Clinical trial NCT04655157
Conditions: Melanoma
Keywords: BRAFV600E/K mutation metastatic melanoma
Sponsor: Jason J. Luke, MD
Start date: 2021-05-28; Completion date: 2022-09-20
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Patients with unresectable or metastatic BRAF-mutant melanoma high-risk patients will be given 450 mg orally (PO) daily (QD) plus binimetinib 45 mg PO twice daily (BID) together with nivolumab administered intravenously (IV) at 3mg/kg and ipilimumab administered IV at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab administered IV at 480mg every 4 weeks until progression or discontinuation due to toxicity. Concurrently, a triple therapy arm will be explored with encorafenib 300 mg PO QD together with ipilimumab administered IV at 1mg/kg and nivolumab 3mg/kg IV every 3 weeks for 4 doses, followed by nivolumab administered at 480mg every 4 weeks until progression or discontinuation due to toxicity. Tolerability of the two arms will be compared, and a recommended phase 2 dose (RP2D) will be determined. After determination of treatment schedule, expansion cohorts will further explore the preliminary efficacy and further describe the toxicity profile of the triplet or quadruplet regimen in high-risk cohorts including symptomatic brain metastases or liver metastases with elevated lactate dehydrogenase (LDH) or bulky systemic disease burden.

Detailed description:
Study participants will consist of metastatic melanoma patients harboring BRAFV600E/K mutation without previous frontline therapy or recently started treatment with up to 6 weeks of targeted therapy (or \> 6 months from adjuvant therapy). Toxicity from prior treatment must have resolved to ≤ Grade 1 and not included previous Grade 3-4 immune-related adverse events (irAEs) that required treatment discontinuation or previous Grade 2 immune-related uveitis or pneumonitis.

Phase I, Cohort 1: Twelve patients will be treated with 300mg encorafenib and 3mg/kg nivolumab and 1 mg/kg ipilimumab. The dose limiting toxicity (DLT) for cohort 1 will be evaluated between weeks 1-6.

Phase I, Cohort 2: Upfront quadruple therapy with 450mg encorafenib, 45mg binimetinib, 3mg/kg nivolumab and 1mg/kg ipilimumab will be investigated with 12 participants. DLT window for phase I, cohort 2 will be evaluated at weeks 1-6.

Upon establishment of RP2R schedule, only participants with advanced melanoma who are treatment naïve in metastatic setting or have had up to 6 weeks of targeted therapy or who have progressed on adjuvant therapy for more than 6 months following completion of adjuvant therapy (either BRAF-MEK or PD1 Ab) will be eligible for participation in high risk disease cohort expansion (Groups 1 or 2).

Phase II will employ the RP2D schedule from Phase I and investigate the early efficacy in participants with high risk features who are less likely to derive benefit from standard treatment approaches and who may benefit from quadruple therapy despite the potential for increased toxicity. These will include: Group 1) symptomatic brain metastases \[up to 30 patients\] and Group 2) Elevated LDH \>1x upper limit of normal (ULN) with: a) liver metastases OR b) bulky visceral disease (sum of longest diameter (SLD) \> 44mm) \[combined with Group 1 up to 60 total patients\].

Following initiation of triple or quadruple therapy, participants will be followed for safety and response. Safety assessments will be a high priority with on-going Bayesian toxicity monitoring and efficacy assessments every 12 weeks. Based on prior targeted, immune, and triplet therapy studies, we anticipate up to 30-50% DLT and will consider temporary suspension of trial enrollment with a DLT \> 75% as determined by CTCAEv5. Treatment efficacy will be documented using RECIST 1.1 and RANO-BM criteria, recorded every 4-12 weeks, and immune-RECIST (iRECIST) and immune-RANO (iRANO) criteria.

Arms: arm 1: Patients will be treated with 300mg encorafenib and 3mg/kg nivolumab and 1 mg/kg ipilimumab (triple therapy). arm 2: Patients will be treated with 450mg encorafenib, 45mg binimetinib, 3mg/kg nivolumab and 1mg/kg ipilimumab (quadruple therapy).
Interventions: intervention 1: encorafenib intervention 2: nivolumab intervention 3: ipilimumab intervention 4: binimetinib
Intervention descriptions: intervention 1: A small molecule BRAF inhibitor that targets key enzymes in the MAPK signaling pathway. intervention 2: A programmed death receptor-1 (PD-1) blocking monoclonal antibody that works by helping the immune system to slow or stop the growth of cancer cells. intervention 3: A monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. intervention 4: A small molecule, selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway that may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Protocol documents:
Prot_SAP_000.pdf: 
Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
1 
 
TITLE: A Multi-Center Phase I/II Open Label Study to Evaluate Safety and Efficacy in 
Participants with Metastatic BRAF-mutant Melanoma Treated with Encorafenib with and 
without Binimetinib in Combination with Nivolumab and Low-dose Ipilimumab. (QUAD 01: 
Quadruple Therapy in Melanoma) 
 
SPONSOR-INVESTIGATOR:  
Jason J. Luke, MD, FACP 
 
HCC#:  
 
 
 
20-190 
 
NCT#:  
 
 
 
NCT04655157 
 
BMS Study #:  
 
 
CA209-7Y4 
 
PRINCIPAL INVESTIGATOR: 
Jason J. Luke, MD, FACP  
Director of the Cancer Immunotherapeutics Center        
UPMC Hillman Cancer Center 
5115 Centre Ave 
Pittsburgh, PA 15232 
Telephone: 412-623-4511 
Fax: 412-623-7948 
lukejj@upmc.edu 
 
CO-PRINCIPAL INVESTIGATOR: 
Max Jameson-Lee, MD, PhD 
Medical Oncology Fellow 
UPMC Hillman Cancer Center 
jamesonleem@upmc.edu 
 
 
 
 
 
 
Version 4, Date: 03/18/2022 
 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
2 
 
DOCUMENT HISTORY 
Document 
Date of Issue 
 
Summary of Change 
Original 
Protocol 
Date 
 
Not Applicable 
Amended 
Protocol 
4/12/21 
Amended inclusion and 
exclusion criteria on pages 4, 
5, 27, and 33 
Allow for up to 6 weeks of 
previous targeted therapy 
Amended 
Protocol 
9/1/21 
Expanded Table 5 to clarify 
assessment and visits 
Clarified provider visits and 
nursing visits through week 14 
Amended 
Protocol 
10/17/21 
Amended inclusion and 
exclusion criteria on pages 4, 
5, 27, and 33 
Allow for up to 1 cycle of previous 
immunotherapy 
Amended 
Protocol  
03/18/2022 
Amended exclusion criteria 
page 33 
Clarification to thromboembolic 
event  
Amendment 1 
Expanded inclusion criteria to allow up to 6 weeks of targeted therapy prior to enrollment 
on trial. 
Rationale: 
High risk patients with elevated LDH, liver metastases, and brain metastases were 
presenting to accrual sites after having received targeted therapy prior to enrollment. This 
expanded inclusion criteria was adopted to expedite trial accrual. 
Major Changes: 
• Expanded inclusion criteria throughout protocol. 
Amendment 2 
Expanded Table 5 to clarify assessments through week 10. After week 14, follow up visits 
will be monthly with CBC, CMP, and TSH laboratory assessments and physical exam 
prior to nivolumab 480mg flat dose, and imaging every 12 weeks while on treatment per 
protocol. 
Rationale: 
Clarify treatment and monitoring. 
Major Changes: 
• Expanded Table 5 to expand schedule through week 10. 
Amendment 3 
Expanded inclusion criteria to allow up to one cycle of immunotherapy prior to enrollment 
on trial. 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
3 
 
Rationale: 
After meeting with Principal Investigators at participating sites to discuss enrollment, 
decision was made to allow one cycle of immunotherapy prior to enrollment based on 
data from SECOMBIT and DREAM-Seq trials which have established sequential therapy 
with upfront immunotherapy as a standard of care. While dual checkpoint inhibition with 
CTLA4 and PD1 is the most likely combination, we will also allow single agent 
immunotherapy as well. This will allow patients who were started on checkpoint inhibition 
in the community to participate and increase accrual. 
Major Changes: 
• Expanded inclusion criteria throughout protocol. 
 
Amendment 4  
Changes to exclusion criteria to allow patients with history of thromboembolic events that 
are on stable dosing of anti-coagulants per investigator discretion.  
Rationale: 
The PI in conjunction with the treating investigators has identified that protocol exclusion 
criteria #12 is at odds with a common presentation of relevant patients for this protocol 
and is potentially adverse to the best treatment of such patients. The treatment population 
for the protocol are those with high-risk and/or large tumor burden, where concurrent 
venous thromboembolism is a common occurrence. 
Major changes: 
• Updates to exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
4 
 
 
SYNOPSIS 
Clinical Protocol HCC 20-190 
Protocol Title:  
A Multi-Center Phase I/II Open Label Study to Evaluate Safety and Efficacy in 
Participants with Metastatic BRAF-mutant Melanoma Treated with Encorafenib 
with and without Binimetinib in Combination with Nivolumab and Low-dose 
Ipilimumab. (QUAD 01: Quadruple Therapy in Melanoma). 
Investigational Product(s), Dose and Mode of Administration, Duration of 
Treatment with Investigational Product(s):   
Encorafenib 450 mg orally (PO) daily (QD) plus binimetinib 45 mg PO twice daily (BID) 
together with nivolumab administered intravenously (IV) at 3mg/kg and ipilimumab 
administered IV at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 
administered IV at 480mg every 4 weeks until progression or discontinuation due to 
toxicity. 
Concurrently, a triple therapy arm will be explored with encorafenib 300 mg PO QD 
together with ipilimumab administered IV at 1mg/kg and nivolumab 3mg/kg IV every 3 
weeks for 4 doses, followed by nivolumab administered at 480mg every 4 weeks until 
progression or discontinuation due to toxicity. 
Tolerability of the two arms will be compared, and a recommended phase II regimen 
(RP2R) will be determined. 
After determination of treatment regimen, expansion cohorts will further explore the 
preliminary efficacy and further describe the toxicity profile of the triplet or quadruplet 
regimen in high-risk cohorts including symptomatic brain metastases or liver metastases 
with elevated lactate dehydrogenase (LDH) or bulky systemic disease burden. 
Study Phase: 1/2 
Research Hypothesis: Treatment with encorafenib + nivolumab + ipilimumab (triple 
therapy) and/or treatment with encorafenib + binimetinib + nivolumab + ipilimumab 
(quadruple therapy) will demonstrate adequate safety and tolerability in unresectable or 
metastatic BRAF-mutant melanoma high-risk patients. 
Objectives 
Primary Objective 
• To nominate a recommended phase II regimen (RP2R) of triple or quadruple 
therapy with encorafenib (+/- binimetinib) + nivolumab and + ipilimumab in BRAF-
mutated, metastatic melanoma. 
 
Secondary Objectives 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
5 
 
• To estimate the RECIST response rate of triple or quadruple therapy in high-risk 
populations of BRAF-mutated, metastatic melanoma. 
• To estimate the CNS clinical benefit rate (CBR, defined as complete response 
[CR] + partial response [PR] + stable disease [SD] > 6 months) per RANO-MB 
criteria of triple or quadruple therapy in BRAF-mutated, metastatic melanoma to 
the CNS 
• To describe the toxicity, using Criteria for Adverse Events version 5 (CTCAEv5), 
of triple or quadruple therapy in BRAF-mutated, metastatic melanoma 
• To summarize the progression-free survival of triple or quadruple therapy in high-
risk populations of BRAF-mutated, metastatic melanoma 
 
Exploratory Objective 
• To evaluate the association between treatment response and baseline tumor 
mutational burden, changes in the tumor microenvironment (interferon [IFN]- 
associated gene expression), T cell clonality, and other biospecimens before and 
after therapy. 
• To evaluate the overall survival (OS) of triple or quadruple therapy in high-risk 
population of BRAF-mutated, metastatic melanoma 
 
Study Design 
This is an open label, multi-site, phase 1/2 study of encorafenib +/- binimetinib + 
nivolumab + ipilimumab for the treatment of patients with unresectable or metastatic 
BRAF-mutated melanoma in high risk cohorts. 
Study participants will consist of metastatic melanoma patients harboring BRAFV600E/K 
mutation without previous frontline therapy or recently started treatment with up to 6 
weeks of targeted therapy, or one cycle of immunotherapy (or > 6 months from adjuvant 
therapy). Toxicity from prior treatment must have resolved to ≤ Grade 1 and not included 
previous Grade 3–4 immune-related adverse events (irAEs) that required treatment 
discontinuation or previous Grade 2 immune-related uveitis or pneumonitis.  
Phase I, Cohort 1: Twelve patients will be treated with 300mg encorafenib and 3mg/kg 
nivolumab and 1 mg/kg ipilimumab. The dose limiting toxicity (DLT) for cohort 1 will be 
evaluated between weeks 1-6. 
Phase I, Cohort 2: Upfront quadruple therapy with 450mg encorafenib, 45mg binimetinib, 
3mg/kg nivolumab and 1mg/kg ipilimumab will be investigated with 12 participants. DLT 
window for phase I, cohort 2 will be evaluated at weeks 1–6.  
Upon establishment of RP2R schedule, only participants with advanced melanoma who 
are treatment naïve in metastatic setting or have had up to 6 weeks of targeted therapy, 
or one cycle of immunotherapy, or who have progressed on adjuvant therapy for more 
than 6 months following completion of adjuvant therapy (either BRAF-MEK or PD1 Ab) 
will be eligible for participation in high risk disease cohort expansion (Groups 1 or 2). 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
6 
 
Phase II will employ the RP2R schedule from Phase I and investigate the early efficacy 
in participants with high risk features who are less likely to derive benefit from standard 
treatment approaches and who may benefit from quadruple therapy despite the potential 
for increased toxicity. These will include: Group 1) symptomatic brain metastases [up to 
30 patients] and Group 2) Elevated LDH >1x upper limit of normal (ULN) with: a) liver 
metastases OR b) bulky visceral disease (sum of longest diameter (SLD) > 44mm) 
[combined with Group 1 up to 60 total patients].  
Following initiation of triple or quadruple therapy, participants will be followed for safety 
and response. Safety assessments will be a high priority with on-going Bayesian toxicity 
monitoring and efficacy assessments every 12 weeks. Based on prior targeted, immune, 
and triplet therapy studies, we anticipate up to 30–50% DLT and will consider temporary 
suspension of trial enrollment with a DLT > 75% as determined by CTCAEv5. Treatment 
efficacy will be documented using RECIST 1.1 and RANO-BM criteria, recorded every 4-
12 weeks, and immune-RECIST (iRECIST) and immune-RANO (iRANO) criteria. 
 
Study Population 
Phase I RP2R finding  
Key Inclusion Criteria: 
• Patients with histologically confirmed metastatic or unresectable BRAFV600E/K 
mutant melanoma 
• Patients must be greater than 6 months from adjuvant therapy (if any given) 
and/or have recently started treatment with up to 6 weeks of targeted therapy, or 
one cycle of immunotherapy 
• Patients must meet criteria for inclusion into either Phase II expansion cohorts 
listed below – Brain Metastases or Elevated LDH/Bulky Visceral Disease  
Key Exclusion Criteria: 
• Uveal melanoma 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
7 
 
• Participants with a non-melanoma related condition requiring systemic treatment 
with either corticosteroids (> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of study drug administration. 
Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily 
prednisone equivalents are permitted in the absence of active autoimmune 
disease. 
• History or current evidence of retinal vein occlusion (RVO) or current risk factors 
for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of 
hyperviscosity or hypercoagulability syndromes); history of retinal degenerative 
disease. 
Phase II: High-risk Expansion Groups 
Group 1: Brain Metastases 
Key Inclusion Criteria: 
• Metastatic melanoma involving the brain but excluding leptomeningeal disease 
• Treatment with stereotactic radiosurgery must have occurred ≥14 days prior to 
start of study treatment. If prior radiosurgery was pursued, then at least one 
evaluable lesion must not have been irradiated. Prior whole-brain radiation is not 
allowed. 
• Symptomatic brain parenchymal metastases not requiring urgent radiation are 
permitted as well as patients on a stable dose of corticosteroids equivalent to 4 
mg dexamethasone daily for the preceding 10 days prior to first dose.  
• Eligible patients with prior local therapy to all brain lesions must have 
demonstrated progression of pre-existing target lesions per RANO-BM criteria. 
Group 2: Elevated LDH with Liver Metastases OR Bulky Visceral Disease 
Key Inclusion Criteria: 
• LDH >1x ULN 
• Total body SLD > 44mm (including but not limited to liver metastases) or 
metastatic melanoma involving the liver 
• 
Study Drug: 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
8 
 
Study Drugs for QUAD 01 
Medication  
 
Potency  
Nivolumab  
 
10 mg/mL 
Ipilimumab  
 
5 mg/mL 
Encorafenib  
Binimetinib   
 
75 mg capsule 
15 mg tablet 
 
Study Assessments 
The primary safety endpoint will be assessed using the CTCAEv5 criteria at 6 weeks with 
continuous Bayesian toxicity monitoring in phase II. 
Statistical Considerations: Rates of DLTs and objective responses will be estimated 
with one sided confidence intervals 
Sample Size: Phase I, two cohorts of 12 patients, 24 in total.  
Phase 2 at RP2R selected from Phase I, two cohorts with up to 30 patients in cohort 1, 
remainder in cohort 2 for a total of 60. 
Endpoints: Rate of DLT attributable to the therapeutic agents; objective response rate 
Analyses 
• For both the phase I and phase II cohorts, once the phases have completed accrual, 
inference for safety will be based on one sided confidence intervals. DLT rates will be 
calculated with one sided upper 90% confidence intervals.  If the upper bound is lower 
than 75% the investigator may declare the regimen to be safe for further evaluation.  
• If 4 or fewer DLTs are observed among 12 patients the upper bound of an exact 90% 
confidence interval will be less than 60% 
• Provision is made for early stopping in the phase II cohorts by invoking a Bayesian 
continuous monitoring plan. Beginning with the 5th patient DLTs will be compiled for 
calculating the posterior probability of excess toxicity. Thereafter if an unexpected 
excess toxicity rate is observed the trial will be suspended pending UPMC Hillman 
DMSC vs. other review. 
• The following table provides a decision table for trial suspension. 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
9 
 
 
• In the phase II cohort, the estimated objective response and clinical benefit rates will 
be estimated with an 80% one sided lower confidence interval. 
 
Operating characteristics of possible decision rules in phase II 
If a 30-patient phase II cohort is completed the following decisions are possible: 
If 23 or more DLTs are observed among 30 patients the combination can be considered 
as too toxic and a DLT rate ≥ 75% cannot be ruled out 
Objective response criteria will be summarized with response rates and calculated 
intervals of progression free survival. 
 
 
 
Number of Evaluable 
Patients (Inclusive) 
Suspend if there are 
This many DLTs 
Number of Evaluable 
Patients (Inclusive) 
Suspend if there are 
This many DLTs 
0-4 
----- 
17 
14 
5 
5 
18-19 
15 
6-7 
6 
20 
16 
8 
7 
21 
17 
9 
8 
22-23 
18 
10-11 
9 
24 
19 
12 
10 
25 
20 
13 
11 
26-27 
21 
14-15 
12 
28 
22 
16 
13 
29 
23 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
10 
 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
DOCUMENT HISTORY.................................................................................................................2 
SYNOPSIS ......................................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................10 
1. 
INTRODUCTION AND STUDY RATIONALE ......................................................13 
1.1 
Study Rationale ...........................................................................................................13 
1.1.1 
Disease Background ...................................................................................................13 
1.1.2 
Treatment of Metastatic BRAF-mutant Melanoma .....................................................14 
1.1.2.1 
Immunotherapy ...........................................................................................................14 
1.1.2.2 
Targeted Therapy ........................................................................................................15 
1.1.2.3 
Combination Targeted and Immunotherapy ...............................................................16 
1.1.3 
High-risk Patient Groups have Unmet Need ..............................................................17 
1.1.3.1 
Brain Metastases ........................................................................................................17 
1.1.3.2 
Elevated Liver Enzymes and Bulky Disease ...............................................................20 
1.1.4 
Quadruple Therapy .....................................................................................................20 
1.2 
Research Hypothesis ...................................................................................................21 
1.3 
Objectives ...................................................................................................................21 
1.4 
Product Development Background .............................................................................22 
1.4.1 
Pharmacology .............................................................................................................22 
1.4.1.1 
Pharmacokinetics .......................................................................................................23 
1.4.2 
Clinical Experience ....................................................................................................25 
2. 
ETHICAL CONSIDERATIONS................................................................................26 
2.1 
Good Clinical Practice ................................................................................................26 
2.2 
Institutional Review Board/Independent Ethics Committee ......................................26 
2.3 
Informed Consent .......................................................................................................26 
3. 
INVESTIGATIONAL PLAN .....................................................................................28 
3.1 
Study Design and Duration .........................................................................................28 
3.1.1 
Screening Phase ..........................................................................................................29 
3.2 
Post Study Access to Drug .........................................................................................30 
3.3 
Study Population .........................................................................................................30 
3.3.1 
Inclusion Criteria ........................................................................................................30 
3.3.2 
Exclusion Criteria .......................................................................................................31 
3.3.3 
Phase II Group 1 Specific Criteria .............................................................................33 
3.3.4 
Women of Childbearing Potential ..............................................................................33 
3.4 
Concomitant Treatments .............................................................................................34 
3.4.1 
Prohibited and/or Restricted Treatments ...................................................................34 
3.4.2 
Other Restrictions and Precautions ............................................................................34 
3.5 
Discontinuation of Participants from Treatment with Study Drugs ...........................34 
3.6 
Post Study Drug Follow Up ........................................................................................35 
3.6.1 
Withdrawal of Consent ...............................................................................................35 
3.6.2 
Lost to Follow-up ........................................................................................................35 
4. 
STUDY DRUG ...........................................................................................................36 
4.1 
Investigational Product ...............................................................................................36 
4.2 
Non-Investigational Product .......................................................................................38 
4.3 
Storage and Dispensing ..............................................................................................38 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
11 
 
4.4 
Method of Assigning Subject Identification ...............................................................39 
4.5 
Selection and Timing of Dose for Each Subject .........................................................40 
4.6 
Concomitant Therapy .................................................................................................43 
4.7 
DLT .............................................................................................................................44 
4.8 
Management Guidelines for Immunotherapy (I-O) Agents .......................................47 
4.9 
Management Guidelines for Targeted Therapy ..........................................................48 
4.10 
Guidelines for Permanent Discontinuation .................................................................48 
4.11 
Treatment of Nivolumab or Ipilimumab Related Infusion Reactions ........................49 
5. 
STUDY DESIGN .......................................................................................................51 
5.1 
Overall Design ............................................................................................................51 
5.1.1 
Retesting During Screening or Lead-in Period ..........................................................55 
5.2 
Safety Assessments .....................................................................................................55 
5.2.1 
Medical History, Physical Exam, Physical Measurements ........................................55 
5.2.2 
Vital Signs ...................................................................................................................56 
5.2.3 
Imaging Assessment for Study ....................................................................................56 
5.2.4 
ECOG Status ...............................................................................................................56 
5.2.5 
AE Monitoring ............................................................................................................56 
5.2.6 
Laboratory Test Assessments ......................................................................................56 
5.3 
Efficacy Assessments .................................................................................................57 
5.3.1 
Confirmation of scans .................................................................................................58 
5.3.2 
Algorithms for Response Assessment..........................................................................58 
5.3.2.1 
Safety ...........................................................................................................................58 
5.3.2.2 
Secondary Endpoints – Efficacy .................................................................................58 
5.4 
Biomarker Assessments ..............................................................................................58 
6. 
ADVERSE EVENTS..................................................................................................61 
6.1 
Serious Adverse Events ..............................................................................................61 
6.1.1 
SAE Collection and Reporting ....................................................................................62 
6.2 
Laboratory Test Result Abnormalities ........................................................................63 
6.3 
Pregnancy ...................................................................................................................64 
6.4 
Overdose .....................................................................................................................64 
6.5 
Other Safety Concerns ................................................................................................64 
7. 
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES ..........................................................................................................65 
8. 
STATISTICAL CONSIDERATIONS .......................................................................66 
8.1 
Objectives ...................................................................................................................66 
8.2 
Endpoints ....................................................................................................................67 
8.3 
Sample Size Considerations .......................................................................................67 
8.4 
Proposed Analysis of Primary and Secondary Endpoints ..........................................69 
9. 
STUDY MANAGEMENT .........................................................................................70 
9.1 
Compliance .................................................................................................................70 
9.1.1 
Compliance with the Protocol and Protocol Revisions ..............................................70 
9.1.2 
Monitoring ..................................................................................................................71 
9.1.2.1 
Source Documentation ................................................................................................71 
9.1.3 
Investigational Site Training ......................................................................................71 
9.2 
Records .......................................................................................................................71 
9.2.1 
Records Retention .......................................................................................................71 


Phase I/II study of encorafenib with and without binimetinib with nivolumab and low dose ipilimumab in metastatic 
BRAF mutant melanoma 
12 
 
9.2.2 
Study Drug Records ....................................................................................................72 
9.2.3 
Case Report Forms .....................................................................................................72 
9.3 
Clinical Study Report and Publications ......................................................................73 
APPENDIX 1 
RECIST 1.1 AND IMMUNE RESPONSE CRITERIA ............................78 
APPENDIX 2 
DOSE REDUCTION FOR ENCORAFENIB RELATED 
ADVERSE EVENTS .................................................................................79 
APPENDIX 3 
DOSE REDUCTION FOR BINIMETINIB RELATED ADVERSE 
EVENTS ....................................................................................................84 
APPENDIX 4 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS V5.0 (CTCAE)...........................................................................89 
APPENDIX 5 
ASSESSMENT OF OVERALL TUMOR BURDEN AND 
MEASURABLE DISEASE .......................................................................90 
5.1a 
MEASURABILITY OF TUMOR .............................................................90 
5.2a 
METHOD OF ASSESSMENT ..................................................................91 
5.3a 
EVALUATION OF TARGET LESIONS .................................................92 
5.4a 
EVALUATION OF NON-TARGET LESIONS .......................................93 
5.5a 
NEW LESIONS .........................................................................................94 
5.6a 
TIME POINT RESPONSE ........................................................................94 
5.7a 
MISSING ASSESSMENTS AND INEVALUABLE 
DESIGNATION ........................................................................................95 
5.8a 
BEST OVERALL RESPONSE: ALL TIMEPOINTS ..............................95 
5.9a 
SPECIAL NOTES ON RESPONSE ASSESSMENT ...............................96 
5.10a 
DURATION OF RESPONSE....................................................................96 
5.11a 
LESIONS THAT DISAPPEAR AND REAPPEAR .................................97 
5.12a 
USE OF FDG-PET ....................................................................................97 
APPENDIX 6 
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS ....................................................................................................98 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
13 
1. INTRODUCTION AND STUDY RATIONALE 
This is a phase I open label study of encorafenib +/- binimetinib + nivolumab + ipilimumab 
in participants with unresectable or metastatic BRAFV600E/K -mutant melanoma. Once a 
recommended phase II regimen (RP2R) is determined, expansion into known high risk 
patient groups: 1) symptomatic brain metastases and 2) elevated liver enzymes with 
hepatic metastases will be investigated for safety and efficacy. 
 
Both targeted therapy (BRAF + MEK inhibitors) and immunotherapy (anti-PD-1 + anti-
CTLA-4) are approved in the US and EU for metastatic or unresectable BRAFV600E/K 
mutant melanoma. Targeted therapy has an initial response rate of 75%, however the 
median PFS is only 11–14 months 1–4. Single agent immunotherapy with anti-PD-1 has a 
lower initial response rate of 30–40%, however the addition of anti-CTLA-4 (ipilimumab) 
can increase that to 60% 5. Relative to targeted therapy, immunotherapy has greater 
potential to induce long- lasting remissions in a subset of patients 1,6. 
 
Early phase trials have combined targeted therapy with anti-PD-1 which report increased 
PFS compared to targeted or immunotherapy alone 4,5,7, and the phase III IMspire 150 
trial of targeted + anti-PD-1 (two targeted + one immunotherapy “triple”) therapy vs. 
targeted therapy alone recently met its primary endpoint of increased PFS 8. Results of 
the proposed study combining targeted (encorafenib +/- binimetinib) and (two) 
immunotherapies (nivolumab + ipilimumab) [*triple or quadruple therapy] will detail the 
safety and efficacy of this novel treatment for high risk patients who historically have not 
responded to doublet or triplet therapy. 
*Triple therapy in this protocol will be with two immunotherapy agents, whereas IMspire150 triple therapy contained two targeted 
agents. 
 
1.1 Study Rationale 
1.1.1 Disease Background 
Cutaneous melanoma is the fifth leading cause of cancer in the United States with 96,480 
estimated new cases in 2019 leading to 7,230 deaths 9. The majority of melanomas have 
mutations in the mitogen-activated kinase (MAPK) pathway, important for cell signaling, 
growth, and survival 10. The most common mutation in the MAPK pathway is through 
constitutive activation of the BRAF kinase via mutation, which occurs in 40-60% of cases. 
More than 97% of BRAF mutations occur at codon 600 11. The most common mutation 
(~90%) results in a substitution of valine for glutamic acid at position 600 (V600E) 12, while 
the V600K mutation represents ~8% 11. BRAF mutant melanoma is clinically more 
aggressive than BRAF wild type, and is more frequent in younger patients and/or in 
anatomical regions without chronic sun damage 13. 
Up to one-third of patients already have multifocal and rapidly progressing disease when 
metastatic melanoma is first detected 14. These high-risk patients commonly have brain 
and visceral organ involvement, and are known to have poorer responses to either 
targeted or immunotherapy 15–17 (see Section 1.1.3). 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
14 
1.1.2 Treatment of Metastatic BRAF-mutant Melanoma 
In 2010, treatment options for metastatic melanoma were systemic chemotherapy with 
dacarbazine or high dose interleukin 2 (IL-2), neither of which significantly impacted OS 
and few survived > 1 year 18,19. Immunotherapy with checkpoint inhibitors targeting 
cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed cell-death 
protein 1 (PD-1), and later targeted therapies against BRAF and MEK kinases have been 
approved, improving OS and leading to durable remissions in a subset of patients. 
1.1.2.1 Immunotherapy 
Ipilimumab 
The inhibitory CTLA-4 receptor is expressed on T cells and regulates the amplitude of T 
cell activation in early stages 20. In 2011, ipilimumab, an anti-CTLA-4 antibody was 
approved as the first drug to demonstrate a survival benefit in melanoma. The pivotal 
phase III study of ipilimumab showed an OS benefit in previously treated metastatic 
melanoma vs. an investigational peptide vaccine gp100 21. In a second phase III trial of 
treatment naïve patients, ipilimumab + dacarbazine had improved OS compared to 
dacarbazine alone 22. Importantly, extended follow up showed that ipilimumab resulted in 
long-term survival in approximately 20% of patients 23. 
Nivolumab 
Programmed death receptor 1 (PD-1) is another inhibitory immune checkpoint receptor 
expressed on the surface of T cells. Its primary ligand, programmed death ligand 1 (PD-
L1), can be expressed in the tumor microenvironment on tumor cells and tumor-infiltrating 
macrophages. Programmed death ligand 2 (PD-L2) is preferentially expressed by antigen 
presenting cells 20. Nivolumab is a monoclonal antibody that blocks the interaction 
between PD-1 and PD-L1/PD-L2. CheckMate 037 was a phase III trial of nivolumab in 
ipilimumab-refractory patients that demonstrated improved ORR and PFS vs. 
chemotherapy 1. CheckMate 066 was a phase III study in previously untreated, BRAF 
V600-non mutated melanoma that demonstrated improved ORR and PFS vs. 
dacarbazine 3. 
Combination ipilimumab and nivolumab 
CheckMate 067 evaluated nivolumab plus ipilimumab in previously untreated stage III/IV 
melanoma against either nivolumab or ipilimumab alone. Both the combination therapy 
and nivolumab monotherapy were more efficacious than ipilimumab monotherapy in 
primary endpoints of ORR, PFS, and OS 6,24–26. Importantly, long term follow up and 
subgroup analysis suggests that nivolumab plus ipilimumab may confer improved OS vs. 
nivolumab monotherapy in patients with PD-L1 expression < 1%, with a HR of 0.68 27. 
Overall, the addition of immunotherapy with PD-1 and CTLA-4 inhibition has increased 
metastatic melanoma 5-year OS to > 50% 28. 
Grade 3/4 adverse events (AEs) in CheckMate 067 occurred in 59% of combined therapy 
patients. The most common Grade 3 event in the combination therapy arm was diarrhea 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
15 
(9%), the most common Grade 4 event was increased lipase (5%). Treatment related AEs 
of any Grade that led to discontinuation of treatment were reported in 40% of patients in 
the combination group, including Grade 3/4 events that led to discontinuation (30%). 
Colitis was the most common cause for discontinuation (10%). Grade 3 increased AST 
and ALT occurred in 18 and 25% of the combination therapy group. 
1.1.2.2 Targeted Therapy 
Encorafenib 
Encorafenib is a second generation, potent and selective ATP-competitive inhibitor of 
BRAFV600-mutant kinase. The most significant difference between encorafenib and 
other second generation BRAF inhibitors is its increased dissociation half-life of 30 hours, 
compared to dabrafenib (2 h) and vemurafenib (0.5 h) 29. This leads to a decreased off-
rate, leading to decreased AEs and prolonged inhibition of target 30,31.  Encorafenib also 
has higher potency with a half-maximal inhibitory concentration (IC50) of 40 nmol/L, 
compared to the higher IC50s of dabrafenib (<100 nmol/L) and vemurafenib (<1 µmol/L) 
32. Encorafenib 450 mg orally QD together with binimetinib 45 mg orally BID have been 
approved by the US FDA and in the EU for the treatment of unresectable or metastatic 
melanoma with a BRAFV600E or V600K mutation as detected by an FDA-approved test. 
Encorafenib is known to induce CYP3A4. Therefore, hormonal birth control agents are 
permissible only when combined with other highly effective means of contraception. 
Binimetinib 
Binimetinib is a selective allosteric, ATP-uncompetitive inhibitor of MEK1 and 2 that has 
a shorter half-life than other MEK1/2 inhibitors, which may provide more rapid resolution 
of toxicity upon dose interruption 33. MEK inhibitors were developed contemporaneously 
with BRAF inhibitors, and fortuitously found to block a common mechanism of resistance 
to BRAF-inhibitor monotherapy 27,34. Binimetinib 45 mg orally BID in combination with 
encorafenib 450 mg orally QD has been approved by the US FDA and in the EU for the 
treatment of unresectable or metastatic melanoma with a BRAFV600E or V600K mutation 
as detected by an FDA-approved test. 
Encorafenib and binimetinib combination 
The COLUMBUS trial is a randomized Phase 3 trial evaluating the efficacy and safety of 
the combination of encorafenib and binimetinib compared to vemurafenib and 
encorafenib monotherapy in patients with locally advanced, unresectable or metastatic 
melanoma with BRAFV600 mutation. COLUMBUS demonstrated improved tolerability in 
the encorafenib 450 mg QD + binimetinib 45 mg BID (COMBO450) arm compared with 
single-agent encorafenib 300 mg QD 33,35. This is consistent with previous literature that 
suggests the combination of a MEK inhibitor and a BRAF inhibitor results in improved 
tolerability compared with either agent alone 3,36–38. The updated PFS for the COMBO450 
arm was 14.9 months, with all subgroups favoring COMBO450 arm 17. 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
16 
A total of 68% of patients experienced Grade 3/4 AEs in the COMBO450 arm, with similar 
rates in other arms. These AEs led to discontinuation of treatment in 16% of patients, and 
dose reduction/interruption in 55%. Among patients receiving encorafenib and binimetinib 
combination therapy in the COLUMBUS study, the most common adverse reactions (≥ 
20%, all grades) were fatigue (43%), nausea (41%), diarrhea (36%), vomiting (30%), 
abdominal pain (28%), arthralgia (26%), myopathy (23%), hyperkeratosis (23%), rash 
(22%), headache (22%), constipation (22%), visual impairment (20%), and serous 
retinopathy (20%). Most of these toxicities were generally reversible and manageable by 
supportive medical care, dose modifications or discontinuation. Other clinically important 
adverse reactions occurring in < 10% of patients were facial paresis, pancreatitis, 
panniculitis, drug hypersensitivity and colitis. The most common laboratory abnormalities 
(≥ 2%, Grade 3 or 4) were increased GGT (11%), increased ALT (6%), increased creatine 
phosphokinase (5%), increased fasting glucose (5%), increased creatinine (4%), anemia 
(4%), hyponatremia (4%), increased AST (3%), neutropenia (3%) and lymphopenia (2%). 
1.1.2.3 Combination Targeted and Immunotherapy 
The combination of the BRAF inhibitor vemurafenib with the CTLA-4 checkpoint-blocking 
antibody ipilimumab resulted in hepatic dose-limiting toxicity (DLT), leading to 
discontinuation of the development of this combination 39. However, this was before 
addition of MEK inhibitors to BRAF inhibitors was shown to decrease toxicity through 
mitigating paradoxical MAPK activation 40.  
Trials are ongoing to compare sequencing of targeted therapy vs. immunotherapy (such 
as EA6134 and SECOMBIT) with retrospective studies postulating predictive markers 
such as severity of disease and specific BRAF mutations to suggest preferred sequential 
therapy 14,41. However, it is well documented across oncology that some patients progress 
rapidly in the 1st line setting making 2nd line therapy unavailable or ineffective. 
Animal model studies suggest that BRAF and MEK inhibition can increase T cell 
infiltration of tumors and upregulate markers of immune activation including IFNγ and 
MHC42, with serial biopsies from patients on treatment describing similar findings. These 
observations have led to on-going registration intent clinical trials with triple therapy 
(BRAF + MEK inhibition + anti-PD-1). These studies appear potentially promising with 
triple therapy being described as tolerable with encouraging ORR of 67%–85% 5,43,44, and 
the AACR 2020 plenary session of the TRILOGY Phase III data which showed that the 
primary endpoint of PFS has been met 45. This has led to FDA approval for this triplet 
regimen. In contrast however the COMBI-I trial of dabrafenib, trametinib and 
spartalizumab did not meet the primary endpoint. Triple therapy therefore is a standard 
of care option for metastatic/unresectable BRAF mutant melanoma, however the exact 
role of the therapy remains unclear and there are still high-risk patient groups that do not 
respond well to BRAF-MEK-PD1/L1 triple therapy. 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
17 
1.1.3 High-risk Patient Groups have Unmet Need 
Patients with brain/liver/bone metastases and high LDH have worse outcomes on BRAF 
+ MEK inhibition 46 as well as checkpoint immunotherapy 18. A retrospective analysis of 
617 patients across three trials treated with dabrafenib and trametinib (targeted therapy) 
details the disparity in outcomes between patients with poor prognostic factors. Shown 
below graphically is the difference in OS in patients with elevated LDH or multiple disease 
sites. LDH 2x the upper limit of normal (ULN) had a one year overall survival of 40%, 
compared to over 90% 1 year survival for normal LDH levels 36. These clinically high-risk 
patients would benefit the most from an escalation in therapy where the increased risk of 
toxicity would be offset by improved survival. 
 
 
 
 
 
 
 
 
 
 
 
Multiple studies suggest that within these populations specifically, CTLA-4 blockade may 
have the most potent ability to generate long term clinical benefit. On a molecular level 
we observe from COMBI-I that triplet therapy appears to disproportionately benefit 
patients with tumors demonstrating high tumor mutational burden (TMB) and an active 
immune tumor microenvironment as measured by an IFNγ linked gene expression profile 
(GEP), i.e. TMB/GEPhi, and does not seem to particularly improve the response rate or 
PFS of patients with TMB/GEPlow tumors relative to historical controls 47. 
1.1.3.1 Brain Metastases 
Melanoma is third leading cause of cranial metastases after lung and breast cancer 9.  
More than 20% of patients with metastatic melanoma have brain metastases at diagnosis 
48,49, and 75% will develop brain metastases 50.  Similar to patients with elevated LDH 
discussed above, patients with brain metastases have much worse outcomes compared 
0.0
0.2 
0.4
0.6
0.8 
1.0
0
12 
24 
36 
OS Probability 
Months
OS by LDH, Number of Disease Sites, and ECOG
a
 
a:Factors Identified by Regression Tree Analysis, Long et al 2015 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
18 
to non-CNS metastases groups. OS with brain metastases after starting dabrafenib and 
trametinib is a median of 5.8 months if asymptomatic, if symptomatic median survival is 
only 2.0 months after progression on dabrafenib and trametinib 36.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Conventional therapy for metastatic melanoma with brain metastases historically 
consisted of whole brain radiation therapy (WBRT) for multiple metastases and 
stereotactic radiosurgery for limited numbers of metastases 51. Prognosis for brain 
metastases remains poor, with an expected OS of only four months 52–54. Recent 
investigations suggest little or no benefit for WBRT and that systemic therapy likely 
improves outcomes over radiation in general 55,56. Targeted and immunotherapy trials for 
brain metastases have had some improvements in OS summarized below, however there 
remain high risk groups with symptomatic disease that have been excluded from most 
trials due to their poor outcomes.  
In the phase 2 BREAK-MB trial, BRAF monotherapy (dabrafenib) exhibited clinical activity 
in BRAF V600E mutant melanoma with brain metastases. The overall intracranial 
response rate was 39% (n = 139) and had a manageable safety profile 36.  
COMBI-MB is a phase 2 BRAF + MEK inhibitor (dabrafenib + trametinib) trial evaluating 
BRAFV600-mutant melanoma brain metastases 0.5–4.0 cm, excluding leptomeningeal 
disease 57. Previous treatment with immunotherapy is allowed and current corticosteroid 
use is permitted however no anti-epileptic treatment is permitted, excluding symptomatic 
0.0
0 
6
12 
24 
Months 
36 
0.2 
0.4
0.6
0.8 
OS Probability 
1.0 
Non-CNS lesion, SLD < 44 mm 
Non-CNS lesion, SLD > 44 mm 
CNS lesion, asymptomatic 
CNS lesion, symptomatic 
OS by site of metastases, size, and CNS symptoms
a
 
a:Factors Identified by Regression Tree Analysis, Long et al 2015. 
Central Nervous System (CNS), Sum of longest diameter (SLD) 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
19 
patients except in exploratory cohorts. The primary endpoint of intracranial response was 
met, with 58% of patients achieving response by investigator review. In exploratory 
cohorts, 59% of symptomatic patients (n = 17) had an intracranial response. Most 
intracranial and extracranial responses were seen by week 4 in primary endpoint cohorts 
and by weeks 4–8 in exploratory cohorts. The most common AEs of COMBI-MB were 
included pyrexia (n = 34/125, 54%), headache (n = 46/125, 37%), asthenia (n = 40/125, 
32%), diarrhea (n = 40/125, 32%), nausea (n = 40/125, 32%), and chills (n = 37/125, 
30%). Dose interruptions and reductions due to AEs were necessary in 62 (50%) and 28 
(22%) of 125 patients, respectively. Discontinuations due to AEs occurred in 12 (10%) of 
125 patients, mostly due to ejection fraction decreased (n = 4/125, 3%) and pyrexia (n = 
3/125, 2%). 
A retrospective, multicenter case series analysis of BRAF-mutant patients harboring 
metastatic brain metastases treated with encorafenib and binimetinib was recently 
published 58. The intracranial objective response rate was 33%, with an intracranial 
benefit rate (CBR: proportion of patients with complete response + partial response + 
stable disease) of 63% with a median duration of response of 22 weeks. Forty-six percent 
of patients (11/24) received steroids during treatment, and median time to intracranial 
response was 6 weeks. This was in a population heavily pre-treated (median of 2.5 prior 
lines of therapy) and 88% (21/24) had previous BRAF + MEK inhibitor therapy. Median 
LDH was 190 U/L, and intracranial objective response rate was similar between LDH > 
250 at baseline vs. LDH < 250 baseline, 29% and 35% respectively. AEs were Grade 1 
and 2 in severity, except for one Grade 3 myalgia. The most common AEs were fatigue 
(17%) and myalgia (13%). Two patients experienced retinal detachment. One patient had 
intra-retinal fluid after one dose of encorafenib + binimetinib that resolved after holding 
binimetinib and patient resumed binimetinib 11 days later. A total of 4 patients (17%) 
dose-reduced one or both agents during study due to myalgia, neuropathy, or 
nausea/vomiting/fatigue. Of the four patients, two continued treatment, one discontinued 
due to progression, and another discontinued due to neuropathy. 
CheckMate 204 is a Phase II trial for melanoma patients with > 1 measurable, non-
irradiated melanoma brain metastases (MBM) 0.5–3.0cm. Asymptomatic patients not on 
steroids or anti-epileptics are treated with nivolumab 1 mg/kg + ipilimumab 3 mg/kg, then 
nivolumab maintenance. The intracranial clinical benefit rate (CBR; proportion of patients 
with complete response + partial response + stable disease) is 29% (n = 101), with 26% 
partial response and 4% stable disease 59. Toxicity was similar to nivolumab + ipilimumab 
in non-brain metastatic patients. An amendment added an exploratory cohort of 
symptomatic patients on steroids (n = 20). For symptomatic patients (n = 18) the 
intracranial overall response rate was 16.7% and CBR was only 22% 60. 
Anti-PD1 Brain Collaboration (ABC) was a phase II trial for melanoma patients with active 
brain metastases, including patients that had previously received targeted therapy with 
BRAF and MEK inhibitors. When patients with asymptomatic untreated brain metastases 
received combined ipilimumab and nivolumab as their first therapy, 56% (15/27) achieved 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
20 
an intracranial response and 19% (5/27) achieved a CR 37. No new or unexpected 
toxicities were associated with drug therapy in this study. 
1.1.3.2 Elevated Liver Enzymes and Bulky Disease 
A meta-analysis of 617 BRAF mutant melanoma patients randomly assigned to 
dabrafenib + trametinib in BRF11320, COMBI-d, and COMBI-v was subjected to 
regression tree analysis to identify prognostic factors for response to therapy 36. Four 
prognostic groups of baseline factors were identified to predict progression free survival: 
normal LDH with less than 3 sites of metastases, normal LDH with more than 3 sites of 
metastases, LDH up to 2x upper limit of normal (ULN), and LDH > 2x ULN. Normal LDH 
with less than 3 sites of metastases had the longest 1-year PFS and (68%) and OS (90%) 
(n = 237). Overall response was seen in 65% (60/93) with LDH concentration of one to 
two times ULN and ECOG of 0; 48% (27/56) with LDH concentration of one to two times 
ULN and ECOG of 1; and 50% (35/70) with LDH concentration at least two times the 
ULN. 
A retrospective recursive portioning analysis modeled associations between pre-specified 
covariates and survival outcomes from BRIM-2, BRIM-3, BRIM-7, and co-BRIM studies 
in which patients were treated with dacarbazine, vemurafenib, or cobimetinib + 
vemurafenib 46. PFS and OS were longest in patients with LDH < 2x ULN and sum of 
longest diameters of target lesions (SLDs) < 44 mm. In the most favorable subgroup 
(normal LDH and SLD < 44 mm), 3-year OS rates were 53.3% in the cobimetinib + 
vemurafenib cohort. Among patients with gene expression data, recursive partitioning 
analysis identified an immune activated gene expression profile (GEP) as significant 
prognostic factor for PFS in those with normal LDH. 
1.1.4 Quadruple Therapy 
A phase I study of low dose ipilimumab in combination with pembrolizumab after 
progression on anti-PD-1 shows that low-dose ipilimumab is well tolerated and potentially 
efficacious as 2nd line therapy 61. Of 22 patients enrolled, 17 were evaluable, with a 
disease control rate (DCR; complete response + partial response + stable disease) of 
76%. PFS at 6 months was 75%, and 14% (3/22 patients) having Grade 3/4 AEs 
(hyperglycemia, acute kidney injury, diarrhea, acneiform rash). Interestingly, out of 11 
response-evaluable patients with staining available, DCR was 100% in PD-L1 positive (n 
= 3) and 88% in PD-L1 negative (n = 8) tumors. The phase II continuation of this study 
had 67/70 accrued patients available for analysis of treatment response, with median 
length of treatment on prior PD1 Ab of 4.8 months. There were 4 CR, 17 PR, and 16 SD 
for a RR of 31 % (21/67) in evaluable patients, and 30% (21/70) in all enrolled patients. 
Median PFS was 4.7 months with 21% (15/70) of patients experiencing > Grade 3–4 drug-
related AEs, the most common being diarrhea and rash. PD-L1 status did not correlate 
with RR62. 
 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
21 
These results marry well with frontline data of the same combination generated in the 
KEYNOTE–029 study (Long 2017). KEYNOTE-029 was a phase 1 study of 4 cycles of 
low-dose ipilimumab + pembrolizumab followed by pembrolizumab maintenance. PFS at 
one year was 69%, with OS of 89%. Grade 3/4 AEs occurred in 45% (n = 69) patients, 
and discontinuation of pembrolizumab and ipilimumab occurred in 14% (n = 22).  
The use of low dose ipilimumab plus anti-PD-1 combination is generally well tolerated 
and only somewhat more toxic than PD1 alone. Observing that the increased toxicity from 
BRAF + MEK + PD1 triplet therapy appears to be disproportionately related to targeted 
therapy and not irAEs, low dose ipilimumab with anti-PD1 may disproportionately benefit 
patient populations that still have high need and would justify increased risk of toxicity. 
Particularly high risk patients include GEP/TMBlow 47, symptomatic brain metastases 59  
and elevated LDH or liver metastases 15,46. 
Therefore, triplet and quadruplet therapy of BRAF+/-MEK+PD1+CTLA4 inhibition will be 
explored in this phase 1/2 study. Phase I will explore the safety and tolerability of triplet 
therapy with BRAF+PD1+CTLA4 inhibition while simultaneously evaluating quadruplet 
therapy of BRAF+MEK+PD1+CTLA4. It will then expand into safety/preliminary efficacy 
cohorts: 1) Symptomatic brain metastases (inverse of CHECKMATE 204) 59, 2) Liver 
metastases with elevated LDH OR sum of target lesion distance (SLD) >44mm 36,46. 
1.2 Research Hypothesis 
Treatment with encorafenib +/- binimetinib combined with both nivolumab and ipilimumab 
will demonstrate adequate safety and tolerability, as well as a favorable benefit/risk 
profile, to support further clinical testing. 
1.3 Objectives 
Primary Objective 
• To nominate a recommended phase II regimen (RP2R) of triple or quadruple 
therapy with encorafenib +/- binimetinib + nivolumab + ipilimumab in BRAF 
mutated, metastatic melanoma. 
 
Secondary Objectives 
• To estimate the RECIST response rate of triple or quadruple therapy in high risk 
populations of BRAF mutated, metastatic melanoma. 
• To estimate the CNS clinical benefit rate (CBR, defined as complete response 
[CR] + partial response [PR] + stable disease [SD] >6 months) per RANO-MB 
criteria of triple or quadruple therapy in BRAF mutated, metastatic melanoma to 
the CNS 
• To describe the toxicity of triple or quadruple therapy in BRAF mutated, 
metastatic melanoma using the Criteria for Adverse Events version 5 (CTCAEv5) 
• To summarize the progression-free survival of triple or quadruple therapy in high 
risk populations of BRAF mutated, metastatic melanoma 
 
Exploratory Objectives 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
22 
2. To evaluate treatment response as correlated with baseline tumor mutational 
burden, changes in the tumor microenvironment (IFN associated gene 
expression), T cell clonality, and other biospecimens before and after triple or 
quadruple therapy. 
• To evaluate the overall survival (OS) of triple or quadruple therapy in high-risk 
population of BRAF-mutated, metastatic melanoma 
 
1.4 Product Development Background 
1.4.1 Pharmacology 
Nivolumab 
Nivolumab is a fully human, IgG4 (kappa) isotype monoclonal antibody that binds to PD-
1 with nanomolar affinity (dissociation constant [Kd], 3.06 nM) and a high degree of 
specificity. Nivolumab blocks binding of PD-1 to its ligands PD-L1 and PD-L2. 
Nonclinical in vitro testing of nivolumab demonstrated that binding to PD-1 results in 
enhanced T-cell proliferation and release of IFNγ in vitro in MLR and cytomegalovirus 
assays. Additional details are provided in the current version of the nivolumab IB. 
Ipilimumab 
Ipilimumab is a fully human IgG1 (kappa) monoclonal antibody that has specificity and a 
high affinity for human CTLA-4. The calculated dissociation constant value from an 
average of several studies was 5.25 nM. Binding of ipilimumab to purified, recombinant 
human CTLA-4 antigen was also demonstrated by enzyme-linked immunosorbent 
assay with half-maximal binding at 15ng/mL, whereas saturation was observed at 
approximately 0.1 µg/mL. No cross-reactivity was observed against human CD28. 
Ipilimumab completely blocked binding of B7.1 and B7.2 to human CTLA-4 at 
concentrations higher than 6 and 1 µg/mL, respectively. Additional details are provided 
in the current version of the ipilimumab IB. 
Encorafenib 
Encorafenib is a selective, ATP-competitive BRAF inhibitor for BRAFV600-mutated 
cells. The most significant difference between encorafenib and other second generation 
BRAF inhibitors is its increased dissociation half-life of 30 h, compared to dabrafenib (2 
h) and vemurafenib (0.5 h) 29. This leads to a decreased off-rate, leading to decreased 
AEs and prolonged inhibition of target 30,31. Encorafenib also has higher potency with 
half-maximal inhibitory concentration (IC50) of 40 nmol/L, compared to the higher IC50s 
of dabrafenib (< 100 nmol/L) and vemurafenib (< 1 µmol/L) 32. 
Binimetinib 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
23 
Binimetinib is a potent, adenosine triphosphate-uncompetitive, highly selective allosteric 
inhibitor of MEK1/2 63. Binimetinib has nanomolar activity against MEK enzyme (half-
maximal inhibitory concentration, 12 nM) and inhibits ERK phosphorylation in human 
cell lines. Binimetinib potently inhibits the proliferation of a subset of cells in human 
cancer cell lines and is particularly active in cells harboring activating mutations in the 
BRAF, NRAS, and KRAS genes. 
1.4.1.1 Pharmacokinetics 
Nivolumab 
The safety and efficacy of the 480 mg Q4W flat dosage of nivolumab are similar to 
those of the approved nivolumab 240 mg flat dose or 3 mg/kg Q2W dosage. The 
nivolumab dosage of 480 mg Q4W was based on clinical data and modeling and 
simulation approaches using population pharmacokinetic (PPK) and exposure-response 
analyses of data from studies in multiple tumor types (melanoma, NSCLC, and RCC) 
where body weight normalized dosing (mg/kg) has been used (BMS Protocol 
CA017003). Nivolumab clearance and volume of distribution were found to increase as 
the bodyweight increases, but less than proportionally with increasing weight, indicating 
that milligram per kilogram dosing represents an over-adjustment for the effect of body 
weight on nivolumab PK. Using the PPK model, the overall distributions of nivolumab 
average steady-state exposures are comparable after treatment with either nivolumab 3 
mg/kg Q2W or nivolumab 480 mg Q4W, although the flat dose regimen of 480 mg Q4W 
is predicted to result in approximately 40% higher steady-state peak concentration 
(Cmaxss) and approximately 20% lower steady-state trough concentrations compared 
to the reference regimen of 3 mg/kg Q2W (BMS Protocol CA017003). Across the 
various tumor types in the clinical program, nivolumab has been shown to be safe and 
well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab 
exposure produced by 3 mg/kg and efficacy and safety has been found to be relatively 
flat. Although nivolumab Cmaxss is predicted to be higher following 480 mg Q4W, these 
exposures are predicted to be lower than or within the exposure ranges observed at 
doses up to 10 mg/kg Q2W used in the nivolumab clinical program and are not 
considered to put participants at increased risk. The exposures predicted following 
administration of nivolumab 480 mg Q4W are on the flat part of the exposure-response 
curves for previously investigated tumors (melanoma and NSCLC) and are not 
predicted to affect efficacy.  
Regarding PK, nivolumab dosing at 480 mg Q4W is expected to result in similar time 
average steady state concentrations (Cavgss) as nivolumab 3 mg/kg Q2W. In addition, 
nivolumab exposures following 480 mg are predicted to be below those observed at 
doses up to 10 mg/kg Q2W (used in the phase 1 nivolumab clinical program) that have 
been shown to be safe and well tolerated 64. 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
24 
Ipilimumab 
Ipilimumab has a terminal half-life of approximately 15.4 days. The expected in vivo 
degradation of monoclonal antibodies into small peptides and amino acids occurs via 
biochemical pathways that are independent of cytochrome P450 enzymes. The 
population pharmacokinetics (PPK) of ipilimumab was studied with 785 participants and 
demonstrated that PK of ipilimumab is linear and exposures are dose proportional 
across the tested dose range of 0.3 to 10 mg/kg, and the model parameters are time 
invariant. Upon repeated dosing of ipilimumab, administered every three weeks, 
minimal systemic accumulation was observed by an accumulation index of 1.5-fold or 
less and ipilimumab steady-state concentrations were achieved by the third dose. The 
ipilimumab clearance of 16.8 mL/h from the PPK analysis is consistent with that 
determined by PK analysis. The terminal half-life (T-HALF) and Vss of ipilimumab 
calculated from the model were 15.4 days, and 7.47 L, which are consistent with that 
determined by non-compartmental analysis (NCA). Volume of central (Vc) and 
peripheral compartment were found to be 4.35 L and 3.28 L, respectively, suggesting 
that ipilimumab first distributes into plasma volume and subsequently into extracellular 
fluid space. Clearance of ipilimumab and Vc were found to increase with an increase in 
body weight. Nevertheless, there was no significant increase in exposure with increase 
in body weight when dosed on a mg/kg basis, supporting dosing of ipilimumab based on 
a weight normalized regimen. Additional details are provided in the ipilimumab 
Investigator Brochure (IB). 
Encorafenib 
Encorafenib is administered orally with 85% bioavailability, reaching maximum post-
dose concentration in 2 h with a 6-h half-life. Food intake delays absorption of the 
medication but does not alter overall absorption. It is metabolized by cytochrome 450 
enzymes (CYP3A4, CYP2C19, and CYP2D6) and 20 unique metabolites have been 
identified, which are excreted equally in urine and feces. Furthermore, 2% and 5% of 
the absorbed medication is excreted unchanged in urine and feces, respectively 29. 
Binimetinib 
Binimetinib is a potent, selective, non-ATP-competitive allosteric inhibitor of MEK1 and 
2. It is taken orally with rapid absorption; median time of maximal absorption is 1.48 
hours 29. A low-fat meal increases maximum plasma concentration (Cmax) by an 
average of 29%, whereas a high-fat meal decreases Cmax by an average of 17%, both 
compared to the fasting state. Both low- and high-fat food intake increased time to 
maximal absorption, however, did not affect the amount of binimetinib absorbed. 
Binimetinib is metabolized by several primary and secondary biotransformations; 
cytochrome 450 enzymes (CYP1A2 and CYP2C19) account for 17.8% of clearance via 
N-demethylation, whereas direct glucuronidation accounts for approximately 62.2% of 


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25 
clearance (Sun 2018). In addition, 62.3% of binimetinib is excreted in the feces, 31.4% 
in urine, and 6.5% is excreted unchanged in urine. 
1.4.2 Clinical Experience 
Nivolumab + Ipilimumab 
The combination of nivolumab and ipilimumab was first evaluated in a phase I trial of 
metastatic/unresectable cutaneous melanoma (CA209-004) 26. Long term follow up from 
all cohorts (n = 94) shows a 3 year OS rate of 63% and the median OS has not yet been 
reached 65. This includes cohort 8, nivolumab 1 mg/kg and ipilimumab 3 mg/kg, the 
dosage selected for the following Phase II and III trials (CheckMate 069 and 067) 2,23,66. 
Long term OS rates have been consistent across nivolumab and ipilimumab trials, with 
the 2 year OS rate in CheckMate 069 of 64% similar to the 3 year OS rate in CheckMate 
067 (58%) and the 3 year OS rate in CA209-004 (63%) 65. 
In both CheckMate 067 and 069, nivolumab was administered at 1 mg/kg and ipilimumab 
at 3 mg/kg (NIVO1 + IPI3), once every 3 weeks for four doses, followed by nivolumab 
monotherapy at 3 mg/kg once every 2 weeks. In CheckMate 067, treatment related Grade 
3 and 4 AEs were reported in 55% of patients who received combination therapy, which 
led to discontinuation of treatment in 29% in the first 9 months 23. 
Phase IIIb/IV CheckMate 511 study was conducted to determine whether nivolumab 3 
mg/kg plus ipilimumab 1 mg/kg (NIVO3 + IPI1) decreases AEs in patients with metastatic 
melanoma. Incidence of treatment-related Grade 3 to 5 AEs was significantly lower in 
patients treated with NIVO3 + IPI1 (61 [33.9%] of 180 patients; 95% CI, 27.0% to 41.3%) 
compared with the NIVO1 + IPI3 group (86 [48.3%] of 178 patients; 95% CI, 40.8% to 
55.9%; P = .006) 67. Rates of treatment-related AEs were lower in patients treated with 
NIVO3 + IPI1; however, the overall lower incidence of treatment-related Grade 3 and 4 
AEs in NIVO3 + IPI1 group compared with the NIVO1 + IPI3 group was a result of lower 
rates of hepatic (7.2% v 16.3%), GI (6.1% v 10.7%), and endocrine (2.8% v 7.3%) AEs. 
ORR and PFS were similar between groups, including across LDH levels, BRAF mutation 
status, and PD-L1 status, although the authors caution that the study was not powered to 
detect these differences. Importantly, duration of therapy was longer for NIVO3+IPI1 
treatment than for NIVO1+IPI3 and is borne out with the higher rate of discontinuation as 
a result of treatment-related AEs in the NIVO1+IIPI3 group. 


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2. 
ETHICAL CONSIDERATIONS 
2.1 Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined 
by the International Conference on Harmonisation (ICH) and in accordance with the 
ethical principles underlying European Union Directive 2001/20/EC and the United States 
Code of Federal Regulations, Title 21, Part 50 (21CFR50).  
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to 
initiation of the study. A serious breach is a breach of the conditions and principles of 
GCP in connection with the study or the protocol, which is likely to affect, to a significant 
degree, the safety or physical or mental integrity of the participants of the study or the 
scientific value of the study.  
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. This study will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific 
misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2 Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials (eg, 
advertisements), and any other written information to be provided to participants. The 
investigator or BMS should also provide the IRB/IEC with a copy of the Investigator 
Brochure or product labeling information to be provided to participants and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures.  
2.3 Informed Consent    
Investigators must ensure that participants are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. In situations where consent cannot be given to participants, their 
legally acceptable representatives (as per country guidelines) are clearly and fully 
informed about the purpose, potential risks, and other critical issues regarding clinical 
studies in which the subject volunteers to participate. 
 
Investigators must:  
1) Provide a copy of the consent form and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. The 
language must be non-technical and easily understood. 


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 2) Allow time necessary for subject or subject's legally acceptable representative to 
inquire about the details of the study.  
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed consent 
discussion.  
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent 
form and any other information to be provided to the participants, prior to the beginning 
of the study, and after any revisions are completed for new information.  
5) If informed consent is initially given by a subject’s legally acceptable representative or 
legal guardian, and the subject subsequently becomes capable of making and 
communicating his or her informed consent during the study, consent must additionally 
be obtained from the subject. 
6) Revise the informed consent whenever important new information becomes available 
that is relevant to the subject's consent. The investigator, or a person designated by the 
investigator, should fully inform the subject or the subject's legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the subject's willingness to continue participation in the study. This 
communication should be documented.  
The confidentiality of records that could identify participants must be protected, respecting 
the privacy and confidentiality rules applicable to regulatory requirements, the 
participants' signed ICF and, in the US, the participants’ signed HIPAA Authorization. The 
consent form must also include a statement that BMS and regulatory authorities have 
direct access to subject records. 
Participants unable to give their written consent (eg, stroke or participants with or severe 
dementia) may only be enrolled in the study with the consent of a legally acceptable 
representative. The subject must also be informed about the nature of the study to the 
extent compatible with his or her understanding, and should this subject become capable, 
he or she should personally sign and date the consent form as soon as possible. The 
explicit wish of a subject who is unable to give his or her written consent, but who is 
capable of forming an opinion and assessing information to refuse participation in, or to 
be withdrawn from, the clinical study at any time should be considered by the investigator. 
The rights, safety, and well-being of the study participants are the most important 
considerations and should prevail over interests of science and society.


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3. 
INVESTIGATIONAL PLAN 
3.1 Study Design and Duration 
This is an open label, multi-site, phase 1/2 study of encorafenib +/- binimetinib + 
nivolumab + ipilimumab for the treatment of participants with unresectable or metastatic 
BRAF-mutated melanoma in high risk cohorts.  
Study participants will consist of metastatic melanoma patients harboring BRAFV600E/K 
mutation without previous frontline therapy or recently started treatment with up to 6 
weeks of targeted therapy, or one cycle of immunotherapy (or >6 months from adjuvant 
therapy). Toxicity from prior treatment must have resolved to ≤ Grade 1 and not included 
previous Grade 3–4 irAEs that required treatment discontinuous or previous Grade 2 
immune-related uveitis or pneumonitis.  
Phase I, Cohort 1: Twelve patients will be treated with triple therapy: 300 mg encorafenib 
and 3mg/kg nivolumab and 1 mg/kg ipilimumab. Dose-limiting toxicity (DLT) for Cohort 1 
will be evaluated at week 6.  
Phase I, Cohort 2: Upfront quadruple therapy (450mg encorafenib, 45mg binimetinib, 
3mg/kg nivolumab, and 1mg/kg ipilimumab) will be investigated with twelve patients. DLT 
for Phase I, Cohort 2 will be evaluated at week 6.  
Prior studies with triplet therapies combining anti PD-1/PD-L1, BRAF, and MEK inhibition 
have shown Grade 3–4 AEs occurring from 58%–73% 5,43,44,68. These initial cohorts were 
small and did not use the newer, more potent and specific BRAF/MEK inhibitor pair 
encorafenib/binimetinib. We are allowing an initial DLT rate up to 75% in a continuous 
Bayesian monitoring protocol (See Statistics Section 8). We anticipate most of the 
toxicities to be additive and not synergistic and based on earlier recognition and treatment 
of immunotherapy AEs (see Appendix 6) and very specific AEs from encorafenib and 
binimetinib (see Appendix 2 and 3), we anticipate being able to create a safe RP2R dosing 
schedule. 
Upon establishment of RP2R schedule, only participants with advanced melanoma who 
are either treatment naïve in the metastatic setting, have recently started treatment with 
targeted therapy within the past 6 weeks, or one cycle of immunotherapy, or who have 
progressed on adjuvant therapy more than 6 months following completion of adjuvant 
therapy (either BRAF-MEK or PD1 Ab) will be eligible for participation in high risk disease 
cohort expansion (Groups 1 or 2, see Schema below). 
Phase II will take the RP2R schedule from Phase I and apply it to patients who may derive 
the most benefit from triple or quadruple therapy: Group 1) symptomatic brain metastases 
[up to 30 patients] and Group 2) LDH > 1x ULN with liver metastases OR bulky visceral 
disease (sum of longest diameter (SLD) > 44 mm) [up to 60 patients when combined with 
Group1].  
 
 


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Enrolled participants will be evaluated for safety and efficacy throughout the study and 
during follow up at the time points indicated on the time and events schedules 
presented in Tables 5.2.1 – 5.2.3. Response to treatment will be assessed in the 
intracranial (Group 1) and extracranial compartments (Group 2) and will be evaluated by 
serial radiographic assessment every 12 weeks until documented progression, 
withdrawal of consent, or the end of the study. 
Follow-up Phase for each enrolled subject begins when the decision to discontinue a 
subject from study therapy is made (no further treatment with study therapy). 
Participants will be followed for efficacy and OS. Treatment decisions will be based on 
local imaging evaluations using RANO-BM for intracranial lesions and RECIST 1.1 for 
extracranial lesions 69,70. 
Additional imaging may be performed for patient care at the discretion of the 
investigator. All efficacy objectives will be based on Investigator assessment at the 
study site. 
Safety will be evaluated for all treated participants using the NCI CTCAE version 5.0. 
Safety assessments will be based on medical review of AE reports, vital sign 
measurement results, physical examinations, and clinical laboratory tests. 
3.1.1 Screening Phase 
3. Screening begins by establishing the subject’s initial eligibility and signing of the 
ICF. 
4. The first 24 patients will be enrolled in the Phase I Cohort 1 (triple therapy with 
encorafenib, nivolumab, and ipilimumab) or Phase I Cohort 2 (upfront quadruple 
therapy of encorafenib, binimetinib, ipilimumab, and nivolumab) 
5. After RP2R is determined, Phase II patients will be enrolled preferentially into 
Group 1 (brain metastases) if possible; otherwise if they meet criteria will be 
enrolled into Group 2 (liver metastases with bulky disease and/or elevated LDH), 
total enrollment goal is 60 between the two groups.  


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3.2 Post Study Access to Drug 
At the end of the study, BMS will not continue to provide BMS supplied study drug to 
participants/investigators unless BMS chooses to extend the study. The investigator 
should ensure that the subject receives appropriate care to treat the condition under 
study. Participants who continue to respond at the end of on study treatment may be 
prescribed study medication through commercial supply. 
3.3 Study Population 
For entry into the study, the following criteria MUST be met. 
3.3.1 Inclusion Criteria 
1. Signed Written Informed Consent 
a. Participants must have signed and dated an IRB/IEC approved written 
informed consent form in accordance with regulatory and institutional 
guidelines. This must be obtained before the performance of any protocol-
related procedures that are not part of normal subject care. 
b. Participants must be willing and able to comply with scheduled visits, 
treatment schedule, laboratory testing, and other requirements of the study. 
2. Age ≥18 years 
3. Histologically confirmed diagnosis of unresectable or metastatic melanoma 
4. Presence of BRAFV600E/K mutation in tumor tissue as determined in a CLIA 
certified laboratory 
5. Patients are required to submit archival biopsy material, if available, and submit 
research blood samples prior to first dose. Ten patients in each Phase I cohort 
will undergo fresh biopsy. These will be the first 10 unless medical or societal 
factors (e.g. COVID19) limit the pursuit of research biopsies. 
6. Patients must be greater than 6 months from completion of adjuvant therapy (if 
any given) and/or treatment naïve in the metastatic setting or have recently 
started targeted therapy within the last 6 weeks, or one cycle of immunotherapy.  
7. Prior radiotherapy must have been completed at least 2 weeks prior to study 
drug administration. 
8. An ECOG Performance Status of 0 or 1. If enrolling in Group 1 of Phase II, can 
have Performance Status from 0-2.  
9. Measurable disease by CT or MRI per RANO-BM (brain metastases) OR 
RECIST v1.1 criteria 
10. Must have high risk features described as described in Phase II expansion cohort 
– EITHER brain metastases as described in Phase II Group 1 OR Elevated 
LDH/Bulky Visceral Disease as described in Phase II Group 2. 


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11. Adequate bone marrow, organ function, and laboratory parameters: 
a. ANC > 1.5 x 109  /L; 
b. Hemoglobin > 8 g/dL with or without transfusions; 
c. Platelet > 100 x 109  /L; 
d. Serum creatinine ≤ 1.5 × ULN, OR calculated creatinine clearance > 50 
mL/min by Cockcroft-Gault formula, OR estimated glomerular filtration rate 
> 50 mL/min/1.73 m 
12. Patient IS permitted to be on corticosteroids if related to disease burden and 
MAY have symptomatic brain lesions as long as radiation or surgical intervention 
is not deemed to be urgently necessary.  
a. Symptomatic intracranial metastases may be on steroids at a total daily 
dose of no higher than 4 mg of dexamethasone or equivalent that is stable 
or tapering for 10 days prior to first treatment,  
b. have no immediate need for SRT or surgery (within 3 week prior to first 
treatment),  
c. have a performance status of 0–2 and  
d. have had no experience of seizure within 10 days prior to first treatment. 
13. Female patients of childbearing potential must have a negative serum β-HCG 
test result during screening prior to first dose 
14. Females of childbearing potential must agree to protocol-approved methods of 
contraception, and to not donate Ova from Screening until 30 days of last dose of 
study drug.  
15. Male patients must use contraception that is highly effective or acceptable, and 
not donate sperm from Screening until 90 days after the last dose of study drug. 
16. The patient is deemed by the Investigator to have the initiative and means to 
comply with scheduled visits, treatment plan and study procedures. 
3.3.2 Exclusion Criteria 
1. Known hypersensitivity or contraindication to any component of study treatment 
or their excipients.   
2. Previous Grade 3-4 AEs, or discontinuation of PD-1 or CTLA-4 inhibitor therapy, 
or BRAF/MEK inhibitor therapy 
3. Inability to swallow and retain study treatment 


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4. Impairment of gastrointestinal function or disease which may significantly alter 
the absorption of study treatment (e.g., active ulcerative disease; uncontrolled 
nausea, vomiting or diarrhea; malabsorption syndrome; small bowel resection). 
5. Participants with a non-melanoma related condition requiring systemic treatment 
with either corticosteroids (> 10 mg daily prednisone equivalents) or other 
immunosuppressive medications within 14 days of study drug administration. 
Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily 
prednisone equivalents are permitted in the absence of active autoimmune 
disease. 
6. Participants with active, known or suspected autoimmune disease including 
those who have required systemic anti-rheumatic therapies in the preceding 2 
years. Participants with vitiligo, type I diabetes mellitus, residual hypothyroidism 
due to autoimmune condition only requiring hormone replacement, psoriasis not 
requiring systemic treatment, or conditions not expected to recur in the absence 
of an external trigger are permitted to enroll. 
7. Impaired cardiovascular function or clinically significant cardiovascular disease 
including, but not limited to, the following: 
a. History of acute coronary syndromes (including myocardial infarction, 
unstable angina, coronary artery bypass grafting, coronary angioplasty or 
stenting) < 6 months prior to Screening 
b. Congestive heart failure requiring treatment (New York Heart Association 
Grade ≥ 2)  
c. A known LVEF < 50% as determined by MUGA or ECHO 
d. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 
150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current 
therapy 
e. History or presence of clinically significant cardiac arrhythmias (including 
resting bradycardia, uncontrolled atrial fibrillation or uncontrolled 
paroxysmal supraventricular tachycardia) 
f. Baseline QTcF interval ≥ 480 ms. 
8. Second malignancy that requires active treatment or would interfere with 
treatment efficacy evaluation. Participants with a second malignancy treated with 
curative intent are eligible. 
9. On-going or use of systemic antibiotics during the preceding 2 weeks prior to 
enrollment 
10. Known acute or chronic infection with hepatitis B or hepatitis C virus. Participants 
treated with curative anti-viral therapy are eligible.  


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11. Known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS) even if fully 
immunocompetent on ART—due to the unknown effects of HIV on the immune 
response to combined nivolumab plus ipilimumab or the unique toxicity spectrum 
of these drugs in patients with HIV. 
12. Clinically unstable thromboembolic event despite anti-coagulation. Patients on 
stable dosing of anti-coagulants per investigator discretion are eligible. 
13. Use of herbal supplements, medications or foods that are moderate or strong 
inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 ≤ 1 week prior to the start 
of study treatment (Section 4.5.1). 
14. History or current evidence of retinal vein occlusion (RVO) or current risk factors 
for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of 
hyperviscosity or hypercoagulability syndromes); history of retinal degenerative 
disease. 
3.3.3  Phase II Group 1 Specific Criteria 
1. For Phase II Group 1 (Brain Metastases): Patients may have an ECOG status of 
0–2 and IS permitted to be on corticosteroids if related to disease burden and 
MAY have symptomatic brain lesions as long as radiation or surgical intervention 
is not deemed to be urgently necessary.  
a. Symptomatic intracranial metastases may be on steroids at a total daily 
dose of no higher than 4 mg of dexamethasone or equivalent that is stable 
or tapering for 10 days prior to first treatment,  
b. have no immediate need for SRT or surgery (within 3 week prior to first 
treatment),  
c. have had no experience of seizure within 10 days prior to first treatment. 
 
3.3.4 Women of Childbearing Potential 
A Women of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization (hysterectomy 
or bilateral oophorectomy) and is not postmenopausal. Menopause is defined as 12 
months of amenorrhea in a woman over age 45 years in the absence of other biological 
or physiological causes. In addition, females under the age of 55 years must have a serum 
follicle stimulating hormone, (FSH) level > 40 mIU/mL to confirm menopause.  
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The 
duration of the washout period below are suggested guidelines and the investigators 
should use their judgment in checking serum FSH levels. If the serum FSH level is >40 


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mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal:  
• 1 week minimum for vaginal hormonal products (rings, creams, gels)  
• 4 weeks minimum for transdermal products 
• 8 weeks minimum for oral products. Other parenteral products may require 
washout periods as long as 6 months. 
 
3.4 Concomitant Treatments 
3.4.1 Prohibited and/or Restricted Treatments 
The following medications are prohibited during the study (unless utilized to treat a drug-
related AE): 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids (except as permitted in 
brain metastasis cohort). 
• Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, 
immunotherapy, extensive, non-palliative radiation therapy, or standard or 
investigational agents for treatment of melanoma with the exception of targeted 
therapy initiated within the last 6 weeks, or one cycle of immunotherapy). 
3.4.2 Other Restrictions and Precautions 
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease. 
3.5 Discontinuation of Participants from Treatment with Study Drugs 
Participants MUST discontinue investigational product (and non-investigational product 
at the discretion of the investigator) for any of the following reasons:  
• Subject’s request to stop study treatment  
• Any clinical AE, laboratory abnormality or intercurrent illness which, in the opinion 
of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject  
• Pregnancy  
• Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious 
disease) illness  
• Additional protocol specified reasons for discontinuation (see Section 4.3.5) 


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All participants who discontinue investigational product should comply with protocol 
specified follow-up procedures as outlined in Section 5 - Study Assessment and 
Procedures. The only exception to this requirement is when a subject withdraws consent 
for all study procedures including post-treatment study follow-up or loses the ability to 
consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness). If study treatment is discontinued prior to the subject’s 
completion of the study, the reason for the discontinuation must be documented in the 
subject’s medical records and entered on the appropriate case report form (CRF) page. 
3.6 Post Study Drug Follow Up 
Post treatment study follow-up is of critical importance and is essential to preserving 
subject safety and the integrity of the study. Participants who discontinue study 
treatment must continue to be followed for collection of outcome and/or survival follow-
up data as required and in line with Section 5 Study Assessments and Procedures until 
death or the conclusion of the study. 
3.6.1 Withdrawal of Consent 
Participants who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol specified follow-up procedures. The only exception to 
this is when a subject specifically withdraws consent for any further contact with him/her 
or persons previously authorized by subject to provide this information. Participants 
should notify the investigator of the decision to withdraw consent from future follow-up in 
writing, whenever possible. The withdrawal of consent should be explained in detail in the 
medical records by the investigator, as to whether the withdrawal is from further treatment 
with study drug only or also from study procedures and/or post treatment study follow-up 
and entered on the appropriate CRF page. In the event that vital status (whether the 
subject is alive or dead) is being measured, publicly available information should be used 
to determine vital status only as appropriately directed in accordance with local law. 
3.6.2 Lost to Follow-up 
All reasonable efforts must be made to locate participants to determine and report their 
ongoing status. This includes follow-up with persons authorized by the participant as 
noted above. Lost to follow-up is defined by the inability to reach the participant after a 
minimum of three documented phone calls, faxes, or emails as well as lack of response 
by subject to one registered mail letter. All attempts should be documented in the 
participant’s medical records. If it is determined that the participant has died, the site will 
use permissible local methods to obtain the date and cause of death. If after all attempts, 
the participant remains lost to follow-up, then the last known alive date as determined by 
the investigator should be reported and documented in the subject’s medical records. 


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4. STUDY DRUG 
4.1 Investigational Product 
An investigational product, also known as investigational medicinal product in some 
regions, is defined a pharmaceutical form of an active substance or placebo being tested 
or used as a reference in a clinical study, including products already with a marketing 
authorization but used or assembled (formulated or packaged) differently than the 
authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form. The investigational product should be stored in a 
secure area according to local regulations. It is the responsibility of the investigator to 
ensure that investigational product is only dispensed to study participants. The 
investigational product must be dispensed only from official study sites by authorized 
personnel according to local regulations.  
In this protocol, investigational products are nivolumab and ipilimumab. See Table 4-1.


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Table 4.1:  
Study Drugs for QUAD-01  
 
 
Product 
Description/Class 
and Dosage Form 
Potency 
IP/Non-
IMP 
Blinded or 
Open Label 
Packaging/Appearance 
Storage 
Conditions (per 
Label) 
Nivolumab 
Solution for 
Injection 
100 mg (10 
mg/mL) 
IP 
Open-Label 
Clear to opalescent colorless to 
pale yellow liquid. May contain 
particles. 
2 to 8°C. Protect 
from light, freezing 
and shaking. 
Ipilimumab 
Solution for 
Injection 
200 mg (5 
mg/mL) 
IP 
Open-Label 
Clear, colorless to pale yellow 
liquid. May contain particles. 
2 to 8°C. Protect 
from light and 
freezing. 
Encorafenib 
50 or 75 mg 
Non-IMP 
Open-Label 
 
 
Binimetinib 
45mg 
Non-IMP 
Open-Label 
 
 
 
 
 
 
 
 
 
 
 


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mutant melanoma 
 
38 
 
4.2 Non-Investigational Product 
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may 
be considered as non-investigational products. In this protocol encorafenib and 
binimetinib are non-investigational products. 
4.3 Storage and Dispensing 
The product storage manager should ensure that the study drug is stored in accordance 
with the environmental conditions (temperature, light, and humidity) as determined by 
BMS. If concerns regarding the quality or appearance of the study drug arise, the study 
drug should not be dispensed and contact BMS immediately.  
Investigational product documentation (whether supplied by BMS or not) must be 
maintained that includes all processes required to ensure drug is accurately administered. 
This includes documentation of drug storage, administration and, as applicable, storage 
temperatures, reconstitution, and use of required processes (eg, required diluents, 
administration sets).  
Infusion-related supplies (eg IV bags, in-line filters, 0.9% NaCl solution) will not be 
supplied by the sponsor and should be purchased locally if permitted by local regulations.  
For non-investigational product, if marketed product is utilized, it should be stored in 
accordance with the package insert, summary of product characteristics (SmPC), or 
similar.  
Please refer to the current version of the encorafenib, binimetinib, nivolumab and 
ipilimumab IBs and/or pharmacy reference sheets for complete storage, handling, 
dispensing, and infusion information.  
Nivolumab  
Nivolumab vials must be stored at a temperature of 2° C to 8° C and should be protected 
from light, freezing, and shaking. If stored in a glass front refrigerator, vials should be 
stored in the carton. Recommended safety measures for preparation and handling of 
nivolumab include laboratory coats and gloves. 
For details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the nivolumab IB section for 
“Recommended Storage and Use Conditions” and/or pharmacy reference sheets. Care 
must be taken to assure sterility of the prepared solution as the product does not contain 
any anti-microbial preservative or bacteriostatic agent. No incompatibilities between 
nivolumab and polyolefin bags have been observed. 
Nivolumab is to be administered as an IV infusion per institution SOC using a volumetric 
pump with a 0.2/0.22 micron in-line filter at the protocol-specified dose. The drug can be 
diluted with 0.9% normal saline for delivery, but the total drug concentration of the solution 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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39 
 
cannot be below 0.35 mg/mL. It is not to be administered as an IV push or bolus injection. 
At the end of the infusion, flush the line with a sufficient quantity of normal saline. 
Ipilimumab  
Ipilimumab injection can be used for IV administration without dilution after transferring to 
a PVC (polyvinyl chloride), non-PVC/non-DEHP (di-(2-ethylhexyl)phthalate) or glass 
containers and is stable for 24 h at 2 ºC–8ºC or room temperature/room light (RT/RL). 
For ipilimumab storage instructions, refer to ipilimumab IB and/or pharmacy reference 
sheets. Recommended safety measures for preparation and handling include protective 
clothing, gloves, and safety cabinets.  
Ipilimumab is to be administered as an IV infusion per institution SOC, using a volumetric 
pump with a 0.2 to 1.2 micron in-line filter at the protocol-specified dose. The drug can be 
diluted with 0.9% normal saline or 5% Dextrose Injection to concentrations between 1 
mg/mL and 4 mg/mL. It is not to be administered as an IV push or bolus injection. Care 
must be taken to assure sterility of the prepared solutions, since the drug product does 
not contain any antimicrobial preservatives or bacteriostatic agents.  
When both study drugs are to be administered on the same day, separate infusion bags 
and filters must be used for each infusion. Nivolumab is to be administered first. The 
nivolumab infusion must be promptly followed by a saline flush to clear the line of 
nivolumab before starting the ipilimumab infusion. 
Encorafenib 
Encorafenib 450 (quadruple) or 300 (triple) mg will be administered PO QD continuously. 
Patients should take encorafenib daily in the morning at approximately the same time 
every day.  
Binimetinib  
Binimetinib 45 mg will be administered PO BID continuously. Patients will be instructed 
to take binimetinib 12 ± 2 h apart in the morning and in the evening at approximately the 
same times every day.  
Encorafenib and binimetinib should be taken together, if applicable, and without regard 
to food. Patients will be instructed to swallow the capsules/tablets whole with a large glass 
of water and not to chew or crush them. 
4.4  Method of Assigning Subject Identification 
QUAD-01 study is an open-label study. Patients must not start protocol treatment prior 
to registration in the Clinical Trials Management Application (CTMA). Participants can 
be enrolled after eligibility criteria are met.  Registration will require the following 
information: 1) protocol name and number, 2) date treatment begins, 3) subject name, 
4) date of birth, 5) primary study physician, 6) confirmation of eligibility, 7) and 
verification that the informed consent was signed.  
 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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40 
 
4.5 Selection and Timing of Dose for Each Subject 
Dosing and schedules for QUAD-01 are outlined in Table 4.5A and 4.5B. The 
investigational products nivolumab at 3mg/kg and ipilimumab at 1mg/kg will be given 
every 3 weeks for the first 4 treatments, then switched to single agent nivolumab at 480mg 
flat dose for up to one year. Encorafenib with or without binimetinib will be dosed as shown 
in Table 4.5A.


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF mutant melanoma 
 
41 
 
Table 4.5A: Dosing Schedule for Phase I   
 
 
 
 
 
Day 1 Week 1 
Day 1 Week 2 
Day 1 Week 3 
Day 1 Week 4 
Day 1 Week 5 
Day 1 Week 6 
Day 1 Week 7 
Cohort 1: 
Triple therapy 
(encorafenib 
+ nivolumab 
+ ipilimumab) 
300 mg 
encorafenib 
PO daily 
3mg/kg 
Nivolumab 
1mg/kg 
Ipilimumab 
300 mg 
encorafenib 
PO daily 
 
300 mg 
encorafenib 
PO daily 
 
300 mg 
encorafenib 
PO daily 
3mg/kg 
Nivolumab 
1 mg/kg 
Ipilimumab 
300 mg 
encorafenib 
PO daily 
 
300 mg 
encorafenib 
PO daily 
 
300 mg 
encorafenib 
PO daily 
3mg/kg 
Nivolumab 
1 mg/kg 
Ipilimumab 
Cohort 2: 
Quadruple 
therapy 
(encorafenib 
+ binimetinib 
+ nivolumab 
+ ipilimumab) 
450 mg 
encorafenib 
PO daily 
45 mg 
binimetinib PO 
BID 
3mg/kg 
Nivolumab 
1mg/kg 
Ipilimumab 
450 mg 
encorafenib 
PO daily 
45 mg 
binimetinib PO 
BID 
 
450 mg 
encorafenib 
PO daily 
45 mg 
binimetinib PO 
BID 
 
450 mg 
encorafenib 
PO daily 
45 mg 
binimetinib PO 
BID 
3mg/kg 
Nivolumab 
1 mg/kg 
Ipilimumab 
450 mg 
encorafenib 
PO daily 
45 mg 
binimetinib PO 
BID 
 
450 mg 
encorafenib 
PO daily 
45 mg 
binimetinib PO 
BID 
 
450 mg 
encorafenib 
PO daily 
45 mg 
binimetinib PO 
BID 
3mg/kg 
Nivolumab 
1 mg/kg 
Ipilimumab 
*Investigational products nivolumab and ipilimumab will be administered every 3 weeks for the first four doses, then single agent nivolumab will be 
administered every 4 weeks at flat dose of 480mg for up to one year. 
 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF mutant melanoma 
 
42 
 
Table 4.5B: Dosing Schedule for Phase II 
 
 
 
 
 
 
Day 1 Week -
2 
Day 1 Week -
1 
Day 1 Week 
1 
Day 1 Week 
2 
Day 1 Week 
3 
Day 1 Week 4 
Day 1 Week 5 
Group 1: Brain 
metastases 
RP2R 
RP2R 
 RP2R 
RP2R 
RP2R 
RP2R 
RP2R 
Group 2: Elevated LDH 
OR 
Bulky 
Visceral 
Disease SLD > 44 mm 
RP2R 
RP2R 
RP2R 
RP2R 
RP2R  
RP2R  
RP2R 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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43 
 
4.6  Concomitant Therapy 
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines and/or herbal supplements) must be recorded in the 
eCRF and medical records. Details regarding all prior anticancer treatment will also be 
recorded in the eCRF and medical records.  
 
Any medication received within 28 days before the first dose of study treatment and 
within 30 days after the last dose of study treatment, or until the patient begins a new 
anticancer therapy, whichever occurs first, will be recorded in the eCRF and medical 
records. Any addition, deletion or change in the dose of these medications will also be 
recorded. Details of prior antineoplastic treatments including number of prior metastatic 
regimens will also be recorded.  
 
Unless specifically prohibited, concomitant medications may be administered at the 
Investigator’s discretion to manage the patient’s medical condition and to conform to 
standard practice during the Treatment Period.  
 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the patient is receiving at the time of 
enrollment or receives during the study must be recorded along with:  
a. Reason for use.  
b. Dates of administration including start and end dates.   
c. Dosage information (using generic drug names when possible), including 
dose and frequency. 
 
Immunotherapy  
Nivolumab and Ipilimumab are monoclonal antibodies that are cleared by catabolic 
processes and do not have drug-drug interaction guidelines. 
 
Targeted therapy 
Encorafenib  
 
Encorafenib is a reversible inhibitor of CYP2B6, CYP2C9, CYP3A4 and UGT1A1. It is 
also a time-dependent inhibitor of CYP3A4 and induced CYP2B6, CYP2C9 and 
CYP3A4 in human primary hepatocytes. Permitted medications to be used with caution 
in this study include those that are sensitive substrates of CYP2B6, CYP2C9, CYP3A4 
and UGT1A1 or those substrates that have a narrow therapeutic index.  
 
There is a potential for encorafenib to induce CYP3A4, which may reduce the 
effectiveness of hormonal contraception methods. Therefore, the use of at least 1 form 
of non-hormonal contraception is required for females of childbearing potential during 
participation in this study. Caution should be used in patients receiving concomitant 
treatment with other drugs that are substrates of CYP3A4 as the efficacy of these drugs 
could be reduced when administered with encorafenib.  
 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
44 
 
Encorafenib has been identified as being metabolized by CYP3A4 and to a lesser 
extent by CYP2C19 in vitro. Concomitant use of moderate CYP3A4 inhibitors should be 
avoided. If use of a moderate CYP3A4 inhibitor is unavoidable, short-term use (≤ 30 
days) following discussion with the Sponsor may be permitted with an accompanying 
dose reduction to one-half of the encorafenib dose prior to use of the moderate CYP3A4 
inhibitor. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, 
resume the encorafenib dose that was taken prior to initiating the CYP3A4 inhibitor.   
 
Investigators should use caution when administering encorafenib with concomitant 
medications with a known, conditional or possible risk to prolong the QT interval and/or 
induce torsade de pointes. Patients receiving such medications must be carefully 
monitored for potentiating of toxicity due to any individual concomitant medication and 
may require dose titration of the concomitant medication. 
 
Binimetinib 
 
In vitro, binimetinib has been identified to be primarily metabolized by glucuronidation. 
Strong inducers of UGT1A1 should be taken with caution when co-administered with 
binimetinib.  
 
For tabulated CYP substrates, inhibitors and inducers to be used with caution or 
avoided, please consult the FDA website: Drug Development and Drug Interactions: 
Table of Substrates, Inhibitors and Inducers. 
 
4.7  DLT 
DLT-evaluable participants will be defined as participants who in the DLT evaluation 
period received ≥66% of encorafenib and/or binimetinib doses and at least one dose 
each of nivolumab and ipilimumab. 
 
For Cohort 1, encorafenib and nivolumab and ipilimumab will be administered on day 1 
week 1. The DLT evaluation period will extend from day 1 of week 1 to the end of week 
6 and captured in the medical records.  
 
For Cohort 2, encorafenib, binimetinib, nivolumab and ipilimumab will be administered 
on day 1 week 1. The DLT evaluation period will extend from day 1 week 1 to the end of 
week 6 and captured in the medical records. 
 
DLT Definition: A DLT is defined as any AE or laboratory abnormality that is not 
explained by underlying disease, disease progression, intercurrent illness, or 
concomitant therapies that either meets the criteria described below or results in the 
inability to tolerate at least 66% of the planned dose of encorafenib +/- binimetinib and 
at least one dose each of nivolumab and ipilimumab during Cycle 1. CTCAEv5 will be 
used for grading. 
 
Dose delay criteria apply for all drug-related AEs (regardless of whether or not the event 
is attributed to nivolumab, ipilimumab, encorafenib, or binimetinib. If investigator can 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
45 
 
attribute AE to either targeted or immunotherapy, may hold one and continue the other, 
otherwise delaying all study drugs is appropriate. 
 
Specific DLT Criteria  
Hematologic 
• Grade 4 anemia 
• Grade 4 neutropenia (for > 7 consecutive days) or Grade 4 febrile neutropenia 
• Grade 4 thrombocytopenia (of any duration).  
• Grade 3 thrombocytopenia with clinically significant bleeding regardless of 
duration or requirement of platelet transfusion  
Pancreas  
• Symptomatic serum amylase or lipase elevation, medical intervention required 
(pancreatitis Grade 3 or higher) 
 Gastrointestinal disorders  
• Nausea and vomiting ≥ Grade 3 for > 3 days despite optimal anti-emetic therapy 
•  ≥ Grade 3 diarrhea for > 5 days despite optimal antidiarrheal treatment (which 
could include steroids).  
Hepatobiliary   
• Total bilirubin Grade ≥ 4 
• For participants with normal baseline AST and ALT values 
o AST or ALT >8x ULN 
• For participants with normal baseline AST and ALT and normal baseline bilirubin 
value: 
o AST or ALT > 3.0 × ULN combined with total bilirubin > 2.0 × ULN without 
evidence of cholestasis  
• For participants with abnormal baseline AST or ALT or abnormal baseline 
bilirubin value: 
o [AST or ALT > 2 × baseline AND > 3.0 × ULN] OR [AST or ALT > 8.0 x 
ULN], combined with [TBIL > 2 × baseline AND > 2.0 × ULN] without 
evidence of cholestasis 
Hypertension 
• ≥ Grade 3 hypertension related to the study medication if it persists > 7 days 
despite optimal anti-hypertensive treatment 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
46 
 
• Grade 4 hypertension of any duration 
Cardiac 
• ≥ Grade 3 cardiac event that is symptomatic or requires medical intervention 
 
Pneumonitis 
• Grade 2 pneumonitis if it persists > 7 days despite treatment with corticosteroids 
• ≥ Grade 3 pneumonitis of any duration 
 
Immune-related Toxicities (except pneumonitis) 
• Grade 3 immune-related toxicities that persist > 14 days with same severity 
despite treatment with corticosteroids. 
• Grade 4 immune related toxicities of any duration ≥ Grade 3 infusion related 
reaction 
 
Eye disorders – Retinal   
• Retinopathy or retinal detachment Grade ≥ 3, confirmed by ophthalmic 
examination    
• Retinal vascular disorder including RVO, confirmed by ophthalmic examination  
Eye disorders – Visual disturbances without ocular (retinal) changes   
• Blurred vision, flashing lights, floaters: Grade ≥ 3  
Eye disorders – Other (specify)   
• Grade ≥ 3 for > 21 consecutive days   
• Grade 4 confirmed by ophthalmic examination  
Other hematologic and nonhematologic toxicities  
• Any other Grade ≥ 3 AE except:  a. Lymphocyte count decreased (lymphopenia) 
Grade ≥ 3 unless clinically significant  
Renal dysfunction  
• Calculated GFR decrease of 50% from baseline   
• Proteinuria 24-h urine protein > 2 g/24 h  
Events which will NOT be considered DLT for the purposes of this protocol: 
• Clinically insignificant laboratory values ≤ Grade 2. For laboratory values ≥ Grade 
3, the maximum allowable time limit for correction of electrolyte abnormalities to 
≤ Grade 1 is 72 h. 
• Cutaneous squamous cell carcinoma (CuSCC), basal cell carcinoma, and new 
primary melanoma which are manageable with surgical excision alone 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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47 
 
4.8  Management Guidelines for Immunotherapy (I-O) Agents 
I-O agents are associated with irAEs that can differ in severity and duration from AEs 
caused by other therapeutic classes. Nivolumab and ipilimumab are considered I-O 
agents in this protocol.  
 
Early recognition and management of irAEs may mitigate severe toxicity. Management 
algorithms have been developed from extensive experience with nivolumab and 
ipilimumab to assist investigators in assessing and managing the following groups of 
irAEs:  
• Gastrointestinal   
• Renal  
• Pulmonary  
• Hepatic  
• Endocrinopathies   
• Skin  
• Neurological 
The clinical nature of AEs noted with encorafenib and binimetinib will determine the role 
of the above algorithms for use in toxicities related to its use in this study. The 
algorithms recommended for utilization in this protocol are included in Appendix 2. 
 
Table 4.2 Reference Adverse Events (AEs) and toxicity Management Guidelines 
 
ADVERSE EVENTS 
NIVOLUMAB 
IPILIMUMAB 
ENCORAFENIB 
BINIMETINIB 
DIARRHEA/COLITIS 
X 
X 
X 
X 
ABNORMAL LIVER 
ENZYME TEST 
X 
X 
X 
X 
SKIN RASH 
X 
X 
X 
X 
SERIOUS SKIN 
REACTION 
X 
X 
X 
X 
NEPHRITIS 
X 
X 
X 
X 
PNEUMONITIS 
X 
X 
 
 
ENDOCRINE EVENTS 
X 
X 
X 
X 
HAND FOOT SKIN 
REACTION 
X 
X 
X 
X 
NEUTROPENIA AND 
THROMBOCYTOPENIA 
X 
X 
X 
X 
ABNORMAL 
LABORATORY 
RELATED AES 
X 
X 
X 
X 
ASYMPTOMATIC 
AMYLASE/LIPASE 
ELEVATION 
X 
X 
X 
X 
INFUSION REACTION 
AND CYTOKINE 
RELEASE SYNDROME 
X 
 
 
 
LVEF 
 
 
X 
X 
HYPERTENSION 
 
 
X 
X 
NEW MALIGNANCIES 
 
 
X 
X 
PYREXIA 
 
 
X 
X 
VISUAL CHANGES 
 
 
X 
X 
HYPERGLYCEMIA 
 
 
X 
X 
HEMORRHAGE 
 
 
X 
X 
THROMBOTIC EVENTS 
 
 
 
X 
*X indicates study treatment that may need to be modified 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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48 
 
4.9  Management Guidelines for Targeted Therapy 
See Appendix 2 and 3. 
 
4.10 Guidelines for Permanent Discontinuation 
• Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment 
• Any Grade 3 non-skin, drug-related AE lasting > 7 days, with the following exceptions 
for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, infusion reactions, and endocrinopathies: 
− Grade 3 drug-related uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or 
infusion reaction of any duration requires discontinuation 
− Grade 3 drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement do not require discontinuation 
− Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
♦ Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
• Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation: 
− AST or ALT > 8 x ULN 
− Total bilirubin > 5 x ULN 
− Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
• Any Grade 4 drug-related AE or laboratory abnormality, except for the following events 
which do not require discontinuation: 
− Grade 4 neutropenia ≤ 7 days 
− Grade 4 lymphopenia or leukopenia 
− Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis. The Study PI should be consulted 
for Grade 4 amylase or lipase abnormalities. 
− Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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49 
 
• Any event that leads to delay in dosing lasting > 6 weeks from the previous dose 
requires discontinuation, with the following exceptions: 
− Dosing delays to allow for prolonged steroid tapers to manage drug-related AEs are 
allowed. Prior to re-initiating treatment in a subject with a dosing delay lasting > 6 weeks 
from the previous dose, the Study PI must be consulted. Tumor assessments should 
continue as per protocol even if dosing is delayed. Periodic study visits to assess safety 
and laboratory studies should also continue every 6 weeks or more frequently if 
clinically indicated during such dosing delays. 
− Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-
related reasons may be allowed if approved by the Study PI. Prior to re-initiating 
treatment in a subject with a dosing delay lasting > 6 weeks, the Study PI must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
delayed. Periodic study visits to assess safety and laboratory studies should also 
continue every 6 weeks or more frequently if clinically indicated during such dosing 
delays. 
• Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subject with continued nivolumab 
or ipilimumab dosing. 
Note: If a subject experiences a severe AE during induction treatment (ie, the 
combination of nivolumab and ipilimumab) that requires discontinuation from further 
treatment with the combination, continuing treatment with nivolumab monotherapy may 
be considered contingent on discussion with and approval by the Study PI. 
Exceptions to Permanent Discontinuation of study drug dosing under the following 
situations: 
• Potentially reversible inflammation (< Grade 4), attributable to a local anti-tumor 
reaction and a potential therapeutic response. This includes inflammatory reactions at 
sites of tumor resections or in draining lymph nodes, or at sites suspicious for, but not 
diagnostic of metastasis. 
• Participants with the following conditions where in the investigator’s opinion continuing 
study drug administration is justified: 
− Endocrinopathies where clinical symptoms are controlled with appropriate hormone 
replacement therapy. 
4.11 Treatment of Nivolumab or Ipilimumab Related Infusion Reactions 
Since nivolumab and ipilimumab contain only human immunoglobulin protein 
sequences, it is unlikely to be immunogenic and induce infusion or hypersensitivity 
reactions. However, if such a reaction were to occur, it might manifest with fever, chills, 
rigors, headache, rash, pruritus, arthralgias, hypotension, hypertension, bronchospasm, 
or other allergic-like reactions. All Grade 3 or 4 infusion reactions should be reported 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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50 
 
within 24 hours to the study medical monitor and reported as an SAE if it meets the 
criteria. Infusion reactions should be graded according to NCI CTCAE (Version 5.0) 
guidelines.  
Treatment recommendations are provided below and may be modified based on local 
treatment standards and guidelines, as appropriate:  
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention 
not indicated):  
• Remain at bedside and monitor subject until recovery from symptoms. The 
following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 
to 1000 mg at least 30minutes before additional nivolumab administrations.  
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment (eg, antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic 
medications indicated for <24 hours):  
Stop the nivolumab or ipilimumab infusion, begin an IV infusion of normal saline, and 
treat the subject with diphenhydramine 50 mg IV (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000mg; remain at bedside and monitor subject 
until resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 
50% of the original infusion rate when symptoms resolve; if no further complications 
ensue after 30 minutes, the rate may be increased to 100% of the original infusion rate. 
Monitor subject closely. If symptoms recur, then no further BMS-936558 will be 
administered at that visit.  
• For future infusions, the following prophylactic premedications are 
recommended: diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg should be administered at least 30 
minutes before nivolumab infusions. If necessary, corticosteroids (up to 25 mg of 
SoluCortef or equivalent) may be used. 
 
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence 
of symptoms following initial improvement; hospitalization indicated for other clinical 
sequelae (eg, renal impairment, pulmonary infiltrates). Grade 4: Life-threatening; 
pressor or ventilatory support indicated):  
• Immediately discontinue infusion of nivolumab or ipilimumab. Begin an IV 
infusion of normal saline and treat the subject as follows: Recommend 
bronchodilators, epinephrine 0.2 to 1 mg of a 1:1000 solution for subcutaneous 
administration or 0.1 to 0.25 mg of a 1:10,000 solution injected slowly f or IV 
administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 
mg IV (or equivalent), as needed. Subject should be monitored until the 
Investigator is comfortable that the symptoms will not recur. Nivolumab or 
ipilimumab will be permanently discontinued. Investigators should follow their 
institutional guidelines for the treatment of anaphylaxis. Remain at bedside and 
monitor subject until recovery of the symptoms.  


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In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be 
given (eg, oral antihistamine or corticosteroids). 
 
5. STUDY DESIGN 
5.1  Overall Design 
Table 5.2.1 details assessments for Phase 1 Cohort 1, and Table 5.2.2 for Phase 1 Cohort 
2. Every effort must be made to follow the schedule of assessments within the windows 
outlined in the protocol.  
• For the first 6 weeks, all assessments have a ± 3 day window unless otherwise 
indicated. 
• After the first 6 weeks, all assessments have a ± 7 day window, unless otherwise 
indicated. Additional assessment may be performed as clinically indicated.  
If study drug is being held due to toxicity, then the scheduled visits and assessments 
should still be performed per protocol (except dose administration), unless otherwise 
specified. 
 
 


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Table 5.2.2: Phase I Cohort 1 
 
 
 
 
 
Trial Period: 
Screen 
Phase 
Treatment 
 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screen 
D1 
W1 
D1 
W2 
D1 
W3 
D1
W4 
 
 
Discon 
Safety 
Follow-
up 
Follow Up Visits 
D1
W5 
D1
W6 
D1
W7 
D1
W8  
D1
W9 
 
D1W 
14 (+) 
Scheduling Window (Days): 
28 days 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
100 days 
post 
discon 
Every 12 weeks 
post discon 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
Trial Treatment Administrationa 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
Review Adverse Events 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
Nursing Call Check-Up 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Physical Examination 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Vital Signs  
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry 
Panel 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
HCV, HIV, HepB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH (T3, FT4 if TSH abnormal) 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Research blood collectionb 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Archival tumor collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumor biopsyc 
X 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
Imagingd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
Encorafenib and binimetinib are given continuously. Nivolumab and ipilimumab are given for four doses every 3 weeks then nivolumab is given monthly for up to one year. 
b. 
Blood will be drawn at baseline, week 4, week 12 (or with first restaging imaging) and at progression/end of treatment 
c. 
Ten patients in each Phase Ib cohort will undergo fresh biopsy prior to treatment and between the 1st and 2nd doses of ipilimumab (between weeks 4-7). These will be the first 
10 unless medical or societal factors (e.g. COVID19) limit the pursuit of research biopsies. 
d. 
During treatment: Every 12 weeks (± 7 days). End of Treatment (EOT): if a scan was not conducted within 30 days prior to end of study treatment. Efficacy follow-up: Every 
12 weeks starting from the last assessment until documented disease progression per RECIST 1.1 (unless meeting criteria for treatment beyond progression), withdrawal of 
consent, lost to follow-up, or death irrespective of start of new anti-neoplastic therapy. 


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e. 
Table 5.2.2: Phase I Cohort 2 
 
 
 
 
 
Trial Period: 
Screen 
Phase 
Treatment 
 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screen 
D1 
W1 
D1 
W2 
D1 
W3 
D1
W4 
 
 
Discon 
Safety 
Follow-
up 
Follow Up Visits 
D1
W5 
D1
W6 
D1
W7 
D1
W8  
D1
W9 
D1W
10 
D1W 
14 (+) 
Scheduling Window (Days): 
28 days 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
100 days 
post 
discon 
Every 12 weeks 
post discon 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication 
Review 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
Trial Treatment Administrationa 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
Review Adverse Events 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
Nursing Call Check-Up 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Physical Examination 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Vital Signs  
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry 
Panel 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
HCV, HIV, HepB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH (T3, FT4 if TSH abnormal) 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
Research blood collectionb 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Archival tumor collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumor biopsyc 
X 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
 
Imagingd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a. 
Encorafenib and binimetinib are given continuously. Nivolumab and ipilimumab are given for four doses every 3 weeks then nivolumab is given monthly for up to one year. 
b. 
Blood will be drawn at baseline, week 4, week 12 (or with first restaging imaging) and at progression/end of treatment 
c. 
Ten patients in each Phase Ib cohort will undergo fresh biopsy prior to treatment and between the 1st and 2nd doses of ipilimumab (between weeks 4-7). These will be the first 
10 unless medical or societal factors (e.g. COVID19) limit the pursuit of research biopsies. 
d. 
During treatment: Every 12 weeks (± 7 days). End of Treatment (EOT): if a scan was not conducted within 30 days prior to end of study treatment. Efficacy follow-up: Every 
12 weeks starting from the last assessment until documented disease progression per RECIST 1.1 (unless meeting criteria for treatment beyond progression), withdrawal of 
consent, lost to follow-up, or death irrespective of start of new anti-neoplastic therapy. 
 


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5.1.1 Retesting During Screening or Lead-in Period 
Retesting of laboratory parameters and/or other assessments during the Screening or 
Lead-in period will not be permitted (this does not include parameters that require a 
confirmatory result) unless there was a technical error in performance of the lab test and 
the first result is invalid.  
Any new result will override the previous result (ie, the most current result prior to dosing) 
and is the value by which study inclusion will be assessed, as it represents the subject’s 
most current, clinical state. 
5.2  Safety Assessments 
5.2.1 Medical History, Physical Exam, Physical Measurements 
At baseline, a medical history will be obtained to capture relevant underlying conditions. 
The baseline examinations should include weight, height, ECOG Performance Status, 
blood pressure (BP), heart rate (HR), temperature, and oxygen saturation by pulse 
oximetry at rest (also monitor amount of supplemental oxygen if applicable) should be 
performed within 28 days prior to first dose.  
Baseline local laboratory assessments should be done within 14 day prior to first dose 
and are to include: CBC w/differential, Chemistry panel including: LDH, AST, ALT, ALP, 
T.Bili, BUN or serum urea level, creatinine, Ca, Mg, Na, K, Cl, Glucose, amylase, lipase, 
TSH, Free T4, Free T3, Hep B/C (HBV sAG, HCV antibody, or HCV RNA). 
While on-study and during follow-up, local laboratory assessments are to be conducted 
as specified below.  
Participants will be evaluated for safety if they have received any study drug. Toxicity 
assessments will be continuous during the treatment phase. Once participants reach the 
survival follow-up, either in-person visits or documented telephone calls/email 
correspondence to assess the subject’s status are acceptable. 
AEs and laboratory values will be graded according to the NCI-CTCAE version 5.0. 
Oxygen saturation by pulse oximetry at rest (also monitor amount of supplemental oxygen 
if applicable) should be assessed at each on-study visit prior to dosing. The start and stop 
time of the study therapy infusions should be documented.  
Physical examinations are to be performed as specified in Section 5.1 and as clinically 
indicated. If there are any new or worsening clinically significant changes since the last 
exam, report changes on the appropriate non-serious or serious AE page.  
On treatment local laboratory assessments are to be completed within 72 hours prior to 
dosing.  
Additional measures, including non-study required laboratory tests, should be performed 
as clinically indicated or to comply with local regulations. Laboratory toxicities (eg, 
suspected drug induced liver enzyme evaluations) will be monitored during the follow-up 


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phase via on site/local labs until all study drug related toxicities resolve, return to baseline, 
or are deemed irreversible.  
If a subject shows changes on pulse oximetry or other pulmonary-related signs (hypoxia, 
fever) or symptoms (eg. dyspnea, cough, fever) consistent with possible pulmonary-
related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, fever) consistent with 
possible pulmonary AEs, the subject should be immediately evaluated to rule out 
pulmonary toxicity, according to the suspected pulmonary toxicity management algorithm.  
Some of the assessments referred to in this section may not be captured as data in the 
eCRF. They are intended to be used as safety monitoring by the treating physician. 
Additional testing or assessments may be performed as clinically necessary or where 
required by institutional or local regulations. 
5.2.2 Vital Signs 
Vital signs consist of blood pressure, heart rate, respiratory rate, pulse oximetry and 
temperature measurements. Vital signs will be obtained as outlined above. 
5.2.3 Imaging Assessment for Study 
CT and MRI scans (section 5.4) will be assessed locally per the modified RECIST 1.1 
criteria and RANO BM criteria 69,70. Up to 5 extracranial and 5 intracranial lesions will be 
followed for efficacy per the criteria. Please refer to Appendix 1 and 5 for guidelines 
regarding images, target lesion selection and response criteria.  
Any incidental findings of potential clinical relevance that are not directly associated with 
the objectives of the protocol should be evaluated and handled by the Study Investigator 
as per standard medical/clinical judgment.  
Clinically significant radiologic findings or changes from baseline scans will be coded as 
AEs or serious AEs according to the criteria described in Section6. 
5.2.4 ECOG Status 
ECOG performance status will be evaluated at the screening evaluation and at each visit 
as outlined.  
5.2.5 AE Monitoring 
AEs will be evaluated according to the NCI CTCAE Version 5.0 on a continuous basis 
starting from when the subject takes the first dose of study administration, up to and 
including Follow-Up and End of Treatment visits (at minimum, for 100 days following last 
dose of study drug). Serious AEs (SAEs) must be collected from the time period following 
p first dose of study drug to and including follow-up (refer to section 5.4). 
5.2.6 Laboratory Test Assessments 
Results of all safety laboratory collections must be obtained and reviewed in advance of 
study drug dosing, as applicable. Amylase and lipase should be collected with the 
chemistry collection, but these lab results do not require review prior to dosing.  


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Serum Chemistry includes comprehensive metabolic panel (albumin, blood urea nitrogen, 
calcium, carbon dioxide, chloride, creatinine, glucose, potassium, sodium, total bilirubin 
and 
protein, alanine 
aminotransferase, 
alkaline 
phosphatase, 
and aspartate 
aminotransferase) 
with 
magnesium, 
phosphorous, 
amylase, 
lipase, 
lactate 
dehydrogenase. A free-T4 and free-T3 will be performed reflexively for out of range TSH 
values. A CBC with differential is to be obtained. The CBC with differential includes 
hemoglobin, hematocrit, white blood cells, platelets (direct platelet count), erythrocyte 
sedimentation rate, WBC differential enumeration of total and percentage of neutrophils, 
lymphocytes, eosinophils, basophils and monocytes. 
5.3 Efficacy Assessments 
Assessment of extracranial disease (by CT scan or other approved modalities) and 
intracranial disease (by MRI scan) will be performed per the schedule above and using 
criteria in Appendix 5. Investigators may obtain more frequent follow-up MRI scans as 
medically indicated. Baseline assessments should be performed within 28 days prior to 
first dose of study drug utilizing CT or MRI for systemic lesions and within 28 days for 
brain lesions (MRI only). In addition to chest, abdomen, pelvis, and brain, all known sites 
of disease should be assessed at baseline. Subsequent assessments should include 
chest, abdomen, pelvis, brain, and all known sites of disease and should use the same 
imaging method as was used at baseline. Participants will be evaluated for tumor 
response beginning at 12 weeks (± 7 days) and every 12 weeks (± 7 days) thereafter, 
until disease progression is documented, or treatment is discontinued (whichever occurs 
later). 
For extracranial disease assessment, contrast-enhanced computed tomography (CT) 
scans acquired on dedicated CT equipment is preferred for this study. CT with contrast 
of the chest, abdomen and pelvis and other areas of disease are to be performed for 
tumor assessments as above. Should a subject have a contraindication for CT IV 
contrast, a non-contrast CT of the chest and a contrast enhanced MRI of the abdomen 
and pelvis may be obtained. MRI’s should be acquired with slice thickness of <5 mm with 
no gap (contiguous). Use of CT component of a PET/CT scanner: Combined modality 
scanning such as with FDGPET/CT is increasingly used in clinical care and is a 
modality/technology that is in rapid evolution; therefore, the recommendations outlined 
here may change rather quickly with time. At present, low dose or attenuation correction 
CT portions of a combined FDG-PET/CT are of limited use in anatomically based efficacy 
assessments and it is therefore suggested that they should not be substituted for 
dedicated diagnostic contrast enhanced CT scans for anatomically based RECIST 
measurements. However, if a site can document that the CT performed as part of a 
FDGPET/CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) 
then the CT portion of the FDG-PET/CT can be used for RECIST 1.1 measurements. 
Note, however, that the FDG-PET portion of the CT introduces additional data which may 
bias an investigator if it is not routinely or serially performed.  


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MRI scans: Bi-dimensional and three-dimensional contrast enhanced MRI of the brain will 
be acquired. Every attempt should be made to image each subject using an identical 
acquisition protocol on the same scanner for all imaging time points. Cases of suspected 
radiologic disease progression will be confirmed by an MRI performed at least 4 weeks 
after the initial radiological assessment of progression. 
5.3.1 Confirmation of scans 
Verification of Response: Confirmation of intracranial response will be confirmed by an 
MRI performed at least 4 weeks after the initial radiological assessment per investigator 
discretion or SOC. If repeat scans confirm overall response (OR), then response should 
be declared using the date of the initial scan. If repeat scans do not confirm OR, then the 
subject is considered not to have had an OR.  
Verification of Progression: Progression of disease should be verified in cases where 
progression is equivocal and will be confirmed by a CT or MRI performed at least 4 weeks 
after the initial radiological assessment of progression per investigator discretion or SOC. 
If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered not to have 
progressive disease. 
5.3.2 Algorithms for Response Assessment 
5.3.2.1 
Safety 
The primary endpoint of the study is safety and tolerability of triple or quadruple therapy 
and will be assessed in Phase I. 
5.3.2.2 
Secondary Endpoints – Efficacy 
Secondary efficacy endpoints of the study include PFS and ORR in all randomized 
participants. 
5.4  Biomarker Assessments 
A variety of factors that could potentially predict clinical response to triplet or quadruple 
therapy will be investigated in peripheral blood and in tumor specimens. Data from these 
investigations will be evaluated for associations with response, survival (OS, PFS) and/or 
safety (AE) data. All samples collected may also be used for future exploratory analyses 
(unless restricted by local requirements) to assess biomarkers associated with melanoma 
or immunotherapy treatment. Complete instructions on the collection, processing, 
handling and shipment of all samples described herein will be provided in a separate Lab 
Manual. 
Biomarkers  
Biomarker measures of baseline and on-treatment peripheral blood, serum, and tumor 
samples will be used to identify pharmacodynamic markers of treatment. Additional 
biomarkers related to mechanism of action and markers associated with clinical response 
to encorafenib +/- binimetinib + nivolumab + low dose ipilimumab will be explored.  


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A detailed description of each biomarker sample analysis and assessment is described 
below and a schedule of biomarker sample collections is provided in the table. Further 
details of blood and tissue collection and processing will be provided in the Lab Manual.  
Peripheral blood and tumor tissue will be collected prior to therapy and at selected time 
points on treatment. If a biopsy or surgical resection is performed at the on treatment or 
at the time of recurrence or suspected recurrence, tumor sample should also be submitted 
for analysis. If biomarker samples are drawn but study treatment(s) is not administered, 
samples will be retained. Detailed instructions of the obtaining, processing, labeling, 
handling, storage and shipment of specimens will be provided in a separate Lab Manual 
at the time of study initiation. 
 
Study Day of 
Sample Collection* 
Seruma 
Whole Blooda 
Tumor Biopsya,b 
Plasma ctDNAa 
Screening 
X 
X 
X 
X 
Prior to dose at 
week 4 
X 
X 
 
X 
Between week 4-7 
 
 
X 
 
At 12 week 
restaging  
X 
X 
 
X 
At progression 
X 
X 
 
X 
* Protocol specified windows apply to biomarker assessments 
a Instructions for the collection and processing of all samples will be provided in the laboratory manual. 
b Fresh tumor biopsy will only be collected in Phase I  
 
Biomarker Measures  
Immunomodulatory properties of encorafenib with and without binimetinib in combination 
with nivolumab and ipilimumab will be investigated in peripheral blood and tumor samples 
as detailed below.  
Peripheral Blood Studies Peripheral blood samples will be taken prior to initiation of 
study therapy and on designated time points post-treatment. Above samples will be 
analyzed for the following measures:  
Peripheral Blood Soluble Factors (Serum and Plasma) Baseline and post-treatment 
modulation of serum levels of chemokines, cytokines and other immune mediators will be 
assessed by techniques that may include, but are not limited to ELISA, LC-MS.  
Immunophenotyping Peripheral blood samples will be taken prior to initiation of study 
therapy and at designated time points on-treatment. These whole blood or PBMC 
samples may be used for characterization of the immune cell subsets in the peripheral 
blood. Analyses may include, but not necessarily be limited to, the proportion of T, B, and 
NK cells; monocytes and MDSCs as well as their function status measured by Ki67.  
Peripheral Blood Genomic and Gene Expression Profiling Peripheral biomarker 
measures: PBMCs, plasma, serum, or RNA/DNA derived from whole blood may be used 
for future exploratory analyses such as, but not limited to assessment of gene expression, 


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tumor mutational burden (TMB), to assess biomarkers of immune cell populations 
associated with tumor type or therapy.  
T Cell Receptor sequencing DNA-derived from whole blood or PBMCs may be used for 
the assessment of T cell receptor repertoire by genomic sequencing technologies.  
Tumor Biopsies and Tumor-Based Biomarker Measures Mandatory tumor biopsy 
specimens will be obtained at baseline and on-treatment to characterize immune cell 
populations and expression of selected tumor markers. Study participants should have 
tumor lesions large enough to undergo repeated biopsies (pre- and on-treatment), 
excisional or at least obtainment of 4 core biopsy specimens. Pathologic confirmation is 
strongly encouraged at the time of tumor biopsy to confirm adequate tissue collection and 
biopsy quality. Participants who undergo biopsy or excision for clinical indications should 
have any tumor that remains preserved for biomarker analysis. Detailed information for 
the collection and processing of all samples will be provided in the Lab Manual.  
In addition to fresh tumor biopsy, participants are required to submit an archival formalin-
fixed paraffin-embedded (FFPE) specimen, if collected prior to the enrollment, if available. 
The archival tumor tissue sample will be used to compare the expression of putative 
biomarkers to expression in the fresh tumor biopsy.  
The pharmacodynamic effects of encorafenib with and without binimetinib in combination 
with nivolumab and ipilimumab on intratumoral immune response in biopsy samples will 
be assessed by gene expression analysis or single cell analysis and calculated as fold 
change (or percent changes) compared to baseline.  
Characterization of tumor microenvironment cell population and immune infiltrates 
in tumor. The number, frequency, and composition of immune infiltrates within the tumor 
may be assessed before and after exposure to encorafenib with and without binimetinib 
in combination with nivolumab and ipilimumab using IHC of the FFPE tumor biopsy 
specimen. IHC assays may be performed using, but not limited to, the following markers: 
CD8, CD3, CD15, and PD-L1. The composition of tumor immune infiltrate may be 
assessed before and after treatment using IHC or multi-plex analysis of the FFPE tumor 
biopsy specimen. IHC assays may be performed using, but not limited to, the following 
markers: CD8, CD3, CD15, and PD-L1. Fresh and archival tumor samples may be 
subjected to correlative gene expression and/or IHC analysis.  
Tumor DNA/RNA analysis: Fresh tumor biopsy samples may be evaluated by gene 
expression analysis using RNAseq, single cell RNA sequencing, qRT-PCR or other 
relevant techniques to interrogate pharmacodynamic effects, mechanism of action, 
and/or response or resistance to encorafenib with and without binimetinib in combination 
with nivolumab and ipilimumab. DNA/RNA derived from tumor tissue may be used for 
analysis of genomic correlates including but not limited to tumor mutational burden and T 
cell receptor repertoire.  


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Other exploratory tumor-based biomarker measures: Tumor tissue or derived 
RNA/DNA may also be evaluated by LCMS, genetic mutation and rearrangement 
detection methods, such as genome and/or exome sequencing, and/or quantitative PCR 
or RT-PCR as part of additional exploratory analyses of putative biomarkers possibly 
associated with response or resistance to encorafenib with and without binimetinib in 
combination with nivolumab and ipilimumab. 
6. 
ADVERSE EVENTS 
An AE is defined as any new untoward medical occurrence or worsening of a preexisting 
medical condition in a clinical investigation subject administered study drug and that does 
not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of study drug, whether or not considered 
related to the study drug.  
The causal relationship to study drug is determined by a physician and should be used to 
assess all AEs. The causal relationship can be one of the following:  
Related: There is a reasonable causal relationship between study drug administration and 
the AE.  
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
AEs can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, participants 
should not be questioned regarding the specific occurrence of one or more AEs.)  
6.1 Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe)  
• requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see NOTE below)  
• results in persistent or significant disability/incapacity  
• is a congenital anomaly/birth defect  
• is an important medical event (defined as a medical event(s) that may not be 
immediately life threatening or result in death or hospitalization but, based upon 


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appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an 
important medical event. 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE. Although pregnancy, overdose, cancer, and potential drug induced 
liver injury (DILI) are not always serious by regulatory definition, these events must be 
handled as SAEs.  
NOTE:  
The following hospitalizations are not considered SAEs in clinical studies:  
• a visit to the emergency room or other hospital department < 24 hours, that does 
not result in admission (unless considered an important medical or life-threatening 
event)  
• elective surgery, planned prior to signing consent  
• admissions as per protocol for a planned medical/surgical procedure  
• routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)  
• medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases  
• admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason).  
• Admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to oncology protocols) 
6.1.1 SAE Collection and Reporting 
Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be 
associated with protocol-specified procedures. All SAEs must be collected that occur 
during the screening period and within 100 days of discontinuation of dosing.  
The investigator should report any SAE that occurs after these time periods and that is 
believed to be related to study drug or protocol-specified procedure. 


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An SAE report should be completed for any event where doubt exists regarding its 
seriousness.  
If the investigator believes that an SAE is not related to study drug but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy or a complication 
of a study procedure), the relationship should be specified in the narrative section of the 
SAE Report Form.  
REPORTING OF SAES  
 
All events meeting the definition of a serious AE should be reported according to the 
departmental SAE checklist and SAE form. The initial SAE form should be sent to the 
following within 24 hours/1 business day of the Principal Investigator becoming aware: 
 
1. Sponsor-Investigator 
2. crssafetysubmissions@upmc.edu 
3. Local Institutional Review Board when reporting requirements are met. 
 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include as applicable the following information that is 
available at the time of report within the Sections B and C of the departmental SAE form: 
 
• CTCAE term(s) and grade(s)  
• current status of study drug 
• all interventions to address the AE (testing and result, treatment and response) 
• hospitalization and/or discharge dates 
• event relationship to study drug 
 
Follow-up reports:   
Additional information may be added to a previously submitted report by adding to the 
original departmental SAE form and submitting it as follow-up or creating supplemental 
summary information and submitting it as follow-up with the original departmental SAE 
form. 
 
6.2 Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the non-serious 
AE CRF page or SAE Report Form (paper or electronic) as appropriate:  
• Any laboratory test result that is clinically significant or meets the definition of an 
SAE  
• Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted  
• Any laboratory test result abnormality that required the subject to receive specific 
corrective therapy. It is expected that wherever possible, the clinical rather than 


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laboratory term would be used by the reporting investigator (eg, anemia versus 
low hemoglobin value). 
 
6.3 Pregnancy 
If, following initiation of the study drug, it is subsequently discovered that a study subject 
is pregnant or may have been pregnant at the time of study exposure, including during at 
least 5 half-lives after product administration, the investigator must immediately notify the 
BMS Medical Monitor/designee of this event and complete and forward a Pregnancy 
Surveillance Form to BMS Designee within 24 hours and in accordance with SAE 
reporting procedures described in Section 6.1.1. In most cases, the study drug will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary, for 
subject safety). In the rare event that the benefit of continuing study drug is thought to 
outweigh the risk, after consultation with BMS, the pregnant subject may continue study 
drug after a thorough discussion of benefits and risk with the subject Protocol-required 
procedures for study discontinuation and follow-up must be performed on the subject 
unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. The investigator must 
immediately notify the BMS (or designee) Medical Monitor of this event and complete and 
forward a Pregnancy Surveillance Form to BMS (or designee) within 24 hours and in 
accordance with SAE reporting procedures described in Section6.1.1. Follow-up 
information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form 
6.4 Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE (see Section6.1.1for reporting details). 
6.5 Other Safety Concerns 
Any significant worsening noted during interim or final physical examinations, 
electrocardiogram, X-ray filming, any other potential safety assessment required or not 
required by protocol should also be recorded as a non-serious or serious AE, as 
appropriate, and reported accordingly.


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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65 
7. 
DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES 
Investigator/Sub-investigators, regulatory, CRS management, clinical research 
coordinators, clinical research associates, data managers, and clinic staff meet regularly 
in disease center Data Safety Monitoring Boards (DSMB) to review and discuss study 
data to include, but not limited to, the following: 
• SAEs 
• subject safety issues 
• recruitment issues 
• accrual 
• protocol deviations 
• unanticipated problems 
• breaches of confidentiality 
Minutes from the disease center DSMB meetings are available to those who are unable 
to attend in person. 
 
All toxicities encountered during the study will be evaluated on an ongoing basis 
according to the NCI Common Toxicity Criteria Version 5.0. All study treatment 
associated AEs that are serious, at least possibly related and unexpected will be 
reported to the IRB.  Any modifications necessary to ensure subject safety and 
decisions to continue or close the trial to accrual are also discussed during these 
meetings. If any literature becomes available which changes the risk/benefit ratio or 
suggests that conducting the trial is no longer ethical, the IRB will be notified in the form 
of an Unanticipated Problem submission and the study may be terminated.  
All study data reviewed and discussed during these meetings will be kept confidential. 
Any breach in subject confidentiality will be reported to the IRB in the form of an 
Unanticipated Problem submission. The summaries of these meetings are forwarded to 
the UPMC Hillman Cancer Center DSMC which also meets monthly following a 
designated format. 
For all research protocols, there will be a commitment to comply with the IRB’s policies 
for reporting unanticipated problems involving risk to participants or others (including 
AEs). DSMC progress reports, to include a summary of all serious AEs and 
modifications, and approval will be submitted to the IRB at the time of renewal. 
Protocols with participants in long-term (survival) follow-up or protocols in data analysis 
only, will be reviewed bi-annually. 
Both the UPMC Hillman Cancer Center DSMC as well as the individual disease center 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
66 
DSMB have the authority to suspend accrual or further investigate treatment on any trial 
based on information discussed at these meetings. 
All records related to this research study will be stored in a locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the 
research records. 
8. 
STATISTICAL CONSIDERATIONS 
This is a combination Phase I/II open label study of encorafenib +/- binimetinib + 
nivolumab + ipilimumab in participants with unresectable or metastatic BRAFV600-
mutant melanoma. Two cohorts that differ by treatment (triple or quadruple therapy) will 
be enrolled in phase I.  The recommended Phase II dosing regimen will be identified when 
following criteria are met: 
- 
at least 10 patients have been evaluated on a regimen with DLT <60% 
- 
the PI, Data and Safety Committee, William Gooding statistician, and interested 
PI’s from participating institutions review all clinical data to determine the RP2R 
Phase II will enroll two high risk cohorts differing by symptoms ((1) symptomatic brain 
metastases and 2) elevated liver enzymes with hepatic metastases) at the selected 
schedule and dose. The two cohorts will be investigated for safety and efficacy 
8.1 Objectives 
Primary Objective 
• To nominate a recommended phase II regimen (RP2R) of triple or quadruple therapy 
with encorafenib +/- binimetinib + nivolumab and + ipilimumab in BRAF mutated, 
metastatic melanoma. 
Secondary Objectives 
• To estimate the RECIST response rate of triple or quadruple therapy in high risk 
populations of BRAF mutated, metastatic melanoma. 
• To estimate the CNS clinical benefit rate (CBR, defined as complete response [CR] 
+ partial response [PR] + stable disease [SD] >6 months) per RANO-MB criteria of 
triple or quadruple therapy in BRAF mutated, metastatic melanoma to the CNS 
• To describe the toxicity, by CTCAEv5, of triple or quadruple therapy in BRAF 
mutated, metastatic melanoma 
• To summarize the progression-free survival of triple or quadruple therapy in high 
risk populations of BRAF mutated, metastatic melanoma 
Exploratory Objectives 
6. To evaluate association between treatment response and baseline tumor mutational 
burden, changes in the tumor microenvironment (IFN associated gene expression), 
T cell clonality, and other biospecimens before and after triple or quadruple therapy. 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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67 
8.2 Endpoints 
The primary endpoint is the frequency of DLTs that are classified as either possibly, 
probably, or definitely related to study treatment according to NCI Common Terminology 
Criteria for Adverse Events (CTCAE v5.0).  DLTs are specified in section 4.5.2.  Adverse 
events and DLTs will be compiled separately for each phase I cohort (triple and quadruple 
therapy).  Any patient receiving at least one dose any of study drug will be evaluable for 
toxicity.  
Secondary endpoints include the clinical response rates in the phase II cohorts by 
RECIST criteria with a lower one sided 80% confidence interval. The clinical benefit rate 
(rate of complete response, partial response or stable disease) will also be computed with 
a lower one-sided confidence bound for the symptomatic brain metastasis group.  Both 
clinical response and clinical benefit rates will apply to evaluable patients defined as 
having completed 4 weeks of therapy. 
8.3 Sample Size Considerations 
Twelve patients will be evaluated in each phase I cohort; 30 patients will be evaluated for 
clinical response and clinical benefit in each phase II cohort. The total enrollment, in the 
absence of early stopping, is 84 patients (24 phase I / 60 phase II). Inference regarding 
safety of each cohort will depend upon the proportion of patients with DLT.  An upper 
90% confidence bound on these estimates can be used as a “rule out” criteria by the 
investigator such that any an unacceptably high DLT rate that is greater than the upper 
confidence interval may be ruled out.   
Table 8.1 Upper Confidence Bounds for DLT Rate 
For example (see table 8.1), if none of 12 patients have 
a DLT one could claim the DLT rate is no higher than 
17%, If 6 of 12 patients have treatment-related DLT the 
upper confidence bound is 71%, that is, the observed 
data (6/12) is consistent with a rate up to but not higher 
71% . thus, one can rule out a DLT rate of 72% or 
greater. 
Phase II cohorts will be used to (1) further refine the 
safety profile by re-estimating the DLT rate and (2) 
providing a preliminary estimate of efficacy.  
While the phase II cohorts are accruing, The DLT rate 
will be continuously monitored and the trial will be 
suspended if the DLT rate appears to be too high.   We 
assume, a priori, the DLT rate is thought to be 50%. A 
continuous monitoring program will be implemented to 
detect if this assumption is an underestimate such that the rate were actually 60% or 
higher.   Beginning with the 5th patient, continuous Bayesian monitoring calculates the 
probability that the DLT rate is too high and provides a stopping rule. We assume a prior 
Number of 
DLTs 
Among 12 
Treated 
Upper Bound of 
90% Confidence 
Interval (%) 
0 
17 
1 
29 
2 
39 
3 
48 
4 
56 
5 
64 
6 
71 
7 
78 
8 
85 
9 
90 
10 
95 
11 
99 
12 
100 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
mutant melanoma 
 
68 
DLT probability of 50% and that the prior probability has a beta distribution with 
parameters 1.5 and 1.5, producing a mean of .5.  As each evaluable patient is evaluated 
for DLT, accumulated data is used to derive the posterior probability.  If the posterior 
probability of a DLT rate of 60% is 50% or greater, the stopping rule in the table is 
triggered.   
The following tables provides rules for suspending the trial if the actual rate is as high as 
60%: 
Table 8.2 DLTs Triggering Trial Suspension at 60% 
 
 
 
 
 
 
For example, if 6 DLTs are observed among the first 9 patients the stopping rule for 60% 
DLT is enacted to signal trial suspension. The accumulated toxicities will then be 
evaluated by the Data and Safety Monitoring Committee for further action.   
 
Inference from a complete 30 patient expansion cohort.   
If either of the expansion cohorts runs to completion without stopping due to excess 
toxicity, confidence intervals can be used for inference. First, to rule out excess toxicity, 
an upper 90% one-sided confidence intervals (table 8.3) provides an upper bound to the 
DLT rate (analogous to the phase I approach). Secondly, a lower 80% one-sided 
confidence bound (table 8.4) can be used to rule out an ineffective regimen. (A narrower, 
80% bound is used here since we want a decision that is only suggestive rather than 
definitive). 
Table 8.3 Upper Confidence Bounds for DLT Rate       Table 8.4 Lower Confidence Bounds for Response 
Number of Evaluable 
Patients (Inclusive) 
Suspend if there are 
This many DLTs 
Number of Evaluable 
Patients (Inclusive) 
Suspend if there are 
This many DLTs 
0-4 
------ 
17 
11 
5-6 
4 
18-19 
12 
7 
5 
20-21 
13 
8-9 
6 
22 
14 
12 
8 
23-24 
15 
13-14 
9 
25-26 
16 
15-16 
10 
 
 
Number of DLTs 
Among 30 Treated 
Upper Bound of 90%  
Confidence Interval (%) 
0 
7% 
1 
12% 
2 
17% 
3 
21% 
4 
25% 
5 
29% 
6 
32% 
7 
36% 
8 
40% 
9 
43% 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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69 
 
Operating characteristics of possible 
decision rules in phase II 
If a 30-patient phase II cohort is completed 
the following decisions are possible: 
If 23 or more DLTs are observed among 30 
patients the combination can be considered 
as too toxic and a DLT rate of 75% or greater 
cannot be ruled out. The probability of 23 or 
more DLTs with a 75% DLT rate is 92%.  If the actual rate is 40% or less, the probability 
of 14 or fewer DLTs is 82% 
Considering a preliminary assessment of efficacy, three or fewer objective responses will 
suggest lack of efficacy with a response rate no better than 5%.  The probability of 
observing 3 or fewer responses when the actual rate is 5% is 94%. However, if the actual 
response rate is 20% the probability of 4 or more responses is 87%. 
8.4 Proposed Analysis of Primary and Secondary Endpoints 
Based on NCI Common Terminology Criteria for Adverse Events (CTCAE v5.0), the term 
toxicity is defined as AEs that are classified as either possibly, probably, or definitely 
related to study treatment. The maximum grade for each type of toxicity will be recorded 
for each patient, and frequency tables will be reviewed to determine toxicity patterns. The 
number of occurrences of each event will be tabulated by event and grade. In addition, 
the total number of patients experiencing AEs over their course of treatment will be 
characterized by type of AE and grade.  For this summary grades will be grouped into 
Grade I/II vs III/IV. In addition, the number of patients experiencing a dose-limiting toxicity 
as defined in table 4.5.2 will be compiled.  Inferences regarding recommended phase II 
regimen and safety in both phase I and phase II cohorts will be made by calculating the 
proportion of patients with a dose-limiting toxicity with a one sided upper 90% confidence 
bound.  
For the phase II cohorts, both the objective response rate (complete or partial response) 
/ total evaluable) and the clinical benefit rate (complete or partial response + stable 
disease / total evaluable) will be computed with lower 80% confidence bounds. Evaluable 
patients are those who got at least one dose of ipi/nivo.  Progression-free survival will be 
estimated with 90% two-sided confidence intervals for each phase II cohort.  For 
progression-free survival, an event is defined as disease-progression or death.   
10 
46% 
11 
50% 
12 
53% 
13 
57% 
14 
60% 
15 
63% 
Number of Responses 
Among 30 Treated 
Lower Bound of 80% 
Confidence Interval (%) 
0 
0% 
1 
0% 
2 
3% 
3 
5% 
4 
8% 
5 
10% 
6 
13% 
7 
16% 
8 
19% 
9 
22% 
10 
25% 
11 
28% 
12 
31% 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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70 
For exploratory biomarker analyses, Spearman’s correlation will be used for continuous 
variables such as Ki67+, T cell-inflamed GEP, pathway enrichment scores, TMB and 
others. Wilcoxon rank-sum test will be used to compare TMB between groups. Fisher’s 
exact test will be used to compare the fraction of mutated and non-mutated samples per 
gene and R vs NR between T cell-inflamed and non-inflamed groups. Recognizing 
RNAseq values are relative, we created a frozen reference set from TCGA using our 
previous work and bring newly collected samples to the same baseline by comparing to 
this reference. We transform new data into the reference set using linear regression and 
determining per sample T cell-inflamed score (>8.24; T cell-inflamed, <6.43; non-T cell-
inflamed and others intermediate). Benjamini-Hochberg procedure will be used to control 
FDR from multiple comparisons. All tests will be two-sided. 
 
9. 
STUDY MANAGEMENT 
9.1 Compliance 
9.1.1 Compliance with the Protocol and Protocol Revisions 
The study shall be conducted as described in this approved protocol. All revisions to the 
protocol must be discussed with, and be prepared by, BMS. The investigator should not 
implement any deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where necessary 
to eliminate an immediate hazard(s) to study participants.  
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) 
prior to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation 
or change will be submitted to:  
• IRB/IEC for review and approval/favorable opinion  
• BMS  
• Regulatory Authority(ies), if required by local regulations 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) 
must be sent to BMS.  
If an amendment substantially alters the study design or increases the potential risk to 
the subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for 
review and approval/favorable opinion; (2) the revised form must be used to obtain 
consent from participants currently enrolled in the study if they are affected by the 
amendment; and (3) the new form must be used to obtain consent from new participants 
prior to enrollment. If the revision is done via an administrative letter, investigators must 
inform their IRB(s)/IEC(s). 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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71 
9.1.2 Monitoring  
BMS representatives will review data centrally to identify potential issues to determine a 
schedule of on-site visits for targeted review of study records.  
Representatives of BMS must be allowed to visit all study site locations periodically to 
assess the data quality and study integrity. On site they will review study records and 
directly compare them with source documents, discuss the conduct of the study with the 
investigator, and verify that the facilities remain acceptable. Certain CRF pages and/or 
electronic files may serve as the source documents.  
In addition, the study may be evaluated by BMS internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, 
and study facilities. BMS audit reports will be kept confidential.  
The investigator must notify BMS promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to BMS. 
9.1.2.1 
Source Documentation 
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper 
or entered electronically. If source data are created (first entered), modified, maintained, 
archived, retrieved, or transmitted electronically via computerized systems (and/or any 
other kind of electronic devices) as part of regulated clinical trial activities, such systems 
must be compliant with all applicable laws and regulations governing use of electronic 
records and/or electronic signatures. Such systems may include, but are not limited to, 
electronic medical/health records (EMRs/EHRs), AE tracking/reporting, protocol required 
assessments, and/or drug accountability records).  
When paper records from such systems are used in place of electronic format to perform 
regulated activities, such paper records should be certified copies. A certified copy 
consists of a copy of original information that has been verified, as indicated by a dated 
signature, as an exact copy having all of the same attributes and information as the 
original. 
9.1.3 Investigational Site Training 
Bristol-Myers Squibb will provide quality investigational staff training prior to study 
initiation. Training topics will include but are not limited to: GCP, AE reporting, study 
details and procedure, electronic CRFs, study documentation, informed consent, and 
enrollment of WOCBP. 
9.2 Records 
9.2.1 Records Retention 
The investigator must retain all study records and source documents for the maximum 
period required by applicable regulations and guidelines, or institution procedures, or for 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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72 
the period specified by BMS, whichever is longer. The investigator must contact BMS 
prior to destroying any records associated with the study.  
BMS will notify the investigator when the study records are no longer needed.  
If the investigator withdraws from the study (eg, relocation, retirement), the records shall 
be transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice 
of such transfer will be given in writing to BMS. 
9.2.2 Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
study drug (inventoried and dispensed) is maintained at the study site to include 
investigational product and the following non-investigational product(s): ipilimumab. 
Records or logs must comply with applicable regulations and guidelines and should 
include:  
• amount received and placed in storage area  
• amount currently in storage area  
• label identification number or batch number  
• amount dispensed to and returned by each subject, including unique subject 
identifiers  
• amount transferred to another area/site for dispensing or storage  
• non-study disposition (e.g., lost, wasted)  
• amount destroyed at study site, if applicable  
• amount returned to BMS  
• retain samples for bioavailability/bioequivalence, if applicable  
• dates 
and 
initials 
of 
person 
responsible 
for 
Investigational 
Product 
dispensing/accountability, as per the Delegation of Authority Form. 
BMS will provide forms to facilitate inventory control if the investigational site does not 
have an established system that meets these requirements. 
9.2.3 Case Report Forms 
An investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated or entered as a control in the investigation. Data that are derived from 
source documents and reported on the CRF must be consistent with the source 
documents or the discrepancies must be explained. Additional clinical information may 
be collected and analyzed in an effort to enhance understanding of product safety. CRFs 
may be requested for AEs and/or laboratory abnormalities that are reported or identified 
during the course of the study.  


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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73 
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for 
all data collection fields except for fields specific to SAEs and pregnancy, which will be 
reported on the paper or electronic SAE form and Pregnancy Surveillance form, 
respectively. Spaces may be left blank only in those circumstances permitted by study-
specific CRF completion guidelines provided by BMS.  
The confidentiality of records that could identify participants must be protected, respecting 
the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s).  
The investigator will maintain a signature sheet to document signatures and initials of all 
persons authorized to make entries and/or corrections on CRFs.  
The completed CRF, including any paper or electronic SAE/pregnancy CRFs, must be 
promptly reviewed, signed, and dated by the investigator or qualified physician who is a 
sub-investigator and who is delegated this task on the Delegation of Authority Form. For 
electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs 
including records of the changes and corrections.  
Each individual electronically signing electronic CRFs must meet BMS training 
requirements and must only access the BMS electronic data capture tool using the unique 
user account provided by BMS. User accounts are not to be shared or reassigned to other 
individuals. 
9.3 Clinical Study Report and Publications 
A Signatory Investigator must be selected to sign the clinical study report.  
For this protocol, the Signatory Investigator will be selected as appropriate based on the 
following criteria:  
• External Principal Investigator designated at protocol development.  
The data collected during this study are confidential and proprietary to BMS. Any 
publications or abstracts arising from this study require approval by BMS prior to 
publication or presentation and must adhere to BMS’s publication requirements as set 
forth in the approved clinical trial agreement (CTA). All draft publications, including 
abstracts or detailed summaries of any proposed presentations, must be submitted to 
BMS at the earliest practicable time for review, but at any event not less than 30 days 
before submission or presentation unless otherwise set forth in the CTA. BMS shall have 
the right to delete any confidential or proprietary information contained in any proposed 
presentation or abstract and may delay publication for up to 60 days for purposes of filing 
a patent application. 
 
 


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Long, G. V. et al. Factors predictive of response, disease progression, and overall survival after 
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Long, G. V. et al. Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma. 
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Raizer, J. J. et al. Brain and leptomeningeal metastases from cutaneous melanoma: Survival 
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Holbrook, K. et al. Intracranial antitumor activity with encorafenib plus binimetinib in patients with 
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Tawbi, H. A. et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N. 
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Tawbi, H. A.-H. et al. Efficacy and safety of the combination of nivolumab (NIVO) plus ipilimumab 
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Olson, D. et al. Phase II trial of pembrolizumab (pembro) plus 1 mg/kg ipilimumab (ipi) immediately 
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Olson, D. et al. Phase II trial of pembrolizumab (pembro) plus 1 mg/kg ipilimumab (ipi) immediately 
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MEK 1/2 Inhibitor. in Cancer Research 70, 2515–2515 (American Association for Cancer 
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Kim, T. et al. Combining targeted therapy and immune checkpoint inhibitors in the treatment of 
metastatic melanoma. Cancer Biology and Medicine 11, 237–246 (2014). 
65. 
Callahan, M. K. et al. Nivolumab plus ipilimumab in patients with advanced melanoma: Updated 
survival, response, and safety data in a phase i dose-escalation study. in Journal of Clinical 
Oncology 36, 391–398 (American Society of Clinical Oncology, 2018). 
66. 
Wolchok, J. D. et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced 
Melanoma. N. Engl. J. Med. 377, 1345–1356 (2017). 
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Lebbé, C. et al. Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in 
patients with advanced melanoma: Results from the phase IIIb/IV CheckMate 511 trial. J. Clin. 
Oncol. 37, 867–875 (2019). 
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Rozeman, E. A. & Blank, C. U. Combining checkpoint inhibition and targeted therapy in 
melanoma. Nature Medicine 25, 879–882 (2019). 
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Lin, N. U. et al. Response assessment criteria for brain metastases: Proposal from the RANO 
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RECIST 1.1 – RECIST. Available at: https://recist.eortc.org/recist-1-1-2/. (Accessed: 31st May 
2020) 
 
 


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78 
APPENDIX 1 
RECIST 1.1 AND IMMUNE RESPONSE CRITERIA 
RECIST version 1.1* and irRC/irRECIST** will be used in this study for assessment of 
tumor response. While either CT or MRI may be utilized, as per RECIST 1.1, CT is the 
preferred imaging technique in this study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
** As published in Clinical Cancer Research: 
 
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune 
therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009 
Dec 1; 15(23):7412-20. 
In addition, volumetric analysis will be explored by central review for response 
assessment. 
 
 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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APPENDIX 2 
DOSE REDUCTION FOR ENCORAFENIB RELATED ADVERSE 
EVENTS 
 
Action 
Recommended Dose 
First Dose Reduction 
300mg (four 75mg capsules) PO once daily 
Second Dose Reduction 
225mg (three 75mg capsules) PO once daily 
Third Dose Reduction 
150mg (two 75mg capsules) PO once daily 
Subsequent Modification 
Discontinue 
 
 
Severity of Adverse Event 
Dose Modification 
New Primary Malignancies 
 
Non-cutaneous RAS positive malignancies 
Permanently Discontinue 
Uveitis 
 
Grade 1–3 
 
 
 
 
 
Grade 4 
If Grade 1 or 2 does not respond to specific 
ocular therapy, or for Grade 3 uveitis, 
withhold encorafenib and binimetinib for up 
to 6 weeks.  
• 
If improved, resume at same or 
reduced dose.  
• 
If 
not 
improved, 
permanently 
discontinue. 
Permanently discontinue encorafenib and 
binimetinib. 
Other Eye Disorders (i.e., non-Uveitis Events 
 


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Severity of Adverse Event 
Dose Modification 
Grade 1–2 
 
 
Grade 3 
 
 
 
 
 
 
 
 
 
Grade 4 
Maintain dose level of encorafenib and 
binimetinib and increase frequency of 
ophthalmic monitoring to at least every 14 
days until stabilization or resolution. 
Interrupt 
dosing 
of 
encorafenib 
and 
binimetinib 
and 
refer 
patient 
to 
ophthalmologist within 7 days.  
1. 1. If resolved to Grade ≤ 1 in ≤ 21 
days, 
resume 
treatment 
at 
1 
reduced dose level of encorafenib 
and binimetinib.  
2.  If not resolved to Grade ≤ 1 in ≤ 21 
days, 
permanently 
discontinue 
encorafenib and binimetinib and 
close follow-up with ophthalmic 
monitoring until stabilization or 
resolution. 
Permanently discontinue encorafenib and 
binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or 
resolution. 
QTc Prolongation 
 
QTcF > 500 ms and ≤ 60 ms increase from 
baseline 
 
 
 
 
 
 
 
 
 
 
QTcF > 500 ms and > 60 ms increase from 
baseline 
1st occurrence:   
• 
Temporarily interrupt dosing of 
encorafenib until QTcF < 500 ms. 
Then 
resume 
treatment 
at 
1 
reduced dose level of encorafenib.  
2nd occurrence:  
• 
Temporarily interrupt dosing of 
encorafenib treatment until QTcF < 
500 ms. Then resume treatment at 
1 
reduced 
dose 
level 
of 
encorafenib.   
3rd occurrence:   
• 
Permanently discontinue 
encorafenib. 
Permanently discontinue. 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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Severity of Adverse Event 
Dose Modification 
Dermatologic (Except Hand-foot Skin Reactions)  
Grade 2 
 
Grade 3 
 
 
Grade 4 
If no improvement within 2 weeks, withhold 
until Grade 0–1. Resume at same dose if 
first occurrence or reduce dose if recurrent. 
Withhold until Grade 0–1. Resume at same 
dose if first occurrence or reduce dose if 
recurrent 
Permanently discontinue. 
Hand-foot Skin Reaction (HFSR)/Palmar-plantar 
Erythrodysesthesia Syndrome (Dose Adjustment 
for Encorafenib ONLY) 
 
Grade 1 
Maintain dose of encorafenib. Promptly 
institute supportive measures, such as 
topical therapy, for symptomatic relief. Give 
instruction on life-style modifications. 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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Severity of Adverse Event 
Dose Modification 
Grade 2 
1st occurrence: 
• 
Maintain dose of encorafenib and 
HFSR should be closely monitored. 
Promptly 
institute 
supportive 
measures, such as topical therapy, 
for 
symptomatic 
relief. 
Give 
instruction 
on 
life-style 
modifications.  
• 
If no improvement ≤ 14 days, 
interrupt dosing of encorafenib until 
resolved to Grade ≤ 1. Resume 
treatment 
with 
encorafenib 
at 
current 
dose 
level. 
Continue 
supportive 
measures, 
such 
as 
topical therapy, for symptomatic 
relief. Give instruction on life-style 
modifications. 
Additional occurrence: 
• 
Treatment with encorafenib may be 
maintained or interrupted based 
upon the Investigator’s discretion. 
Continue 
supportive 
measures, 
such 
as 
topical 
therapy, 
for 
symptomatic relief. Give instruction 
on life-style modifications. 
If interrupted dosing of encorafenib per 
Investigator’s judgment, 
interrupt 
until 
resolved to Grade ≤ 1. Resume treatment 
with encorafenib at the same dose level or 
1 reduced dose level based upon the 
Investigator’s discretion. 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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Severity of Adverse Event 
Dose Modification 
Grade 3 
1st or additional occurrence: 
• 
Interrupt dosing of encorafenib until 
resolved to Grade ≤ 1. Promptly 
initiate supportive measures, such 
as topical therapy, for symptomatic 
relief. Give instruction on life-style 
modifications. Reassess the patient 
weekly. Then resume treatment at 
one 
reduced 
dose 
level 
of 
encorafenib. 
• 
Consider referral to dermatologist 
and 
manage 
HFSR 
per 
dermatologist’s recommendation. 
3nd occurrence: 
Interrupt 
dosing 
of 
encorafenib 
until 
resolved to Grade ≤ 1, decision to resume 
treatment with encorafenib at one reduced 
dose level or permanently discontinue 
encorafenib should be based upon the 
Investigator’s discretion. 
Nausea/Vomiting 
 
Grade 1–2 
 
Grade 3 
Maintain dose level of encorafenib and 
binimetinib. Promptly institute antiemetic 
measure. 
Interrupt 
dosing 
of 
encorafenib 
and 
binimetinib until resolved to Grade ≤ 1. 
Then resume treatment at 1 reduced dose 
level of encorafenib. Resume treatment 
with binimetinib at the current dose if, in the 
judgment of the Investigator, the toxicity is 
considered to be unrelated to binimetinib, or 
at 1 reduced dose level. Note: Interrupt 
dosing of encorafenib and binimetinib for ≥ 
Grade 3 vomiting or Grade 3 nausea only if 
the vomiting or nausea cannot be controlled 
with optimal antiemetics (as per local 
practice). 
 
 
 
 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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APPENDIX 3 
DOSE REDUCTION FOR BINIMETINIB RELATED ADVERSE 
EVENTS 
Action 
Recommended Dose 
First Dose Reduction 
30mg PO BID 
Subsequent Modification 
Discontinue 
 
 
Severity of Adverse Event 
Dose Modification 
Cardiomyopathy 
 
Asymptomatic, absolute decrease in LVEF of > 
10% from baseline that is also below the LLN 
 
 
 
 
 
 
 
 
Grade 3–4 (Symptomatic congestive heart failure 
or absolute decrease in LVEF of > 20% from 
baseline that is also below LLN) 
Withhold binimetinib for up to 4 weeks, 
evaluate LVEF every 2 weeks. Resume 
binimetinib at a reduced dose if the 
following are present:  
• 
LVEF is at or above the LLN and   
• 
Absolute decrease from baseline is 
10% or less and   
• 
Patient is asymptomatic.  
If LVEF does not recover within 4 weeks 
permanently discontinue binimetinib 
 
Permanently 
discontinue 
binimetinib. 
Closely monitor LVEF until resolution or up 
to 16 weeks. 
Venous Thromboembolism 
 
Uncomplicated DVT or PE 
 
 
 
 
Life Threatening PE 
Withhold binimetinib.  
• 
If improves to Grade 0–1, resume at 
a reduced dose. 
• 
If no improvement, permanently 
discontinue binimetinib. 
Permanently discontinue encorafenib 
and binimetinib. 
Serous Retinopathy 
 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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85 
Severity of Adverse Event 
Dose Modification 
Symptomatic 
serous 
retinopathy/ 
Retinal 
pigment epithelial detachments  
 
 
 
 
 
Retinal Vein Occlusion (RVO) 
Withhold binimetinib for up to 10 days.  
• 
If 
improves 
and 
becomes 
asymptomatic, resume at the same 
dose.  
• 
If not improved, resume at a lower 
dose 
level 
or 
permanently 
discontinue binimetinib 
Any Grade 
Permanently discontinue binimetinib. 
Uveitis  
 
Grade 1–3 
 
 
 
 
 
 
Grade 4 
If Grade 1 or 2 does not respond to specific 
ocular therapy, or for Grade 3 uveitis, 
withhold binimetinib and encorafenib for up 
to 6 weeks.  
• 
If improved, resume at same or 
reduced dose.  
• 
If 
not 
improved, 
permanently 
discontinue binimetinib 
Permanently Discontinue 
Other Eye Disorders (i.e., Non-retinal Events, 
non-Uveitis Events) 
 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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Severity of Adverse Event 
Dose Modification 
Grade 1–2 
 
 
Grade 3 
 
 
 
 
 
 
 
 
 
Grade 4 
Maintain dose level of encorafenib and 
binimetinib and increase frequency of 
ophthalmic monitoring to at least every 14 
days until stabilization or resolution. 
Interrupt 
dosing 
of 
encorafenib 
and 
binimetinib 
and 
refer 
patient 
to 
ophthalmologist within 7 days.  
• 
If resolved to Grade ≤ 1 in ≤ 21 days, 
resume treatment at 1 reduced 
dose level of encorafenib and 
binimetinib.  
• 
If not resolved to Grade ≤ 1 in ≤ 21 
days, 
permanently 
discontinue 
encorafenib and binimetinib and 
close follow-up with ophthalmic 
monitoring until stabilization or 
resolution 
Permanently discontinue encorafenib and 
binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or 
resolution. 
Interstitial Lung Disease 
 
Grade 2 
 
 
 
 
 
Grade 3 or Grade 4 
Withhold binimetinib for up to 4 weeks.  
• 
If improved to Grade 0–1, resume at 
a reduced dose.  
• 
If not resolved within 4 weeks, 
permanently discontinue 
 
Permanently discontinue 
Rhabdomyolysis or Creatine Phosphokinase 
(CPK) elevations 
 
Grade 4 asymptomatic CPK elevation or Any 
Grade CPK elevation with symptoms or with 
renal impairment 
Withhold binimetinib dose for up to 4 
weeks.  
• 
If improved to Grade 0–1 resume at 
a reduced dose.  
• 
If not resolved within 4 weeks, 
permanently discontinue binimetinib 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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87 
Severity of Adverse Event 
Dose Modification 
Dermatologic 
 
Grade 2 
 
 
Grade 3 
 
Grade 4 
If no improvement within 2 weeks, withhold 
until Grade 0–1. Resume at same dose if 
first occurrence or reduce dose if recurrent. 
Withhold until Grade 0–1. Resume at same 
dose if first occurrence or reduce dose if 
recurrent. 
Permanently discontinue 
Nausea/Vomiting 
 
Grade 1–2 
 
Grade 3 
 
 
 
 
 
 
 
 
 
 
Grade 4 
Maintain dose level of encorafenib and 
binimetinib. Promptly institute antiemetic 
measure. 
Interrupt 
dosing 
of 
encorafenib 
and 
binimetinib until resolved to Grade ≤ 1. 
Then resume treatment at 1 reduced dose 
level of encorafenib. Resume treatment 
with binimetinib at the current dose if, in the 
judgment of the Investigator, the toxicity is 
considered to be unrelated to binimetinib, or 
at 1 reduced dose level.  
Note: Interrupt dosing of encorafenib and 
binimetinib for ≥ Grade 3 vomiting or Grade 
3 nausea only if the vomiting or nausea 
cannot 
be 
controlled 
with 
optimal 
antiemetics (as per local practice). 
Permanently discontinue encorafenib and 
binimetinib 
Other Adverse Reactions (including hemorrhage)  


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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88 
Severity of Adverse Event 
Dose Modification 
Recurrent Grade 2 or  First occurrence of any 
Grade 3 
 
 
 
First occurrence any Grade 4 
 
 
 
 
 
Recurrent Grade 3 
 
Recurrent Grade 4 
Withhold for up to 4 weeks.  
• 
If improves to Grade 0–1 or to 
pretreatment/baseline 
levels, 
resume at reduced dose.  
• 
If no improvement, permanently 
discontinue. 
Permanently discontinue or withhold for up 
to 4 weeks.  
• 
If improves to Grade 0–1 or to 
pretreatment/baseline levels, then 
resume at a reduced dose.   
• 
If no improvement, permanently 
discontinue. 
Consider permanently discontinuing. 
 
Permanently discontinue participants 
 
 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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APPENDIX 4 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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APPENDIX 5 
ASSESSMENT OF OVERALL TUMOR BURDEN AND 
MEASURABLE DISEASE 
 
5.1a 
MEASURABILITY OF TUMOR 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows. All baseline evaluations should be performed as close as possible 
to the treatment start and never more than 4 weeks before the beginning of the treatment.  
Measurable lesions must be accurately measured in at least one dimension (longest 
diameter in the plane of the measurement to be recorded) with a minimum size of:  
• 10 mm by CT scan -(CT scan slice thickness no greater than 5 mm)  
• Brain lesions: Intracranial lesions can be measured only by gadolinium-enhanced 
MRI.  For brain metastases less than or equal to 10 mm LD, an MRI scan slice 
thickness of 1 mm is necessary.  Lesions greater than 10 mm LD may use a slice 
thickness of 5 mm.  
• Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed.  
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  
Special considerations regarding lesion measurability 
Bone Lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging 
techniques to measure bone lesions. However, these techniques can be used to 
confirm the presence or disappearance of bone lesions.  
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above.  
• Blastic bone lesions are non-measurable. 
Cystic Lesions  
• Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.  
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
Lesions with Prior Local Treatment 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other locoregional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. 
Non-measurable lesions are all other lesions, including small lesions (longest diameter < 
10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as non-
measurable lesions. Lesions considered non-measurable include leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
 
5.2a METHOD OF ASSESSMENT 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging based 
evaluation should always be performed rather than clinical examination unless the 
lesion(s) being followed cannot be imaged but are assessable by clinical examination. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. Measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. Chest x-ray: Chest CT is preferred over chest x-ray, particularly when 
progression is an important endpoint, since CT is more sensitive than x-ray, particularly 
in identifying new lesions. However, lesions on chest x-ray may be considered 
measurable if they are clearly defined and surrounded by aerated lung. 
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
Target lesions: When more than one measurable lesion is present at baseline all lesions 
up to a maximum of 10 lesions total (a maximum of 2 lesions per organ systemically and 
up to 5 brain lesions) representative of all involved organs should be identified as target 
lesions and will be recorded and measured at baseline. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, and should lend themselves to reproducible repeated measurements. 
Brain lesions are considered target lesions if the lesion is 0.5 cm and 3 cm in longest 
diameter. Lymph nodes merit special mention since they are normal anatomical 
structures which may be visible by imaging even if not involved by tumor. Pathological 
nodes which are defined as measurable and may be identified as target lesions must 
meet the criterion of a short axis of ≥15 mm by CT scan. Only the short axis of these 
nodes will contribute to the baseline sum. All other pathological nodes (those with short 


Phase I/II study of encorafenib and binimetinib with nivolumab and low dose ipilimumab in metastatic BRAF 
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92 
axis ≥ 10 mm but < 15 mm) should not be considered nontarget lesions. Nodes that have 
a short axis < 10 mm are considered non-pathological and should not be recorded or 
followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. The baseline 
sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. Non-target lesions: All other 
lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not 
required, and these lesions should be followed as ‘present’, ‘absent’, or ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or “multiple liver metastases”). 
 
5.3a EVALUATION OF TARGET LESIONS 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial 
Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% 
increase in the sum of diameters of target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. Note: the appearance of one or more new lesions is also considered progression. 
Stable Disease (SD): Neither sufficient shrinkage from the baseline study to qualify for 
PR nor sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
Special notes on the assessment of target lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded and should be measured in the same anatomical plane 
as the baseline examination, even if the nodes regress to below 10 mm on study. This 
means that when lymph nodes are included as target lesions, the “sum” of lesions may 
not be zero even if complete response criteria are met, since a normal lymph node is 
defined as having a short axis of < 10 mm.  
Target lesions that become “too small to measure”: All lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). If the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm. 
However, when such a lesion becomes difficult to assign an exact measure to then:  


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1. if it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm.  
2. if an extracranial lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned (note: in case of a lymph node 
believed to be present and faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well). This default value is derived from the 5 
mm CT slice thickness (but should not be changed with varying CT slice thickness). 
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have coalesced such that they are no longer separable, 
the vector of the longest diameter in this instance should be the maximal longest diameter 
for the “coalesced lesion.”  
 
5.4a EVALUATION OF NON-TARGET LESIONS 
While some non-target lesions may actually be measurable, they need not be measured 
and instead should be assessed only qualitatively at the time points specified in the 
protocol. Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-pathological in size (< 
10 mm short axis). Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits. Progressive Disease 
(PD): Unequivocal progression of existing non-target lesions. (Note: the appearance of 
one or more new lesions is also considered progression). 
The concept of progression of non-target disease requires additional explanation as 
follows: 
• When the patient also has measurable disease: To achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level 
of substantial worsening in nontarget disease such that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in the size of one or more non-
target lesions is usually not sufficient to qualify for unequivocal progression status.  
• When the patient has only non-measurable disease: To achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level 
of substantial worsening such that the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest “increase” in the size of 
one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are non-measurable) a useful test that can be 


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applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing 
an additional 73% increase in “volume” (which is equivalent to a 20% increase 
diameter in a measurable lesion). Examples include an increase in a pleural 
effusion from “trace” to “large,” an increase in lymphangitic disease from localized 
to widespread or may be described in protocols as “sufficient to require a change 
in therapy.” If “unequivocal progression” is seen, the patient should be considered 
to have had overall PD at that point. 
 
5.5a NEW LESIONS 
The appearance of new malignant lesions denotes disease progression. The finding of a 
new lesion should be unequivocal: ie, not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other 
than tumor (for example, some “new” bone lesions may be simply healing or flare of pre-
existing lesions). This is particularly important when the patient’s baseline lesions show 
partial or complete response. For example, necrosis of a liver lesion may be reported on 
a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of 
this is the patient who has visceral disease at baseline and while on study has a CT or 
MRI brain ordered which reveals metastases. The patient’s brain metastases are 
considered to be constitute PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents new disease. If repeat scans confirm that 
there is a new lesion, then progression should be declared using the date of the initial 
scan. 
 
5.6a TIME POINT RESPONSE 
A response assessment should occur at each time point specified in the protocol. 
For patients who have measurable disease at baseline the table below provides a 
summary of the overall response status calculation at each time point. 
 
Target Lesions 
Non-target 
Lesions 
New Lesions 
Overall Response 
CR 
CR 
NO 
CR 


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CR 
Non-CR/non-PD 
No 
PR 
CR 
Not Evaluated 
No 
PR 
PR 
Non-PD 
or 
Not 
Evaluated 
No 
PR 
SD 
Non-PD 
or 
Not 
Evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
Not Evaluable 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
5.7a 
MISSING ASSESSMENTS AND INEVALUABLE DESIGNATION 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case 
of PD. 
 
5.8a 
BEST OVERALL RESPONSE: ALL TIMEPOINTS 
Best response determination in trials where confirmation of complete or partial response 
IS required: Complete or partial responses may be claimed only if the criteria for each are 
met at a subsequent time point as specified in the protocol. In this circumstance, the best 
overall response can be interpreted as below: 
 
Overall 
Response 
First 
Timepoint 
Overall 
Response 
Subsequent 
Timepoint 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 


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CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, and NE = not evaluable 
 
5.9a 
SPECIAL NOTES ON RESPONSE ASSESSMENT 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
“normal” size (< 10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that patients with CR may not have a total sum of “zero” on the case 
report form (CRF). Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at that 
time should be reported as “symptomatic deterioration.” Every effort should be made to 
document objective progression even after discontinuation of treatment. Symptomatic 
deterioration is not a descriptor of an objective response: it is a reason for stopping study 
therapy. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. Ifat the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
5.10a 
DURATION OF RESPONSE 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are first met for CR/PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded on study). The duration of 
overall complete response is measured from the time measurement criteria are first met 


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for CR until the first date that recurrent disease is objectively documented. Duration of 
stable disease: Stable disease is measured from the start of the treatment (in randomized 
trials, from date of randomization) until the criteria for progression are met, taking as 
reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD).  
 
5.11a 
LESIONS THAT DISAPPEAR AND REAPPEAR 
If a lesion disappears and reappears at a subsequent time point it should continue to be 
measured. However, the patient’s response at the point in time when the lesion reappears 
will depend upon the status of his/her other lesions. For example, if the patient’s tumor 
had reached a CR status and the lesion reappeared, then the patient would be considered 
PD at the time of reappearance. In contrast, if the tumor status was a PR or SD and one 
lesion which had disappeared then reappears, its maximal diameter should be added to 
the sum of the remaining lesions for a calculated response: in other words, the 
reappearance of an apparently “disappeared” single lesion amongst many which remain 
is not in itself enough to qualify for PD: that requires the sum of all lesions to meet the PD 
criteria. The rationale for such a categorization is based upon the realization that most 
lesions do not actually “disappear” but are not visualized because they are beyond the 
resolving power of the imaging modality employed. 
 
5.12a 
USE OF FDG-PET 
While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible “new” disease). New lesions on the 
basis of FDG-PET imaging can be identified according to the following algorithm:  
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. Confirmatory CT is recommended.  
No FDG-PET at baseline and a positive FDG-PET at follow-up:  
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.   
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  
If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
 


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APPENDIX 6 
MANAGEMENT ALGORITHMS FOR IMMUNO-ONCOLOGY 
AGENTS 
Participants should receive appropriate supportive care measures as deemed necessary 
by the treating investigator.  Where appropriate, these guidelines include the use of oral 
or intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.   Note that 
several courses of steroid tapering may be necessary as symptoms may worsen when 
the steroid dose is decreased. For each disorder, attempts should be made to rule out 
other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care. The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to nivolumab/urelumab or 
nivolumab/cabiralizumab.  
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  
• 
Pneumonitis:  
 
o 
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
o 
For Grade 3–4 events, immediately treat with intravenous steroids.  Administer additional 
anti-inflammatory measures, as needed. 


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o 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
• 
Diarrhea/Colitis:  
 
Participants should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus).   
o 
All participants who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
o 
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o 
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.   
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 


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o 
For T1DM or Grade 3–4 Hyperglycemia 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria.  
Evaluate participants with serum glucose and a metabolic panel, urine ketones, glycosylated hemoglobin, 
and C-peptide.  
• 
Hypophysitis: 
o 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
o 
For Grade 3–4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor participants for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
o 
Grade 2 hyperthyroidism events (and Grade 2–4 hypothyroidism): 
▪ 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 


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▪ 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o 
Grade 3-4 hyperthyroidism  
▪ 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
• 
Hepatic: 
 
o 
For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). 
▪ 
Treat with IV or oral corticosteroids 
o 
For Grade 3–4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o 
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
 


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• 
Renal Failure or Nephritis: 
 
o 
For Grade 2 events, treat with corticosteroids. 
o 
For Grade 3–4 events, treat with systemic corticosteroids. 
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.  
 


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