Indinavir 
nelfinavir 
ritonavir 
clarithromycin itraconazole ketoconazole 
nefazodone 
saquinavir 
telithromycin 
aprepitant 
erythromycin 
fluconazole 
grapefruit 
juice 
verapamil 
diltiazem 
cimetidine amiodarone chloramphenicol 
ciprofloxacin delaviridine 
diethyldithiocarbamate fluvoxamine 
gestodene 
imatinib 
mibefradil 
mifepristone 
norfloxacin norfluoxetine star fruit 
voriconazole 
Efavirenz nevirapine barbiturates 
carbamazepine 
efavirenz 
glucocorticoids 
modafinil 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone rifabutin 
rifampin 
St. John's wort troglitazone 
• 
1 Concomitant administration of these drugs may increase Vemurafenib exposure 
• 
2 Concomitant administration of these drugs may reduce Vemurafenib exposure 
 
 
 

Protocol BeyPro2, Version 2.0, November 15, 2017 
 
 
 
 
 
 
      Page 62 of 64 
Appendix 2. Translational biomarker study 
 
● Tumor biopsies 
The ancillary study requires tumor biopsies at baseline and upon progression for all enrolled patients when 
feasible.  
At baseline, tumor tissues will be obtained from fresh baseline biopsies performed in patients with easily 
accessible biopsy sites (subcutaneous and lymph nodes) and from archived samples for patients that cannot 
be biopsied. Tissue sample will remain in 10% neutral buffered formalin for a minimum of 24-48 hours 
but no more than 96 hours. A matched paraffin embedded (FFPE) tissue block will then be stored at room 
temperature at the site until shipment. Path assessments will be regularly performed to ensure that collected 
samples are of good quality. 
Upon progression, fresh biopsies will be obtained for patients with accessible tumor lesions provided they 
have given their consent to participate in the biomarker study. Accessible lesions are defined as tumor 
lesions that can easily biopsied i.e. cutaneous, sub-cutaneous and palpable lymph nodes. Failure to obtain 
sufficient tumor sample, after making best efforts, will not be considered a protocol violation. Lesions 
with the biggest change in size should be excised at time of progressive disease.  
A minimum of 10-15 x 5-6 micron-thick tissue sections will be collected for each patient/time point. 
Biopsies will be immediately transferred into the provided vials filled with formalin. The biopsies will be 
fixed for 24±2 hours, transferred into 70% ethanol and then (still in ethanol) shipped to a central pathology 
lab for paraffin embedding. 
As tumor tissue biomarkers, aberrations in main molecular pathways involved in melanoma pathogenesis 
(i.e., MAPK, CDKN2A-CDK4/6, PI3K-AKT) will be measured through gene panels. Using Ion Torrent 
technology, the following gene-panels - already tested on DNA samples from FFPE tissues - will be used 
for assessing the alterations in the main gene pathway candidates: 
1) Hotspot regions in Ion Ampliseq Cancer Hotspot panel (~2,800 mutations of 50 oncogenes and tumor 
suppressor genes): 1 pool (10-15 ng per DNA sample). 
 
 
 
 
 
 

Protocol BeyPro2, Version 2.0, November 15, 2017 
 
 
 
 
 
 
      Page 63 of 64 
 
ABL1 
EGFR 
GNAS 
KRAS 
PTPN11 
AKT1 
ERBB2 
GNAQ 
MET 
RB1 
ALK 
ERBB4 
HNF1A 
MLH1 
RET 
APC 
EZH2 
HRAS 
MPL 
SMAD4 
ATM 
FBXW7 
IDH1 
NOTCH1 
SMARCB1 
BRAF 
FGFR1 
JAK2 
NPM1 
SMO 
CDH1 
FGFR2 
JAK3 
NRAS 
SRC 
CDKN2A 
FGFR3 
IDH2 
PDGFRA 
STK11 
CSF1R 
FLT3 
KDR 
PIK3CA 
TP53 
CTNNB1 
GNA11 
KIT 
PTEN 
VHL 
2) Exons within melanoma-associated genes from IMI Somatic DNA panel: 3 pools (10-15 ng per pool, 
30-45 ng per DNA sample). 
 
● Peripheral blood samples: 
Approximately 10 ml of peripheral venous blood samples must be collected in EDTA tubes and 
immediately centrifuged at 1900 x g (4000 rpm) for 15 minutes at room temperature, for about 5 ml of 
plasma separation; this is a crucial step, because circulating tumor DNA has a very short half-life, ranging 
from 15-30 minutes to a maximum of two hours. Samples will be collected before therapy with 
BRAF+MEK inhibitors and after progression.  
 
Aspirated supernatant plasma must be transferred in polypropylene tubes (RNase, DNase and pyrogen-
free, for cryopreservation use) as 1ml aliquots and stored at -80°C (plasma is stable at this temperature for 

Protocol BeyPro2, Version 2.0, November 15, 2017 
 
 
 
 
 
 
      Page 64 of 64 
a long time).  
Samples will be shipped on ice dry, avoiding freeze-thaw cycles. 
 
Libraries were generated starting from 10-15 ng of DNA per primer pool using the Ion AmpliSeq Library 
Kit 2.0, barcoded with Ion Xpress Barcode Adapters (Life Technologies), purified with Agencourt Ampure 
XT Beads, diluted at a final concentration of 50 pM, pooled together, placed into the Ion Chef for emulsion 
PCR and Chip (316™ v2 BC) loading steps, then subsequently sequenced on the Ion PGM using the Ion 
Hi-Q™ Sequencing Chemistry.