An Open-label Phase 1b/2 Study of Binimetinib Administered in Combination With Nivolumab or Nivolumab Plus Ipilimumab in Patients With Previously Treated Microsatellite-stable (MSS) Metastatic Colorectal Cancer With RAS Mutation
Phase: PHASE2
Conditions: MSS, RAS-mutant Colorectal Cancer
Sponsor: Pfizer

Cli nic al St u d y A R R A Y- 1 6 2- 2 0 2  
A n O pe n-l a bel P h ase 1 b/ 2 St u d y of Bi ni meti ni b A d mi nistere d i n C o m bi n ati o n wit h 
Ni v ol u m a b or Ni v ol u m a b Pl us I pili m u m a b i n P ati e nts wit h Pre vi o usl y Tre ate d 
Micr os at ellite-st a bl e ( M S S) Met ast atic C ol orect al C a ncer wit h R A S  M ut ati o n 
Pr ot oc ol V ersi o n 1. 0  
1 8  J ul y 2 0 1 7  
Pr ot oc ol V ersi o n 2. 0  
3 0  Oct o ber 2 0 1 7  
Pr ot oc ol V ersi o n 3. 0  
1 0  N o ve m ber 2 0 1 7  
Pr ot oc ol V ersi o n 4. 0  
0 2 Marc h  2 0 1 8  
E u dr a C T N u m ber:  
2 0 1 7 -0 0 3 4 6 4 -1 2  
I N D N u m ber: 
 
Arr a y Bi o P h ar m a I nc. 
3 2 0 0 Wal n ut Street 
B o ul der, C O 8 0 3 0 1 
P h o ne: ( 3 0 3) 3 8 1- 6 6 0 0 
Fa x: ( 3 0 3) 3 8 6- 1 2 4 0 
C O N FI D E N TI A L I N F O R M A TI O N  
T his d oc u me nt c o nt ai ns tr a d e secrets a n d ot her c o nfi de nti al a n d pr o priet ar y i nf or m ati o n bel o n gi n g t o 
Arr a y Bi o P h ar m a I nc. E xce pt as ot her wise a gree d t o i n w riti n g, b y acce pti n g or re vie wi n g t his 
d oc u me nt y o u a gree t o h ol d t his i nf o r m ati o n i n c o nfi de n ce a n d n ot t o discl ose it t o ot hers (e xce pt w here 
re quire d b y a p plic a ble l a w) or t o use it f or u n a ut h orize d p ur p oses. I n t he e ve nt of a n y act u al or 
s us pecte d bre a c h of t his o bli g ati o n, Arr a y Bi o P h ar m a I n c. s h o ul d be pr o m ptl y n otifie d.  
C CI

P P D
P P D
P P D
P P D

Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-162-202 
 
Version 4.0 
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PRINCIPAL INVESTIGATOR AGREEMENT 
I have read and understand the contents of the clinical protocol for Clinical Study 
ARRAY-162-202 dated 02 March 2018 and will adhere to the study requirements as presented, 
including all statements regarding confidentiality. In addition, I will conduct the study in 
accordance with the requirements of this protocol and also protect the rights, safety, privacy and 
well-being of study patients in accordance with the following: 
 
International Conference on Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Harmonised Tripartite Guideline for Good 
Clinical Practice (GCP) E6(R1) 
 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations 
 
Requirements for reporting serious adverse events (SAEs) defined in Section 10.9 of this 
protocol 
 
Terms outlined in the Clinical Study Site Agreement 
My signature also acknowledges that: 
 
Neither my subinvestigators nor I are members of the Ethics Committee (EC) reviewing this 
protocol, or 
 
I and/or my subinvestigators are members of the EC, but I/we will not participate in the 
initial review or continuing review of this study 
 
 
 
 
 
Name of Principal Investigator 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
4 
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
P R O T O C O L S Y N O P SI S 
Title  
A n O pe n -la b el P hase 1 b / 2 St u d y of Bi ni meti ni b A d mi nistere d i n 
C o m bi nati o n wit h Ni v ol u ma b or Ni v ol u ma b pl us  I pili m u ma b i n Patie nts 
wit h Pre vi o usl y Treat e d Micr osatellite -sta ble ( M S S) Metastatic C ol orectal 
Ca ncer  wit h R A S  M utati o n  
Pr ot oc ol N u m ber  
A R R A Y -1 6 2 -2 0 2  
P h ase  
1 b / 2 
O bjecti ves  
Pri m ar y : 
 P hase 1 b : 
o  D eter mi ne t he ma xi m u m t olerate d d ose ( M T D) a n d 
rec o m me n de d P has e 2 d ose ( R P 2 D) of bi ni meti ni b a d mi nistere d 
i n c o m bi nati o n wit h ni v ol u ma b  
o  D eter mi ne t he M T D a n d R P 2 D of bi ni meti ni b a d mi nistere d i n 
c o m bi nati o n wit h ni v ol u ma b pl us i pili m u ma b 
 P hase  2 : A ssess t he preli mi nar y a ntit u m or acti vit y of t he treat me nt 
c o m bi nati o n s base d o n Res p o nse  E val uati o n  Criteria in S oli d 
T u m ors ( R E CI S T) v ersi o n 1. 1  
Sec o n d ar y : 
B ot h P hases : 
 F urt her assess t he preli mi nar y a ntit u m or acti vit y of t he treat me nt 
c o m bi nati o n s base d o n R E CI S T v ersi o n 1. 1  
 C haracterize  t he safet y pr ofile of t he tr eat me nt co m bi nati o n s 
 C haracterize t he p har mac o ki netics ( P K) of bi ni meti ni b i n b ot h 
treat me nt c o m bi nati o n s 
E x pl or at or y : 
B ot h P hases : 
 O btai n preli mi nar y esti mates of pr o gressi o n -free s ur vi val ( P F S) a n d 
o verall  s ur vi val ( O S) 
C CI

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
5 
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
E n d p oi nts  
Pri m ar y :  
 P hase 1 b : 
o  I n ci de nce of d ose -li miti n g t o xicities ( D L Ts) res ulti n g fr o m 
bi ni meti ni b i n c o m bi nati o n wit h ni v ol u ma b  
o  I n ci de nce of D L Ts res ulti n g fr o m bi ni meti ni b i n c o m bi nati o n 
wit h ni v ol u ma b pl us i pili m u ma b 
 P hase 2 : O bjecti ve res p o nse rate ( O R R)  per R E CI S T v 1. 1  
Sec o n d ar y : 
 P hase 1 b o nl y : O R R per R E CI S T v 1. 1 
B ot h  P hases : 
 D urati o n of res p o ns e ( D O R)  per R E CI S T v 1. 1  
 R ate of c o m plete res p o ns e ( C R)  per R E CI S T v 1. 1  
 I n ci de nce a n d se v erit y of a d verse e ve nts (A Es ) gra de d acc or di n g t o 
t he Nati o nal Ca ncer I nstit ute (N CI ) C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts  (C T C A E ) v 4. 0 3, a n d c h a n ges i n cli nical 
la b orat or y para meters 
 S parse plas ma c o n ce ntr ati o ns f or bi ni meti ni b  
E x pl or at or y:  
B ot h P hases : 
 P F S per R E CI S T  v 1. 1  
 O S  
Desi g n  
T his is a m ultice nter , o pe n-la bel P hase 1b / 2 st u d y t o deter mi ne t he M T D  
a n d R P 2 D  a n d sc he d ule of bi ni meti ni b,  a n d t o assess t he safet y, efficac y, 
a n d P K of bi ni meti ni b a d mi nistere d  i n c o m bi nati o n wit h ni v ol u ma b or 
C CI

Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-162-202 
 
Version 4.0 
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02 March 2018 
nivolumab plus ipilimumab in patients with previously treated MSS 
metastatic colorectal cancer (mCRC) with documented RAS mutation. The 
study will include a dose-finding period in Phase 1b followed by a 
randomized Phase 2 period. 
The total number of patients enrolled in Phase 1b of the study will depend 
on the number of dose levels tested and the number of patients treated in 
each cohort before the MTD has been determined for each arm.  
Approximately 90 patients are planned. A maximum of approximately 42 
patients will be enrolled in Phase 1b and a minimum of approximately 48 
patients will be enrolled in Phase 2. Randomization into Phase 2 will 
continue until at least 33 patients have received the doublet and the triplet, 
respectively, at the RP2D (Phase 1b and Phase 2 combined). 
One treatment cycle is defined as 28 days (4 weeks) for all arms. Individual 
treatments will be dosed on the schedules as outlined below. 
Phase 1b of the study will consist of dose-finding cohorts in Arm 1A and 
Arm 1B. All dose-escalation and de-escalation decisions will be driven by 
the modified toxicity probability interval (mTPI-2) design (Guo et al. 
2017).   
 Patients assigned to Arm 1A (Doublet) will be dosed with 480 mg 
nivolumab every 4 weeks (Q4W) and 45 mg twice daily (BID) of 
binimetinib initially as starting Dose Level 4. In the event that this 
dose level is not tolerated, lower dose levels, or an intermittent 
binimetinib dosing schedule, may be tested per Table 1 below.  
 Patients assigned to Arm 1B (Triplet) will be dosed with the RP2D 
of binimetinib from Arm 1A plus 480 mg nivolumab Q4W and 
1 mg/kg ipilimumab Q8W. Dose de-escalation will proceed if the 
treatment is not tolerated. Intermittent dose schedules for 
binimetinib may also be evaluated as per Table 1 below. 
There will be a period of at least 7 days between Cycle 1 Day 1 (C1D1) of 
the first patient and C1D1 of the second patient enrolled during Phase 1b 
(Arms 1A and 1B).  
Intra-patient dose escalation will not be permitted. 
Note: In both arms, there will be flexibility to evaluate intermittent dosing 
schedule of binimetinib (30 or 45 mg BID; e.g., 3 weeks on/1 week off) if 
continuous dosing is not tolerated (Table 1) depending on the time of onset 
of DLTs. 
In Phase 1b: The target DLT probability for Cycle 1 is 30%, with an 
equivalence interval, i.e., an acceptable interval, of 25% to 35%. Dosing in 

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Phase 1b will continue within an arm until 9 patients (from the dose-
determining set) have been treated at one dose level with a recommendation 
to stay (or a recommendation to escalate if there is not a higher dose level 
or if the tolerability of the next dose level is unacceptable), or the 
maximum sample size within a Phase 1b arm (n=21) has been reached. If 
further safety evaluations are required, additional patients may be added to 
a cohort.  
Toxicities will only be considered DLTs if they occur in Cycle 1 although 
overall safety including later cycles will be considered for dose escalations 
and for each RP2D determination.  
Patients are required to complete Cycle 1 (≥ 75% of the planned cumulative 
dose of binimetinib) to be considered evaluable for MTD determination 
unless discontinuation occurred due to a DLT (i.e, in the dose-determining 
set). 
Phase 2 of the study will consist of 2 arms to investigate the safety and 
clinical activity of the RP2Ds established from Phase 1b: Arm 2A 
(nivolumab in combination with binimetinib) and Arm 2B (nivolumab plus 
ipilimumab in combination with binimetinib). 
Treatment 
Regimens 
Phase 1b: 
Table 1: 
Dosing Scheme for Phase 1b 
Arm 
Dose Level 
(*Starting 
Dose 
Level) 
Binimetinib 
Nivolumab 
Ipilimumab 
1A 
(Doublet) 
4* 
45 mg BID  
480 mg 
Q4W 
N/A 
3 
45 mg BID 3W on / 1W off  
2 
30 mg BID 
1 
30 mg BID 3W on / 1W off 
1B 
(Triplet)a 
4 
45 mg BID  
480 mg 
Q4W 
1 mg/kg 
Q8W 
3 
45 mg BID 3W on / 1W off  
2 
30 mg BID 
1 
30 mg BID 3W on / 1W off 
a The starting Dose Level of Arm 1B (Triplet) will be the RP2D of binimetinib 
from Arm 1A. If tolerated, the RP2D of binimetinib from Arm 1A will be 
considered the RP2D for Arm 1B. If not tolerated, any dose level below the 
RP2D for Arm 1B may be explored. 
Phase 2: 
Arm 2A: Patients randomized to the nivolumab and binimetinib arm will 
receive nivolumab administered as 480 mg Q4W as a 30-minute (± 5 
minutes) intravenous (IV) infusion on Day 1 of each treatment cycle and 

Binimetinib (MEK inhibitor) 
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the recommended dose of binimetinib in Arm 1A of Phase 1b. 
Arm 2B: Patients randomized to the nivolumab, ipilimumab, and 
binimetinib arm will receive nivolumab administered as 480 mg Q4W as a 
30-minute (± 5 minutes) IV infusion on Day 1 of each treatment cycle, 
ipilimumab IV as a dose of 1 mg/kg Q8W as a 30-minute IV infusion (± 5 
minutes), and the recommended dose of binimetinib in Arm 1B of Phase 
1b. 
Study Population 
This study will be conducted in adult patients with MSS mCRC with a RAS 
mutation.  
Participants in both Phase 1b and Phase 2 must have received at least 
one prior line of systemic therapy in the metastatic setting and were unable 
to tolerate the prior first-line therapy, experienced disease progression 
during or after the prior treatment regimen for mCRC, or progressed during 
or within 6 months of completing adjuvant chemotherapy.  
Participants must also have received no more than 2 prior lines of systemic 
therapy in the metastatic setting. Maintenance therapy given in the 
metastatic setting will not be considered a separate regimen. 
Duration of 
Study 
Participation 
Following a screening period of up to 28 days, patients will receive the 
doublet or triplet treatment regimens in 28-day cycles until disease 
progression, unacceptable toxicity, withdrawal of consent, initiation of 
subsequent anticancer therapy, the patient is lost to follow-up, or death. 
Patients will be monitored for OS until 1 year after the randomization date 
of the last patient enrolled, or until withdrawal of consent for such follow 
up, lost to follow up, or death. 
Eligibility 
Criteria for 
Prescreening 
Prescreening Inclusion Criteria: 
Patients must meet all of the following inclusion criteria to be eligible for 
participation in the prescreening period: 
1. Provide a signed and dated Prescreening informed consent form (ICF). 
2. Male or female ≥ 18 years of age at the time of signing the Screening 
ICF. 
3. Measurable, histologically/cytologically confirmed mCRC per RECIST 
v1.1. 
4. Have willingness and ability to participate in the study.  
5. Able to provide a sufficient amount (tumor block or minimum of 
6 slides) of representative tumor specimen (primary or metastatic, 
archival or newly obtained) for central laboratory testing of RAS 
mutation status and MSS. 

Binimetinib (MEK inhibitor) 
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a. If a fresh tissue sample is provided, a blood sample is required. 
6. Have received no more than 2 prior lines of systemic therapy in the 
metastatic setting (maintenance therapy given in the metastatic setting 
will not be considered a separate regimen). Generally, treatments that 
are separated by an event of progression are considered different 
regimens.   
7. Have received prior systemic treatment as recommended by National 
Comprehensive Cancer Network (NCCN) or European Society for 
Medical Oncology (ESMO) guidelines, including fluoropyrimidines, 
oxaliplatin, irinotecan or bevacizumab in the metastatic setting or 
similar treatments, as per local guidelines. 
8. No known contraindications to study treatment. 
Prescreening Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for enrollment 
in the study: 
1. Prior treatment with any MEK inhibitor. 
2. Prior treatment with an anti-programmed death-1 (PD-1), anti-PD-L1, 
anti-PD-L2, anti-CD137, or anti- cytotoxic T-cell lymphoma-4 antigen 
(CTLA-4) antibody, or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways. 
3. Any untreated central nervous system (CNS) lesion. However, patients 
are eligible if: a) all known CNS lesions have been treated with 
radiotherapy or surgery, and b) patients remained without evidence of 
CNS disease progression ≥ 4 weeks after treatment, and c) patients must 
be off corticosteroid therapy for ≥ 3 weeks.  
4. Patients with an active, known or suspected autoimmune disease, with 
the following exceptions: patients with type I diabetes mellitus, 
hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic 
treatment, or conditions not expected to recur in the absence of an 
external trigger are permitted to enroll.  
5. Partial or complete bowel obstruction. 
6. Impaired gastrointestinal function or disease that may significantly alter 
the absorption of binimetinib (e.g., ulcerative diseases, uncontrolled 
vomiting, malabsorption syndrome, small bowel resection with 
decreased intestinal absorption) or baseline diarrhea ≥ Grade 1. 
7. Known history of retinal vein occlusion (RVO). 

Binimetinib (MEK inhibitor) 
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8. Concurrent or previous other malignancy within 5 years of study entry, 
except cured basal or squamous cell skin cancer, superficial bladder 
cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the 
cervix, or other noninvasive or indolent malignancy  
9. Known history of Gilbert’s syndrome. 
10. Severe uncontrolled medical illness. 
11. Psychiatric illness inhibiting informed consent or protocol compliance. 
12. Pregnant or breastfeeding females. 
13. History of severe hypersensitivity reactions to monoclonal antibodies 
(mAbs). 
14. History of allergy or intolerance (unacceptable AEs) to study drug 
components or polysorbate-80-containing infusions. 
Eligibility 
Criteria for 
Screening 
Screening Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for 
enrollment into the study: 
1. Patients must meet all Prescreening inclusion criteria. 
2. Provide a personally signed and dated Screening ICF. 
3. mCRC categorized as MSS by immunohistochemistry (IHC) or 
polymerase chain reaction (PCR)-based local assay at any time prior to 
Screening or by the central laboratory (Section 7.1.1). 
4. RAS mutation per local assay at any time prior to Screening or by the 
central laboratory. 
5. Have received at least one prior line of systemic therapy in the 
metastatic setting as recommended by National Comprehensive Cancer 
Network (NCCN) or European Society for Medical Oncology (ESMO) 
guidelines, including fluoropyrimidines, oxaliplatin, irinotecan or 
bevacizumab, or similar treatments, as per local guidelines, and meets 
at least one of the following criteria: 
a. were unable to tolerate the prior first-line regimen 
b. experienced disease progression during or after prior first-line 
regimen for metastatic disease 
c. progressed during or within 6 months of completing adjuvant 
chemotherapy 
Note: Generally, treatments that are separated by an event of 
progression are considered different regimens. 
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 

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of 0 or 1. 
7. Female patients are either postmenopausal for at least 1 year, are 
surgically sterile for at least 6 weeks; if a female patient is of 
childbearing potential, she must agree to follow instructions for 
acceptable or highly effective method(s) of contraception for the 
duration of study treatment and for 5 months after the last dose of study 
treatment with nivolumab (i.e., 30 days [duration of ovulatory cycle] 
plus the time required for the investigational drug to undergo 
approximately 5 half-lives) (Section 5.3). 
8. Non-sterile male patients who are sexually active with female partners 
of childbearing potential must agree to follow instructions for 
acceptable or highly effective method(s) of contraception for the 
duration of study treatment and for 7 months after the last dose of study 
treatment with nivolumab (i.e., 90 days [duration of sperm turnover] 
plus the time required for the investigational drug to undergo 
approximately 5 half-lives) (Section 5.3). 
9. Adequate renal and bone marrow function as measured by the 
following Screening laboratory values: 
a. White blood cells (WBC) ≥ 2000/µL 
b. Neutrophils ≥ 1500/µL 
c. Platelets ≥ 100 ×103/µL 
d. Hemoglobin ≥ 9.0 g/dL 
e. Serum creatinine  1.5 × upper limit of normal (ULN) or calculated 
creatinine clearance > 50 mL/min (using the Cockcroft Gault 
formula) or estimated glomerular filtration rate > 50 mL/min/1.73 
m2 (using the Modification of Diet in Renal Disease [MDRD] Study 
formula) 
10. Adequate hepatic function characterized by the following Screening 
laboratory values: 
a. Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL 
Note: Patients who have a total bilirubin level > 1.5 × ULN will be 
allowed if their indirect bilirubin level is ≤ 1.5 × ULN. 
b. Alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases 
11. Adequate cardiac function as follows:  
a. Left ventricular ejection fraction (LVEF) ≥ 50% or above 
institutional normal value as determined by a MUGA scan or 
echocardiogram 

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b. QTcF interval ≤ 480 msec (preferably the mean from triplicate 
electrocardiograms [ECGs]) 
12. Willingness and ability to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures including computed 
tomography (CT)/magnetic resonance imaging (MRI) scans. 
Screening Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for enrollment 
in the study: 
1. Patients must not meet any of the Prescreening exclusion criteria. 
2. Treatment with systemic immunosuppressive medications (including 
but not limited to prednisone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] 
agents) within 2 weeks prior to first day of study treatment: 
a. The use of inhaled corticosteroids and mineralocorticoids 
(e.g., fludrocortisone) and topical steroids are allowed. Patients who 
have received acute and/or low-dose systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea or 
chronic use of ≤ 10 mg/day of prednisone or dose-equivalent 
corticosteroid) may be enrolled in the study after discussion with 
and approval by the Sponsor’s Medical Monitor. 
3. Impaired gastrointestinal function or disease that may significantly alter 
the absorption of binimetinib (e.g., ulcerative diseases, uncontrolled 
vomiting, malabsorption syndrome, small bowel resection with 
decreased intestinal absorption) or baseline diarrhea ≥ Grade 1. 
4. History of thromboembolic or cerebrovascular events ≤ 6 months prior 
to starting study treatment, including transient ischemic attacks, 
cerebrovascular accidents, deep vein thrombosis or pulmonary emboli. 
5. Uncontrolled hypertension defined as persistent systolic blood pressure 
≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current 
therapy. 
6. Concurrent neuromuscular disorder that is associated with the potential 
of elevated creatine kinase (CK) (e.g., inflammatory myopathies, 
muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular 
atrophy). 
7. History or current evidence of RVO or current risk factors for RVO 
(e.g., uncontrolled glaucoma or ocular hypertension, history of 
hyperviscosity or hypercoagulability syndromes). 

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8. Clinically significant cardiac disease, including, but not limited to, any 
of the following: 
a. Congestive heart failure requiring treatment (New York Heart 
Association Grade ≥ 2). 
b. Clinically significant and uncontrolled atrial fibrillation. 
c. History of acute coronary syndromes including myocardial 
infarction, unstable angina, coronary artery bypass grafting, 
coronary angioplasty, or stenting < 6 months prior to screening. 
d. Symptomatic chronic heart failure, history or current evidence of 
clinically significant cardiac arrhythmia and/or conduction 
abnormality < 6 months prior to screening except controlled atrial 
fibrillation and paroxysmal supraventricular tachycardia.  
9. Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, 
with the exception of Grade 2 alopecia or Grade 2 neuropathy. 
10. Known history of positive test for human immunodeficiency virus 
(HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: 
Testing for HIV must be performed at sites where mandated locally. 
11. Any positive test for hepatitis B virus or hepatitis C virus indicating 
acute or chronic infection, and/or detectable virus. 
Pharmacokinetics Peripheral venous blood (3 mL) will be collected from all patients on 
Cycle 1 Day 1 at 1.5 hours post-binimetinib dose, on Cycle 1 Day 15 pre-
binimetinib dose and 1.5 hours post-binimetinib dose, and on Cycles 2-5 
Day 15 pre-binimetinib dose during treatment for quantitation of 
binimetinib and active metabolite AR00426032.  
Biomarkers  
Peripheral blood and tumor tissue (fresh or archival) will be collected prior 
to therapy and at selected time points on treatment (tumor biopsy optional). 
Residual sample material available after completion of the designated 
analyses may be used in the future for identification of additional 
pharmacodynamic or predictive markers or to enhance understanding of 
disease biology unless prohibited by local laws or regulations. Samples will 
be de-identified to ensure patient privacy. 
Sample Size 
Determination 
For the dose-finding period of this study (Phase 1b), the primary objective 
is to determine the RP2D of binimetinib in combination with nivolumab 
with or without ipilimumab. The total number of patients enrolled in the 
dose-finding period will depend on the number of dose levels tested and the 
number of patients treated in each cohort before the RP2D has been 
determined.  
Approximately 90 patients are planned. A maximum of approximately 

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42 patients will be enrolled in Phase 1b and a minimum of approximately 
48 patients will be enrolled in Phase 2. 
In Phase 1b, a maximum of approximately 21 patients will be treated in 
each arm, with a target of 9 patients at the MTD. In the Phase 2 period of 
the study, a minimum of approximately 24 patients will be treated in each 
arm. Randomization into Phase 2 will continue until at least 33 patients 
have received the doublet and the triplet, respectively, at the RP2D 
(Phase 1b and Phase 2 combined). 
The primary analysis of the response rate and efficacy endpoints will 
include all Phase 2 patients plus those treated at the same dose/schedule in 
Phase 1b; thus, it is expected that a minimum of 33 patients in each arm 
will be available for the primary efficacy evaluation. In the doublet arm, a 
response rate of 5% or less will be considered unacceptably low. Hence, the 
null hypothesis that the response rate is at most 5% will be tested against 
the alternative hypothesis that the response rate is greater than 5%. The 
targeted response rate is 20%. With these assumptions, and a 2-tailed alpha 
= 0.10 significance level, 33 patients will provide approximately 86% 
power. 
In the triplet arm, a response rate of 10% or less will be considered 
unacceptably low. Hence, the null hypothesis that the response rate is at 
most 10% will be tested against the alternative hypothesis that the response 
rate is greater than 10%. The targeted response rate is 30%. With these 
assumptions, and a two-tailed alpha = 0.10 significance level, 33 patients 
will provide approximately 91% power. 
The study is not adequately powered to compare the response rate between 
treatment arms; these comparisons will be descriptive only. 
 
 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
1 5  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
Ta ble of C o nte nts 
SI G N A T U R E P A G E ( S P O N S O R) .......................................................................................... 2  
P RI N CI P A L I N V E S TI G A T O R A G R E E M E N T ................................................................... 3  
P R O T O C O L S Y N O P SI S ........................................................................................................ 4  
T A B L E O F C O N T E N T S ....................................................................................................... 1 5  
LI S T O F T A B L E S .................................................................................................................. 2 0  
LI S T O F FI G U R E S ............................................................................................................... 2 1  
LI S T O F A P P E N DI C E S ........................................................................................................ 2 1  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S ........................................ 2 2  
S U M M A R Y O F C H A N G E S F O R P R O T O C O L V E R SI O N 4. 0 ....................................... 2 8  
S U M M A R Y O F C H A N G E S F O R P R O T O C O L V E R SI O N 3. 0 ....................................... 3 1  
S U M M A R Y O F C H A N G E S  F O R P R O T O C O L V E R SI O N 2. 0 ....................................... 3 2 
1. 0  I N VE S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E S T R U C T U R E .................. 3 7  
2. 0  I N T R O D U CTI O N ......................................................................................................... 3 8  
2. 1  
Meta static C ol orectal Ca ncer .................................................................................... 3 8 
2. 1. 1  
Treat me nt wit h I m m u ne C hec k p oi nt I n hi bit ors i n M S S vers us M SI- H Dise ase 3 9  
2. 1. 2  
R A S m utati o n i n m C R C .................................................................................... 4 0  
2. 2  
In v esti gati o nal Me dici nal Pr o d ucts: Ni v ol u ma b, I pili m u ma b a n d Bi ni meti ni b, ...... 4 0  
2. 2. 1  
N o ncli nical Safet y P har mac ol o g y a n d To xic ol o g y of Bi ni meti ni b ................... 4 1  
2. 2. 2  
P har mac o ki netics of Bi ni meti ni b ...................................................................... 4 2  
2. 2. 3  
Cli nical Safet y of Bi ni meti ni b ........................................................................... 4 2  
2. 2. 3. 1  
S i n gle-a ge nt Bi ni meti ni b i n O nc ol o g y ..................................................... 4 3 
2. 3  
R ati o nale f or t he St u d y .............................................................................................. 4 9  
2. 3. 1  
St u d y Desi g n...................................................................................................... 4 9  
2. 3. 1. 1  
R ati o nale f or t he D o u blet C o m bi nati o n ( Ni v ol u ma b a n d a M E K 
I n hi bit or) ................................................................................................... 5 1 
2. 3. 1. 2  
R ati o nale f or t he Tri ple C o m bi nati o n i n Ar ms 1 B a n d 2 B: Bi ni meti ni b 
wit h Ni v ol u ma b a n d I pili m u ma b ............................................................. 5 2  
2. 3. 2  
Rati o nale f or D ose Sel ecti o n ............................................................................. 5 3  
2. 3. 2. 1  
R ati o nale f or Ni v ol u ma b D oses ............................................................... 5 3  
2. 3. 2. 2  
Rati o nale f or Bi ni meti ni b D oses u p t o 4 5 m g BI D .................................. 5 4  
2. 3. 2. 3  
Rati o nale f or I pili m u ma b D osi n g Sc he d ul e ............................................. 5 5  
2. 3. 2. 4  
Rati o nale f or t he D os es of Ni v ol u ma b a n d I pili m u ma b i n C o m bi nati o n . 5 6  
2. 3. 2. 5  
Rati o nale f or I nf usi o n Ti mes f or Ni v ol u ma b a n d I pili m u ma b  ................. 5 9  
2. 3. 2. 6  
R ati o nale f or D urati o n of T hera p y ........................................................... 6 0  
2. 3. 3  
Ris ks f or O verall Safet y of C o m bi nati o n T hera p y ............................................ 6 1  
 
 
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2.4 
Risk-benefit Assessment Summary ........................................................................... 63 
3.0 STUDY OBJECTIVES AND ENDPOINTS ................................................................ 65 
3.1 
Study Objectives ....................................................................................................... 65 
3.1.1 
Primary Objectives ............................................................................................ 65 
3.1.2 
Secondary Objectives ........................................................................................ 65 
3.1.3 
Exploratory Objectives ...................................................................................... 65 
3.2 
Study Endpoints ........................................................................................................ 65 
3.2.1 
Primary Endpoints ............................................................................................. 65 
3.2.2 
Secondary Endpoints ......................................................................................... 66 
3.2.3 
Exploratory Endpoints ....................................................................................... 66 
4.0 STUDY DESIGN ........................................................................................................... 67 
4.1 
Study Design Overview ............................................................................................ 67 
4.1.1 
Phase 1b: Dose-Finding Period and Dose De-Escalation/Escalation ................ 69 
4.1.1.1 
Tolerability Assessment ............................................................................ 73 
4.1.1.2 
Dose-limiting Toxicities ........................................................................... 74 
4.1.2 
Phase 2: Randomized Dose Cohorts .................................................................. 78 
4.1.2.1 
Measures to Minimize Bias ...................................................................... 78 
4.2 
Duration of Treatment ............................................................................................... 78 
4.3 
End of Study .............................................................................................................. 79 
4.4 
Safety Review ........................................................................................................... 79 
5.0 PATIENT POPULATION ............................................................................................. 80 
5.1 
Number of Patients .................................................................................................... 80 
5.2 
Selection of Patients .................................................................................................. 80 
5.2.1 
Eligibility Criteria for Prescreening .................................................................. 80 
5.2.1.1 
Prescreening Inclusion Criteria ................................................................ 80 
5.2.1.2 
Prescreening Exclusion Criteria ............................................................... 81 
5.2.2 
Patient Eligibility at Screening .......................................................................... 82 
5.2.2.1 
Screening Inclusion Criteria ..................................................................... 82 
5.2.2.2 
Screening Exclusion Criteria .................................................................... 83 
5.3 
Lifestyle Guidelines - Contraception ........................................................................ 85 
6.0 STUDY TREATMENT AND CONCOMITANT MEDICATIONS/THERAPIES .. 87 
6.1 
Patient Numbering ..................................................................................................... 87 
6.2 
Allocation to Treatment ............................................................................................. 87 
6.3 
Doses and Schedule of Administration ..................................................................... 87 
6.3.1 
Administration of Nivolumab ............................................................................ 87 
6.3.2 
Administration of Binimetinib........................................................................... 88 
6.3.3 
Administration of Ipilimumab ........................................................................... 89 
6.4 
Dose Modifications ................................................................................................... 89 
6.4.1 
Nivolumab and Ipilimumab Modifications ....................................................... 89 

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6.4.1.1 
Dose Reductions ....................................................................................... 89 
6.4.1.2 
Dose Interruptions or Delays .................................................................... 90 
6.4.1.3 
Criteria to Resume Nivolumab and Ipilimumab ...................................... 90 
6.4.1.4 
Criteria to Discontinue Nivolumab and Ipilimumab ................................ 91 
6.4.1.5 
Treatment of Nivolumab- or Ipilimumab-related Infusion Reactions ...... 92 
6.4.2 
Binimetinib Modifications ................................................................................. 94 
6.5 
Concomitant Medications/Therapies ....................................................................... 100 
6.5.1 
Permitted Concomitant Medications/Therapies .............................................. 100 
6.5.1.1 
Antidiarrheals ......................................................................................... 100 
6.5.1.2 
Antiemetics ............................................................................................. 100 
6.5.2 
Permitted Concomitant Therapy Requiring Caution and/or Action ................ 101 
6.5.2.1 
UGT Substrates and Inhibitors ............................................................... 101 
6.5.2.2 
Transporter Substrates and Inhibitors ..................................................... 101 
6.5.3 
Prohibited Concomitant Therapy ..................................................................... 101 
6.5.3.1 
Anticancer Therapy ................................................................................ 101 
6.5.3.2 
Other Prohibited Therapies..................................................................... 101 
6.6 
Study Drug Supply .................................................................................................. 102 
6.6.1 
Manufacturing, Formulation, Packaging and Labeling ................................... 102 
6.6.2 
Shipping, Storage and Handling ...................................................................... 102 
6.6.3 
Accountability and Return of Study Drug Supply........................................... 103 
6.7 
Treatment Compliance ............................................................................................ 103 
7.0 STUDY PROCEDURES AND ASSESSMENTS ...................................................... 104 
7.1 
Prescreening/Screening Assessments and Procedures ............................................ 104 
7.1.1 
MSS and RAS Mutation Testing ...................................................................... 104 
7.1.2 
Prescreening ..................................................................................................... 105 
7.1.3 
Screening ......................................................................................................... 105 
7.1.4 
Information Collected for Screen Failures ...................................................... 105 
7.1.5 
Patient Demographics and Other Baseline Characteristics ............................. 105 
7.2 
Safety Assessments ................................................................................................. 106 
7.2.1 
Adverse Events ................................................................................................ 106 
7.2.2 
Clinical Laboratory Tests ................................................................................. 106 
7.2.2.1 
Hematology, Coagulation and Clinical Chemistry ................................. 108 
7.2.2.2 
Urinalysis ................................................................................................ 108 
7.2.2.3 
Pregnancy and Assessments of Fertility ................................................. 108 
7.2.3 
Vital Signs ........................................................................................................ 109 
7.2.4 
Physical Examination ...................................................................................... 109 
7.2.5 
Ophthalmic Assessments ................................................................................. 109 
7.2.5.1 
Routine Testing ....................................................................................... 109 
7.2.5.2 
Additional Testing .................................................................................. 110 
7.2.6 
Dermatologic Evaluations ............................................................................... 110 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
1 8  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
7. 2. 7  
Electr ocar di o gra ms .......................................................................................... 1 1 0  
7. 2. 8  
Ec h ocar di o gra m/ M ulti- gate d Ac q uisiti o n Sca ns ............................................. 1 1 1  
7. 2. 9  
E C O G Perf or ma n ce Stat us .............................................................................. 1 1 1  
7. 3  
P har mac o ki netic Assess me nts ................................................................................. 1 1 2  
7. 4  
B i o mar ker Ass ess me nts ........................................................................................... 1 1 3 
7. 4. 1  
C-reacti ve Pr ot ei n ............................................................................................ 1 1 3  
7. 4. 2  
T u m or Mar kers ( C E A a n d C A 1 9- 9) ............................................................... 1 1 3  
 
 
7. 4. 4  
O pti o nal T u m or Sa m ple C ollecti o n at Disease Pr o g ressi o n ............................ 1 1 4 
7. 4. 5  
Rete nti o n of Sa m ples f or F ut ure A nal y sis ....................................................... 1 1 4 
7. 5  
Ef ficac y Assess me nts .............................................................................................. 1 1 5 
7. 5. 1  
T u m or Res p o nse .............................................................................................. 1 1 5  
7. 5. 2  
S ur vi val ............................................................................................................ 1 1 6  
8. 0  S C H E D U L E O F P R O C E D U R E S A N D A S S E S S M E N T S ....................................... 11 7  
8. 1  
P rescree ni n g ( All Ar ms a n d P hases) ....................................................................... 1 3 0 
8. 2  
Scree ni n g ( All Ar ms a n d P hases) ............................................................................ 1 3 0  
8. 3  
P hase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u ma b + bi ni meti ni b): C ycle 1 ......... 1 3 2  
8. 3. 1  
P hase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u ma b + bi ni meti ni b): C ycle 1 
Da y 1................................................................................................................ 1 3 2  
8. 3. 2  
P hase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u ma b + bi ni meti ni b): C ycle 1 
Da y 1 5.............................................................................................................. 1 3 3  
8. 3. 3  
P hase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u ma b + bi ni meti ni b): C ycle 1 
Da y 2 2.............................................................................................................. 1 3 4  
8. 4  
P hase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u ma b + bi ni meti ni b): C ycle 2 ......... 1 3 4  
8. 4. 1  
P hase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u ma b + bi ni meti ni b): C ycle 2 
Da y 1................................................................................................................ 1 3 4  
8. 4. 2  
P hase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u ma b + bi ni meti ni b): C ycle 2 
Da y 1 5.............................................................................................................. 1 3 5  
8. 5  
P hase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u ma b + bi ni meti ni b): S u bse q ue nt 
C ycles ...................................................................................................................... 1 3 5  
8. 5. 1  
P hase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u ma b + bi ni meti ni b): S u bse q ue nt 
C ycles Da y 1 ................................................................................................ .... 1 3 5 
8. 5. 2  
P hase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u ma b + bi ni meti ni b): S u bse q ue nt 
C ycles Da y 1 5 ................................................................ .................................. 1 3 6 
8. 6  
P hase 1 b Ar m 1 B a n d P h ase 2 Ar m 2 B ( ni v ol u ma b + bi ni meti ni b + i pili m u ma b): 
C ycle 1 ..................................................................................................................... 1 3 6  
8. 6. 1  
P hase 1 b Ar m 1 B a n d P h ase 2 Ar m 2 B ( ni v ol u ma b + bi ni meti ni b + 
i pili m u ma b): C ycle 1 Da y 1 ............................................................................ 1 3 6 
8. 6. 2  
P hase 1 b Ar m 1 B a n d P h ase 2 Ar m 2 B ( ni v ol u ma b + bi ni meti ni b + 
i pili m u ma b): C ycle 1 Da y 1 5 .......................................................................... 1 3 8 
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8.6.3 
Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + 
ipilimumab): Cycle 1 Day 22 .......................................................................... 138 
8.7 
Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Cycle 2 ..................................................................................................................... 139 
8.7.1 
Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + 
ipilimumab): Cycle 2 Day 1 ............................................................................ 139 
8.7.2 
Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + 
ipilimumab): Cycle 2 Day 15 .......................................................................... 140 
8.8 
Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Subsequent Cycles ................................................................................................... 140 
8.8.1 
Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + 
ipilimumab): Subsequent Cycles Day 1 .......................................................... 140 
8.8.2 
Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + 
ipilimumab): Subsequent Cycles Day 15 ........................................................ 141 
8.9 
Follow-up Visits (All Arms and Phases) ................................................................. 141 
8.9.1 
End of Treatment Visit ..................................................................................... 141 
8.9.2 
30-Day Safety Follow-up Visit ........................................................................ 142 
8.9.3 
100-Day Safety Follow-Up Visit ..................................................................... 142 
8.9.4 
150-Day Safety Follow-Up Assessment (Phone Call) .................................... 143 
8.9.5 
Tumor Assessment Follow-up Visits ............................................................... 143 
8.9.6 
Survival Follow-up .......................................................................................... 143 
8.10 Collection of Data for Ongoing Patients Following Database Lock ....................... 143 
9.0 STUDY DISCONTINUATION .................................................................................. 144 
9.1 
Termination of the Study by the Sponsor ................................................................ 144 
9.2 
Treatment Discontinuation for Individual Patients ................................................. 144 
9.3 
Study Discontinuation for Individual Patients ........................................................ 145 
9.4 
Replacement of Patients .......................................................................................... 145 
10.0 SAFETY MONITORING: DEFINITIONS AND REPORTING ............................ 146 
10.1 Adverse Event ......................................................................................................... 146 
10.2 Immune-Mediated Adverse Events ......................................................................... 146 
10.3 Events Related to Progression of Disease ............................................................... 146 
10.4 Clinical Laboratory Abnormalities .......................................................................... 146 
10.5 Overdose .................................................................................................................. 146 
10.6 Assessment of Severity ........................................................................................... 147 
10.7 Assessment of Causality .......................................................................................... 147 
10.8 Assessment of Seriousness ...................................................................................... 148 
10.9 Reporting of Serious and Nonserious Adverse Events............................................ 149 
10.10 Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) ......... 149 
10.11 Pregnancy or Drug Exposure during Pregnancy ..................................................... 150 
11.0 STATISTICAL METHODS ........................................................................................ 151 

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11.1 Sample Size ............................................................................................................. 151 
11.2 Analysis Sets ........................................................................................................... 152 
11.2.1 
Full Analysis Set .............................................................................................. 152 
11.2.2 
Safety Set ......................................................................................................... 152 
11.2.3 
Dose-Determining Set ..................................................................................... 152 
11.2.4 
Per Protocol Set ............................................................................................... 152 
11.2.5 
Pharmacokinetic Set ........................................................................................ 152 
11.3 Statistical Analyses and Methods ............................................................................ 152 
11.3.1 
General Considerations .................................................................................... 152 
11.3.2 
Patient Characteristics ..................................................................................... 152 
11.3.3 
Efficacy Analyses ............................................................................................ 153 
11.3.3.1 
Objective Response Rate ........................................................................ 153 
11.3.4 
Safety Analyses................................................................................................ 153 
11.3.5 
Pharmacokinetic Analysis................................................................................ 154 
11.4 Operating Characteristics ........................................................................................ 154 
12.0 DATA RECORDING, RETENTION AND MONITORING ................................... 157 
12.1 Data Management ................................................................................................... 157 
12.2 Data Monitoring ...................................................................................................... 157 
12.3 Quality Control and Quality Assurance .................................................................. 158 
13.0 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS .................................. 159 
13.1 Good Clinical Practice ............................................................................................ 159 
13.2 Ethics Committee Approval .................................................................................... 159 
13.3 Regulatory Authority Approval ............................................................................... 159 
13.4 Other Required Approvals ....................................................................................... 159 
13.5 Informed Consent .................................................................................................... 160 
13.6 Patient Confidentiality ............................................................................................. 160 
13.7 Disclosure of Information ....................................................................................... 160 
13.8 Publication of Study Data ....................................................................................... 161 
14.0 ADHERENCE TO THE PROTOCOL ...................................................................... 162 
14.1 Amendments to the Protocol ................................................................................... 162 
APPENDICES ...................................................................................................................... 163 
REFERENCES ..................................................................................................................... 198 
 
List of Tables 
Table 1: 
Dosing Scheme for Phase 1b ............................................................................. 7 
Table 2: 
Dosing Scheme for Phase 1b ........................................................................... 69 
Table 3: 
Guidance for Safety Review based on Observed Toxicity Outcomes ............. 72 
Table 4: 
Criteria for Defining Dose-limiting Toxicities................................................. 75 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
2 1  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
Ta ble 5:  
Per mitte d Bi ni meti ni b D ose Re d ucti o ns d ue t o A d verse E ve nt ...................... 9 4  
Ta ble 6:  
C T C A E Gra di n g f or E ye Dis or ders ................................................................. 9 4  
Ta ble 7:  
C T C A E Gra di n g f or Re ti nal Detac h m e nt ........................................................ 9 5 
Ta ble 8:  
Bi ni meti ni b – Rec o m me n de d D ose M o dificati o ns Ass ociate d wit h Treat me nt-
Relate d A d v erse E v e nts ................................................................................... 9 5  
Ta ble 9:  
S u m mar y of Cli nical La b orat or y Tests .......................................................... 1 0 7  
Ta ble 1 0:  
Easter n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us Scale ... 1 1 1  
Ta ble  1 1: 
Sc he d ule of E ve nts: Pres cree ni n g a n d Scree ni n g ( All ar ms a n d p hases) ...... 1 1 8 
Ta ble 1 2:  
Sc he d ule of E ve nts: P has e 1 b Ar m 1 A ( Ni v ol u ma b + Bi ni meti ni b) ............. 1 2 0  
Ta ble 1 3:  
Sc he d ule of E ve nts: P has e 1 b Ar m 1 B ( Ni v ol u ma b + I pili m u ma b + 
Bi ni meti ni b) ................................................................................................... 1 2 3 
Ta ble 1 4:  
Sc he d ule of E ve nts: P has e 2 Ar m 2 A ( Ni v ol u ma b + Bi ni meti ni b) ............... 1 2 6  
Ta ble  1 5: 
Sc he d ule of E ve nts: P has e 2 Ar m 2 B ( Ni v ol u ma b + I pili m u ma b + 
Bi ni meti ni b) ................................................................................................... 1 2 8 
Ta ble 1 6:  
D ose Le vels .................................................................................................... 1 5 5  
Ta ble 1 7:  
D ose-li miti n g To xicities Pr o ba bilit y Sce nari os ............................................. 1 5 6  
 
List of F i g ures 
Fi g ure 1:  
Bi ni meti ni b E n ha nces α P D -1 A nti -T u m or Acti vit y i n I m m u n oc o m pete nt C R C 
M o del  ............................................................................................................... 5 1  
Fi g ure 2:  
St u d y Desi g n Sc he me f or P hase 1 b a n d P hase 2 ............................................. 6 8  
Fi g ure 3:  
Ar m 1 A/ Ar m 2 A: Ti mi n g of E C Gs a n d Bl o o d C ollecti o ns i n Relati o n t o 
St u d y Dr u g A d mi nistrati o n o n C ycle 1 Da y 1 ............................................... 1 3 3  
Fi g ure 4:  
Ar m 1 B/ Ar m 2 B: Ti mi n g of E C Gs a n d Bl o o d C ollecti o ns i n Relati o n t o St u d y 
Dr u g A d mi ni strati o n o n C ycle 1 Da y 1 ......................................................... 1 3 8 
 
List of A p pe n dices 
A p pe n di x 1:  Rec o m me n de d G ui deli nes f or t he Ma na ge me nt of Bi ni meti ni b-I n d u ce d 
Diarr hea.......................................................................................................... 1 6 4  
A p pe n di x 2:  Rec o m me n de d G ui deli nes f or t he Ma na ge me nt of Bi ni meti ni b- i n d uce d 
c uta ne o us r eacti o ns ........................................................................................ 1 6 7 
A p pe n di x 3:  Rec o m me n de d G ui deli nes f or t he Ma na ge me nt of Bi ni meti ni b-ass ociate d 
i nterstitial l u n g disease ................................................................................... 1 7 0 
A p pe n di x 4:  Rec o m me n de d Ma n a ge me nt Al g orit h ms f or Gastr oi nte sti nal, Re nal, 
P ul m o nar y, He patic, E n d ocri n o pat h y, S ki n, a n d Ne ur ol o gi c A d verse E v e nts 
fr o m Ni v ol u ma b or I pili m u ma b Treat me nt.................................................... 1 7 2 
A p pe n di x 5:  S nelle n E q ui vale nce ( Vis ual Ac uit y C o n versi o n C hart) ................................ 1 7 9  
A p pe n di x 6:  List of C o nc o mita nt Me dicati o ns ................................................................... 1 8 0 
A p pe n di x 7:  Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T), versi o n 1. 1 ......... 1 8 1  
 
 
 
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List of Abbreviations and Definition of Terms 
The following abbreviations and special terms are used in this study protocol.  
Abbreviation or  
special term 
Explanation 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALT  
alanine aminotransferase  
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST  
aspartate aminotransferase  
ATP 
adenosine triphosphate 
AUC 
area under the concentration-time curve 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
BNP 
brain natriuretic peptide 
BOR 
best overall response 
BRAF 
B-RAF proto-oncogene, serine/threonine kinase 
BSA 
body surface area 
BSC 
best supportive care 
BUN 
blood urea nitrogen 
C1D1 
Cycle 1 Day 1 or CXDX 
CA 19-9 
cancer antigen 19-9 
CAPOX 
capecitabine and oxaliplatin 
Cavgss 
average steady-state exposures 
CEA 
carcinoembryonic antigen 
cHL 
classical Hodgkin’s lymphoma 
CI 
confidence interval 
CK 
creatine kinase 
Cmax 
maximum concentration 
Cmaxss 
steady-state peak concentrations 
Cminss 
steady-state trough concentrations 
CMS 
consensus molecular subtypes 
CNS 
central nervous system 

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Abbreviation or  
special term 
Explanation 
CR 
complete response 
CRA 
clinical research associate 
CRC 
colorectal cancer 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-cell lymphoma-4 antigen 
CV 
curriculum vita 
CYP 
cytochrome P450 
DDS 
Dose-determining Set 
DLT 
dose-limiting toxicity 
dMMR 
DNA mismatch repair 
DOR 
duration of response 
DVT 
deep vein thrombosis 
EC 
ethics committee (includes institutional review board, research ethics board, and 
institutional ethics committee) 
EC50 
half maximal effective concentration 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture system 
EGFR 
epidermal growth factor receptor 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
ER 
exposure-response 
ESMO 
European Society for Medical Oncology 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
FOLFIRI 
leucovorin, 5-FU and irinotecan 
FOLFOX 
leucovorin , 5-FU and oxaliplatin 
FSH 
follicle-stimulating hormone 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
2 4  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
A b bre vi ati o n or  
s peci al ter m 
E x pl a n ati o n  
5 -F U  
5 -fl u or o uracil 
G C P  
G o o d Cli nical Practice  
GI  
G astr oi ntesti nal  
H & N  
hea d a n d nec k  
H B V  
he p atitis B vir us  
H C V  
he p atitis C vir us  
H D P E  
hi g h -de nsit y p ol yet h yle ne  
H F S R  
ras h, ha n d f o ot s ki n reacti o n 
HI V  
h u ma n i m m u n o deficie nc y vir us  
H L A  
h u ma n le u k oc yte a nti ge n  
I B 
I n vesti gat or’s Br oc h ure 
I C5 0 
≥ 5 0 % i n hi biti o n of M E K acti vit y  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce o n H ar m o nisati o n of T ec h nical Re q uire me nts f or Re gistrati o n 
of P har mace uticals f or H u ma n Use  
I g 
Im m u n o gl o b uli n  
I H C 
i m m u n o hist oc he mistr y 
I L D 
i nterstitial l u n g disease 
i m A E 
i m m u ne-me diate d a d verse e ve nt  
I N R 
i nter nati o nal n or malize d rati o 
 
 
I R B 
I nstit uti o nal Re vie w B oar d 
ir P R 
i m m u ne-relate d partial res p o nse 
ir S D 
i m m u ne-relate d sta ble disease  
I U D 
i ntra uteri ne de vice 
I U S 
i ntra uteri ne h or m o ne-releasi n g s yste m 
I V 
i ntra ve n o us(l y) 
I W R S 
i nteracti ve we b res p o nse s yste m 
K R A S  
V -Ki -ras 2 Kirste n rat sarc o ma viral o nc o ge ne h o m ol o g 
L C -M S -M S  
li q ui d c hr o mat o gra p h y ta n de m mass s pectr o metr y 
L H  
l utei nizi n g h or m o ne 
L L N  
l o wer li mit of t he n or mal refer e nce ra n ge 
L V E F  
left ve ntric ular ej ecti o n fracti o n  
C CI

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Abbreviation or  
special term 
Explanation 
mAb 
monoclonal antibody 
MAP 
mitogen activated protein 
MAPK 
mitogen activated protein kinase 
mCRC 
metastatic colorectal cancer 
MDRD 
Modification of Diet in Renal Disease (Study) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen/extracellular signal regulated kinase 
MHC 
major histocompatibility complex  
MLR 
mixed lymphocyte reaction 
mOS 
median overall survival 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MSI-H 
high-frequency microsatellite instability 
MSS 
microsatellite stable 
MTD 
maximum tolerated dose 
mTPI 
modified toxicity probability interval 
MUGA 
multi-gated acquisition  
mWHO 
Modified World Health Organization (criteria) 
NCCN 
National Comprehensive Cancer Network 
NCI  
National Cancer Institute  
NGS 
next generation sequencing 
NSCLC 
non-small cell lung cancer 
OCT 
optical coherence tomography 
ORR 
objective response rate (overall response rate) 
OS 
overall survival 
PAS 
PK Analysis Set 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PD-1 
programmed death-1 
PDF 
portable document format 
PD-L1 
programmed death-ligand 1 
PE 
pulmonary embolism 

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Abbreviation or  
special term 
Explanation 
pERK 
phosphorylated ERK 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
pH 
hydrogen ion concentration 
PK 
pharmacokinetic(s) 
PO 
oral(ly) 
PPK 
population pharmacokinetics 
PPS 
Per-protocol Set 
PR 
partial response 
PS 
performance status 
PT 
prothrombin time 
QXW 
every X weeks (X varies based on number of weeks specified) 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
red blood cell 
RCC 
renal cell cancer 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPED 
retinal pigment epithelial detachment 
RP2D 
recommended Phase 2 dose 
RVO 
retinal vein occlusion 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SOC 
standard of care 
SOP 
standard operating procedure 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse event 
t1/2 
terminal half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
TCGA 
The Cancer Genome Atlas 
Tmax 
time of maximum plasma concentration 
TME 
tumor microenvironment 

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Abbreviation or  
special term 
Explanation 
TNF 
tumor necrosis factor 
TSH 
thyroid-stimulating hormone 
UC 
urothelial carcinoma 
UGT 
UDP-glucuronosyl transferase 
ULN 
upper limit of normal  
US 
United States 
vs 
version 
VEGF 
vascular endothelial growth factor 
VTE 
venous thromboembolism 
WBC 
white blood cell 
WES 
whole exosome sequencing 
WHO 
World Health Organization 
 
 

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SUMMARY OF CHANGES FOR PROTOCOL VERSION 4.0 
Rationale 
The objective of this amendment is to (1) specify that all patients must have received prior 
systemic treatment as recommended by National Comprehensive Cancer Network (NCCN) or 
European Society for Medical Oncology (ESMO) guidelines, including fluoropyrimidines, 
oxaliplatin, irinotecan or bevacizumab in the metastatic setting or similar treatments, as per local 
guidelines; (2) add a delay of at least 7 days between Cycle 1 Day 1 (C1D1) of the first patient 
and C1D1 of the second patient enrolled during Phase 1b (Arms 1A and 1B); (3) add a post-
treatment 150-day safety follow-up assessment; and (4) decrease the burden of visual field 
testing for sites and patients. Other minor changes or clarifications have also been made as 
described below. 
Changes to the Protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough font for deletions and underlined font for insertions. 
Summary of Changes for Protocol Version 4.0: Section added to summarize this amendment. 
Protocol Synopsis: Section was updated to match the body of the protocol. 
Section 2.1 was modified to describe likely outcomes relating to standard-of-care therapies after 
the first-line setting as well as potential outcomes of the study regimen. 
Title for Section 2.4 was changed to “Risk-benefit Assessment Summary.” 
Section 2.4 was modified to provide an overview of the informed consent process and to describe 
likely outcomes relating to standard-of-care therapies after the first-line setting as well as 
potential outcomes of the study regimen. 
Sections 3.1.2, 3.1.3 and 3.2.3 were modified to clarify that all elements of the sections apply to 
both Phase 1b and Phase 2 of the study. 
Title for Section 4.1.1 was changed to add the following: “and Dose De-Escalation/Escalation”. 
Section 4.1.1 was modified to include a statement that there will be a period of at least 7 days 
between C1D1 of the first patient and C1D1 of the second patient enrolled during Phase 1b 
(Arms 1A and 1B).  

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Section 4.1.1 was modified to include the statement "The Sponsor’s Medical Monitor and the 
Investigators will review, at a minimum, all the available data from Cycle 1 once 3 to 
6 evaluable patients in subsequent cohorts have been treated for at least 1 cycle", which was 
moved from Section 4.1.1.1 to improve organization. 
Section 4.1.1.1 was modified to remove the statement "The Sponsor’s Medical Monitor and the 
Investigators will review, at a minimum, all the available data from Cycle 1 once the first 3 to 
6 evaluable patients in a cohort have been treated for at least 1 cycle", which was moved to 
Section 4.1.1. 
Section 5.2.1.1 was modified to include a new prescreening inclusion criterion (criterion 7) that 
requires that all patients must have received prior systemic treatment as recommended by NCCN 
or ESMO guidelines, including fluoropyrimidines, oxaliplatin, irinotecan or bevacizumab in the 
metastatic setting or similar treatments, as per local guidelines. Wording of an existing 
prescreening criterion (criterion 5) was also adjusted to specify that patients must have 
willingness and ability to participate in the study. 
Section 5.2.2.1 (criterion 5) was modified to specify that the required line(s) of prior systemic 
therapy were consistent with recommendations by NCCN or ESMO guidelines, including 
fluoropyrimidines, oxaliplatin, irinotecan or bevacizumab in the metastatic setting or similar 
treatments, as per local guidelines. 
Section 6.3.1 was updated to include a ± 5-minute window around the 30-minute nivolumab 
infusions and to clarify this time does not include the time required to flush the IV lines. 
Section 6.3.3 was updated to include a ± 5-minute window around the 30-minute ipilimumab 
infusions and to clarify this time does not include the time required to flush the IV lines. 
Section 6.4.1.4 was modified to align with guidelines in the nivolumab prescribing information. 
Section 7.2.5.1 was updated: (1) to remove visual field testing as part of the full ophthalmic 
examination; (2) to state that visual field testing will only be performed when clinically 
indicated; and (3) to allow visual field testing to be performed by either an optometrist or 
ophthalmologist. 
Table 11 Footnote “A” was updated to remove visual field testing as part of the full ophthalmic 
examination and to instead state that visual field testing will be performed when clinically 
indicated. 

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Tables 12 to 15 have been updated: (1) to add a 150-day safety follow-up assessment; (2) to 
remove visual field testing as part of the full ophthalmic examination; and (3) to state that visual 
field testing will only be performed when clinically indicated. 
Section 8.4.2 was updated to remove tumor assessments at this visit (C2D15) as they are to be 
performed every 8 weeks (±7 days) from C1D1 through Week 24, then every 12 weeks (±7 days) 
thereafter. 
Section 8.5.1 was updated to clarify that tumor assessments are to be performed in subsequent 
cycles every 8 weeks (±7 days) from C1D1 through Week 24, then every 12 weeks (±7 days) 
thereafter. 
Section 8.7.2 was updated to remove tumor assessments at this visit (C2D15) as they are to be 
performed every 8 weeks (±7 days) from C1D1 through Week 24, then every 12 weeks (±7 days) 
thereafter. 
Section 8.8.1 was updated to clarify that tumor assessments are to be performed in subsequent 
cycles every 8 weeks (±7 days) from C1D1 through Week 24, then every 12 weeks (±7 days) 
thereafter. 
Section 8.9.2 was updated to remove details of survival follow-up, which have been moved into 
a separate section. 
Section 8.9.3 was updated to remove details of survival follow-up, which have been moved into 
a separate section. 
Section 8.9.4 was added to describe the events of the 150-day safety follow-up assessment. 
Section 8.9.5 was added to clarify tumor assessment follow-up visits. 
Section 8.9.6 was added to clarify survival follow-up. 
Section 10.3 was updated with administrative changes/corrections. 
Section 10.6 was updated with administrative changes/corrections. 
Section 10.9 was updated to reflect the 150-day safety follow-up assessment. 
References were updated. 

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SUMMARY OF CHANGES FOR PROTOCOL VERSION 3.0 
Rationale 
At the time of this protocol amendment, the study had been initiated at 3 study centers, 1 patient 
had received study drug and 1 patient was in screening. 
The objective of this amendment is to add immunohistochemistry (IHC) as a permitted method 
of local MSS determination. 
Changes to the Protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough font for deletions and underlined font for insertions. 
Summary of Changes for Protocol Version 3.0:  Section added to summarize this amendment. 
Protocol Synopsis:  Section has been updated to match the body of the protocol. 
Section 5.2.2.1:  Screening Inclusion Criterion 3 modified to include IHC as a permitted method 
of local MSS determination. 
Section 7.1.1:  Section modified to include IHC as a permitted method of local MSS 
determination and to specify the mismatch repair proteins that must be assayed and reported. 
Section 8.0:  Table 11 modified to include IHC as a permitted method of local MSS 
determination. 
Section 8.1:  Section modified to include IHC as a permitted method of local MSS 
determination.   
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and health authorities. The changes described in 
this amended protocol require IRB/IEC approval prior to implementation. 
The changes herein do not affect the informed consent.  

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SUMMARY OF CHANGES FOR PROTOCOL VERSION 2.0 
Rationale 
At the time of this protocol amendment, the study had been initiated at 1 study center and 
1 patient has been screened. 
The main objectives of this amendment are: 
 To modify eligibility criteria as follows: 
o Allow progression within 6 months of completing adjuvant chemotherapy prior to 
enrollment (previously 3 months) 
o Permit use of estimated glomerular filtration rate measurement per Modification 
of Diet in Renal Disease (MDRD) Study formula (previously only allowed a 
qualifying creatinine or calculated creatinine clearance measurement) 
 To specify that permanent discontinuation of nivolumab will also result in permanent 
discontinuation of ipilimumab 
 To clarify permitted binimetinib treatment modifications 
 To update protocol instructions regarding documentation of adverse events to align with 
current Sponsor language 
 Administrative changes (clarifications and corrections) 
Changes to the Protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough font for deletions and underlined font for insertions. 
Summary of Changes for Protocol Version 2:  Section added to discuss this amendment. 
Protocol Synopsis:  Section has been updated to match the body of the protocol. 
Protocol Synopsis, Study Design:  Redundant presentation of study objectives was deleted. 
Section 2.1.1:  Section updated to reflect the approval of nivolumab for the treatment of 
colorectal cancer. 
Section 2.2.3.1:  Section updated with administrative changes. 
Section 2.3.1.1:  Section updated with administrative changes. 
Section 2.3.1.2:  Section updated with administrative changes. 
Section 2.3.2.3:  Section heading updated with administrative changes. 
Section 4.1:  Figure 2 updated with administrative changes. 
Section 4.1.1:  Clarification added that de-escalation decisions will also be guided by the 
modified toxicity probability interval (mTPI-2) design. 

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Section 4.1.1, Table 2: Clarification added to footnote. 
Section 4.1.1: Table 3 expanded to provide mTPI-2 dose-escalation and de-escalation guidance 
for a broader range of cohort sizes; paragraph referencing TPI-2 algorithm removed, as it is no 
longer necessary given the expanded table. 
Section 4.1.1.1:  Clarification added that de-escalation decisions will also be guided by the 
mTPI-2 design. 
Section 4.1.1.1.1:  Removed statement allowing doses of ipilimumab and/or nivolumab to be 
reduced. 
Section 4.1.1.2:  Table 4 updated to clarify that relevant CK comparator value for assessment of 
dose-limiting toxicities is the baseline, rather than the screening, value. 
Section 5.1:  Estimated number of study centers participating in Phase 1b was reduced to 5 
(previously 12 to 15). 
Section 5.2.1.1:  Prescreening Inclusion Criterion 3 modified to specify use of RECIST v1.1. 
Section 5.2.1.1:  Prescreening Inclusion Criterion 6 modified to specify that the maximum of 
2 permitted prior therapies refers to systemic therapy in the metastatic setting. 
Section 5.2.1.2:  Prescreening Exclusion Criterion 4 wording modified for clarity. 
Section 5.2.2.1:  Screening Inclusion Criterion 5 modified to specify that the requirement 
regarding prior therapy refers to systemic therapy in the metastatic setting, and criterion 5c 
modified to allow progression within 6 months of completing adjuvant chemotherapy 
(previously 3 months). 
Section 5.2.2.1:  Screening Inclusion Criteria 9e modified to allow estimated glomerular 
filtration rate measurement per Modification of Diet in Renal Disease (MDRD) Study formula 
(previously only allowed a qualifying creatinine or calculated creatinine clearance 
measurement). 
Section 6.1:  Corrected to state that manual assignment of patient numbers will be performed in 
Phase 2 as well as Phase 1b. 
Section 6.3.2:  Reference to binimetinib capsules removed (binimetinib is provided as tablets). 
Section 6.3.2:  Statements regarding ipilimumab and nivolumab administration timing were 
removed, as they are not relevant to this section. 
Section 6.3.3:  Timing of ipilimumab administration in relation to nivolumab administration 
clarified, and stipulation added that permanent discontinuation of nivolumab will also result in 
permanent discontinuation of ipilimumab. 
Section 6.4.1.3:  Duration of ipilimumab dose interruption necessitating permanent 
discontinuation specified as > 18 weeks to ensure consistency in the protocol. 
Section 6.4.1.4:  Stipulation added that permanent discontinuation of nivolumab will also result 
in permanent discontinuation of ipilimumab. 

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 Section 6.4.2:  Permitted binimetinib dose modifications were clarified in text and via addition 
of Table 5; instructions pertaining to binimetinib treatment after interruption of more than 
28 days and after discontinuation of nivolumab (and, if applicable, ipilimumab) were clarified. 
Section 6.4.2: Added a restriction to permit only a single dose re-escalation after dose reduction 
due to toxicity. 
Section 6.4.2:  Table 7 footnote updated with administrative changes. 
Section 6.4.2:  Incorrect statement describing conditions required for re-escalation of binimetinib 
dose was removed; the correct information is presented earlier in the section. 
Section 7.1.1:  Section modified to specify time window for central confirmation of locally 
determined MSS disease and RAS mutation. 
Section 7.1.2:  Section modified to specify that collection of fresh tumor biopsy must include 
blood sample and corrected to state that manual assignment of patient numbers will be performed 
in Phase 2 as well as Phase 1b. 
Section 7.2.1:  Statement regarding severity grading scale was removed, as it is presented 
elsewhere. 
Section 7.2.2:  Table 9 was modified to include amylase and lipase, changes in which may meet 
criteria for dose-limiting toxicities, and was updated with administrative changes. 
Section 7.2.2.1:  Section modified to correct typographical error and to specify that assessment 
of renal function for a given patient should use the same method throughout the study. 
Section 7.2.2.3:  To address inconsistency within protocol, section modified to state that serum 
or urine pregnancy tests are permitted at post-screening assessments. 
Section 7.2.3:  Modified section to clarify that all vital signs assessments will include blood 
pressure, pulse and temperature. 
Section 7.2.4.1:  Section deleted, as ipilimumab dosing in this study is not dependent on body 
surface area. 
Section 7.4:  Numbering of section headings corrected (Sections previously numbered 7.4.1.1 
through 7.4.1.4 have become Sections 7.4.1 through 7.4.4). 
Section 7.5.1:  To address inconsistency within protocol, section modified to specify tumor 
response assessments after Week 24 are to be performed every 12 weeks. 
Section 8.0, Table 11:  Corrected to state that manual assignment of patient numbers will be 
performed in Phase 2 as well as Phase 1b; to address inconsistencies within protocol, table 
modified to specify that women sterile by oophorectomy alone require LH, FSH and/or estradiol 
testing, and to specify that assignment of patient number in Phase 1b will occur during 
prescreening. 

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Section 8.0, Tables 12-15: 
 To address inconsistency within protocol, tables modified to specify tumor response 
assessments after Week 24 are to be performed every 12 weeks. 
 Study days on which binimetinib is dispensed in Cycle 1 corrected for consistency with 
the body of the protocol. 
 References to binimetinib capsules removed (binimetinib is provided as tablets). 
 Timing of ophthalmic examinations in Cycle 1 (Tables 12 and 13) and Cycle 2 (Table 15) 
modified for consistency across treatment groups and with body of protocol. 
 Terminology clarified around blood sample collected with optional tumor biopsy. 
 Guidance regarding timing of PK blood draw in relation to ipilimumab infusion added to 
footnote q (Tables 13 and 15 only). 
Section 8.2:  To address inconsistency within protocol, text modified to specify that women 
sterile by oophorectomy alone require LH, FSH and/or estradiol testing at screening. 
Section 8.3.1:  Figure 3 added to clarify sequence of events on Cycle 1 Day 1 for Arms 1A and 
2A. 
Section 8.6.1:  Figure 4 added to clarify sequence of events on Cycle 1 Day 1 for Arms 1B and 
2B, and timing of ipilimumab was specified to occur after 1.5-hour PK sample collected. 
Section 8.8.1:  Sequence of listed activities modified for clarity. 
Section 8.9:  Statement regarding timing of tumor assessments removed, as the information is 
presented elsewhere. 
Section 9.2:  Duration of ipilimumab dose interruption necessitating permanent discontinuation 
changed to > 18 weeks to ensure consistency in the protocol; clinical progression per Investigator 
discretion added as a potential reason for treatment discontinuation.  
Section 10.0:  Section heading updated to reflect updated Sponsor language. 
Section 10.2:  Section updated to include characterization of immune-mediated adverse events. 
Section 10.6:  Sponsor language regarding documentation of adverse events updated. 
Section 10.7:  Sponsor language regarding documentation of adverse events updated. 
Section 10.8:  Sponsor language regarding documentation of adverse events updated. 
Section 10.9:  Sponsor language regarding documentation of adverse events updated. 
Section 10.10:  Section updated to reflect updated Sponsor terminology. 
Section 11.1:  Rationale added for why Phase 2 enrollment may exceed the protocol-specified 
minimum of approximately 48 patients, and erroneous statement that 90 patients are required to 
complete the study was removed.  

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Section 11.4:  Clarification added that de-escalation decisions will also be guided by the mTPI-2 
design. 
Section 11.4, Table 16: Clarification added to footnote. 
References:  Unnecessary literature citation deleted. 
Appendix 7:  Numbering of section headings corrected. 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and health authorities. The changes described in 
this amended protocol require IRB/IEC approval prior to implementation. 
The changes herein affect the informed consent. Sites are required to update and submit for 
approval a revised informed consent that takes into account the changes described in this 
protocol amendment. 

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1.0 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
The Principal Investigator is the person responsible for the conduct of the study at the 
investigational site. A subinvestigator is any member of the clinical study team designated and 
supervised by the Principal Investigator to perform critical study-related procedures and/or to 
make important study-related decisions. 
Prior to study initiation, the Principal Investigator at each site must provide to Array BioPharma 
Inc. (Array BioPharma/Sponsor) a signed protocol signature page, a fully executed and signed 
United States (US) Food and Drug Administration (FDA) Form 1572 (or equivalent) and a 
Qualified Investigator Undertaking form for Investigators at Canadian sites, a current curriculum 
vita (CV), medical license and a financial disclosure form. Financial disclosure forms, current 
CVs and medical licenses must also be provided for all subinvestigators listed on Form 1572 
who will be directly involved in the treatment or evaluation of patients in this study. 
The study will be administered and monitored by employees or representatives of Array 
BioPharma and/or a contract research organization (CRO) in accordance with all applicable 
regulations. Clinical research associates (CRAs) will monitor each site on a periodic basis and 
perform verification of source documentation for each patient. The Array BioPharma Drug 
Safety Department (and/or the CRO, if applicable) will be responsible for ensuring timely 
reporting of expedited serious adverse event (SAE) reports to regulatory authorities and 
Investigators. 

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2.0 
INTRODUCTION 
2.1 
Metastatic Colorectal Cancer 
Colorectal cancer is a serious, life-threatening condition. In 2015, colorectal cancer accounted 
for 774,000 deaths world wide (WHO 2017). In the US and Europe, it is the second and fourth 
most common cancer type, respectively. Approximately 130,000 new cases are diagnosed per 
year in the US and it is the second leading cause of cancer mortality (Siegel et al. 2015). In 
Europe, approximately 450,000 new cases are diagnosed per year and colorectal cancer was 
responsible for 215,000 deaths in 2012. A quarter of patients initially present with metastases 
and the majority of patients will eventually develop metastatic disease (Van Cutsem et al. 2016). 
Standard systemic therapy in patients with unresectable metastatic colorectal cancer (mCRC) 
includes combination regimens with cytotoxic and targeted agents. In the last decade, substantial 
advances in the treatment of mCRC have resulted in an improvement in overall survival (OS) 
from 10 to 12 months to more than 20 months (Grothey and Goldberg 2004). This improvement 
has occurred with the addition of irinotecan, oxaliplatin, bevacizumab, cetuximab, and 
panitumumab to the standard treatment with 5-fluorouracil (5-FU)/folinic acid (leucovorin).  
First-line treatment options for patients with mCRC are partially determined by performance 
status, age and the presence or absence of specific genomic alterations in the tumor. Treatments 
in the US and EU are predominantly 5-FU- and leucovorin-containing regimens in combination 
with either oxaliplatin or irinotecan (FOLFOX or FOLFIRI) with a biologic agent such as 
bevacizumab. Both the FOLFOX and FOLFIRI regimens are considered to be equivalent with a 
median first-line progression-free survival (PFS) of 8.5 months for FOLFIRI and 8 months for 
FOLFOX (Mayer et al. 2015). If a KRAS or NRAS mutation in exons 2, 3 or 4 is absent (i.e., 
“RAS wild-type”), an epidermal growth factor receptor (EGFR) inhibitor (cetuximab or 
panitumumab) is indicated (Tournigand et al. 2004; Lea et al. 2007). In Europe, based on a 
similar efficacy and safety profile, the combination of capecitabine and oxaliplatin (CAPOX) is 
an alternative to standard 5-FU/LV and oxaliplatin-based regimens (Van Cutsem et al. 2015).  
Second line and subsequent treatment choices are limited and dependent on therapy chosen in the 
first line. For those patients who were previously treated with FOLFOX or another 5-FU 
containing therapy, the median PFS for patients receiving FOLFIRI is approximately 4.5 months 
(Peeters et al. 2010). Bevacizumab and ziv-aflibercept have indications for second-line treatment 
in combination with chemotherapy and have demonstrated slight improvement in median OS 
(mOS), but for both biologic agents, the improvement in mOS is less than 2 months when 
comparing the investigational agent with standard of care (SOC) to SOC alone: 11.2 vs. 9.8 
months for bevacizumab (Avastin Package Insert [PI]. 12/2016) and 13.50 vs. 12.06 months for 
ziv-aflibercept (Zaltrap PI. 6/2016). Single-agent cetuximab also has demonstrated an 

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improvement in median OS of less than 2 months (6.1 vs. 4.6 months) in patients who have 
previously received chemotherapy when compared to best supportive care (BSC) (Erbitux PI. 
10/2016). In patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and 
irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) therapy, and, 
if RAS wild type, an EGFR directed therapy, the multikinase inhibitor regorafenib has 
demonstrated an improvement in mOS of 1.4 months (6.4 vs. 5 months) when compared to BSC 
(Stivarga PI. 4/2017). Another treatment option is tipiracil/trifluoridine (TAS-102), which 
demonstrated an improvement in mOS from 5.3 months with placebo to 7.1 months, with an 
objective response rate (ORR) of 1.6% (Mayer et al. 2015). The median PFS was 2.0 months in 
the tipiracil/trifluoridine group and 1.7 months in the placebo group.  
Despite numerous treatment options for mCRC after first-line therapy, the overall benefit of 
these treatments is limited, with low response rates and minimal OS benefits of generally less 
than 2 months. Options are even further limited in patients with RAS mutated disease as the 
entire class of EGFR-directed therapies is not indicated for these patients. New options are, 
therefore, needed to improve outcomes for these patients.  
2.1.1 Treatment with Immune Checkpoint Inhibitors in MSS versus MSI-H Disease 
Immune checkpoint blockade has shown benefit in several cancer types, including melanoma, 
non-small cell lung cancer, renal cell, head and neck, classical Hodgkin’s and bladder cancer 
(Ott et al. 2017). Additional indications with and without combination chemotherapy or targeted 
kinase inhibitors are likely (Sharma et al, 2015). Nivolumab administered as monotherapy or in 
combination with ipilimumab has demonstrated impressive benefit in metastatic CRC with high 
microsatellite instability (MSI-H) (RR: 26% in single-agent nivolumab-treated patients, and, 
33% in combination with ipilimumab) (Boland et al. 2017; Opdivo US PI 2017). Although MSI-
H mCRC shows sensitivity to immunotherapy, these patients represent only a small fraction 
(4%) of the mCRC population (Overman et al. 2016). 
Data indicate that the majority (~96%) of CRC patients have tumors with a microsatellite-stable 
(MSS) phenotype. In this population, immunotherapeutic agents have been largely ineffective 
(Diaz et al. 2013). While the high mutational load of MSI tumors have been well documented in 
whole exosome sequencing (WES) studies, with some research suggesting the number of 
mutations in MSI tumors is 10 to 50 times higher than in MSS tumors (Llosa et al. 2015), MSS 
CRC exhibits a demonstrable level of neoantigens and mutational burden capable of being 
recognized by the immune system (Giannakis et al. 2017). Moreover, The Cancer Genome Atlas 
(TCGA) data has revealed a sizeable number of CRC tumors are both MSS and hypermutated 
(22%; The Cancer Genome Atlas Network 2012). Although MSS CRC lesions have mutations 
which can enhance susceptibility to immunotherapy, the tumor microenvironment is relatively 

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immunosuppressive, inhibiting the activation of T cell dependent anti-tumor immune responses 
and yielding a more immunologically quiescent tumor (Angelova et al. 2016; O’Toole et al. 
2014; Xiao and Freeman. 2015). Two recent clinical studies support these observations: a single-
agent study of pembrolizumab comparing MSI-H versus MSS mCRC patients found an ORR of 
57% vs. 0%, respectively (Le et al. 2015), and a combination immunotherapy study of 
nivolumab with ipilimumab in a similar patient population found an ORR of 26% vs. 5%, 
respectively (Overman et al., 2016). Thus in comparison to MSI-H CRC, patients with MSS 
CRC were less likely to respond to immune checkpoint blockade. 
2.1.2 RAS mutation in mCRC 
The RAS oncogene is mutated in 30-40% of CRC. Mutations in specific codons within exons 2, 3 
or 4 of RAS lead to constitutive activation of mitogen activated protein kinase (MAPK) pathway, 
causing cell growth, division and dysplasia. Patients with activating mutations in RAS have more 
limited treatment options as the use of anti-EGFR monoclonal antibodies (cetuximab and 
panitumumab) is not effective due to the dominant (downstream) activity of RAS in the MAPK 
pathway (Douillard et al. 2010; Douillard et al. 2014).  
Activating RAS mutation leads to MAPK pathway activation which reduces immune cell 
infiltration and inflammatory mediators in the tumor microenvironment (Loi et al., 2016; 
Zelenay et al. 2016; Hugo et al. 2015). A bioinformatics analysis of CRC data in The Cancer 
Genome Atlas (TCGA) involving two-dimensional hierarchical clustering to define an immune 
signature comprising 28 genes showed that RAS mutation predicts for a relatively poor immune 
infiltration (Lal et al. 2016). In addition to effects on the TME and immune cell infiltration, RAS 
mutation may contribute to immune escape mechanisms by downregulating MHC class I 
required for antigen processing in tumor cells, and pharmacologic inhibition of MAPK signaling 
can improve peptide/MHC target recognition and killing by T cells (Brea et al. 2016; Atkins et 
al. 2004; Seliger et al. 1998). Thus, CRC with RAS mutation represents a clinical setting where 
MAPK pathway inhibition may positively modulate the efficacy of checkpoint inhibition. 
2.2 
Investigational Medicinal Products: Nivolumab, Ipilimumab and Binimetinib, 
Nivolumab (also referred to as BMS-936558-01 and BMS-936558) and ipilimumab (also 
referred to as BMS-734016, MDX-010 and MDX-CTLA4) continue to be investigated in the 
oncology setting including mCRC.  
Nivolumab is a human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that 
targets the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface 
membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B 
lymphocytes. Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-

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L2), results in the down-regulation of lymphocyte activation. Inhibition of the interaction 
between PD-1 and its ligands promotes immune responses and antigen-specific T-cell responses 
to both foreign antigens as well as self-antigens. 
OPDIVO™ (nivolumab) is approved for use in multiple countries including the US (Dec 2014), 
the European Union (Jun 2015), and Japan (Jul 2014). 
Ipilimumab is a fully human monoclonal immunoglobulin (Ig) G1κ that binds to the cytotoxic T-
cell lymphoma-4 antigen (CTLA-4) antigen expressed on a subset of T cells from human and 
nonhuman primates. CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a mAb that 
binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade 
of CTLA-4 has been shown to augment T-cell activation and proliferation, including the 
activation and proliferation of tumor-infiltrating T-effector cells. Inhibition of CTLA-4 signaling 
can also reduce Treg function, which may contribute to a general increase in T-cell 
responsiveness, including the anti-tumor response. 
YERVOY™ (ipilimumab) 3 mg/kg has been approved for use in advanced melanoma in over 
47 countries, including the US (25 Mar 2011), the European Union (13 Jul 2011), and Australia 
(Jul 2011). Yervoy 10 mg/kg is approved as adjuvant treatment of unresectable or metastatic 
melanoma in the US.  
Binimetinib (also known as MEK162 or ARRY-438162) is a potent and selective allosteric, 
adenosine-triphosphate (ATP)-uncompetitive inhibitor of MEK1 and MEK2 that is active in 
inhibiting Ras/Raf/Erk pathway signalling and growth of cancer cells (KRAS-mutant, BRAF-
mutant and wild-type) in the low nanomolar range. In oncology settings, binimetinib is currently 
being investigated both as a single agent and in combination with other agents in patients with 
selected advanced or metastatic solid tumors, including biliary cancer, CRC, and melanoma.  
2.2.1 Nonclinical Safety Pharmacology and Toxicology of Binimetinib 
Acute, subchronic, chronic and reproductive toxicity, genotoxicity and phototoxicity studies 
were completed in rats and monkeys to support the chronic administration of binimetinib to adult 
patients. There was no evidence of a genotoxic potential in vitro or in vivo. The adverse effects 
of mitogen/extracellular signal regulated kinase (MEK) inhibitors in humans are similar to those 
observed in rats and monkeys, with the exception of ocular findings (only seen in humans). 
These adverse effects include gastrointestinal intolerance, diarrhea, and rash (skin findings in rats 
only). In vitro and in vivo phototoxicity studies conducted in mice indicate that binimetinib has a 
low risk of weak phototoxic potential at therapeutic doses. Furthermore, there has been no 
evidence of phototoxicity or photosensitivity in humans being treated with binimetinib for cancer 
or for rheumatoid arthritis. 

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Given the embryo-lethal effects seen in rats and rabbits and the teratogenic effects seen in 
rabbits, binimetinib should not be used in pregnant women. Women of childbearing potential 
must be advised to use acceptable or highly effective contraception methods (Section 5.3). 
For details regarding nivolumab clinical pharmacology and safety pharmacokinetics, refer to 
local labeling for OPDIVO™. 
For details regarding ipilimumab clinical pharmacology and safety pharmacokinetics, refer to 
local labeling for YERVOY™. 
For details regarding binimetinib clinical pharmacology and safety pharmacokinetics, please 
refer to the current binimetinib Investigator’s Brochure (IB). 
2.2.2 Pharmacokinetics of Binimetinib 
Nonclinical in vitro and in vivo data indicated that binimetinib is metabolized by multiple routes 
but primarily by glucuronidation pathways (mainly via UDP-glucuronosyl transferase [UGT] 
1A1, 1A3 and 1A9) and to a lesser extent by oxidation pathways (mainly via cytochrome p450 
[CYP] 1A2 and 2C19). In vitro, binimetinib reversibly inhibits CYP2B6, but in vivo inhibition 
of CYP2B6 is anticipated to be insignificant. It is not considered a time-dependent inhibitor of 
CYP1A2, CYP2C9, CYP2D6, and CYP3A. Binimetinib has also induced CYP3A in vitro; 
however, in a drug-drug interaction study in healthy subjects, binimetinib did not alter the 
exposure of midazolam, indicating this induction is not clinically relevant. 
In vitro experiments indicate that binimetinib is a substrate of P-glycoprotein (P-gp) and breast 
cancer resistance protein (BCRP). Inhibition of P-gp or BCRP is unlikely to result in a clinically 
important increase in binimetinib concentrations as binimetinib exhibits moderate to high passive 
permeability. 
Binimetinib is rapidly absorbed after oral administration with a median time (Tmax) to reach the 
maximum concentration (Cmax) around 1.5 hours at steady state. The mean terminal half-life (t1/2) 
in healthy subjects is approximately 10 hours. 
For further details on the pharmacokinetics (PK) and metabolism of binimetinib, please refer to 
the current binimetinib IB. 
2.2.3 Clinical Safety of Binimetinib 
As of 20 January 2017, a total of 2750 healthy subjects and patients have received at least one 
dose of binimetinib either as monotherapy or in combination with other agents. This includes 
229 healthy subjects, 164 patients with rheumatoid arthritis, 17 patients with hepatic dysfunction, 

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6 patients with renal dysfunction, and 2334 patients with advanced cancer. Please refer to the 
binimetinib IB for a detailed discussion of the safety profile of binimetinib. 
2.2.3.1 
Single-agent Binimetinib in Oncology 
Available clinical data indicate a predictable safety profile consistent with that reported for other 
allosteric MEK1/2 inhibitors. The most frequent treatment-emergent AEs by MedDRA preferred 
term (PT) in patients receiving binimetinib include rash, dermatitis acneiform, nausea, vomiting, 
diarrhea, peripheral edema, fatigue, and creatine kinase (CK) elevation. Other clinically relevant 
toxicities are retinal events, increased blood pressure, decreased ejection fraction, and 
noninfectious pneumonitis/interstitial lung disease, all of which should be monitored closely with 
appropriate diagnostic evaluations. These observed AEs are generally reversible and manageable 
by appropriate supportive medical care and/or dose modifications. 
The experience of binimetinib in patients with advanced cancer as a single agent includes 
889 patients who have received at least 1 dose of binimetinib in 7 clinical studies. Safety results 
are summarized in the IB as pooled data for 4 of these studies and individually for 3 trials. 
Pooled data from 4 clinical studies includes 566 patients with advanced solid tumors, primarily 
patients with melanoma, but also patients with biliary, colorectal, lung, pancreatic, and other 
solid tumors, treated at doses of 30 mg BID to 80 mg BID of binimetinib as a single agent. Of 
these patients, 427 patients with melanoma in two studies were treated at the recommended dose 
of 45 mg BID. The median age of patients in the pooled studies of single-agent binimetinib in 
advanced cancer was 61.5 years, 61.8% were male, and 89.0% were Caucasian. AEs were 
reported most frequently (> 20.0% of patients) under the PTs of diarrhea (44.7%), blood CK 
increased (40.3%), edema peripheral (41.2%), rash (36.6%), dermatitis acneiform (36.2%), 
nausea (34.3%), fatigue (30.0%) and vomiting (25.3%). Adverse events were reported most 
frequently (> 5.0% of patients) as Grade 3/4 in severity under the PTs of blood CK increased 
(18.9%) and hypertension (6.5%) and 22.3% of patients experienced AEs that resulted in 
permanent discontinuation of binimetinib treatment. The most common PTs leading to 
discontinuation of binimetinib were ejection fraction decreased (2.7%), blood CK increased 
(1.8%), RVO and dermatitis acneiform (1.2% each), and AST increased (1.1%). 
Adverse Reactions with Binimetinib at the Recommended Dose 
The safety of binimetinib monotherapy at the recommended dose of 45 mg BID was evaluated in 
2 studies of patients with metastatic melanoma (n=427). In this pooled evaluation, for the 
purposes of describing adverse reactions, preferred terms describing a similar pathophysiology 
are grouped under a single Adverse Reaction (e.g., Left Ventricular Dysfunction includes the 

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preferred terms of “left ventricular dysfunction,” “ejection fraction decreased,” and “ejection 
fraction abnormal”).  
A number of selected Adverse Reactions associated with binimetinib were identified from 
pooled data from these 2 studies and are described below.  
Cardiac Disorders 
Left Ventricular Dysfunction (Includes preferred terms of left ventricular dysfunction, ejection 
fraction decreased, and ejection fraction abnormal) 
Left ventricular dysfunction occurred in 10% (44/427) of patients and was Grade 3 in 4.4% 
(19/427) of patients. No Grade 4 events were reported.  
It was the most frequent cause of treatment discontinuation, which was required in 3.3% of 
patients. Median time of onset of left ventricular dysfunction was 1.4 months.  
Vascular Disorders 
Hypertension (Includes preferred terms of hypertension, increased blood pressure, hypertensive 
crisis, orthostatic hypertension) 
New onset or increased hypertension was reported in 16% (68/427) of patients and was reported 
as Grade 3 in 8% (34/427) of patients. No Grade 4 events were reported. Hypertensive events 
requiring additional therapy were reported for 13.1% of patients. Median time of onset of first 
grade ≥ 3 hypertension event was 1 month.  
Venous thromboembolism (Includes preferred terms of pulmonary embolism, deep vein 
thrombosis, mesenteric vein thrombosis, portal vein thrombosis, thrombophlebitis, and others) 
Venous thromboembolism (VTE) occurred in 4.2% (18/427) of patients, including 1.4% (6/427) 
of patients with pulmonary embolism. VTE was reported as Grade 1/2 in 2.5% (11/427) of 
patients and Grade 3/4 in 1.6% (7/427) of patients. Grade 3 pulmonary embolism was reported in 
below 1% (3/427) of patients. 
Hemorrhage (includes preferred terms of epistaxis, retinal hemorrhage, hematuria, hemoptysis, 
gastrointestinal hemorrhages, and others) 
The observed events are predominantly mild to moderate, whereas Grade 3/4 hemorrhagic events 
were reported in comparable frequency with the control arm in a Phase 3 trial (1.5 % vs 1.8%, 

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respectively). In melanoma patients treated at the recommended dose of binimetinib, the most 
frequent hemorrhage events were epistaxis, reported in 2.8%, retinal hemorrhage in 1.6%, and 
hematuria in 1.4% of patients.  
Eye Disorders 
Retinal events including serous retinopathy (also referred to as retinal pigment epithelial 
detachment [RPED] or chorioretinopathy) and retinal vein occlusion are class effects reported 
with MEK inhibitors.  
With the recognition of this class-related toxicity, clinical programs for MEK inhibitors have 
included extensive monitoring (including optical coherence tomography [OCT]) to fully evaluate 
the retinal effects of MEK inhibitors, better defining the overall rate of this toxicity. 
Retinal Pigment Epithelium Detachment (includes preferred terms of retinal pigment 
epithelial detachment, retinal detachment, detachment of retinal pigment epithelium, detachment 
of macular retinal pigment epithelium, subretinal fluid and others) 
RPED was reported in 32% (135/427) of patients. RPED was reported as Grade 1 
(asymptomatic) in 18% (78/427) of patients, Grade 2 in 12% (52/427) of patients, and Grade 3 in 
1.2% (5/427) of patients. No Grade 4 events were reported. For patients who developed RPED, 
the median time to onset was 22 days (range: 1 to 251 days). This is consistent with data reported 
by Urner-Bloch et al. In their reports on patients with MEK inhibitor-related RPED, RPED 
generally appeared during the first 4 weeks of treatment, and in some cases during the first few 
days of treatment. Patients reported mild and only short-lived visual symptoms. Optical 
coherence tomography revealed neuroretinal elevations. Central retinal thickness and volume 
showed dose-dependent increases after the start of treatment, followed by a marked decrease 
despite continued treatment, which was associated with symptom resolution. No vascular 
abnormalities were found with fluorescein and indocyanine green angiography. Retinopathy was 
mild, self-limiting and tolerable as visual function was not seriously impaired (Urner-Bloch et al. 
2014; Urner-Bloch et al. 2016). 
Visual Impairment (includes preferred terms of visual impairment, vision blurred and reduced 
visual acuity) 

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Visual impairment occurred in 13% (56/427) of patients and was generally reversible. 
Retinal Vein Occlusion (RVO)1 
Retinal vein occlusion was reported in 1.6% (9/566) of treated patients across all studies; 0.9% 
(5/566) were reported as Grade 3/4. For patients who developed RVO, the median time to onset 
was 2.9 months. 
Respiratory, Thoracic and Mediastinal Disorders 
Pneumonitis/Interstitial lung disease1 
Across all studies, pneumonitis and interstitial lung disease were respectively reported in 0.9% 
(5/566) and 0.4% (2/566) of treated patients; while 0.2% (1/566) of each were reported as 
Grade 3/4. The median time to first grade ≥ 2 event was 2.5 months. 
Investigations 
Blood Creatine Phosphokinase Increased 
Blood creatine phosphokinase increased was reported as an AE in 43.3% of patients. In the 
majority of cases it was asymptomatic. It was the most frequent cause of dose adjustment or 
interruption, which was required in 18.3% of patients. Median time of onset of the first 
grade ≥ 2 events was 1 month. 
Liver Transaminases Increase 
The incidence of AEs reported as Grade 3 or 4 increases in liver laboratory tests among patients 
receiving binimetinib were: 2.3% (10/427) for alanine aminotransferase (ALT) and 2.1% (9/427) 
for aspartate aminotransferase (AST). 
                                               
 
1 *: The rate of rare events was calculated using the larger pool of 566 patients in order to capture all relevant events. 

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Musculoskeletal and Connective Tissue Disorders  
Rhabdomyolysis2 
Across clinical trials of binimetinib, rhabdomyolysis was reported in 0.4% (2/566) of treated 
patients. In one patient, fatal rhabdomyolysis was characterized by CK elevation, muscle 
symptoms, and evidence of renal dysfunction. 
Skin and Subcutaneous Tissue Disorders 
Rash (Includes preferred terms of rash, rash maculo-papular, rash papular, rash erythematous, 
rash follicular, and others) 
Rash occurred in 44% of patients. Rash was reported as Grade 1 in 22% (95/427) of patients, 
Grade 2 in 18% (75/427) of patients, and Grade 3 in 4% (17/427) of patients. No Grade 4 events 
were reported.  
Acneiform Dermatitis  
Acneiform dermatitis is a characteristic rash associated with MEK inhibition. Acneiform 
dermatitis occurred in 41% (173/427) of patients. Acneiform dermatitis was reported as Grade 1 
in 20% (85/427) of patients, Grade 2 in 18% (77/427) of patients, and Grade 3 in 2.6% (11/427) 
of patients. No Grade 4 events were reported. 
Infections and Infestations 
Skin Infection (Includes preferred terms of skin infection, rash pustular, folliculitis, erysipelas, 
paronychia and others) 
Skin infection, often secondary to other dermatologic reactions, occurred in 23% (98/427) of 
patients. Skin infection was reported as Grade 1 in 9.6% (41/427) of patients, Grade 2 in 8.9% 
(38/427) of patients, and Grade 3 in 4.4 % (19/427) of patients. No Grade 4 events were 
reported. 
                                               
 
2 The rate of rare events was calculated using the larger pool of 566 patients in order to capture all relevant events. 

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Gastrointestinal Disorders 
Diarrhea, Nausea, and Vomiting (Includes preferred terms of vomiting, retching) 
Diarrhea, nausea, and vomiting occurred in 43%, 30%, and 20% of patients, respectively. 
Gastrointestinal events required dose adjustment or study drug interruption in 11% of patients 
and led to discontinuation of binimetinib in 1.2% of patients. Prophylaxis was not used in 
clinical trials.  
Study ARRAY-162-311 
Study ARRAY-162-311 (MILO) is an ongoing multinational, randomized, open-label Phase 3 
study to evaluate single-agent binimetinib vs. physician’s choice of selected chemotherapies in 
patients with low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. 
The study enrollment was discontinued after the planned interim analysis showed that the hazard 
ratio for PFS crossed the predefined futility boundary. As of the cutoff date of 20 January 2016 
for the primary analysis, a total of 303 patients (201 binimetinib and 102 physician’s choice) 
were randomized to treatment. The Safety Set included all patients who were enrolled in the 
study and received any dose of study drug (binimetinib or physician’s choice therapy), and was 
comprised of 200 patients in the binimetinib arm and 94 patients in the physician’s choice arm. 
The most frequently reported AEs (≥ 20% of all patients) in the binimetinib arm, regardless of 
relationship to study drug, by PT, included diarrhea (70%), nausea (55%), vomiting (54%), blood 
CK increased (50%), fatigue (48%), peripheral edema (46%), acneiform dermatitis (46%), 
abdominal pain (32%), ejection fraction decreased (28%), dry skin (28%), constipation (26%), 
alopecia (25%), stomatitis (23%), decreased appetite (22%), rash maculo-papular (22%), pruritus 
(20%), and vision blurred (20%). The rate of Grade 3 or higher AEs in the binimetinib arm was 
76%, with blood CK increased accounting for a large percentage of these AEs. AEs with Grade 3 
or higher severity reported for ≥ 10% of patients included blood CK increased (26%), 
hypertension (10%), and vomiting (10%). 
Adverse events that led to permanent discontinuation of study drug occurred in 31% of patients 
in the binimetinib arm. Adverse events leading to binimetinib discontinuation in at least 5 
patients were ejection fraction decreased (4%), vomiting (3%), intestinal obstruction and RVO 
(2% each).  
Gastrointestinal obstruction events (intestinal obstruction, large intestinal obstruction, small 
intestinal obstruction, colonic obstruction, and gastrointestinal obstruction) were reported at a 
higher incidence in the binimetinib group (26 patients [13%]) versus the physician’s choice 
group (7 patients [7%]); most of these events resolved with conservative supportive care. This 

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observed difference with binimetinib treatment was not seen in melanoma and may be related to 
underlying risk factors present in ovarian cancers with extensive intraperitoneal involvement 
such as peritoneal carcinomatosis, prior abdomino-pelvic surgery, or a history of abdominal 
adhesions. The majority of gastrointestinal obstruction events did not result in gastrointestinal 
perforation, and although events of obstruction and perforation have been seen in other trials of 
binimetinib, association with binimetinib treatment seems to be confined to this particular 
clinical setting. In the CRC expansion of a Phase 1 study, bowel obstruction (small bowel 
obstruction) was seen in 2 out of 46 (4.3%) patients.  
Safety Conclusions 
The overall safety profile of binimetinib is consistent with the known safety profile of other 
drugs in this class. In general, AEs can be managed with interruption, dose modification and 
occasionally require discontinuation of binimetinib in conjunction with established medical 
interventions.  
2.3 
Rationale for the Study 
2.3.1 Study Design 
Recent preclinical studies have shown that the use of a MEK1/2 inhibitor can increase the 
number of CD8+ T cells within tumors, in addition to increasing MHC class I expression (Ebert 
et al. 2016; Mimura et al. 2014). By combining MEK inhibition with anti-PD-L1 antibodies, 
there is documented evidence of remarkable tumor regression even where either agent alone was 
only modestly effective. Further studies have been conducted in a clinical setting with the 
combination of cobimetinib (MEK1/2 inhibitor) and atezolizumab (anti-PD-L1 antibody) in 
metastatic treatment refractory tumors (preliminary results were presented at the 2016 American 
Society of Clinical Oncology [ASCO] meeting; Bendell et al. 2016). A response rate of 17% was 
identified in largely KRAS-mutant MSS CRCs. Many of these responses were shown to be 
durable indicating great promise for the combination of MEK1/2 inhibition with immune 
targeted agents, even in the MSS setting. 
Nivolumab is a fully human monoclonal IgG4 antibody that binds to the PD-1 cell surface 
membrane receptor, a negative regulatory molecule expressed by activated T and B lymphocytes. 
Blockade of the PD-1 pathway by nivolumab was studied using the mixed lymphocyte reaction 
(MLR). PD-1 blockade resulted in a reproducible enhancement of both proliferation and 
interferon release in the MLR. The effect of nivolumab on antigen-specific recall response was 
investigated using a cytomegalovirus-restimulation assay with human peripheral blood 
mononuclear cells (PBMCs), and was evaluated by enzyme-linked immunosorbent assay 
(ELISA). Nivolumab 3 mg/kg monotherapy is currently approved for the treatment of advanced 

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melanoma and lung cancer, metastatic renal carcinoma, and Hodgkin lymphoma, and is being 
studied in several Phase 3 and 2 clinical trials in advanced and metastatic solid and hematologic 
malignancies. 
Ipilimumab is a fully humanized IgG1 mAb binding to CTLA-4. Ipilimumab is an approved 
therapy for metastatic melanoma and has demonstrated improved OS as monotherapy and in 
combination with dacarbazine (Hodi et al. 2010; Robert et al. 2011). It has been studied in 
combination with multiple standards of care therapies including chemotherapy for squamous and 
non-squamous non-small cell lung cancer (NSCLC) and radiotherapy for hormone-resistant 
prostate cancer (ipilimumab IB v.11). Ipilimumab is currently also approved as adjuvant therapy 
in Stage 3 melanoma. 
Nonclinical studies have shown that MEK inhibition increases tumor responsiveness to 
immunotherapy through multiple mechanisms including: increasing the number of active 
immune cells (e.g., CD8+ cells) in the tumor by inhibition of activation induced cell death, 
reducing the expression of immune suppressive factors in the tumor microenvironment factors 
and increasing the expression of human leukocyte antigen (HLA)-class I molecules (Ebert et al 
2016; Liu et al, 2015). 
For example, in the syngeneic CT26 colorectal allograft tumor model, combining binimetinib 
with an anti-PD1 antibody resulted in enhanced tumor growth inhibition relative to treatment 
with either drug as a single agent (Figure 1). 

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Figure 1: 
Binimetinib Enhances αPD-1 Anti-Tumor Activity in Immunocompetent CRC 
Model 
 
 
In light of the nonclinical data and the increased clinical efficacy observed with combination 
approaches in other tumor types, adding binimetinib may potentially offer patients the benefit of 
treatment for mCRC, and may have specific benefit in the population with RAS-mutant tumors.  
2.3.1.1 
Rationale for the Doublet Combination (Nivolumab and a MEK Inhibitor) 
Combined PD-1 Blockade and MEK Inhibition 
To build on the hypothesis that a combined immunotherapy approach will be necessary to 
significantly impact MSS mCRC, a MEK inhibitor will be combined with nivolumab in Arm 1A 
and combined with nivolumab and ipilimumab in Arm 1B.  
While MSI-H tumors have significant levels of immune cell infiltration (Ohrling et al. 2010), 
lesions from MSS mCRC patients generally have fewer infiltrative CD8+ T-cell populations 
(Chirica et al. 2015). Immuno-oncologic approaches with checkpoint inhibition alone might not 
be sufficient in patients who have limited tumor immune cell infiltration. In the fraction of 
patients whose tumors are resistant to anti-PD-L1 mAb therapy, CD8+ T cells localize at the 
edge of the tumors, whereas they accumulate in the tumor mass in patients who respond to PD-
L1 blockade, suggesting that, in addition to PD-L1 inhibition, strategies aimed at promoting T 
cell accumulation in the tumor mass are essential for the induction of therapeutic immunity 
(Salmon et al. 2016). 

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The mitogen activated protein (MAP) kinase (MAPK) pathway is one of the most frequently 
disregulated pathways in cancer. The signaling molecule MEK is a key intermediate in the 
MAPK pathway. Two MEK isoforms (MEK1 and MEK2) are known, both of which 
phosphorylate ERK1 and/or ERK2 downstream of RAS and BRAF. MEK has been well 
characterized as a critical mediator of the constitutively active mutant form of KRAS, 
KRASG12D, in many cancers (Ebert et al. 2016). The MEK pathway is presumed to be 
upregulated in a large fraction of colorectal tumors due to mutation of several components of the 
pathway, most notably KRAS, NRAS, HRAS, and BRAF. In addition to RAS and RAF mutations, 
many tumors are activated by amplification or overexpression of upstream pathway components 
(Hoeflich et al. 2012). Importantly, there is likely a role of the activated MAPK pathway in 
immune evasion by tumors (see Section 2.1.2). 
Early experience with MEK-inhibition in mCRC demonstrated no single-agent activity for this 
class of agents (Rinehart et al. 2004). However, MEK inhibitors have been combined 
preclinically with anti-PD-1 and anti-CTLA-4 agents to provide additional efficacy in mouse 
models (Liu et al. 2015). Using melanoma cell lines, the MEK inhibitor trametinib increased 
expression of HLA-I and/or II expression in 5 of 6 lines tested, and a similar effect was found in 
an in vivo mouse model which demonstrated that the combination of trametinib with anti–PD-1 
increased tumor-infiltrating CD8+ T cells in CT26 tumors and potentiated antitumor activity 
with PD-1 blockade (Sorich et al. 2014; Brahmer et al. 2010). MEK inhibition alone in 
immunocompetent mice harboring a colon carcinoma cell line with mutant KRASG12D who 
were treated with the MEK inhibitor G-38963 (which is similar to cobimetinib) can result in 
intratumoral CD8+T cells accumulation and class I MHC upregulation (Ebert et al. 2016). These 
increased up to 4-fold among several mouse and human tumor cell lines as determined by flow 
cytometry. In further experiments in preclinical models, MEK inhibition synergized with anti-
PD-1 to promote durable tumor regression while promoting the effector phenotype and longevity 
of tumor-infiltrating CD8+ T cells (Ebert et al. 2016; Ohrling et al. 2010).  
2.3.1.2 
Rationale for the Triple Combination in Arms 1B and 2B: Binimetinib with 
Nivolumab and Ipilimumab 
Promising preclinical data combining MEK inhibition with PD-1 and/or CTLA-4 blockade have 
been published by Liu et al., (2015) and Ebert et al., (2016). Particularly in Ebert et al., it was 
found that a syngeneic mouse model of colon cancer treated with a MEK inhibitor and either an 
anti-CTLA-4 or anti-PD-1 antibody showed substantial tumor regression after 3 weeks of 
exposure, and also demonstrated that CTLA-4 blockade is as effective as PD-1 blockade in this 
model.   

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In clinical studies, the additive activity of ipilimumab over nivolumab single-agent has been 
shown in both MSI-H and MSS treatment-refractory mCRC patients. Among 77 patients with 
MSI-H mCRC (Overman et al. 2016), the response rate for PD-1 blockade alone was 26%, yet 
was 33% when PD-1 and CTLA-4 blockade were combined. Moreover, among those with MSS 
disease, the response rate for PD-1 blockade alone was 0%, but was 5% when PD-1 and CTLA-4 
blockade were combined. 
In addition to colorectal studies, cumulative data from other cancer types suggest nivolumab in 
combination with ipilimumab is more efficacious than single agent immunotherapy treatment. 
Although the minimum follow-up period of 28 months has not been reached, landmark results 
from the Checkmate-067 Phase 3 trial among advanced treatment-naïve melanoma patients 
treated with the combination of nivolumab and ipilimumab shows 2-year OS of 64% versus 59% 
or 45% for patients assigned to either nivolumab or ipilimumab monotherapy, respectively 
(Larkin et al. 2017). This finding highlights the distinct advantage of combination immune 
blockade treatment. Preclinical data from Figure 1 as well as studies outlined above which show 
clear effects on immune cell infiltration and major histocompatibility complex (MHC) 
upregulation following MEK inhibition, present a compelling argument for exploring the 
treatment of MEK inhibition of binimetinib in combination with anti-PD-1 (nivolumab) and 
CTLA-4 (ipilimumab) checkpoint blockade.  
2.3.2 Rationale for Dose Selection 
2.3.2.1 
Rationale for Nivolumab Doses 
Nivolumab monotherapy has been extensively studied in multiple tumor types, including 
melanoma, NSCLC, renal cell carcinoma (RCC), classical Hodgkin’s lymphoma (cHL), head 
and neck (H&N) and urothelial carcinoma (UC), using body weight normalized dosing (mg/kg), 
and has been safely administered at doses up to 10 mg/kg every 2 weeks (Q2W). Nivolumab is 
currently approved for the treatment of various tumors, including melanoma, NSCLC, RCC, 
cHL, squamous cell carcinoma of the head and neck (SCCHN), and UC, using a regimen of 
either nivolumab 240 mg Q2W or nivolumab 3 mg/kg Q2W. 
The nivolumab dose of 480 mg Q4W was selected for this study based on clinical data and 
modeling and simulation approaches using population PK (PPK) and exposure-response (ER) 
analyses examining relationships between nivolumab exposures and efficacy (e.g. OS, ORR) and 
safety responses, using data from studies in multiple tumor types (melanoma, NSCLC, and RCC) 
with body weight-normalized dosing (mg/kg). The PPK analyses have shown that exposure to 
nivolumab increased dose proportionally over the dose range of 0.1 to 10 mg/kg administered 
Q2W, and no clinically meaningful differences in PK across ethnicities and tumor types were 

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observed. Nivolumab clearance and volume of distribution were found to increase as body 
weight 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 and ER models, nivolumab exposures and probabilities of efficacy responses and 
risks of AEs were predicted following nivolumab 480 mg Q4W and compared to those following 
nivolumab 3 mg/kg Q2W. The overall distributions of average nivolumab steady-state exposures 
(Cavgss) are comparable following administration with either nivolumab 480 mg Q4W or 
nivolumab 3 mg/kg Q2W. Nivolumab 480 mg Q4W is predicted to result in approximately 43% 
greater steady-state peak concentrations (Cmaxss) compared to nivolumab 3 mg/kg Q2W. 
Although the Cmaxss of nivolumab is expected to be greater following nivolumab 480 mg Q4W 
compared to nivolumab 3 mg/kg Q2W, the predicted Cmaxss following nivolumab 480 mg Q4W 
is well below the median Cmaxss achieved following administration of nivolumab 10 mg/kg Q2W, 
a safe and tolerable dose level.  
Exposure-safety analysis demonstrated that the exposure margins for safety are maintained 
following nivolumab 480 mg Q4W, and the predicted risks of AEs leading to discontinuation or 
death, AEs ≥ Grade 3, and immune-related AEs ≥ Grade 2, are predicted to be similar following 
nivolumab 480 mg Q4W relative to nivolumab 3 mg/kg Q2W across tumor types. Safety 
analyses using available data following nivolumab 3 mg/kg Q2W and 10 mg/kg Q2W 
administration indicated there were no differences in AE profiles across body weight groups. 
Finally, initial evidence indicates that the nivolumab 480 mg Q4W schedule is well tolerated. 
Nivolumab 480 mg Q4W is predicted to have approximately 16% lower steady-state trough 
concentrations (Cminss) compared to nivolumab 3 mg/kg Q2W. While these exposures are 
predicted to be lower, they are on the flat part of the exposure-response curves and are not 
predicted to affect efficacy (Wang et al 2017). Exposure-efficacy analyses of multiple PK 
measures and efficacy endpoints (e.g. OS, ORR) indicated that following administration of 
nivolumab 480 mg Q4W efficacy is predicted to be similar to that following administration of 
nivolumab 3 mg/kg Q2W across multiple tumor types. Based on these data, nivolumab 480 mg 
Q4W is expected to have similar efficacy and safety profiles to nivolumab 240 mg Q2W or 
nivolumab 3 mg/kg Q2W.  
2.3.2.2 
Rationale for Binimetinib Doses up to 45 mg BID 
In a Phase 1 dose escalation study, 60 mg twice daily (BID) was initially declared the maximum 
tolerated dose (MTD) for binimetinib. Following completion of the dose-escalation phase, 74 
patients were enrolled in an expansion phase, including 31 patients in a KRAS-mutant CRC 

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cohort, 15 patients in a BRAF-mutant CRC cohort and 28 patients in a biliary cancer cohort. 
After initiation of the expansion phase, AEs resulting in reduction of binimetinib dose were 
reported at a 3-fold higher incidence in patients in the 60 mg BID dose group compared with the 
45 mg BID dose group; thus, 45 mg BID was determined to be the recommended Phase 2 dose 
(RP2D). 
Nonclinical data with MEK inhibitors support a continuous dosing schedule to consistently 
inhibit MEK activation. The in vivo EC50 for MEK inhibition based on inhibition of 
phospho-ERK, a downstream marker of MEK activity, is ~60 ng/mL. Prediction of mean plasma 
concentrations vs time using a cross-study human PPK model for binimetinib indicate that the 
45 mg BID dosing regimen should result in ≥ 50% inhibition of MEK activity (IC50)at steady 
state for the majority of human patients. This amount of target engagement is consistent with 
nonclinical models of efficacy and expectations for clinical activity. 
Doses less than 45 mg BID are expected to result in fewer patients maintaining plasma 
concentrations above the MEK IC50, potentially resulting in less efficacy. This expectation is 
consistent with observed exposure response  analysis results. 
Analyses exploring the relationship between exposure and efficacy in a Phase 3 Study in 
unresectable metastatic melanoma in which binimetinib was administered at 45 mg BID, showed 
that efficacy was observed across the range of observed exposures with a trend towards greater 
efficacy both in terms of PFS and ORR with higher exposures. This supports the conclusion that 
binimetinib 45 mg BID maximizes the potential for benefit while providing a tolerated starting 
dose.  
2.3.2.3 
Rationale for Ipilimumab Dosing Schedule 
In a Phase 1b trial evaluating the safety and tolerability of nivolumab in patients with 
chemotherapy-naïve advanced NSCLC (Study NCT01454102; Hellman et al. 2016), ipilimumab 
1 mg/kg using Q6W and Q12W schedules were assessed and were found to be safe in 
combination with nivolumab 3 mg/kg Q2W. Both the Q6W and Q12W arms were associated 
with improved and manageable tolerability compared to the arms with more frequent ipilimumab 
dosing (Q3W). Both arms also had encouraging efficacy in all participants and enhanced benefit 
in participants with PD-L1 expression, with Q6W arm having numerically higher median PFS 
compared to the Q12W arm. There were some imbalances observed between the Q6W and 
Q12W arms, as follows: 
 
There were more never smokers in the Q6W arm than in the Q12W arm. Current and former 
smokers have been shown to respond better to immunotherapy. 

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 
Participants on the Q6W schedule progressed, died or came off treatment more frequently in 
the first 3 months; however, this did not appear to be related to the schedule. 
o Overall treatment-related AEs leading to discontinuation as rates were 11% and 13% 
in the Q12W and Q6W arm, respectively. While there were more AEs leading to 
discontinuation in the first 3 months in the Q6W arm (n=3) vs the Q12W arm (n=1), 2 
of the 3 participants who discontinued < 3 months on Q6W discontinued before 
receiving the 2nd dose of ipilimumab; therefore, these discontinuations are unlikely to 
be due to the more frequent dosing on the Q6W arm.  
o There were early clinical progressors and (unrelated) deaths in the Q6W arm 
compared to the Q12W arm (8% and 15%), which were more likely due to 
imbalances in baseline characteristics, rather than differences in treatment schedule. 
With both schedules showing a similar safety and efficacy profile, the Q8W schedule was chosen 
for this trial for scheduling purposes as Q8W works well with nivolumab and binimetinib dosing 
schedules. 
2.3.2.4 
Rationale for the Doses of Nivolumab and Ipilimumab in Combination 
Study NCT01454102: Non-Small Cell Lung Cancer 
In a multi-arm Phase 1b trial evaluating the safety and tolerability of nivolumab in patients with 
chemotherapy-naïve advanced NSCLC, nivolumab was adminstered as either a monotherapy or 
in combination with other agents, including ipilimumab, at different doses and schedules 
(Hellman et al. 2016). The primary endpoint of the study was safety with secondary endpoints of 
ORR and 24-week PFS. Exploratory endpoints included OS and efficacy by PD-L1 expression. 
In the study, patients were tested for PD-L1 expression and 68% of participants in the Q12W 
cohort and 77% of patients in the Q6W cohort expressed PD-L1. Participants were randomized 
to nivolumab 3 mg/kg (N3) Q2W + ipilimumab 1 mg/kg (I1) Q12W (n=38), nivolumab 3 mg/kg 
Q2W + ipilimumab 1 mg/kg Q6W (n=39) and nivolumab 3 mg/kg Q2W (n=52). The confirmed 
ORR was 47% (N3 Q2W + I1 Q12W), 39% (N3 Q2W + I1 Q6W) and 23% (N3 Q2W). The 
median duration of response (DOR) was not reached (Hellman et al. 2016).  
The rate of treatment-related AEs in the Q12W (82%) and Q6W (72%) arms were comparable to 
monotherapy (72%). In the study, Grade 3/4 AEs were 37%, 33%, and 19% for the Q12W, Q6W 
and nivolumab monotherapy arms, respectively. Treatment-related Grade 3-4 AEs lead to 
discontinuation in 5% and 8% of patients in the Q12W and Q6W cohorts, respectively and were 
similar to nivolumab monotherapy. There were no treatment-related deaths. The treatment-
related select AEs in patients administered the optimized dosing scheduled (3 mg/kg of 
nivolumab Q2W plus 1 mg/kg of ipilimumab Q6W) were skin related (36%), gastrointestinal 

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(23%), endocrine (20%), and pulmonary (5%), and there were ≤ 5% treatment-related Grade 3/4 
AEs per category. 
Study NCT01472081: Metastatic Renal Cell Cancer 
The combination of nivolumab with ipilimumab at different doses and schedules was evaluated 
in another Phase 1, dose-finding trial (Study NCT01472081). Patients with mRCC 
(favorable/intermediate Memorial Sloan Kettering Cancer Center score; Karnofsky performance 
status ≥ 80%; untreated or any number of prior therapies) were randomized to receive nivolumab 
3 mg/kg + ipilimumab 1 mg/kg (arm N3 + I1) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg (arm 
N1 + I3) Q3W for 4 doses then nivolumab 3 mg/kg Q2W until progression/toxicity. The primary 
objective was to assess safety/tolerability; secondary objective was to assess antitumor activity. 
Patients were randomized to N3 + I1 (n = 21) and N1 + I3 (n = 23). Most patients (n = 34; 77%) 
had prior systemic therapy (N3 + I1: 16; N1 + I3: 18). The confirmed ORR was 43% (N3 + I1) 
and 48% (N1 + I3). Duration of response (DOR) was 4.1+ to 42.1+ weeks (7 of 9 responses 
ongoing) in N3 + I1, and 12.1+ to 35.1+ weeks (9 of 11 responses ongoing) in N1 + I3. Best 
response of stable disease (SD) was seen in 5 (24%) patients (N3 + I1) and 8 (35%) patients (N1 
+ I3). Median PFS was 36.6 weeks (N3 + I1) and 38.3 weeks (N1 + I3); these data are still 
immature, with 11 of 21 events reported for N3 + I1 and 10 of 23 events reported for N1 + I3. 
Treatment-related AEs were seen in 83/94 patients (88%), including 39/47 (83%) in N3 + I1 and 
44/47 (94%) in N1 + I3. The most frequently reported drug-related AEs in patients treated with 
3 mg/kg nivolumab + 1 mg/kg ipilimumab included fatigue (23 patients, 48.9%), rash and 
pruritus (12 subjects, 25.5% each), and diarrhea and nausea (11 patients, 23.4% each); the 
majority were Grade 1-2. The most frequently reported drug-related AEs in patients treated with 
1 mg/kg nivolumab + 3 mg/kg ipilimumab included fatigue (30 patients, 63.8%); nausea and 
diarrhea (20 patients, 42.6% each), and lipase increased (16 patients, 34.0%). The majority were 
Grade 1-2 (Nivolumab IB version 15, June 2016). 
Treatment-related AEs leading to discontinuation (21% vs 11%), and treatment-related SAEs 
(34% vs 21%) all occurred more commonly in subjects in the N1 + I3 arm than in the N3 + I1 
arm, respectively (Nivolumab IB version 15, June 2016). 
Study NCT01024231: Unrectable or Metastatic Melanoma 
In a Phase 1 study in patients with unresectable or metastatic melanoma, ascending doses of 
nivolumab have been studied concomitantly with ascending doses of ipilimumab (Study 
NCT01024231). In each arm of this multi-arm study, ipilimumab was administered Q3W for 
4 doses with nivolumab administered Q3W for 8 doses. Starting at Week 24, ipilimumab and 

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nivolumab were administered Q12W for 8 doses. The 3 initial dose-escalation cohorts consisted 
of Cohort 1 (nivolumab 0.3 mg/kg plus ipilimumab 3 mg/kg; n=14), Cohort 2 (nivolumab 
1.0 mg/kg plus ipilimumab 3 mg/kg; n=17) and Cohort 3 (nivolumab 3.0 mg/kg plus ipilimumab 
3 mg/kg; n=6). Later, the study was amended to include Cohort 2a which evaluated nivolumab 
3 mg/kg plus ipilimumab 1 mg/kg (n=16). 
As of the 15 February 2013 data cut-off, of the 52 patients evaluable for response, 21 patients 
(40%) had an objective response by modified World Health Organization (mWHO) criteria. In 
Cohort 1 (0.1 mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of 14 evaluable patients had an 
objective response by mWHO (21%); 1 complete response (CR) and 2 partial responses (PRs) 
with an additional PR by immune-related mWHO criteria (irPR) (Wolchok et al. 2009). In 
Cohort 2 (1 mg/kg nivolumab + 3 mg/kg ipilimumab), 9 out of 17 evaluable patients had an 
objective response by mWHO (53%; 3 CRs, 18%), 6 PRs (35%) with 2 additional patients 
experiencing immune-related SD (irSD). In Cohort 2a (3 mg/kg nivolumab + 1 mg/kg 
ipilimumab), 6 out of 15 response evaluable patients had an objective response rate by mWHO 
(40%; 1 CR, 7%), 5 PRs, 33%) and 2 irSDs and 1 irPR. In Cohort 3 (3 mg/kg nivolumab + 3 
mg/kg ipilimumab), 3 out of 6 evaluable patients had an objective response by mWHO (50%; 3 
PRs with 1 additional irPR and 1 irSD. 
Preliminary analysis revealed 16 of the 52 evaluable patients (31%) had > 80% reduction in the 
size of target tumor lesions by the Week 12 evaluation. This is compared to < 2% for 3 mg/kg 
ipilimumab monotherapy based on a Phase 3 study in patients with previously treated, 
unresectable or metastatic melanoma (N=540; Study NCT00094653), and < 3% for nivolumab 
monotherapy based on a Phase 1 study in patients with various advanced or recurrent metastatic 
cancers (N=94, 0.1-10 mg/kg; Study NCT00730639). 
The following dose-limiting toxicities (DLTs) were observed: Cohort 1 - Grade 3 elevated 
AST/ALT (1 patient); Cohort 2 - Grade 3 uveitis (1 patient) and Grade 3 elevated AST/ALT 
(1 patient); Cohort 3 - Grade 4 elevated lipase (2 patients) and Grade 3 elevated lipase 
(1 patient). Based on these data, Cohort 2 was identified as the MTD and Cohort 3 exceeded the 
MTD. 
A total of 53 melanoma patients were treated with nivolumab combined with ipilimumab across 
Cohorts 1, 2, 2a, and 3. At least one AE regardless of causality has been reported in 98% of 
patients treated. The most common (reported at > 10% incidence) treatment-related AEs (any 
Grade %; Grade 3-4 %: 93; 53) are rash (55; 4), pruritus (47; 0), vitiligo (11; 0), fatigue (38; 0), 
pyrexia (21, 0), diarrhea (34; 6), nausea (21, 0), vomiting (11, 2), ALT increased (21; 11), AST 

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increased (21; 13), lipase increased (19; 13), amylase increased (15, 6), headache (11, 0), and 
cough (13, 0). 
The majority of AEs leading to discontinuation (regardless of causality) were Grade 3 or 4 
(reported in 11 of 53 patients, 21%). Grade 3 events included lipase increased, ALT increased, 
AST increased, troponin I increased, colitis, diverticular perforation, pancreatitis, tachycardia, 
renal failure acute, choroiditis, autoimmune disorder, and pneumonitis. One patient each 
discontinued due to Grade 4 events of blood creatinine increased and AST increased. No drug-
related deaths were reported (Wolchok et al. 2013). 
2.3.2.5 
Rationale for Infusion Times for Nivolumab and Ipilimumab 
Long infusion times place a burden on patients and treatment centers. Establishing that 
nivolumab and ipilimumab can be safely administered using shorter infusion times will diminish 
the burden, provided that there is no change in the safety profile. Previous clinical studies of 
nivolumab and ipilimumab monotherapies and the combination of nivolumab and ipilimumab 
have used a 60-minute infusion duration for nivolumab and a 90-minute infusion duration for 
ipilimumab (1 - 3 mg/kg dosing for both). However, both nivolumab and ipilimumab have been 
administered at up to 10 mg/kg with the same infusion duration (i.e. 60 minutes). 
Establishing that nivolumab can be safely administered using a shorter infusion time 
(30 minutes) is under investigation. Previous clinical studies of nivolumab monotherapy have 
used a 60-minute infusion duration wherein nivolumab has been safely administered up to 
10 mg/kg over long treatment periods. Infusion reactions including high-grade hypersensitivity 
reactions have been uncommon across nivolumab clinical program. In a Phase 2 dose-ranging 
study of nivolumab in patients with advanced or metastatic clear-cell RCC, a dose association 
was observed for infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% 
at 2 mg/kg and 18.5% at 10 mg/kg) (Martín-Algarra et al. 2016). All the events were Grade 1 - 2 
and were manageable. An infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the 
dose provided at 10 mg/kg) is not expected to present any safety concerns compared to the prior 
experience at 10 mg/kg nivolumab dose infused over a 60-minute duration. The safety of 
nivolumab 3 mg/kg administered as a 30-minute infusion was assessed in a Phase 3 study in 
patients (n=322) with previously treated, advanced NSCLC (Study NCT02066636). Overall, 
there were no clinically meaningful differences in the frequency of 
hypersensitivity/infusion-related reactions (of any cause or treatment-related) in patients 
administered nivolumab over a 30-minute infusion compared with that reported for patients with 
the 60-minute infusion. Also, as discussed in Section 2.3.2.1, the Cmaxss for nivolumab 480 mg 
Q4W, even when infused over 30 minutes instead of 60 minutes, is expected to be well below 

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the median Cmaxss achieved following administration of nivolumab 10 mg/kg Q2W, a safe and 
tolerable dose level. Thus, it is expected that nivolumab can be safely infused over 30 minutes.  
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In a Phase 2 
study in patients with advanced Stage 2 or Stage 4 melanoma where ipilimumab was 
administered up to a dose of 10 mg/kg, on-study drug related hypersensitivity events (Grade 1/2) 
were reported in 1 patient (1.4%) in the 0.3 mg/kg and in 2 patients (2.8%) in the 10 mg/kg 
group (Study NCT00289640). There were no drug-related hypersensitivity events reported in the 
3 mg/kg group. Across the 3 treatment groups, no Grade 3/4 drug-related hypersensitivity events 
were reported and there were no reports of infusion reactions. Ipilimumab 10 mg/kg 
monotherapy has also been safely administered as a 90-minute infusion in a large Phase 3 study 
in patients with prostate cancer (Study NCT00861614) and as adjuvant therapy for patients with 
Stage 3 melanoma (Study NCT00636168). A retrospective analysis of 138 patients treated with 
10 mg/kg of ipilimumab monotherapy as a 90-minute infusion determined that few (6/138; 4.3%) 
patients experienced infusion reactions (Momtaz et al. 2015). As part of this study, 120 patients 
were treated prospectively with 3 mg/kg ipilimumab infused over 30 minutes, i.e., approximately 
one-third of the 10 mg/kg dose, and 7 patients (5.8%) had an infusion-related reaction; it was 
concluded that 3 mg/kg ipilimumab can be infused safely over 30 minutes with an acceptably 
low incidence of infusion-related reactions. 
Overall, infusion reactions, including high-grade hypersensitivity reactions, have been 
uncommon across clinical studies of nivolumab, ipilimumab, and nivolumab/ipilimumab in 
combination. Furthermore, a 30-minute break after the first infusion for the combination cohort 
will ensure the appropriate safety monitoring before the start of the second infusion. Overall, a 
change in safety profile is not anticipated with 30-minute infusions of either nivolumab or 
ipilimumab. 
2.3.2.6 
Rationale for Duration of Therapy 
The optimal duration of immunotherapy is currently unknown. However, because 
immunotherapy engages the immune system to control the tumor, continuous treatment as is 
required with targeted agents or cytotoxic therapy may not be necessary.  
Accumulating evidence from different clinical trials in different tumor types with nivolumab or 
nivolumab combined to ipilimumab indicates that most of the responses are generally occurring 
early, with a median time to response of 2-4 months (Brahmer et al. 2015; Borghaei et al. 2015). 
A recent analysis in a melanoma study suggests the majority of patients who discontinue 
nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of further 
treatment (Schadendorf et al. 2016).  

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For these reasons, in this current study, treatment with nivolumab or nivolumab with ipilimumab 
will be given for up to 24 months in the absence of disease progression or unacceptable toxicity. 
Patients who complete 24 months of treatment and have subsequent disease progression may 
reinitiate nivolumab or nivolumab with ipilimumab at the same dose and schedule given 
previously on study and continue such treatment for up to 1 additional year.  
2.3.3 Risks for Overall Safety of Combination Therapy 
The safety profile of each agent proposed for the triplet combination is well defined. Nivolumab 
and ipilimumab are already commercially available for the treatment of several advanced and 
metastatic tumor types. The safety and efficacy of binimetinib has been evaluated as a single 
agent and in combination. As of 20 January 2016, a total of 2555 healthy subjects and patients 
have received at least 1 dose of binimetinib and are therefore eligible for inclusion in the overall 
safety population of binimetinib, which comprises 220 healthy subjects, 164 patients with 
rheumatoid arthritis, 12 patients with hepatic dysfunction and 2159 patients with advanced 
cancer. 
With regards to the effect of MEK inhibition on T-cell mediated responses, nonclinical studies 
have shown that inhibition of MEK in the setting of cancer leads to enhancement of the immune 
response. This immune-mediated activity of MEK inhibitors is due to a positive effect on tumor 
antigen-specific T-cells maintaining their activation state (preventing exhaustion-induced T-cell 
death) leading to synergy with checkpoint inhibitors (Ebert et al 2016). Thus, MEK inhibition 
enhances the activity of tumor antigen-primed t-cells (post-naïve t-cells) without adversely 
effecting naïve T-cell priming. Based on the latter biological effects, the potential for augmented 
toxicity related to immune activation is unlikely.  
For the combination of nivolumab with ipilimumab, related AEs of Grade 3-4 severity have been 
limited to toxicities in gastrointestinal, skin, liver, and endocrine system expected based on the 
mechanism of action of both compounds. It has been observed in a several previous trials that the 
toxicity of the nivolumab + ipilimumab combination correlated with the ipilimumab dose 
(Wolchok et al. 2013; Postow et al. 2015; Reardon et al. 2016; Wolchok et al. 2016). With 
increasing doses of ipilimumab there has been an increase in frequency of AEs, and potentially 
the severity of these events; however, no novel toxicities have been demonstrated versus either 
agent alone. In the proposed regimen for this clinical study, the dose of ipilimumab will be 
cumulatively lower than on prior cohorts studied in the proposed indication as well as the 
approved dose level for the combination for the treatment of advanced and metastatic melanoma. 
The toxicity profile with lower doses of ipilimumab has been established to be very similar to 
that of nivolumab monotherapy (Hellmann et al. 2016). 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
6 2  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
T he safet y of t he c o m bi n ati o n of ni v ol u ma b, wit h bi ni meti ni b a n d i pili m u ma b has n ot bee n 
esta blis he d. Bas e d o n re p orte d data fr o m t he c o-a d mi nistrati o n of a n a nti- P D - L 1 a ge nt 
(atez oliz u ma b) an d a M E K i n hi bit or (c o bi meti ni b) c haracterize d as well t olerate d at f ull si n gle-
a ge nt d oses f or b ot h a ge nts i n a P hase 1 st u d y ( Be n dell et al. 2 0 1 6 ) it is h y p ot hesize d t hat if t here 
we re t o be a n i ncrease i n t o xicity wit h t he 3-a ge nts a d mi nistere d i n c o m bi nati o n, it is n ot 
e x pecte d t o be si g nifi ca n tl y differe nt t ha n t hat see n i n t he c o m bi nati o n of ni v ol u ma b wit h t he 
hi g her d os e of i pili m u ma b, w hic h has bee n t olera ble. N o ne w t o xicities are a ntici pate d ( Be n d ell 
et al. 2 0 1 6); h o we ver, o v erlap pi n g t o xicities ma y occ ur a n d m a y i ncl u de d er mat ol o gi c reacti o ns, 
diarr hea, b o wel o bstr ucti o n, ile us, li ver t o xicit y, p ne u m o nitis/i nterstitial l u n g diseas e (I L D). 
T hese ca n be m o nit ore d a n d ma na g e d wit h a p pr o priate d ose m o dificati o n.  
O verall, it is a ntici pate d t hat t hese re gi me ns will b e well t olerate d f or t his p atie nt p o p ulati o n a n d 
t hat t he p ote ntial t o xicities are well u n derst o o d a n d ca n be a p pr o priat el y m o nit ore d a n d 
ma na ge d.   
Please refer t o t he I B a n d/ or t he l ocall y a p pr o ve d prescri bi n g i nf or mati o n f or ni v ol u ma b a n d 
i pili m u ma b f or a d diti o nal g ui da nce an d t o t he c urre nt bi ni meti ni b I n vesti gat or’s Br oc h ure (I B).  
C CI

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2.4 
Risk-benefit Assessment Summary 
The proposed study will be conducted in adult patients with advanced mCRC with MSS and a 
RAS mutation, a clinical setting in which therapy after first line has limited value (Section 2.1).  
This trial studies a novel combination of a targeted therapeutic and 2 immunotherapy agents that 
inhibit two different immune checkpoint targets. In patients with MSS mCRC, the combination 
of a different MEK inhibitor (cobimetinib) and atezolizumab, a PD-L1 directed antibody, 
produced a modest 8% ORR but a median OS of 10 months in a heavily pretreated population in 
which the majority of patients had ≥ 5 prior lines of therapy (Bendell et al. 2018).  
The potential for immunotherapy to produce meaningful benefits for patients, particularly those 
with an intact immune response, is maximized by offering it to patients earlier in their treatment 
when the immune suppressive effects of prior therapy and of advanced metastatic cancer are less 
pronounced. Given the limited benefit of SOC options after first-line therapy, it is not 
unreasonable for an appropriately informed patient to opt to delay these SOC treatment options 
in favor of participation in a clinical trial. This paradigm of a “window of opportunity” type trial 
allows for the testing of new treatments in settings where there is an opportunity to properly 
evaluate their potential value (Glimelius et al. 2011). 
Patients participating in the trial will go through an informed consent process and be required to 
sign an informed consent document. This process will provide patients with information on their 
treatment options, including all SOC options available to them, and allow them to make a 
decision in conjunction with their physician with regard to trial participation. 
Potential risks of the combination are discussed in Section 2.3.3. The safety profile of each agent 
proposed for the triplet combination is well defined. The safety and efficacy of binimetinib has 
been evaluated as a single agent and in combination in over 2500 exposures. Nivolumab and 
ipilimumab are already commercially available for the treatment of several advanced and 
metastatic tumor types. It has been observed in several previous trials that the toxicity of the 
nivolumab + ipilimumab combination correlated with the ipilimumab dose (Wolchok et al. 2013; 
Postow et al. 2015; Reardon et al. 2016; Wolchok et al. 2016). The toxicity profile with lower 
doses of ipilimumab, such as those being used in this study, has been established to be very 
similar to that of nivolumab monotherapy (Hellmann et al. 2016).  
The safety of the combination of nivolumab with binimetinib and ipilimumab has not been 
established. Based on reported Phase 1 data from the co-administration of an anti-PD-L1 agent 
(atezolizumab) and a MEK inhibitor (cobimetinib) characterized as well tolerated at full 
single-agent doses for both agents (Bendell et al. 2016), it is hypothesized that if there were to be 

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an increase in toxicity with the 3 agents administered in combination, it is not expected to be 
significantly different than that seen in the combination of nivolumab with the higher dose of 
ipilimumab, which has been tolerable. No new toxicities are expected. Overall, it is anticipated 
that these regimens will be well tolerated for this patient population and that potential toxicities 
are well understood and can be appropriately monitored and managed.  
Immunotherapy with a checkpoint inhibitor combined with a MEK inhibitor has shown activity 
in patients with MSS CRC after 5 or more lines of therapy (Bendell et al. 2018). The potential 
for benefit may be further optimized by allowing appropriately informed patients to enter the 
study earlier in the course of their disease. The potential for risk is appropriate for patients with 
advanced malignancy, and the risks associated with early disease progression and toxicity will be 
closely monitored. The overall assessment of benefit and risk is appropriate for the proposed 
study population. 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
6 5  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
3. 0  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S  
3. 1  
S t u d y O bjecti ves 
3. 1. 1  Pr i m ar y O bjecti ves 
 
P hase 1 b : 
o  Deter mi ne t he M T D a n d R P 2 D of bi ni meti ni b a d mi nistere d i n c o m bi nati o n wit h 
ni v ol u ma b  
o  D eter mi ne t he M T D a n d R P 2 D of bi ni meti ni b a d mi nistere d i n c o m bi nati o n wit h 
ni v ol u ma b pl us i pili m u ma b 
 
P hase 2 : Assess t he preli mi nar y a ntit u m or acti vit y of t he treat me nt c o m bi nati o ns base d o n 
R es p o nse E val uati o n Criter ia i n S oli d T u m ors ( R E CI S T) v ersi o n 1. 1 
3. 1. 2  Sec o n d ar y O bjecti ves 
B ot h P hases:  
 
F urt her assess t he preli mi nar y a ntit u m or acti vit y of t he treat me nt c o m bi nati o ns base d o n 
R E CI S T ve rsi o n 1. 1 
 
C haracte rize t he safet y pr ofile of t he tr eat me nt c o m bi nati o ns 
 
C haracterize  t he P K of bi ni meti ni b i n b ot h treat me nt c o m bi nati o ns 
3. 1. 3  E x pl or at or y O bjecti ves 
B ot h P hases:  
 
O btai n preli mi nar y esti mates of P F S a n d O S 
3. 2  
S t u d y E n d p oi nts 
3. 2. 1  Pri m ar y E n d p oi nts 
 
P hase 1 b :  
o  I n ci de nce of d ose-li miti n g t o xicities ( D L Ts) res ulti n g fr o m bi ni meti ni b i n 
c o m bi nati o n wit h ni v ol u ma b  
o  I n ci de nce of D L Ts r es ulti n g fr o m bi ni meti ni b i n c o m bi nati o n wit h ni v ol u ma b pl us 
i pili m u ma b 
 
P hase 2 : O R R per R E CI S T v 1. 1  
C CI

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
6 6  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
3. 2. 2  Sec o n d ar y E n d p oi nts 
 
P hase 1 b o nl y : O R R per R E CI S T v 1. 1 
B ot h P hases : 
 
D O R  per R E CI S T v 1. 1  
 
R ate of C R per R E CI S T v 1. 1  
 
In ci de nce a n d se v erit y of A Es gra d e d acc or di n g t o t he Nati o nal Ca ncer I nstit ute ( N CI ) 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E v e nts ( C T C A E) v 4. 0 3, a n d c h a n ges i n cli nical 
la b orat or y para meters 
 
S parse plas ma c o n ce ntr ati o ns f or bi ni meti ni b  
3. 2. 3  E x pl or at or y E n d p oi nts 
B ot h P hases : 
 
P F S per R E CI S T v 1. 1  
 
O S  
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4.0 
STUDY DESIGN 
4.1 
Study Design Overview 
This is a multicenter, open-label Phase 1b/2 study to determine the MTD and RP2D and schedule 
of binimetinib, and to assess the safety, efficacy and PK of binimetinib administered in 
combination with nivolumab or nivolumab plus ipilimumab in patients with previously treated 
MSS mCRC with documented RAS mutation. The study will include a dose-finding period in 
Phase 1b followed by a randomized Phase 2 period (Figure 2). 
Phase 1b Dose Determination: 
 
Arm 1A - Binimetinib plus nivolumab (Doublet): To determine the MTD and RP2D and 
schedule of binimetinib in combination with nivolumab. 
 
Arm 1B - Binimetinib with nivolumab plus ipilimumab (Triplet): To determine the MTD and 
RP2D and schedule of binimetinib in combination with nivolumab + ipilimumab.   
Phase 2 Efficacy Assessment: 
 
Arm 2A - Binimetinib plus nivolumab (Doublet): To determine the efficacy of binimetinib in 
combination with nivolumab. 
 
Arm 2B - Binimetinib with nivolumab plus ipilimumab (Triplet): To determine the efficacy 
of binimetinib in combination with nivolumab + ipilimumab 

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Figure 2: 
Study Design Scheme for Phase 1b and Phase 2 
Phase 1b 
 
Phase 2 
 

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One treatment cycle is defined as 28 days (4 weeks) for all arms. Individual treatments will be 
dosed on the schedules as outlined below. 
4.1.1 Phase 1b: Dose-Finding Period and Dose De-Escalation/Escalation 
Phase 1b of the study will consist of dose-finding cohorts in Arm 1A and Arm 1B. Enrollment of 
patients in the dose-finding period and all dose-escalation and de-escalation decisions will be 
guided by the modified toxicity probability interval (mTPI-2) design (Guo et al. 2017). The 
mTPI-2 design is a model-based approach that is guided by a prespecified decision matrix that 
recommends escalating, reducing, or maintaining the same dose or stopping dose escalation 
based on the number of patients with DLTs observed in the dose level under evaluation 
(Section 4.1.1.2). Doses of binimetinib, nivolumab, and ipilimumab to be explored in the dose-
finding period are presented in Table 2.  
There will be a period of at least 7 days between C1D1 of the first patient and C1D1 of the 
second patient enrolled during Phase 1b (Arms 1A and 1B).  
Table 2: 
Dosing Scheme for Phase 1b 
Arm 
Dose Level 
(*Starting 
Dose 
Level) 
Binimetinib 
Nivolumab 
Ipilimumab 
1A 
(Doublet) 
4* 
45 mg BID  
480 mg Q4W 
N/A 
3 
45 mg BID 3W on / 1W off  
2 
30 mg BID 
1 
30 mg BID 3W on / 1W off 
1B 
(Triplet)a 
4 
45 mg BID  
480 mg Q4W 
1 mg/kg Q8W 
3 
45 mg BID 3W on / 1W off  
2 
30 mg BID 
1 
30 mg BID 3W on / 1W off 
a The Starting Dose Level of Arm 1B (Triplet) will be the Recommended Phase 2 Dose (RP2D) of binimetinib from Arm 1A. If 
tolerated, the RP2D of binimetinib from Arm 1A will be considered the RP2D for Arm 1B. If not tolerated, any dose level 
below the RP2D for Arm 1B may be explored. 
Arm 1A (Doublet): 
The first patient enrolled will receive 480 mg nivolumab Q4W in combination with the Starting 
Dose Level of 45 mg BID binimetinib (Dose Level 4; Table 2). Subsequent patients will receive 
480 mg nivolumab Q4W in combination with binimetinib at a dose and schedule that will be 
determined based on the cumulative toxicities observed in current and prior patients.  

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For binimetinib only: dose de-escalation and dose escalation will follow the mTPI-2 design (Guo 
et al. 2017). Dose escalation above 45 mg BID (Dose Level 4) is not permitted, nor is de-
escalation below 30 mg BID intermittent schedule (Dose Level 1) permitted.  
If 45 mg BID (Dose Level 4) is not tolerated during Cycle 1, dose de-escalation to either 30 mg 
BID (Dose Level 2) or 45 mg BID intermittent dosing (Dose Level 3) is permitted. Subsequent 
dose escalation or de-escalation of cohorts may only increase or decrease one dose level at a 
time, except de-escalation from 45 mg BID intermittent dosing (Dose Level 3) to 30 mg BID 
intermittent dosing (Dose Level 1), which may be permitted after discussion and upon agreement 
between the Sponsor’s Medical Monitor and the Investigators (Figure 2).  
Arm 1B (Triplet): 
The first patient enrolled will receive 480 mg nivolumab Q4W with 1 mg/kg ipilimumab Q8W in 
combination with binimetinib. The binimetinib Starting Dose Level will be assigned once the 
RP2D from Arm 1A has been determined. Subsequent patients will receive 480 mg nivolumab 
Q4W with 1 mg/kg ipilimumab Q8W in combination with binimetinib, at a dose and schedule 
that will be determined based on the cumulative toxicities observed in current and prior patients.  
For binimetinib only: dose de-escalation and dose escalation will follow the mTPI-2 design (Guo 
et al. 2017). Dose escalation above 45 mg BID (Dose Level 4) or above the RP2D determined in 
Arm 1A (if the RP2D is not 45 mg BID) is not permitted, nor is de-escalation below 30 mg BID 
intermittent schedule (Dose Level 1) permitted.  
The Starting Dose Level of Arm 1B will be the RP2D of binimetinib from Arm 1A. If 45 mg 
BID (Dose Level 4) is the Starting Dose Level and is not tolerated during Cycle 1, dose de-
escalation to either 30 mg BID (Dose Level 2) or 45 mg BID intermittent dosing (Dose Level 3) 
is permitted. Subsequent dose escalation or de-escalation of cohorts may only increase or 
decrease one dose level at a time, except de-escalation from 45 mg BID intermittent dosing 
(Dose Level 3) to 30 mg BID intermittent dosing (Dose Level 1), which may be permitted after 
discussion and upon agreement between the Sponsor’s Medical Monitor and the Investigators 
(Figure 2). 
At each dose level after the first 3 evaluable patients have completed Cycle 1, the Sponsor’s 
Medical Monitor and the Investigators will meet to clinically assess the available data from the 
dose cohort. The decision to escalate, continue to enroll in the current cohort, or dose de-escalate 
will be based on available data combined with the recommendations of the mTPI-2 matrix 
(Table 3). The Sponsor’s Medical Monitor and the Investigators will review, at a minimum, all 

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the available data from Cycle 1 once 3 to 6 evaluable patients in subsequent cohorts have been 
treated for at least 1 cycle.  

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Table 3: 
Guidance for Safety Review based on Observed Toxicity Outcomes 
No. of 
Patients 
with DLTs 
Number of Patients Treated 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 14 15 16 17 18 19 20 21 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
D 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
2 
- 
D 
D 
D 
D 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
3 
- 
- 
DU DU D 
D 
D 
D 
S 
S 
S 
S 
E 
E 
E 
E 
E 
E 
E 
E 
E 
4 
- 
- 
- 
DU DU DU D 
D 
D 
D 
D 
S 
S 
S 
S 
S 
E 
E 
E 
E 
E 
5 
- 
- 
- 
- 
DU DU DU DU DU D 
D 
D 
D 
D 
S 
S 
S 
S 
S 
S 
E 
6 
- 
- 
- 
- 
- 
DU DU DU DU DU DU D 
D 
D 
D 
D 
D 
S 
S 
S 
S 
7 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU DU DU D 
D 
D 
D 
D 
D 
D 
S 
8 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU DU DU DU DU D 
D 
D 
D 
D 
9 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU DU DU DU DU DU DU D 
D 
10 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU DU DU DU DU DU DU DU 
11 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU DU DU DU DU DU DU 
12 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU DU DU DU DU DU 
13 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU DU DU DU DU 
14 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU DU DU DU 
15 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU DU DU 
16 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU DU 
17 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU DU 
18 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU DU 
19 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU DU 
20 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU DU 
21 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
DU 
D = De-escalate to the next lower dose; DLT = Dose-limiting toxicity; DU = De-escalate to the next lower dose and the current 
dose will not be revisited; E = Escalate to the next higher dose; S = Stay at the current dose. 

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Intra-patient dose escalation will not be permitted. 
Note: In both arms, there will be flexibility to evaluate an intermittent dosing schedule of 
binimetinib (30 or 45 mg BID; e.g., 3 weeks on/1 week off) if continuous dosing is not tolerated 
depending on the time of onset of DLTs (Section 4.1.1.2). De-escalation may only decrease a 
maximum of 2 dose levels at a time. A reduction in dose levels from 45 mg BID (Dose Level 4) 
to 30 mg BID intermittent schedule (Dose Level 1) is not permitted.  
The target DLT probability for Cycle 1 is 30%, with an equivalence interval, i.e., an acceptable 
interval, of 25% to 35%. Dosing in Phase 1b will continue within an arm until 9 patients have 
been treated at one dose level with a recommendation to stay (or a recommendation to escalate if 
there is not a higher dose level or if the tolerability of the next dose level is unacceptable), or the 
maximum sample size within a Phase 1b arm (n=21) has been reached. If further safety 
evaluations are required, additional patients may be added to a cohort.  
If the first 2 patients in a previously untested dose level experience a DLT, the next cohort will 
be opened at the next lower dose level/schedule or an intermediate dose level. However, if the 
first 2 patients in a new cohort at a previously tested dose combination/schedule experience a 
DLT, further enrollment to that cohort will stop and the Sponsor’s Medical Monitor and the 
Investigators will meet to discuss all available data for that dose level/schedule and determine if 
additional patients may be enrolled in the dose cohort or if a new cohort of patients will be 
enrolled at a lower dose level. 
Toxicities will only be considered DLTs if they occur in Cycle 1 although overall safety 
including later cycles will be considered for dose escalations and for each RP2D determination.  
Patients are required to complete Cycle 1 (≥ 75% of the planned cumulative dose of binimetinib) 
to be considered evaluable for MTD determination unless discontinuation occurred due to a 
DLT. 
The dose-finding period of the study will evaluate the safety and tolerability of the combinations 
of nivolumab and binimetinib with or without ipilimumab for 1 cycle (the first 28 days of 
treatment in Phase 1b). 
4.1.1.1 
Tolerability Assessment 
All dose-escalation and de-escalation decisions will be driven by the mTPI-2 design. For each 
dose-finding cohort, the tolerability assessment will be based upon occurrence of DLTs (see 
Section 4.1.1.2) in all patients. An End-of-Cohort meeting scheduled by the Sponsor between the 
Sponsor’s Medical Monitor and the Investigators will occur after the last patient in each cohort 

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has completed at least 1 treatment cycle (28 days) for careful assessment of AEs before 
escalating to the next dose. Pending the documented outcome of the meeting, doses will be 
escalated or de-escalated as agreed by the Sponsor’s Medical Monitor and the Investigators. 
4.1.1.1.1 
Special Considerations for Tolerability Assessment 
If the first occurrence of a Grade 3 immune-mediated AE (imAE; see the nivolumab and 
ipilimumab IBs for further details) is reported in a given cohort outside of Cycle 1, enrollment in 
that cohort will continue at the same dose until the toxicity is evaluated. If a second Grade 3 
imAE is reported or a first Grade 3 imAE is reported in addition to a previous DLT in a given 
cohort, enrollment of new patients in that cohort will be stopped until the Grade 3 imAE is 
evaluated. If the event is not a DLT (as determined by the Investigators in consultation with the 
Sponsor’s Medical Monitor), then enrollment may be resumed, or the cohort may be expanded. 
If the Grade 3 imAE is deemed a DLT, the MTD has been exceeded and additional patients will 
be enrolled at the previous dose level or at an intermediate dose level. 
Patients are required to complete Cycle 1 (≥ 75% of the planned cumulative dose of binimetinib) 
to be considered evaluable unless discontinuation occurred due to a DLT. Patients will be 
replaced if they have received less than 75% planned dose intensity ([administered dose in 
mg/planned dose in mg] x 100) of binimetinib for any reason other than an AE or abnormal 
laboratory value that is not related to disease, disease progression, intercurrent illness or 
concomitant medications/therapies before completing Cycle 1.  
If an acceptable combination dose cannot be identified, following discussions between the 
Sponsor’s Medical Monitor and the Investigators, the protocol may be amended.  
4.1.1.2 
Dose-limiting Toxicities 
For purposes of tolerability decisions, a DLT is defined as any AE or abnormal laboratory value 
assessed as unrelated to disease, disease progression, intercurrent illness or concomitant 
medications/therapies occurring within the first 28 days of treatment that satisfies at least 1 of the 
criteria listed in Table 4. 
Whenever a patient experiences toxicity that fulfills the criteria for a DLT, treatment with the 
study drug will be interrupted and the toxicity will be followed up. 
 

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Table 4: 
Criteria for Defining Dose-limiting Toxicities 
Any of the following will be considered a DLT 
 
Any AE or laboratory value considered unrelated to underlying disease, disease progression, intercurrent illness or concomitant medications/therapies 
resulting in the inability to tolerate 75% dose intensity ([administered dose in mg/planned dose in mg] x 100) of binimetinib during Cycle 1 
Laboratory/Investigation Abnormalities 
 
Total bilirubin Grade ≥ 3 (>3.0 x ULN)
 
AST or ALT > 5 - 8 x ULN for > 5 consecutive days
 
AST or ALT > 8 x ULN
 
AST or ALT > 3 x ULN with concurrent total bilirubin > 2 x ULN (For patients with abnormal ALT, AST or total bilirubin at baseline, AST or ALT or 
total bilirubin elevated to  2 × baseline) without initial findings of cholestasis (elevated serum alkaline phosphatase  2 × ULN) or other reasons to 
explain the combination of increased aminotransferases and total bilirubin
 
Serum creatinine Grade ≥ 3
 
CK elevation ≥ Grade 3 associated with an increase in creatinine ≥ 1.5 × the patient’s baseline creatinine
 
ECG QTcF prolonged ≥ Grade 3 (on at least 2 separate ECGs)
 
Grade 3 or 4 increase in amylase and/or lipase associated with symptoms or clinical manifestations of pancreatitis 
 
Grade 3 troponin associated with any sign of cardiac toxicity (as determined by a cardiac evaluation) 
 
Grade 3 electrolyte abnormality (and Grade 4 hyperglycemia) that lasts > 72 hours, is clinically complicated, or does not resolve spontaneously or respond 
to conventional medical intervention
 
Note: Isolated laboratory changes (e.g. alkaline phosphatase, cholesterol) or those due to sampling or laboratory errors without associated clinical signs or 
symptoms may be determined to not be DLTs upon review and agreement upon discretion of the Sponsor and Investigator.
Hematologic abnormalities 
 
ANC Grade 4 for > 7 consecutive days
 
Platelet count Grade 3 with signs of clinically significant bleeding
 
Platelet count Grade 4
 
Any other hematologic AE  Grade 3 except lymphocyte count decrease (lymphopenia)  Grade 3 unless clinically significant

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Any of the following will be considered a DLT 
Eye disorders 
 
Retinopathy or retinal detachment Grade ≥ 3, confirmed by ophthalmic examination
 
Retinal vascular disorder including retinal vein occlusion (RVO), confirmed by ophthalmic examination
 
Any Grade 2 immune-related uveitis or eye pain or blurred vision or decreased visual acuity that does not improve to Grade 1 despite topical therapy OR 
requires systemic treatment
 
Any other eye disorder ≥ Grade 3 for > 21 consecutive days
 
Any other eye disorder Grade 4 confirmed by ophthalmic examination
Cardiac disorders 
 
Absolute decrease of LVEF > 10% compared to Baseline and the LVEF is below the institution’s lower limit of normal (LLN)
 
Symptomatic left ventricular systolic dysfunction Grade ≥ 3
 
Other cardiac disorders Grade ≥ 3
Vascular disorders 
 
Grade 3 hypertension for > 14 consecutive days
 
Grade 4 hypertension
General disorders, administration site conditions, other or immune system disorders 
 
Grade 3 Fatigue for ≥ 7 consecutive days
 
Grade 3 Hypersensitivity reaction
 
Grade 3 Infusion reaction which does not return to ≤ Grade 1 within 6 hours
 
Grade 3 fever that lasts ≥ 72 hours, or is associated with hemodynamic compromise (including hypotension, or clinical or laboratory evidence of end 
organ perfusion impairment)
 
Grade 3 endocrinopathy which is not well-controlled by hormone replacement
Respiratory disorders 
 
Interstitial lung disease/ pneumonitis Grade ≥ 2
 
Bronchospasm Grade 3

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Any of the following will be considered a DLT 
Skin and subcutaneous tissue disorders a 
 
Rash, hand foot skin reaction (HFSR), or photosensitivity CTCAE Grade 3 for > 14 consecutive days despite maximal skin toxicity treatment (as per local 
practice)
 
Grade 3 rash that does not improve to Grade 1 within 14 days, limits self-care, or which is associated with infection
 
Rash, HFSR, or photosensitivity CTCAE Grade 4
Gastrointestinal disorders a 
 
Grade 3 Colitis 
 
Grade 3 Diarrhea for ≥ 48 hours despite optimal use of antidiarrheal therapy, results in hospitalization, or does not resolve to Grade 1 spontaneously or 
with conventional medical intervention
 
Grade 4 Diarrhea 
 
Nausea or vomiting Grade 3 for ≥ 48 hours despite optimal use of antiemetic therapy
 
Grade 4 Nausea/vomiting 
Neurologic toxicity 
 
Neurologic toxicity Grade 3
Other hematologic and nonhematolic toxicities  
 
Any other Grade≥ 3 AE  
NOTE: Tumor flare (defined as pain, irritation, or rash that localizes to site of known or suspected tumor) is NOT a DLT. 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CK = creatine kinase; DLT = dose-
limiting toxicities; ECG = electrocardiogram; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; QTcF = QT interval corrected for heart rate using 
Fridericia’s formula; RVO = retinal vein occlusion. 
a Prophylactic treatment for nausea/vomiting or skin AEs is not required with binimetinib. However, antiemetics and treatments for skin AEs should be used at the discretion 
of the Investigator if the patient experiences nausea/vomiting and/or skin AEs Grade ≥ 1. 
 

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4.1.2 Phase 2: Randomized Dose Cohorts 
Phase 2 of the study will consist of two arms to investigate the safety and clinical activity of the 
RP2Ds established from Phase 1b, Arm 2A (nivolumab in combination with binimetinib) and 
Arm 2B (nivolumab plus ipilimumab in combination with binimetinib). 
 
Arm 2A: Patients randomized to the nivolumab and binimetinib arm will receive nivolumab 
administered as 480 mg Q4W as a 30-minute IV infusion on Day 1 of each treatment cycle 
and the recommended dose of binimetinib in Arm 1A of Phase 1b. 
 
Arm 2B: Patients randomized to the nivolumab, ipilimumab, and binimetinib arm will 
receive nivolumab administered as 480 mg Q4W as a 30-minute IV infusion on Day 1 of 
each treatment cycle, ipilimumab administered as 1 mg/kg Q8W as a 30-minute IV infusion, 
and the recommended dose of binimetinib determined in Arm 1B of Phase 1b. 
Dosing calculations for ipilimumab should be based on the body weight assessed at baseline. It is 
not necessary to re-calculate subsequent doses if the patient weight is within 10% of the weight 
used to calculate the initial dose.  
4.1.2.1 
Measures to Minimize Bias 
During the randomized Phase 2 period of the study, treatments will be assigned according to a 
computerized central randomization list using an interactive web response system (IWRS) (see 
Section 6.2) in order to minimize any possible bias. 
4.2 
Duration of Treatment 
Patients may continue receiving study drug as long as none of the treatment discontinuation 
criteria are met (see Section 9.2), with the following exceptions: In the absence of disease 
progression, nivolumab or ipilimumab may be dosed continuously for a maximum of 2 years.  
Continuing study treatment beyond disease progression for any patient is only to be considered 
under special circumstances when it is believed that the patient may clinically benefit from 
continued treatment beyond progression. If it is judged by the Investigator in consultation with 
the Sponsor, to be in the best interest of the patient, the patient may remain on study treatment 
as long as the patient continues to receive benefit from the study treatment per Investigator 
assessment. Circumstances in which treatment beyond disease progression might be appropriate 
include mixed responses or the appearance of new brain metastases treatable with stereotactic 
radiotherapy or surgery but not requiring whole brain radiotherapy. 

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Dosing beyond progression is not allowed in the following cases: 
 
Patients with clear evidence of disease progression at multiple sites or clear evidence of new 
lesions outside the central nervous system  
 
Patients with rapid progression of disease at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention  
 
Patients who have clinically relevant worsening of laboratory values 
 
Patients who have a clinically significant decline in performance status at time of 
progression. 
4.3 
End of Study 
End of study will be defined as the point when all patients have the opportunity to be followed 
for at least 1 year after the randomization date of the last patient enrolled. The Sponsor will 
notify all applicable regulatory agencies in accordance with local requirements when the study 
has ended. After the end of the study, access to study drugs will be provided only in accordance 
with local regulations and requirements. 
4.4 
Safety Review  
Safety Review will be performed by the Sponsor’s Medical Monitor and the Investigators. This 
team will be responsible for ongoing review of safety data during the study in order to evaluate 
the safety and tolerability of the combinations of nivolumab and binimetinib, and nivolumab and 
binimetinib plus ipilimumab.  
For the dose-finding cohorts, after the last patient in a given cohort has completed at least 1 cycle 
of study treatment, the Sponsor’s Medical Monitor and the Investigators will meet to review all 
safety data and decide whether to continue or halt dose escalation, expand individual dose levels 
to gain additional safety data, determine the MTD and/or RP2D, or explore other dose 
levels/schedules.  
In addition to end-of cohort meetings, safety meetings between the Sponsor’s Medical Monitor 
and the Investigators will be scheduled periodically during Phase 2 of the study to review safety 
data for ongoing patients and patients who are being monitored during the follow-up period. 

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5.0 
PATIENT POPULATION 
5.1 
Number of Patients 
Approximately 90 adult patients are planned. A maximum of approximately 42 patients will be 
enrolled in Phase 1b at approximately 5 study centers, and a minimum of approximately 48 
patients will be enrolled in Phase 2 at approximately 30 study centers. The total number of 
patients enrolled in Phase 1b of the study will depend on the number of dose levels tested and the 
number of patients treated in each cohort before the RP2D has been determined for each arm.  
5.2 
Selection of Patients 
The eligibility criteria described in this study protocol are designed to identify patients for whom 
study treatment is considered appropriate. All relevant medical conditions should be considered 
when deciding whether a patient is suitable for enrollment in the study. 
Eligibility will be determined separately for molecular tumor testing during a Prescreening Phase 
and for enrollment/randomization in the study during a Screening Phase. Questions regarding 
patient eligibility should be addressed to the Sponsor or delegate prior to 
enrollment/randomization. Patients will be considered enrolled in the study once they have 
signed the Screening informed consent form (ICF).   
5.2.1 Eligibility Criteria for Prescreening 
5.2.1.1 
Prescreening Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for participation in the 
prescreening period: 
1. Provide a signed and dated Prescreening ICF. 
2. Male or female ≥ 18 years of age at the time of signing the Screening ICF. 
3. Measurable, histologically/cytologically confirmed mCRC per RECIST v1.1. 
4. Have willingness and ability to participate in the study.  
5. Able to provide a sufficient amount (tumor block or minimum of 6 slides) of representative 
tumor specimen (primary or metastatic, archival or newly obtained) for central laboratory 
testing of RAS mutation status and MSS. 
a. If a fresh tissue sample is provided, a blood sample is required. 
6. Have received no more than 2 prior lines of systemic therapy in the metastatic setting 
(maintenance therapy given in the metastatic setting will not be considered a separate 
regimen). Generally, treatments that are separated by an event of progression are considered 
different regimens. 

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7. Have received prior systemic treatment as recommended by National Comprehensive Cancer 
Network (NCCN) or European Society for Medical Oncology (ESMO) guidelines, including 
fluoropyrimidines, oxaliplatin, irinotecan or bevacizumab in the metastatic setting or similar 
treatments, as per local guidelines. 
8. No known contraindications to study treatment. 
5.2.1.2 
Prescreening Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for enrollment in the study: 
1. Prior treatment with any MEK inhibitor. 
2. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways. 
3. Any untreated central nervous system (CNS) lesion. However, patients are eligible if: a) all 
known CNS lesions have been treated with radiotherapy or surgery, and b) patients remained 
without evidence of CNS disease progression ≥ 4weeks after treatment, and c) patients must 
be off corticosteroid therapy for ≥ 3 weeks.  
4. Patients with an active, known or suspected autoimmune disease, with the following 
exceptions: patients with type I diabetes mellitus, hypothyroidism only requiring hormone 
replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic 
treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll.  
5. Partial or complete bowel obstruction. 
6. Impaired gastrointestinal function or disease that may significantly alter the absorption of 
binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small 
bowel resection with decreased intestinal absorption) or baseline diarrhea ≥ Grade 1. 
7. Known history of RVO. 
8. Concurrent or previous other malignancy within 5 years of study entry, except cured basal or 
squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, 
carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy  
9. Known history of Gilbert’s syndrome. 
10. Severe uncontrolled medical illness. 
11. Psychiatric illness inhibiting informed consent or protocol compliance. 
12. Pregnant or breastfeeding females. 
13. History of severe hypersensitivity reactions to mAbs. 

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14. History of allergy or intolerance (unacceptable AEs) to study drug components or 
polysorbate-80-containing infusions. 
5.2.2 Patient Eligibility at Screening 
5.2.2.1 
Screening Inclusion Criteria  
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Patients must meet all Prescreening inclusion criteria. 
2. Provide a personally signed and dated Screening ICF. 
3. mCRC categorized as MSS by immunohistochemistry (IHC) or polymerase chain reaction 
(PCR)-based local assay at any time prior to Screening or by the central laboratory 
(Section 7.1.1). 
4. RAS mutation per local assay at any time prior to Screening or by the central laboratory. 
5. Have received at least 1 prior line of systemic therapy in the metastatic setting as 
recommended by National Comprehensive Cancer Network (NCCN) or European Society for 
Medical Oncology (ESMO) guidelines, including fluoropyrimidines, oxaliplatin, irinotecan 
or bevacizumab, or similar treatments, as per local guidelines, and meets at least one of the 
following criteria: 
a. were unable to tolerate the prior first-line regimen 
b. experienced disease progression during or after prior first-line regimen for metastatic 
disease  
c. progressed during or within 6 months of completing adjuvant chemotherapy 
Note: Generally, treatments that are separated by an event of progression are considered 
different regimens. 
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 
7. Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 
6 weeks; if a female patient is of childbearing potential, she must agree to follow instructions 
for acceptable or highly effective method(s) of contraception for the duration of study 
treatment and for 5 months after the last dose of study treatment with nivolumab (i.e., 
30 days [duration of ovulatory cycle] plus the time required for the investigational drug to 
undergo approximately 5 half-lives) (Section 5.3). 

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8. Non-sterile male patients who are sexually active with female partners of childbearing 
potential must agree to follow instructions for acceptable or highly effective method(s) of 
contraception for the duration of study treatment and for 7 months after the last dose of study 
treatment with nivolumab (i.e., 90 days [duration of sperm turnover] plus the time required 
for the investigational drug to undergo approximately 5 half-lives) (Section 5.3). 
9. Adequate renal and bone marrow function as measured by the following Screening 
laboratory values: 
a. White blood cells (WBC) ≥ 2000/µL 
b. Neutrophils ≥ 1500/µL 
c. Platelets ≥ 100 ×103/µL 
d. Hemoglobin ≥ 9.0 g/dL 
e. Serum creatinine  1.5 × upper limit of normal (ULN) or calculated creatinine clearance 
> 50 mL/min (using the Cockcroft Gault formula) or estimated glomerular filtration rate 
> 50 mL/min/1.73 m2 (using the Modification of Diet in Renal Disease [MDRD] Study 
formula) 
10. Adequate hepatic function characterized by the following Screening laboratory values: 
a. Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL 
Note: Patients who have a total bilirubin level > 1.5 × ULN will be allowed if their 
indirect bilirubin level is ≤ 1.5 × ULN. 
b. ALT and/or AST ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases 
11. Adequate cardiac function as follows:  
a. LVEF ≥ 50% or above institutional normal value as determined by a MUGA scan or 
ECHO 
b. QTcF interval ≤ 480 msec (preferably the mean from triplicate electrocardiograms 
(ECGs) 
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures including computed tomography (CT)/magnetic resonance imaging 
(MRI) scans. 
5.2.2.2 
Screening Exclusion Criteria  
Patients meeting any of the following criteria are not eligible for enrollment in the study: 
1. Patients must not meet any of the Prescreening exclusion criteria. 

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2. Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor [anti-TNF] agents) within 2 weeks prior to first day of study treatment: 
a. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) and 
topical steroids are allowed. Patients who have received acute and/or low-dose systemic 
immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea or 
chronic use of ≤ 10 mg/day of prednisone or dose-equivalent corticosteroid) may be 
enrolled in the study after discussion with and approval by the Sponsor’s Medical 
Monitor. 
3. Impaired gastrointestinal function or disease that may significantly alter the absorption of 
binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small 
bowel resection with decreased intestinal absorption) or baseline diarrhea ≥ Grade 1. 
4. History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study 
treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein 
thrombosis or pulmonary emboli. 
5. Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or 
diastolic blood pressure ≥ 100 mmHg despite current therapy. 
6. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular 
atrophy). 
7. History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled 
glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability 
syndromes). 
8. Clinically significant cardiac disease, including, but not limited to, any of the following: 
a. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2). 
b. Clinically significant and uncontrolled atrial fibrillation. 
c. History of acute coronary syndromes including myocardial infarction, unstable angina, 
coronary artery bypass grafting, coronary angioplasty, or stenting < 6 months prior to 
screening. 
d. Symptomatic chronic heart failure, history or current evidence of clinically significant 
cardiac arrhythmia and/or conduction abnormality < 6 months prior to screening except 
controlled atrial fibrillation and paroxysmal supraventricular tachycardia.  
9. Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of 
Grade 2 alopecia or Grade 2 neuropathy. 

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10. Known history of positive test for human immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites 
where mandated locally. 
11. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic 
infection, and/or detectable virus. 
5.3 
Lifestyle Guidelines - Contraception 
Female patients are either postmenopausal (defined as without menses for at least 12 consecutive 
months before screening AND a follicle-stimulating hormone [FSH] value > 30 IU/L at 
Screening), are surgically sterile for at least 6 weeks, or if of childbearing potential, must agree 
to use acceptable or highly effective methods of contraception to avoid pregnancy for the 
duration of study treatment through 5 months after the last dose of study treatment with 
nivolumab (i.e., 30 days [duration of ovulatory cycle] plus the time required for the 
investigational drug to undergo approximately 5 half-lives).  
Non-sterile male patients who are sexually active with female partners of childbearing potential 
must agree to use acceptable or highly effective methods of contraception to avoid fathering a 
child for the duration of study treatment and for 7 months after the last dose of study treatment 
with nivolumab (i.e., 90 days [duration of sperm turnover] plus the time required for the 
investigational drug to undergo approximately 5 half-lives).   
Please refer to the IB and/or the locally approved prescribing information for nivolumab and 
ipilimumab for additional guidance (as applicable).  
The following methods have been determined to be highly effective and are permitted under this 
protocol for use by the patient and his/her partner (Clinical Trials Facilitation Group Guidelines 
2014)a: 
 
Complete abstinence from heterosexual intercourse during the entire period of risk associated 
with the study treatments; the reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical trial and the preferred and usual lifestyle of the patient 
 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
o Oral (It is recommended that patients experiencing vomiting or diarrhea should be 
counseled to use non-oral methods of contraception.) 
o Intravaginal 
o Transdermal 

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 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
o Oral (It is recommended that patients experiencing vomiting or diarrhea should be 
counseled to use non-oral methods of contraception.) 
o Injectable 
o Implantable 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
 
Vasectomised partner (considered highly effective provided the vasectomized male has 
received medical assessment of surgical success and that the male is a female patient’s sole 
sexual partner) 
a Section 2.2.5 of the Clinical Trials Facilitation Group Guidelines 2014 states that the choice of 
contraceptive methods may be adapted in special circumstances dictated by factors such as study 
duration, fertility of study population, and seriousness of the treated medical condition. 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action 
 
A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double-barrier methods)  
 
Male or female condom with or without spermicide 
 
Cap, diaphragm or sponge with spermicide 

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6.0 
STUDY TREATMENT AND CONCOMITANT MEDICATIONS/THERAPIES 
The term “study drug” is used to refer to nivolumab, binimetinib, and ipilimumab, collectively. 
In addition to the information provided in this protocol, refer to the IB and/or the locally 
approved prescribing information for nivolumab and ipilimumab for additional guidance (as 
applicable) for the management of patients concerning contraindications, duration of 
contraception, special warnings and precautions, and concomitant medications that are 
contraindicated or that must be used with caution. 
6.1 
Patient Numbering 
In Phase 1b and Phase 2 of the study, patients will be manually assigned a patient study number 
at prescreening.  
In Phase 2 of the study, patients who sign informed consent to participate in Screening will be 
assigned a unique number by interactive web response system (IWRS). Once a patient is enrolled 
in the study, that patient will be identified only by the assigned patient number. Once assigned, 
the patient number must not be reused for any other patient.  
6.2 
Allocation to Treatment 
In Phase 1b, patients will first enroll into Cohort 1 of Arm 1A (45 mg BID binimetinib) (Table 2 
and Section 4.1.1.1). Enrollment in Arm 1A will continue until the RP2D has been determined. 
At this time, new patients may be enrolled into Cohort 1 of Arm 1B.  
In Phase 2, patients will be randomized in a 1:1 ratio to receive either nivolumab and binimetinib 
(Arm 2A) or nivolumab and binimetinib plus ipilimumab (Arm 2B).  
The randomization schedule will be created and managed by a statistician not assigned to support 
the study and treatments will be assigned according to a computerized central randomization list 
using an IWRS. 
6.3 
Doses and Schedule of Administration 
The investigational products in this study are nivolumab and binimetinib (Arms 1A and 2A) and 
nivolumab, binimetinib, and ipilimumab (Arms 1B and 2B) (Table 2). 
6.3.1 Administration of Nivolumab  
Nivolumab will be administered IV on a Q4W schedule as a fixed dose and not by body weight 
or body surface area (BSA). Nivolumab may be diluted in 0.9% sodium chloride solution. 

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Nivolumab will be administered at the study site according to institutional standards. The initial 
nivolumab dose is 480 mg administered as a 30-minute (± 5 minutes) IV infusion (not including 
time required to flush the IV lines). Close monitoring is required during the infusion and for at 
least 1 hour after the end of the infusion. If an infusion reaction occurs while nivolumab is being 
administered, the infusion should be stopped immediately, and the patients should be closely 
monitored and treated in line with institutional standards. Any rechallenge with nivolumab 
following an infusion reaction should be first discussed with the Sponsor.  
Antiemetic premedications should not be routinely administered prior to dosing of nivolumab. 
See Section 6.4.1.5 for premedication recommendations following a nivolumab-related infusion 
reaction. 
Doses of nivolumab that are omitted for AEs or any other reason should not be made up. If 
nivolumab is discontinued, the frequency of study visits may be decreased after discussion with 
Sponsor. 
6.3.2 Administration of Binimetinib 
Binimetinib will be administered orally (PO) on a BID schedule (Table 2). Binimetinib should be 
taken without regard to food. Patients should be instructed to swallow the tablets whole and not 
to chew or crush them. 
 
BID Dosing: Patients should be instructed to take binimetinib tablets 12 ± 2 hours apart with 
a large glass of water (~250 mL) in the morning and in the evening at approximately the 
same times every day. Doses of binimetinib that are omitted for AEs or any other reason 
should not be made up later in the day, or at the end of the dosing period. 
On days when a blood collection is scheduled at the investigational site, patients will take the 
morning dose of binimetinib at the site, after the collection, under the supervision of the 
Investigator or designee. On the evening of the visit day, patients will take binimetinib at home. 
On all other days, patients will take binimetinib at home. Predose PK samples for binimetinib 
analysis should be collected just prior to intake of binimetinib. 
If a patient vomits at any time after dosing, the dose of study drug should not be re-administered. 
If vomiting occurs within the first 4 hours post dosing with binimetinib, the exact time of 
vomiting should be recorded whenever possible (Section 7.3). 
Binimetinib will be co-administered at the start of the nivolumab infusion (± 5 minutes).  

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The pharmacist or study nurse will ensure that the appropriate dose is dispensed and will provide 
the patient with at least the appropriate number of binimetinib tablets for the number of doses to 
be taken prior to the next scheduled visit. The site personnel will train the patient and/or the 
patient’s caregiver on dosing procedures for the study drug. 
Patients will receive a diary to document self-administered dosing of binimetinib in each cycle to 
include the dose of study drug taken, the date of dosing (and times if applicable), and if any 
doses were missed and the reason for the missed dose. One diary will be provided per cycle. 
Patients will be instructed to return unused binimetinib and the patient diary to the site at the end 
of each cycle. Patient compliance and accountability must be performed every 4 weeks (Table 12 
[Phase 1b Arm 1A], Table 13 [Phase 1b Arm 1B], Table 14 [Phase 2 Arm 2A] and Table 15 
[Phase 2 Arm 2B]). 
The Investigator or responsible site personnel should instruct the patient to take binimetinib per 
protocol (promote compliance). The dosage prescribed and dispensed to the patient and all dose 
changes and all missed doses during the study must be recorded in the electronic case report 
form (eCRF). 
6.3.3 Administration of Ipilimumab 
Ipilimumab will be administered IV Q8W (Table 2) according to institutional standards. The 
ipilimumab dose is 1 mg/kg administered as a 30-minute (± 5 minutes) IV infusion (not 
including time required to flush the IV lines), and will occur after the completion of the 
nivolumab infusion. Ipilimumab may be diluted in 0.9% sodium chloride solution or 5% 
dextrose solution. 
Antiemetic premedications should not be routinely administered prior to dosing of ipilimumab. 
See Section 6.4.1.5 for premedication recommendations following an ipilimumab-related 
infusion reaction. 
Doses of ipilimumab that are omitted for AEs or any other reason should not be made up.  
If nivolumab is permanently discontinued for any reason, ipilimumab must also be permanently 
discontinued. 
6.4 
Dose Modifications  
6.4.1 Nivolumab and Ipilimumab Modifications 
6.4.1.1 
Dose Reductions 
Dose reductions are not permitted for nivolumab and ipilimumab.  

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6.4.1.2 
Dose Interruptions or Delays 
Nivolumab and ipilimumab administration should be delayed for the following: 
 
Any Grade ≥ 2 non-skin, study drug-related AE, with the exception of fatigue 
 
Any Grade ≥ 2 study drug-related creatinine, AST, ALT and/or total bilirubin abnormalities 
 
Any Grade 3 skin, study drug-related AE 
 
Any Grade 3 study drug-related laboratory abnormality, with the following exceptions: 
o Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay 
o Grade ≥ 3 AST, ALT, and/or total bilirubin will require dose discontinuation 
 
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study drug. 
Participants who require delay of nivolumab should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met. 
Management algorithms for nivolumab- and ipilimumab-related AEs are provided in Appendix 4 
for suspected gastrointestinal, renal, pulmonary, hepatic, endocrinopathy, skin, and neurologic 
toxicities.  
6.4.1.3 
Criteria to Resume Nivolumab and Ipilimumab 
Patients may resume treatment with study drug when the study drug-related AE(s) resolve to 
Grade ≤ 1 or baseline value, with the following exceptions: 
 
Patients may resume treatment in the presence of Grade 2 fatigue. 
 
Patients who have not experienced a Grade 3 study drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity. 
 
For patients with Grade 2 AST/ALT and/or total bilirubin, dosing may resume when 
laboratory values return to baseline and management with corticosteroids, if needed, is 
complete. 
 
Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters (Section 6.4.1.4) should have treatment permanently 
discontinued. 
 
Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Patients with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the Sponsor Medical Monitor(s). 

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 
Patients with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the Sponsor Medical 
Monitor(s). Adrenal insufficiency requires discontinuation regardless of control with 
hormone replacement. 
If the criterion to resume treatment is met, the patient should restart treatment at the next 
scheduled time point as per protocol. However, if the treatment is delayed past the next 
scheduled time point per protocol, the next scheduled time point will be delayed until dosing 
resumes. 
Dose interruption of > 6 weeks in administration of nivolumab or > 18 weeks in administration 
of ipilimumab will result in permanent discontinuation, except as specified in Section 6.4.1.4. 
6.4.1.4 
Criteria to Discontinue Nivolumab and Ipilimumab 
If nivolumab is permanently discontinued for any reason, ipilimumab must also be permanently 
discontinued. 
Treatment with nivolumab and ipilimumab should be permanently discontinued for the 
following: 
 
Any Grade 2 study drug-related uveitis, 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 recurrent Grade 3 non-skin, study drug-related AE  
 
Any Grade 4 study drug-related AE or laboratory abnormality including, but not limited to 
creatinine, AST, ALT, or total bilirubin, except for the following events which do not require 
discontinuation: 
o Grade 4 neutropenia ≤ 7 days 
o Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of onset. 
o Grade 4 drug-related endocrinopathy AEs, such as hyper- or hypothyroidism or 
glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling 
agents, respectively, may not require discontinuation after discussion with and 
approval from the Sponsor Medical Monitor(s). 

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 
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose for 
nivolumab or > 18 weeks from the previous dose for ipilimumab requires discontinuation 
with the following exceptions: 
o Dosing delays to allow for prolonged steroid tapers to manage study drug-related AEs 
are allowed.  
o Dosing delays lasting > 6 weeks from the previous dose that occur for non-study 
drug-related reasons may be allowed if approved by the Sponsor Medical Monitor(s).  
o Prior to re-initiating treatment in a patient with a dosing delay lasting > 6 weeks from 
the previous dose for nivolumab or > 18 weeks from the previous dose for 
ipilimumab, the Sponsor Medical Monitor(s) must be consulted. Tumor assessments 
should continue as per protocol even if dosing is interrupted. 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 that, in the judgment of the 
Investigator, presents a substantial clinical risk to the patient with continued nivolumab or 
ipilimumab dosing. 
6.4.1.5 
Treatment of Nivolumab- or Ipilimumab-related Infusion Reactions 
Because 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, hypo- or hypertension, bronchospasm, or other allergic-like reactions. All Grade 3 or 
4 infusion reactions should be reported within 24 hours to the Sponsor Medical Monitor(s) and 
reported as an SAE if criteria are met. Infusion reactions should be graded according to NCI 
CTCAE v4.03 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) 
Monitor patient until recovery from symptoms. The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen 325 to 1000 mg at least 30 minutes before additional nivolumab administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-

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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 
patient with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 
to 1000 mg; remain at bedside and monitor patient until resolution of symptoms. Corticosteroid 
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 patient closely. If symptoms recur, then no further nivolumab or ipilimumab will 
be administered at that visit. The amount of study drug infused must be recorded on the eCRF. 
The following prophylactic premedications are recommended for future infusions: 
diphenhydramine 50 mg (or equivalent) and/or acetaminphen 325 to 1000 mg should be 
administered at least 30 minutes before additional nivolumab or ipilimumab administrations. If 
necessary, corticosteroids (recommended dose: up to 25 mg of hydrocortisone or equivalent) 
may be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [i.e., not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[e.g., 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 patient as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1,000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Patient 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 patient until recovery from symptoms.  
In the case of late-occurring hypersensitivity symptoms (e.g., appearance of a localized or 
generalized pruritus within 1 week after treatment), symptomatic treatment may be given (e.g., 
oral antihistamine, or corticosteroids). 

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6.4.2 Binimetinib Modifications 
Patients will be monitored for AEs at each visit with the NCI CTCAE v4.03 used for all grading. 
Doses of binimetinib should be adjusted for AEs throughout the study. In general, doses should 
not be reduced or interrupted for Grade 1 AEs unless the AE is a specific treatment-related 
ocular AE. Treatment to control symptoms should be provided as appropriate. All dose 
modifications should be based on the worst preceding toxicity (CTCAE v4.03).  
Permitted binimetinib dose reductions due to AE are specified in Table 5. 
Table 5: 
Permitted Binimetinib Dose Reductions due to Adverse Event 
Dose Level 
Binimetinib Dose 
Binimetinib Dose Reduction 
due to AE 
4 
45 mg BID  
30 mg BID 
3 
45 mg BID 3W on / 1W off  
30 mg BID 
2 
30 mg BID 
no dose reduction permitted 
1 
30 mg BID 3W on / 1W off 
no dose reduction permitted 
 
When the AE that resulted in a dose reduction improves to and remains stable at the patient’s 
Baseline for a minimum of 14 days, the dose can be re-escalated to the next dose level at the 
discretion of the Investigator, provided there are no other concomitant binimetinib-related 
toxicities that would prevent drug re-escalation. Following a dose reduction due to toxicity, an 
individual patient’s dose may be re-escalated only one time; however, no dose re-escalation is 
allowed after a dose reduction due to LVEF dysfunction or prolonged QTcF > 500 msec.  
A dose reduction below 30 mg BID is not permitted. Patients requiring additional reductions 
must be discontinued from study treatment. Dose interruptions of more than 28 days are not 
allowed and will result in permanent discontinuation unless resuming treatment is judged by the 
Investigator and the Sponsor’s Medical Monitor or designee to be in the best interest of the 
patient. 
Eye disorders should be graded according to CTCAE v4.03 as described below in Table 6. 
Table 6: 
CTCAE Grading for Eye Disorders 
Grade 
Description 
1 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL 

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Grade 
Description 
3 
Severe or medically significant but not immediately sight threatening; 
Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting 
self-care ADL 
4 
Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or 
worse) in the affected eye 
ADL= activities of daily living 
 
Retinal detachment should be graded according to the CTCAE v4.03 as described below in 
Table 7. 
Table 7: 
CTCAE Grading for Retinal Detachment 
Grade 
Description 
1 
Asymptomatic 
2 
Exudative and visual acuity 20/40* or better 
3 
Rhegmatogenous or exudative detachment; operative intervention indicated; decline in 
vision 
(worse than 20/40*but better than 20/200*) 
4 
Blindness (20/200* or worse) in the affected eye 
* Please refer to the Snellen Equivalence Chart (Visual Acuity Conversion Chart) (Appendix 5). 
 
Missed/skipped doses will not be made up (i.e. the patient should not double their dose if the 
previous dose was missed).  
Dose reduction/interruption/discontinuation decisions should be based on the CTCAE grade of 
the toxicity and the guidelines provided below. All AEs should be followed weekly or as 
clinically appropriate until stabilization or resolution. 
Note: In the event that nivolumab (and, if applicable, ipilimumab) is permanently discontinued, 
binimetinib single agent should not be administered for more than 28 days, at which time it will 
be permanently discontinued. 
Table 8 presents dose adjustment recommendations for binimetinib-induced toxicities.  
Table 8: 
Binimetinib – Recommended Dose Modifications Associated with Treatment-
Related Adverse Events  
Severity of Adverse Reaction 
(CTCAE v4.03) 
Binimetinib 
Cutaneous Reactions (see also Appendix 2) 

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Severity of Adverse Reaction 
(CTCAE v4.03) 
Binimetinib 
 
Grade 1 
Maintain dose level of binimetinib 
Initiate Initial Rash Treatment Regimen if it was not already started and rash 
should be closely monitored 
 
Grade 2 
1st occurrence: 
 
Maintain dose level of binimetinib 
 
Initiate Initial Rash Treatment Regimen if it was not already 
started and rash should be closely monitored 
 
Reassess within ≤ 14 days. If rash worsens or does not 
improve, interrupt dosing of binimetinib until resolved to 
Grade ≤ 1. Then resume treatment at current dose level 
binimetinib.  
2nd occurrence: 
 
Reassess within ≤ 14 days. If rash worsens or does not 
improve, interrupt dosing of binimetinib until resolved to 
Grade ≤ 1. Then resume treatment at a reduced dose level of 
binimetinib.  
 
Grade 3 
1st occurrence:  
 
Interrupt dosing of binimetinib until resolved to Grade ≤ 1. 
Reassess weekly. Then resume treatment at current dose level 
of binimetinib. 
 
Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation. 
2nd occurrence:  
 
Interrupt dosing of binimetinib until resolved to Grade ≤ 1. 
Then resume treatment at 1 reduced dose level of binimetinib. 
Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation. 
 
Grade 4 
Permanently discontinue binimetinib. 
Ocular Events:  - Retinal Events (including serous detachment of the retina) 
Note: Results and images of ocular coherence tomography (OCT) must be made available upon request. 
Any visual acuity impairment at screening should be documented and should be considered as baseline. 
 
Grade 1 
Maintain dose levels of binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days 
 
If patient remains asymptomatic (Grade 1), maintain dose 
level of binimetinib and continue the schedule of visual 
assessments established per protocol 
 
If patient becomes symptomatic (blurred vision, photophobia, 
etc.) or visual acuity assessment shows Grade 2, follow Grade 
2 dose guidelines below 
 
Grade 2 
Interrupt dosing of binimetinib and repeat ophthalmic monitoring 

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Severity of Adverse Reaction 
(CTCAE v4.03) 
Binimetinib 
including visual acuity assessment and OCT within 10 days 
 
If resolved to baseline or Grade ≤ 1, resume treatment at 
current dose level of binimetinib and continue the schedule of 
visual assessments established per protocol 
 
If not resolved to baseline or Grade ≤ 1, resume treatment at 1 
reduced dose level of binimetinib and continue the schedule 
of visual assessments established per protocol 
 
Grade 3 
Interrupt dosing of binimetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days: 
 
If resolved to baseline or Grade ≤ 2, resume treatment at 1 
reduced dose level of binimetinib and continue the schedule 
of visual assessments established per protocol  
 
If not resolved to baseline or Grade ≤ 2, continue the 
interruption and repeat the ophthalmic assessment in 10 days. 
o If resolved to baseline or Grade ≤ 2, resume treatment at 
1 reduced dose level of binimetinib and continue the 
schedule of visual assessments established per protocol 
 
If remains Grade 3, permanently discontinue binimetinib 
 
Grade 4 
Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring 
Ocular Events: Retinal Vein 
Occlusion of Any Grade 
Permanently discontinue binimetinib and immediately follow-up with 
ophthalmic monitoring. 
Ocular Events: Non-retinal Events 
 
Grade 1-2 
Maintain dose level of binimetinib and increase frequency of 
ophthalmic monitoring to at least every 14 days until stabilization or 
resolution 
 
Grade 3 
Interrupt dosing of 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 binimetinib 
 
If not resolved to Grade ≤ 1 in ≤ 21 days, permanently 
discontinue binimetinib and close follow-up with ophthalmic 
monitoring until stabilization or resolution 
 
Grade 4 
Permanently discontinue binimetinib and immediate follow-up with 
ophthalmic monitoring until stabilization or resolution 

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Severity of Adverse Reaction 
(CTCAE v4.03) 
Binimetinib 
Cardiac 
 
Symptomatic or 
Asymptomatic, absolute 
decrease in LVEF of 
greater than 10% from 
baseline that is below the 
lower limit of normal 
(LLN)  
 
 
 
 
Symptomatic congestive 
heart failure 
Withhold binimetinib and evaluate LVEF every 2 weeks. 
 
Resume binimetinib at a reduced dose if all of the following are 
present within 21 days: 
 
LVEF is at or above the lower limit of normal 
 
Absolute decrease from baseline is 10% or less 
 
Patient is asymptomatic 
 
If the LVEF does not recover within ≤ 21 days or if patient is 
symptomatic, permanently discontinue binimetinib 
 
 
Permanently discontinue binimetinib. 
Interstitial Lung Disease/Pneumonitis (see also Appendix 3) 
 
Grade 1 
 
Maintain dose level of binimetinib and monitor weekly 
 
If not resolved within 3 weeks, permanently discontinue 
binimetinib 
 
Grade 2 
 
Withhold binimetinib for up to 3 weeks. If improved to Grade 
0 or 1, resume treatment at 1 reduced level.  
 
Grade 3-4 
 
Permanently discontinue binimetinib 
Venous Thromboembolism 
 
Uncomplicated DVT or 
PE 
Withhold binimetinib for up to 3 weeks. 
 
If improved to Grade 0 or 1, resume at reduced dose. 
 
If not improved, permanently discontinue. 
 
Life threatening PE 
Permanently discontinue binimetinib. 
Liver Laboratory Abnormalities and Hepatotoxicity 
AST or ALT 
 
Grade 2  
 
 
 
 
 
Grade 3 or 4 
Maintain binimetinib dose. 
 
If no improvement within 2 weeks, withhold binimetinib until 
improved to Grade 0 or 1 or to pretreatment/baseline levels 
and then resume at the same dose.  
 
See Other 
Rhabdomyolysis/Creatine Phosphokinase (CPK) elevation 
 
Grade 1-2 
Maintain dose of binimetinib. Ensure patient is adequately hydrated. 
Closely monitor CK and serum creatinine  

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Severity of Adverse Reaction 
(CTCAE v4.03) 
Binimetinib 
 
If total CK ≥ 3 × ULN, measure CK isoenzymes and 
myoglobin in blood or urine 
 
Grade 3 
> 5.0 - 10.0 x ULN 
without  
renal impairment (i.e., 
serum creatinine < 1.5 × 
ULN or  
1.5 × baseline) 
If asymptomatic, maintain dosing of binimetinib. Ensure patient is 
adequately hydrated. Monitor and measure isoenzymes and myoglobin 
in blood or urine and serum creatinine. 
If symptomatic (muscle pain/spasms/muscle weakness), interrupt 
dosing of binimetinib until resolved to CTCAE Grade ≤ 1 and monitor 
closely, then: 
 
If resolved in ≤ 21 days, resume treatment at 1 reduced dose 
level of binimetinib 
 
If not resolved in ≤ 21 days, permanently discontinue 
binimetinib 
 
Grade 4 
without  
renal impairment (i.e., 
serum creatinine < 1.5 × 
ULN or  
1.5 × baseline) 
If asymptomatic, interrupt dosing of binimetinib. Ensure patient is 
adequately hydrated. Monitor and measure isoenzymes and 
myoglobin in blood or urine and serum creatinine 
 
If resolved in ≤ 21 days, resume treatment at 1 reduced dose 
level of binimetinib 
 
If not resolved in ≤ 21 days, permanently discontinue 
binimetinib 
If symptomatic (muscle pain/spasms/muscle weakness), permanently 
discontinue binimetinib 
 
Grade 3 or 4  
with  
renal impairment 
(i.e., serum creatinine ≥ 
1.5 × ULN or 1.5 × 
baseline) 
Interrupt dosing of binimetinib until resolved to CTCAE Grade < 1 or 
baseline level. Ensure patient is adequately hydrated. Monitor closely 
and measure isoenzymes and myoglobin in blood or urine and serum 
creatinine, then: 
 
If resolved in ≤ 21 days, consider resuming treatment at 1 
reduced dose level of binimetinib 
 
If not resolved in ≤ 21 days, permanently discontinue 
binimetinib 
2nd occurrence: 
 
Permanently discontinue binimetinib 
All Other Adverse Events (Suspected To Be Related To Binimetinib) 
 
Grade 1-2 
 
If the event is a persistent Grade 2 AE not responsive to a 
specific therapy, consider interruption or reduction of 
binimetinib 
 
Grade 3 
 
Interrupt dosing of binimetinib until resolved to Grade ≤1 or 
to pretreatment/baseline level. If the event resolves ≤ 21 days, 
then study drug may be resumed at 1 reduced dose level 
based upon the Investigator’s discretion. 

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Severity of Adverse Reaction 
(CTCAE v4.03) 
Binimetinib 
 
Grade 4 
 
Permanently discontinue binimetinib 
Abbreviations: AE = adverse event; DVT = deep vein thrombosis; LLN = lower limit of normal; PE = pulmonary embolism. 
 
6.5 
Concomitant Medications/Therapies 
6.5.1 Permitted Concomitant Medications/Therapies 
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
patient is permitted, unless otherwise specified. For additional information regarding 
concomitant medications/therapies, please refer to the IB and/or the locally approved prescribing 
information for binimetinib, nivolumab, and ipilimumab (as applicable). 
Patients receiving medications outlined below must be carefully monitored for potentiating of 
toxicity due to any individual concomitant medication and may require dose titration of the drug 
substance. Investigators should use caution when prescribing concomitant medications, as 
clinical experience with these compounds in patients with cancer is often limited. Investigators 
should contact the Sponsor when they are unsure whether a drug should be prescribed to a 
patient in the clinical study. All concomitant medications/therapies, transfusions, procedures and 
dietary supplements must be documented on the eCRF. Refer to Appendix 6 for a list of 
medications to be used with caution as mentioned above. 
6.5.1.1 
Antidiarrheals 
Patients should be treated for diarrhea as per institutional guidelines, and/or as indicated in the 
locally approved prescribing information, or for patients receiving binimetinib, per the 
supportive care recommended guidelines for the management of binimetinib-induced diarrhea 
(Appendix 1).  
6.5.1.2 
Antiemetics 
Prophylactic antiemetics should be started only once the patient experiences nausea or vomiting 
and at the discretion of the Investigator. It is recommended that patients use drugs that do not 
cause QT prolongation.  

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6.5.2 Permitted Concomitant Therapy Requiring Caution and/or Action 
6.5.2.1 
UGT Substrates and Inhibitors 
Binimetinib has been identified to be primarily metabolized by glucuronidation. It is advised that 
inhibitors and inducers of UGT1A1 should be taken with caution when co-administered with 
binimetinib (Appendix 6).  
Patients should be closely monitored for the occurrence of AEs. 
6.5.2.2 
Transporter Substrates and Inhibitors 
In vitro data showed that binimetinib is a substrate of the transporter P-gp. Binimetinib is also a 
substrate of BCRP. Thus, drugs that are known to inhibit or induce P-gp or BCRP (Appendix 6) 
should be used with caution.  
6.5.3 Prohibited Concomitant Therapy 
6.5.3.1 
Anticancer Therapy 
No additional anticancer agents such as cytotoxic chemotherapy, small-molecule targeted agents, 
biological agents, immune response modifiers or hormonal therapy are to be administered to 
patients while they are receiving study drug. 
6.5.3.2 
Other Prohibited Therapies 
The following therapies are prohibited during the study (unless otherwise noted or utilized to 
treat AEs): 
 
Investigational drugs and devices 
 
Radiation therapy (not including palliative radiotherapy at focal sites that covers ≤ 10% of 
the bone marrow reserve) 
 
Herbal preparations/medications. Patients should stop using herbal medications 7 days prior 
to first dose of study treatment. 
 
Immunosuppressive agents 
 
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 6.4.1.4 and 
6.4.1.5) 
 
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
treatment assignment are excluded. Inhaled or topical steroids, and adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease. 

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6.6 
Study Drug Supply 
6.6.1 Manufacturing, Formulation, Packaging and Labeling 
Binimetinib is supplied by the Sponsor as film-coated tablets for PO administration in a dosage 
strength of 15 mg and packaged into high-density polyethylene (HDPE) bottles with an induction 
seal and child-resistant cap. Binimetinib film-coated tablets consist of binimetinib drug 
substance; colloidal silicon dioxide/silica colloidal anhydrous; croscarmellose sodium; lactose 
monohydrate; magnesium stearate; microcrystalline cellulose/cellulose, microcrystalline; and a 
commercial film coating. The capsule-shaped tablets are yellow to dark yellow. 
For binimetinib, each bottle will be labeled, at a minimum, with a unique identifier (medication 
number), the lot number, contents (number of tablets), dosage strength, storage conditions and 
the name and address of the Sponsor.  
Nivolumab is manufactured by Bristol-Myers Squibb Company and supplied as a solution at 
10 mg/mL in a 100 mg/10 mL single-dose vial.  
Ipilimumab is manufactured by Bristol-Myers Squibb Company and supplied as a solution at 
5 mg/mL, either as a 50 mg/10 mL single-use vial or a 200 mg/40 mL single-use vial.  
All drug labels will be in the local language and comply with the regulatory requirements of each 
country, as applicable. Responsible site personnel will identify the study treatment bottle/bag to 
dispense to the patient. Site personnel will add the patient number to the label. 
6.6.2 Shipping, Storage and Handling 
Labeled, packaged study drug will be shipped to each site by the Sponsor or designee, as 
described in the Pharmacy Manual. The Investigator or an approved representative 
(e.g., registered pharmacist) will ensure that all study drug is stored as outlined in the Pharmacy 
Manual and in accordance with applicable regulatory requirements. The drug storage area at the 
site must be secure, with access limited to authorized personnel. 
Binimetinib film-coated tablets should not be stored above 25°C and should be protected from 
light. Storage conditions will be described on the medication label.  
Stability studies to support drug storage conditions have been conducted by the Manufacturer or 
an affiliate. The Manufacturer will continue to monitor the stability of binimetinib and the 
Sponsor will alert the site if a lot is nearing the end of its anticipated shelf life. 
Detailed instructions for storage and handling of binimetinib will be provided in the Pharmacy 
Manual. 

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Store nivolumab under refrigeration at 2ºC to 8ºC (36ºF to 46ºF). Protect from light by storing in 
the original package until time to use. Do not freeze or shake. 
Store ipilimumab under refrigeration at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Protect vials 
from light. 
6.6.3 Accountability and Return of Study Drug Supply 
The Investigator or an approved representative (e.g., pharmacist) must maintain accurate records 
of dates and quantities of study drug received, to whom study drug is dispensed (patient-by-
patient accounting), and accounts of any study drug accidentally or deliberately destroyed. The 
Investigator must retain all unused or expired study drug supplies until the study monitor has 
confirmed the accountability records. If site policy prohibits holding study drug supplies for 
monitor review, then a copy of the standard operating procedure (SOP) for processing drug 
returns must be provided to the Sponsor. 
To ensure adequate records, all study drugs (nivolumab, binimetinib, ipilimumab) will be 
accounted for on a drug accountability inventory form as instructed by the Sponsor. Refer to the 
Pharmacy Manual for details on how to process all unused or expired study supplies. 
6.7 
Treatment Compliance 
All patients will receive binimetinib and should be instructed to bring their study drug supply 
and bottles, if applicable, to the site at each study visit. Compliance will be evaluated at each 
visit by review of patient diary entries, an accounting of returned study drug and patient 
interviews.  
Nivolumab and ipilimumab will be administered per protocol in the clinic by study personnel. 
Information regarding individual study drug infusions is to be documented as described in 
Section 6.4.1.4 and Section 6.4.1.5, respectively. Treatment compliance will be monitored by 
drug accountability (Section 6.6.3) and the patient’s medical record and eCRF. 

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7.0 
STUDY PROCEDURES AND ASSESSMENTS 
The procedures and assessments that will be conducted during this study are described in this 
section in narrative form and are presented by study visit in Section 7.5.2 and summarized in 
Table 11 (Prescreening and Screening Phases), Table 12 (Phase 1b Arm 1A), Table 13 (Phase 1b 
Arm 1B), Table 14 (Phase 2 Arm 2A) and Table 15 (Phase 2 Arm 2B). 
Written informed consent (Prescreening and Screening informed consents) must be granted by 
each patient prior to the initiation of any study procedure or assessment (other than those 
considered SOC). 
7.1 
Prescreening/Screening Assessments and Procedures 
7.1.1 MSS and RAS Mutation Testing 
Patients will be eligible for the study based on identification of MSS and a RAS mutation in the 
tumor as determined by the central or local laboratory as part of Prescreening for the trial or by a 
local assay result obtained any time prior to Screening (see Table 11). Acceptable local assays 
are limited to PCR-based assays (including next generation sequencing [NGS]) and IHC showing 
intact expression of all mismatch repair (MMR) proteins with no loss of MLH1, MSH2, MSH6 
or PMS2.  
Patients must have central laboratory confirmation of MSS disease and RAS mutation within 
30 days after initiation of study treatment (i.e., Cycle 1 Day 1) if it was not confirmed during 
screening. In cases where the central laboratory is not able to confirm presence of MSS or a RAS 
mutation (due to inadequate or poor sample condition or due to a discordant result by the central 
laboratory) within 30 days of initiating study therapy, patients may only continue treatment if 
there is no clinical indication of deterioration or disease progression and the investigator 
determines that the patient is deriving benefit. In such instances, patients must be informed that 
the MSS and RAS mutation status is unconfirmed and must sign a separate ICF that includes this 
information and describes alternative treatment options.  
Central laboratory MSS or RAS mutation tests with a definitive result (positive or negative) 
cannot be repeated to resolve a discordant result. Patients whose sample is determined to be 
inadequate or who have an indeterminate result on central testing may have samples resubmitted 
for testing.  
Tumor samples previously determined to be MSS or RAS mutation-positive by local assessment 
may be submitted to the central laboratory. In particular, tumors with clinicopathological features 
of MSS and RAS mutations such as right colon tumors; poorly differentiated, mucinous, or 
signet-ring carcinomas; or tumors metastasized to the peritoneum (Yokota et al. 2011) should be 

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considered for testing by central laboratory regardless of the results of prior local MSS or RAS 
mutation testing.  
7.1.2 Prescreening 
The molecular prescreening can be performed at any time prior to Screening (see Section 5.2.1). 
An informed consent must be signed prior to any prescreening procedure for confirmation of 
MSS and RAS status. If a patient’s archival specimen was collected >1 year prior to 
prescreening, collection of a fresh biopsy (with blood sample) is recommended, if feasible. In 
patients with documented MSS or RAS status determined by local assay prior to the study, when 
possible, the same tissue source should be submitted to the central laboratory in order to 
minimize the potential for discordance. Information regarding tissue specimen requirements, 
sample handling and shipment will be provided in the Laboratory Manual.  
Patient numbers will be assigned manually in Phase 1b and Phase 2.  
7.1.3 Screening 
Patients with documented MSS or RAS mutation status determined by a central laboratory during 
Prescreening or by local assay prior to this study must sign a Screening ICF before additional 
screening procedures to determine eligibility for participation in the study are performed. A copy 
of the ICF will be given to the patient or their legal representative. The date that informed 
consent was obtained must be documented in source documents.  
Patient eligibility will be verified against the inclusion and exclusion criteria once all screening 
procedures are completed. The eligibility check will be embedded in the IWRS system.  
7.1.4 Information Collected for Screen Failures 
Patients who provide informed consent (i.e., via the Prescreening ICF or the Screening ICF) but 
are not enrolled/randomized for any reason will be considered screen failures.  
Date of informed consent and review of inclusion/exclusion criteria will be collected for screen 
failures as well as any AEs or SAEs possibly related to a study procedure during the screening 
period and any medications used to treat those AEs or SAEs (see Section 10.9 for SAE reporting 
details). For prescreening failures, results of the MSS and RAS assay available at Prescreening, 
AEs or SAEs possibly related to a study procedure will be collected. 
7.1.5 Patient Demographics and Other Baseline Characteristics 
Demographics, prior medications/therapies/procedures that were administered/conducted within 
28 days prior to Day 1, current medications, diagnosis and extent of tumor, baseline tumor 

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mutation status including site of disease, and details of prior antineoplastic treatments including 
number of prior metastatic regimens and prior irinotecan will be recorded. Past and present 
medical history considered by the Investigator to be significant will also be recorded.  
7.2 
Safety Assessments 
7.2.1 Adverse Events 
Adverse events will be assessed by direct observation and patient interviews on an ongoing 
basis. Patients should be questioned using non-leading questions. Definitions and reporting of 
AEs are described in detail in Section 10.0. 
7.2.2 Clinical Laboratory Tests 
Laboratory parameters to be assessed are listed in Table 9. During the course of the study, blood 
sampling for safety monitoring will be consistent with standard-of-care. 
Details regarding the collection of blood and urine samples will be outlined in the Laboratory 
Manual. 
Additional clinical laboratory tests may be obtained at any time during the study at the 
Investigator’s discretion. 

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Table 9: 
Summary of Clinical Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Coagulation 
Basophils 
Eosinophils 
Hematocrit 
Hemoglobin 
Lymphocytes 
Monocytes 
Neutrophils/ANC 
Platelets 
RBC 
WBC 
ALT 
Amylase 
AST 
Albumin 
Alkaline phosphatase 
Bicarbonate (CO2) 
Bilirubin (total and direct)a 
BNP 
BUN/urea 
CA 19-9 
Calcium 
Chloride 
CKb 
CEA 
Creatinine 
Glucose 
LDH 
Lipase 
Magnesium 
Potassium 
Sodium 
Total protein 
Troponin I  
Uric acid 
Blood 
Glucose 
Ketones 
Leukocytes 
pH 
Protein 
 
PT/INR 
aPTT 
 
Thyroid Panel 
Others 
TSH 
T3, free 
T4, free 
At Screening only: 
 
Hepatitis B surface 
antigen 
 
Hepatitis C antibody 
 
HIV, as applicable 
 
CRP 
 
If applicable: 
 
Serum pregnancy 
test 
 
LH, FSH and/or 
estradiol 
 
Serum CK 
isoenzymesb 
 
Myoglobin 
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BNP = 
brain natriuretic peptide; BUN = blood urea nitrogen; CA 19-9 = cancer antigen 19-9; CEA = carcinoembryonic antigen; CK = 
creatine kinase; CRP = C-reactive protein; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; INR = 
International Normalized Ratio; LDH = lactate dehydrogenase; LH = luteinizing hormone; pH = hydrogen ion concentration; PT 
= prothrombin time; aPPT = activated partial thromboplastin time; RBC = red blood cell(s); T3 = triiodothyronine; T4 = 
thyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cell(s). 
a Direct bilirubin will be measured at screening only if total bilirubin values are abnormal; the result will be used to calculate 
indirect bilirubin level for purposes of determining eligibility to participate in the study.  
b For Grade 2 total CK that is also > 3 × ULN or asymptomatic Grade 3 total CK: measure CK, CK isoenzymes and myoglobin 
in blood or urine weekly for 3 weeks. If total CK remains above the grade that led to the increased monitoring, continue to 
assess CK, CK isoenzymes and myoglobin, along with regularly scheduled clinical chemistry assessments, until normalization 
or improvement to Grade 1. When CK is elevated, ensure patient is adequately hydrated.   
 

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7.2.2.1 
Hematology, Coagulation and Clinical Chemistry 
Blood samples for the hematology, coagulation and chemistry laboratory tests listed in Table 9 
will be collected at the time points specified in Table 11 (Prescreening and Screening Phases), 
Table 12 (Phase 1b Arm 1A), Table 13 (Phase 1b Arm 1B), Table 14 (Phase 2 Arm 2A) and 
Table 15 (Phase 2 Arm 2B). 
Blood sample collections occurring on dosing days must be performed prior to study drug 
administration. Laboratory test results required to make decisions regarding potential dose 
modifications (as specified in Section 6.4) should be reviewed prior to study treatment 
administration. 
When assessing renal function, a single method (calculated creatinine clearance using the 
Cockroft Gault formula or estimated glomerular filtration rate using the MDRD Study formula) 
should be used consistently for a given patient throughout the study. 
7.2.2.2 
Urinalysis 
Urine samples for the laboratory tests listed in Table 9 will be collected at the time points 
specified in Table 11 (Prescreening and Screening Phases), Table 12 (Phase 1b Arm 1A), 
Table 13 (Phase 1b Arm 1B), Table 14 (Phase 2 Arm 2A) and Table 15 (Phase 2 Arm 2B). 
All urine collections occurring on dosing days must be performed prior to study treatment 
administration. 
7.2.2.3 
Pregnancy and Assessments of Fertility 
All females of childbearing potential are required to undergo a serum pregnancy assessment at 
Screening and serum or urine pregnancy assessments at subsequent time points specified in 
Table 11 (Prescreening and Screening Phases), Table 12 (Phase 1b Arm 1A), Table 13 (Phase 1b 
Arm 1B), Table 14 (Phase 2 Arm 2A) and Table 15 (Phase 2 Arm 2B). Female patients of 
nonchildbearing potential (as defined in Section 5.3) do not require pregnancy tests. Any positive 
pregnancy test will result in immediate cessation of study treatment administration.  
Female patients who have undergone female sterilization using oophorectomy alone will have a 
blood sample for measurement of luteinizing hormone (LH), follicle-stimulating hormone (FSH), 
and/or estradiol as described in Section 5.3. 
All urine collections for pregnancy tests occurring on dosing days must be performed and 
assessed prior to study treatment administration. 

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7.2.3 Vital Signs 
Vital signs (blood pressure, pulse and temperature) will be measured per institutional standards 
at the time points specified in Table 11 (Prescreening and Screening Phases), Table 12 (Phase 1b 
Arm 1A), Table 13 (Phase 1b Arm 1B), Table 14 (Phase 2 Arm 2A) and Table 15 (Phase 2 Arm 
2B). 
All vital sign measurements occurring on dosing days must be performed prior to study treatment 
administration. Any treatment-emergent abnormal findings will be recorded as AEs. 
7.2.4 Physical Examination 
Physical examinations will be performed by trained medical personnel at the time points 
specified in Table 11 (Prescreening and Screening Phases), Table 12 (Phase 1b Arm 1A), 
Table 13 (Phase 1b Arm 1B), Table 14 (Phase 2 Arm 2A) and Table 15 (Phase 2 Arm 2B).  
At Screening in both phases, full physical examinations should include the examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular and neurological. If indicated based on 
medical history and/or symptoms, rectal, external genitalia, breast and pelvic examinations will 
be performed. Full physical examinations are required throughout Phase 1b, but in Phase 2 for 
subsequent visits, the physical examinations should be targeted as clinically indicated. 
Body weight will be measured as part of the physical examination. Height will be measured only 
at Screening. All physical examinations occurring on dosing days must be performed prior to 
study treatment administration. Any treatment-emergent abnormal findings will be recorded as 
AEs. 
7.2.5 Ophthalmic Assessments 
7.2.5.1 
Routine Testing 
Full ophthalmic examination, including best corrected visual acuity for distance testing, slit lamp 
examination, intraocular pressure and dilated fundoscopy with attention to retinal abnormalities, 
especially RPED, serous detachment of the retina and RVO (or associated symptoms), will be 
performed by an ophthalmologist at the time points specified in Table 11 (Prescreening and 
Screening Phases), Table 12 (Phase 1b Arm 1A), Table 13 (Phase 1b Arm 1B), Table 14 (Phase 
2 Arm 2A) and Table 15 (Phase 2 Arm 2B). Visual field testing will be performed for patients 
only when clinically indicated. For visual field testing only, an optometrist may also perform the 
assessment. For all patients, ophthalmic assessments may be performed more frequently per 
standard of care or if clinically indicated for evaluation of any visual signs or symptoms.  

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7.2.5.2 
Additional Testing 
Patients with clinical suspicion of retinal abnormalities (i.e., RPED, serous detachment of the 
retina, RVO, photopsia, metamorphopsia, impairment of visual acuity, etc.) must complete at 
least one of the following additional assessments: 
 
For non-vascular abnormalities: OCT of the macula (spectral domain OCT recommended) 
 
For vascular abnormalities: fluorescein angiography of the central 30 degrees 
Images/results of the ophthalmic examinations (at a minimum, OCT and/or fluorescein 
angiography) should be sent to the study site and be maintained in the patient’s source document 
file. These images/results may be requested to be sent to the Sponsor or designee. 
7.2.6 Dermatologic Evaluations 
Immune-mediated rash can occur with nivolumab and immune-mediated dermatitis can occur 
with ipilumumab treatment. Patients should be monitored for rash, and signs and symptoms of 
dermatitis, such as rash and pruritus (Opdivo US PI 2017; Yervoy US PI 2017). Dermatologic 
evaluations will be performed at the time points specified in Table 11 (Prescreening and 
Screening Phases), Table 12 (Phase 1b Arm 1A), Table 13 (Phase 1b Arm 1B), Table 14 (Phase 
2 Arm 2A) and Table 15 (Phase 2 Arm 2B). Dermatologic evaluations should be performed by a 
dermatologist as clinically indicated. 
7.2.7 Electrocardiograms 
Standard single 12-lead ECGs will be performed at the time points specified in Table 11 
(Prescreening and Screening Phases), Table 12 (Phase 1b Arm 1A), Table 13 (Phase 1b Arm 
1B), Table 14 (Phase 2 Arm 2A) and Table 15 (Phase 2 Arm 2B). A triplicate ECG (3 serial 
ECGs conducted within approximately 5 to 10 minutes total time) will only be performed 
predose on Cycle 1 Day 1. 
Prior to performing the 12-lead ECG, patients should rest in the supine position for at least 
5 minutes. The ECG measurement performed at the Screening Visit will be used to determine 
eligibility. The mean of the triplicate ECG measurements recorded pre-morning dose on Cycle 1 
Day 1 will serve as the patient’s Baseline value for all postdose comparisons. The ECG 
measurement at any time point should be used for AE grading and recommended dose 
modifications. 
The Investigator will be responsible for verifying the accuracy of the electronic QTc interval 
recording using Fridericia’s correction formula: 

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QTcF = QT ÷ cube root of the RR interval 
In calculations of QTc, QT is measured in milliseconds, and RR, the duration of the entire 
cardiac cycle, is measured in seconds. 
When an ECG is to be performed at the same time point as a blood collection, the ECG is to be 
performed first.  
Interpretation of the tracing should be made by a qualified physician and documented in the 
eCRF. Clinically significant abnormalities present when the patient signed the Screening 
informed consent should be reported in the eCRF. New or worsened clinically significant 
findings occurring after the Screening informed consent must be recorded in the eCRF. 
7.2.8 Echocardiogram/Multi-gated Acquisition Scans 
Cardiac ejection fraction will be assessed by transthoracic ECHO or MUGA scans at the time 
points specified in Table 11 (Prescreening and Screening Phases), Table 12 (Phase 1b Arm 1A), 
Table 13 (Phase 1b Arm 1B), Table 14 (Phase 2 Arm 2A) and Table 15 (Phase 2 Arm 2B). The 
same method should be used throughout the study. Patients who develop signs/symptoms of 
congestive heart failure at any point during the study are required to have an evaluation of LVEF 
measurement by ECHO or MUGA. 
7.2.9 ECOG Performance Status 
Assessment of ECOG PS (Table 10) will be performed at the time points specified in Table 11 
(Prescreening and Screening Phases), Table 12 (Phase 1b Arm 1A), Table 13 (Phase 1b Arm 
1B), Table 14 (Phase 2 Arm 2A) and Table 15 (Phase 2 Arm 2B). 
ECOG PS should be obtained on the scheduled day, even if study treatment is being held. 
Table 10: 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
1 1 2  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
7. 3  
P h ar m a c o ki netic Assess me nts 
Peri p heral bl o o d sa m ples ( ~ 3 m L eac h) will be c ollecte d at t he f oll o wi n g ti me p oi nts: 1. 5 h o urs 
± 1 5 mi n utes p ost- bi ni meti ni b d ose o n C 1 D 1, pre d ose a n d 1. 5 h o urs ± 1 5 mi n utes p ost-
bi ni meti ni b d ose o n C 1 D 1 5, a n d pr e d ose o n D 1 5 d uri n g c ycles 2- 5. Pre d os e sa m ples s h o ul d be 
c ollecte d bef ore t he p atie nt ta kes t he m or ni n g d os e of bi ni meti ni b. Bi ni meti ni b a n d its acti ve 
meta b olite, A R 0 0 4 2 6 0 3 2, will be q ua ntifie d usi n g a vali date d bi oa nal ytical met h o d. 
St u d y visits f or P K sa m p li n g s h o ul d be sc he d ul e d i n t he m or ni n g s o t hat pre d ose a n d p ost d ose 
P K bl o o d sa m ples ca n be c ollecte d. O n t he P K visit da ys, t he m or ni n g d ose of bi ni meti ni b 
s h o ul d be ta ke n at t he st u dy site, o nl y aft er c ollecti n g t he pre d ose P K sa m pl e f or plas ma. Pre d ose 
sa m pli n g i nf or mati o n s h o ul d i ncl u de t he d ose a m o u nt ta ke n a n d t he dat e a n d a p pr o xi mate ti me 
of t he m ost rece nt pre vi o us d ose of bi ni meti ni b. P ost d ose sa m pli n g i nf or m ati o n s h o ul d i ncl u de 
t he date a n d a p pr o xi mate ti me of t he m or ni n g d os e, i ncl u di n g t he d os e a m o u nt ta ke n, a n d t he 
ti me of t he P K sa m ples. E x ce pt f or t he C ycl e 1 Da y 1 P K s a m ples, w hic h ha ve t o be o btai ne d o n 
t he sc he d ule d da y, ot h er P K sa m ples ma y b e o btai ne d 1 da y fr o m t he sc he d ule d date.  
If v o miti n g occ urs wit hi n 4 h o urs f oll o wi n g oral st u d y dr u g a d mi nistrati o n o n t he da y of P K 
sa m pli n g, n o a d diti o nal st u d y treat me nt s h o ul d be ta ke n i n a n eff ort t o re pl ace t he material t hat 
has bee n v o mite d. O n C ycle 1 Da y 1 a n d C ycl e 1 Da y 1 5, w he n e ver p ossi ble, t he e x act ti me 
( usi n g t he 2 4- h o urs cl oc k) of v o miti n g wit hi n t he first 4 h o urs p ost- d ose s h o ul d be rec or de d i n a 
se parat e sectio n of t he e C R F. I n a d diti o n, f or C ycles 1- 5 Da y 1 5, w he ne v er p ossi ble, t he e x act 
ti me of v o miti n g wit hi n t he first 4 h o urs p ost- d ose d uri n g t he last d a y pri or t o t he P K da y s h o ul d 
be rec or de d i n a s e parate secti o n of t he e C R F. 
If a patie nt r ecei vi n g a n y of t he treat me nts defi ne d i n t his pr ot oc ol e x perie nces a n A E t h at res ults 
i n a n u nsc he d ule d visit or meets t he criteria f or a n S A E (Secti o n 1 0. 0 ), a bl o o d sa m ple f or 
mea s ure me nt of pl as ma c o nce ntrati o ns of dr u g-rel ate d a nal ytes s h o ul d be c ollecte d, if feasi ble, if 
less t ha n 2 4 h o urs ha ve ela pse d si nce t he last d ose of st u d y dr u g. 
Bl o o d s h o ul d be c ollect e d i n acc or d a nce wit h i nstit uti o nal g ui deli nes. A n y sa m pli n g pr o ble ms 
s h o ul d be n ote d i n t he e C R F a n d o n a p pr o priate s o urce d oc u m e ntati o n. C o m plete i nstr ucti o ns f or 
sa m ple pr ocessi n g, ha n dli n g a n d s hi p me nt will be pr o vi de d i n t he La b orat or y M a n ual.  
Plas ma c o nce ntr ati o n data will be s u m marize d a n d p o p ulati o n P K a nal ysis will be perf or me d, as 
a p pr o priate. 
 
 
 
  
C CI

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
1 1 3  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
7. 4  
Bi o m ar ker Assess me nts 
7. 4. 1  
C -re a cti ve Pr otei n 
A bl o o d sa m ple ( u p t o ~ 1 0 m L) f or a n al ysis of C-reacti ve pr otei n ( C R P) will be c ollecte d at t he 
ti me p oi nts s pecifie d i n Ta ble 1 1  ( Prescree ni n g a n d Scree ni n g P hases), Ta ble 1 2  ( P hase 1 b Ar m 
1 A),  Ta ble 1 3  ( P hase 1 b Ar m 1 B),  T a ble 1 4 ( P hase 2 Ar m 2 A) a n d Ta ble 1 5  ( P hase 2 Ar m 2 B ). 
C o m plete i nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, ha n dli n g, a n d s hi p me nt t o t he ce ntral 
la b orat or y will be pr o vi d e d i n t he La b orat or y Ma n ual. 
7. 4. 2  
T u m or M a r kers ( C E A a n d C A 1 9- 9) 
Bl o o d sa m ples ( u p t o ~ 1 0 m L) f or a n al ysis of t u m or mar kers carci n oe m br y o nic a nti ge n ( C E A) 
a n d ca n cer a nti ge n 1 9- 9 ( C A 1 9- 9) will be c ollecte d at t he ti me p oi nts s pecifie d i n Ta ble 1 1  
( Prescree ni n g a n d Scree ni n g P hases), T a ble 1 2  ( P hase 1 b Ar m 1 A), Ta ble 1 3  ( P hase 1 b Ar m 
1 B ), Ta bl e 1 4  ( P hase 2 Ar m 2 A) a n d T a ble 1 5  ( P h ase 2 Ar m 2 B ). 
C o m plete i nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, ha n dli n g, a n d s hi p me nt t o t he ce ntral 
la b orat or y will be pr o vi d e d i n t he La b orat or y Ma n ual. 
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Complete instructions for sample collection, processing, handling and shipment to the central 
laboratory will be provided in the Laboratory Manual.  
Further exploratory biomarker research may be conducted on collected blood (including PK) 
samples. These studies would extend the search for other potential biomarkers relevant to the 
effects of the drugs given in combination in this study, and/or prediction of these effects, and/or 
resistance to the treatment, and/or safety, and these additional investigations would be dependent 
upon clinical outcome, reagent and sample availability. 
7.4.4 
Optional Tumor Sample Collection at Disease Progression 
Patients will be offered the option to have fresh tumor samples collected at the time of 
progression. Patients will be asked to sign a separate ICF prior to the procedure. These optional 
biopsy collections should be offered to patients with accessible lesions. Accessible lesions are 
defined as tumor lesions which are easily biopsied. Lesions with the greatest change in 
dimensional size are the recommended lesions to be excised at the time of progressive disease 
(PD). Whenever possible, biopsies at progression should be performed within 3 days of study 
drug discontinuation. The tissue from these biopsies will be used for potential pharmacodynamic 
biomarker assessments and to determine possible mechanisms of resistance. Possible 
pharmacodynamic biomarkers that would be investigated include phosphorylated ERK (pERK), 
p27, DUSP6, CyclinD1, and the cell proliferation marker Ki67 among possible others. 
Resistance mechanisms to be explored could include the acquisition of genetic alterations that 
result in the activation of MAPK pathway signaling or cause the activation of compensatory 
growth pathways (e.g., the loss of PTEN, or activating mutations in PIK3a) as well as changes in 
immune markers or gene expression profile of the tumor. Methods to examine possible 
epigenetic causes of resistance (e.g., increased expression of specific kinases that allow MAPK 
bypass) could also be explored.   
7.4.5 Retention of Samples for Future Analysis 
If the patient agrees, and in accordance with local laws, any tumor (archival or fresh) samples 
remaining after determination of MSS and RAS status may be stored for up to 2 years after the 
completion of the study. The samples may be further analyzed to address scientific questions 
and/or development of biological tests related to administration of nivolumab and binimetinib 
with or without ipilimumab and/or cancer. The decision to perform such exploratory biomarker 
research studies would be based on outcome data from this study or from new scientific findings 
related to the drug class or disease, as well as reagent and assay availability.  
The Sponsor and Bristol-Myers Squibb Company will be the exclusive owners of any data and 
discoveries resulting from this study. 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
1 1 5  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
7. 5  
Effic ac y Assess me nts 
7. 5. 1  T u m or R es p o nse  
T u m or res p o nse will be e val uate d l ocall y b y t he I n vesti gat or acc or di n g t o R E CI S T, v 1. 1 
(A p pe n di x 7 ) 
 
All p ote ntia l sites of t u m or lesi o ns will be assesse d at t he ti me p oi nts s pecifie d i n Ta ble 1 1  
( Prescree ni n g a n d Scree ni n g P hases), T a ble 1 2  ( P hase 1 b Ar m 1 A), Ta ble 1 3  ( P hase 1 b Ar m 
1 B),  Ta bl e 1 4  ( P hase 2 Ar m 2 A) a n d T a ble 1 5  ( P h ase 2 Ar m 2 B ). 
At scree ni n g, t he f oll o wi n g s h o ul d be p erf or m e d: 
 
A C T sca n wit h I V c o ntr ast of c hest, a b d o me n a n d pel vis is t he preferre d t ec h ni q ue. If t here 
is c o ncer n a b o ut ra diati o n e x p os ure, a n M RI m a y be use d i nstea d of a C T. 
 
I n p atie nts wit h a hist or y of as y m pt o matic brai n m etastases, a brai n M RI or C T sca n 
If a C T sca n or M RI was pre vi o usl y p erf or me d wit hi n 6 wee ks of C 1 D 1, t he pr oce d ure d oes n ot 
nee d t o be re peat e d at scree ni n g.  
E ver y eff ort m ust be ma d e t o assess eac h lesi o n t hat is meas ure d at s cree ni n g b y t he s a me 
met h o d t hr o u g h o ut t he st u d y s o t hat t he c o m p aris o n is c o nsiste nt.  
All p ost-scree ni n g ass ess me nts s h o ul d be perf or m e d e ver y 8 wee ks ( ± 7 da ys) fr o m C 1 D 1 
t hr o u g h Wee k 2 4, t he n e ver y 1 2 wee ks ( ± 7 da ys) t hereafter u ntil disease pr o gressi o n, wit h dra wal 
of c o nse nt, i nitiati o n of s u bse q ue nt a ntica n cer t h e ra p y, p atie nt is l ost t o f oll o w- u p, deat h or 
defi ne d e n d of st u d y ( Secti o n 4. 3 ). Re gar dless of w het her st u d y treat me nt is disc o nti n ue d, t he 
f oll o wi n g s h o ul d be perf or me d: 
 
C hest, a b d o me n, a n d pel vis C T ( or M RI) sca ns  
 
Brai n M RI or C T s ca n, if metastases were d oc u m e nte d at baseli ne 
 
A d diti o nal i ma gi n g e val u ati o ns  ma y be p erf or me d if t here is s y m pt o matic e vi de nce 
s u g gesti n g t he p ossi bilit y of disease pr o gressi o n b ase d o n cli nical s y m pt o ms or p h ysic al 
e x a mi nati o n at a n y ti me. 
If off-sc he d ule i ma gi n g e val uati o ns are p erf or m e d or if pr o gressi o n is s us p ecte d, e v er y eff ort 
s h o ul d be ma de t o perf or m s u bse q ue nt i ma gi n g e v al uati o ns i n acc or d a nce wit h t he ori gi nal 
i ma gi n g sc he d ul e.  
If a patie nt h as disease pr o gressi o n d uri n g t h e first 1 2 wee ks of st u d y treat me nt, t hat patie nt’s 
best o bjecti ve res p o ns e ( B O R) is P D. T he B O R i n patie nts w h o ha ve bee n partici pati n g i n t he 
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study for at least 6 weeks and who have not experienced a CR or PR per RECIST will be stable 
disease (SD).  
All CT scans should be performed with IV contrast. If a patient is known to have a medical 
contraindication to the contrast agent or develops a contraindication during the study, a CT scan 
without IV contrast of the chest and MRI with IV contrast, if possible, of the abdomen and pelvis 
may be performed. A CT scan of the brain, preferably with IV contrast, may be performed if 
MRI is contra-indicated. 
Chest X-ray or ultrasound should not be used for tumor response assessments in this study. 
Any lesions that have been subjected to loco-regional therapies (e.g., radiotherapy, ablation, etc.) 
should not be considered measurable, unless they have clearly progressed since the therapy. 
Previously treated lesions that have not progressed should be considered non-measurable and 
therefore, assessed as non-target lesions. 
While fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans are not required 
for this study, sites may perform combined PET/CT scans per their local standard of care, 
provided the CT is of similar diagnostic quality as CT performed without PET, including the use 
of oral and IV contrast media. If acquired according to local standard of care, FDG-PET may be 
relied upon to document PD in accordance with RECIST.  
When possible, each center should have a designated radiologist responsible for the 
interpretation of scans and response evaluations for study patients. At a minimum, a single 
radiologist should perform all evaluations for an individual patient. 
7.5.2 Survival 
Patients will be followed for survival at the time points specified in Table 12 (Phase 1b Arm 1A), 
Table 13 (Phase 1b Arm 1B), Table 14 (Phase 2 Arm 2A), and Table 15 (Phase 2 Arm 2B). 
Patients will be contacted via telephone every 12 weeks ± 2 weeks after treatment 
discontinuation until the End of Study (see Section 4.3) or until withdrawal of consent for such 
follow up, lost to follow up, or death. Patients may be contacted at additional time points to 
obtain survival status prior to planned data analyses. Survival assessment of patients who 
withdraw consent for such follow up or are lost to follow up will be conducted via public 
records. 

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8.0 
 SCHEDULE OF PROCEDURES AND ASSESSMENTS 
The procedures and assessments that will be conducted during this study are described in this 
section by study visit, described in narrative form in Section 7.0, and presented in separate tables 
for:  Table 11 (Prescreening and Screening Phases), Table 12 (Phase 1b Arm 1A), Table 13 
(Phase 1b Arm 1B), Table 14 (Phase 2 Arm 2A) and Table 15 (Phase 2 Arm 2B).  
For all visits except C1D1, there is a general ±3-day window on assessments to take into account 
scheduling over public or religious holidays, if not explicitly specified otherwise. For PK 
sampling, the samples may be obtained ±1 day from the scheduled date (except for PK sampling 
on C1D1). For imaging assessments, a ±7-day window is allowed. 
 

Bi ni meti ni b ( M E K i n hi bit or) 
 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
1 1 8  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
Ta ble 11 : 
Sc he d ule of E ve nts: Prescree ni n g a n d Scree ni n g ( All ar ms a n d p h ases) 
Pr o ce d ure/ Assess me nt  
Prescree ni n g  
Scree ni n g  
Pri or t o D a y -2 8  
D a y -2 8 t o -1  
D a y -1 4 t o -1  
Prescree ni n g i nf or me d c o nse nt  
X  
 
 
Prescree ni n g i ncl usi o n/e xcl usi o n criteria  
X  
 
 
T u m or sa m ple (arc hi val or fres h) t o c o nfir m R A S  a n d M S S stat us  
X  
 
 
Bl o o d c ollecti o n if fres h bi o ps y c ollecte d  
X  
 
 
R A S m utati o n assess me nt (ce ntral or l ocal test is acce pta ble f or eli gi bilit y 
deter mi nati o n)  
X  
 
 
M S S testi n g b y P C R or I H C ( ce ntral or l ocal test is acce pta ble f or eli gi bilit y 
deter mi nati o n)  
X  
 
 
Pri mar y i nf or me d c o nse nt  
 
X  
 
Ce ntral R A S  a n d M S S c o nfir mati o n  
 
X  
 
2 bl o o d sa m ples ( u p t o 1 0  m L eac h)  c ollecte d f or bi o mar ker a nal yses  
 
X  
 
Bl o o d sa m ple f or t u m or mar kers ( C E A, C A 1 9 -9)  
 
X  
 
De m o gra p h y  
 
X  
 
Verif y i ncl usi o n/e xcl usi o n crit eria  
 
X  
X  
Me dical hist or y  
 
X  
 
Ca ncer dia g n osis a n d e xte nt of disease  
 
X  
 
Pri or s yste mic ca ncer t hera pies, ra diati o n,  s ur ger y 
 
X  
 
T u m or b ur de n assess me nt ( R E CI S T 
 
 
X  
 
B o d y wei g ht/ hei g ht  
 
 
X  
Vital si g ns  
 
 
X  
P h ysical e xa mi nati o n  
 
 
X  
E C O G P S  
 
 
X  
O p ht hal mic e xa mi nati o na  
 
X  
 
Der mat ol o gic e xa mi nati o n 
 
X  
 
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Bi ni meti ni b ( M E K i n hi bit or) 
 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
Versi o n 4. 0 
1 1 9  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
Pr o ce d ure/ Assess me nt  
Prescree ni n g  
Scree ni n g  
Pri or t o D a y -2 8  
D a y -2 8 t o -1  
D a y -1 4 t o -1  
E C H O/ M U G A  
 
 
X  
Si n gle 1 2 -lea d E C G 
 
 
X  
Ser u m p re g na nc y test f or w o me n of c hil d beari n g p ote ntial 
 
 
 X b  
L H, F S H, a n d/ or estra di ol test f or p ost -me n o pa usal w o me n  a n d w o me n s ur gicall y 
sterile b y o o p h orect o m y al o ne 
 
 
X  
H B V a n d H C V ser ol o g y testi n g  a n d HI V w here a p plica ble  
 
 
X  
He mat ol o g y  
 
 
X  
Cli nical c he mistr y i ncl u di n g B N P a n d tr o p o ni n I 
 
 
X  
C oa g ulati o n  
 
 
X  
Car diac/ m uscle e nz y mes  
 
 
X  
T h yr oi d pa nel  
 
 
X  
C -reacti ve pr otei n le vel 
 
 
X  
Uri nal ysis (ce ntral la b)  
 
X  
 
C T or M RI of c hest, a b d o me n / pel vis, a n d brai n ( o nl y in pati e nts wit h a hist or y  of 
as y m pt o matic brai n metastases )c 
 
X  
 
C o nc o mita nt me dicati o ns/t her a pies  
 
X  
 
P hase 1 b  a n d P hase 2 : Ma n ual assi g n me nt of patie nt n u m ber 
X  
 
 
P hase 2 o nl y: Re gister i n I W R S f or ra n d o mizati o n  
 
 
X  
A b bre viati o ns: B N P = brai n natri uretic pe pti de; C A 1 9- 9 = ca ncer a nti ge n 1 9-9;  C E A =carci n oe m br y o nic a nti ge n; C T =c o m p ute d t o m o gr a p h y; E C G =electr o car di o gra m; 
E C H O =ec h ocar di o gra m; E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p; F S H =f ollicle-sti m ulati n g h or m o ne; H B V = he patitis B vir us; H C V = he patitis C vir us; HI V = h u ma n 
i m m u n o deficie nc y vir us; I H C =i m m u n o hist o c he mistr y; 
 I W R S = i nteracti ve we b res p o nse s yste m; 
L H =l utei n izi n g h or m o ne; M RI = ma g netic res o na nce i ma gi n g; M S S = micr osatellite sta ble; M U G A = m ulti gate d ac q uisiti o n; P C R = p ol y merase c hai n reacti o n; P S = perf or ma nce 
stat us; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d T u m ors.  
a F ull o p h t hal mic e xa mi n ati o n, i ncl u di n g best c orrecte d vis ual ac uit y f or dista nce testi n g, slit la m p e xa mi n ati o n, i ntra oc ular press ure a n d dilate d f u n d osc o p y wit h atte nti o n t o 
reti nal a b n or malities, es peciall y R P E D, ser o us detac h me nt of t h e reti na a n d R V O ( or ass ociate d s y m pt o ms), will be perf or me d . O ptical c o here nce t o m o gra p h y  ( O CT) a n d 
fl u orescei n a n gi o gra p h y perf or me d f or a n y n o n- vasc ular/ vasc ular a b n or malit y, res pecti vel y. Vis ual fiel d testi n g will o nl y be perf or me d w he n cli nicall y i n dicate d. 
b P erf or me d wit hi n 2 4 h o urs pri or t o Da y 1. 
c If a C T sca n or M RI was pre vi o usl y perf or me d wit hi n 6 wee ks of C 1 D 1, t he pr oce d ure d oes n ot nee d t o be re pe ate d at scree ni n g 
 
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Table 12: 
Schedule of Events: Phase 1b Arm 1A (Nivolumab + Binimetinib) 
Procedure/ Assessment 
(± 3-day window for all visits except for C1D1 
[no window] and 100-day follow up [± 7 days] 
and 150-day follow-up [+7 days]) 
Treatment Phase 
Follow-up Phase 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of 
Treatmenta 
30-Day 
Follow 
upb 
100-Day 
Follow 
upb 
150-Day 
Follow 
upb 
Day 1 
Day 15 Day 22 
Day 1 
Day 15 
Day 1 
Day 15 
Verify inclusion/exclusion criteria pre-
treatment 
X 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Physical examination 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
ECOG PS 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Ophthalmic examinationc 
 
 
 
X 
 
Xd 
 
X 
Xe 
 
 
Dermatologic examination 
X 
 
 
 
 
Xf 
 
X 
X 
 
 
ECHO/MUGA 
 
 
 
X 
 
Xg 
 
X 
 
 
 
Triplicate 12-lead ECGh 
Xi 
 
 
 
 
 
 
 
 
 
 
Single 12-lead ECGh 
Xj 
 
 
Xk 
 
Xl 
 
X 
 
 
 
Pregnancy test 
Xm 
 
 
Xn 
 
Xn 
 
Xn 
Xn 
 
 
Hematology 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
Clinical chemistry incl. BNP and troponin I 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Coagulation 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Cardiac/muscle enzymeso 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Thyroid panel 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Urinalysisp 
X 
 
 
X 
 
X 
 
 
 
 
 
PK blood sample 
Xq 
Xq,r 
 
 
Xr 
 
Xr,s 
 
 
 
 
Tumor biopsy (optional)  
 
 
 
X 
 
 
 
X 
 
 
 
Blood sample (if optional biopsy performed) 
 
 
 
X 
 
 
 
X 
 
 
 
Blood sample for biomarkers 
X 
 
 
X 
 
X 
 
X 
 
 
 
Blood sample for tumor markers (CEA, 
CA19-9) 
X 
 
 
X 
 
X 
 
X 
 
 
 
Blood sample for genomic profiling 
X 
 
 
 
 
 
 
 
 
 
 

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Procedure/ Assessment 
(± 3-day window for all visits except for C1D1 
[no window] and 100-day follow up [± 7 days] 
and 150-day follow-up [+7 days]) 
Treatment Phase 
Follow-up Phase 
Cycle 1 
Cycle 2 
Subsequent 
Cycles 
End of 
Treatmenta 
30-Day 
Follow 
upb 
100-Day 
Follow 
upb 
150-Day 
Follow 
upb 
Day 1 
Day 15 Day 22 
Day 1 
Day 15 
Day 1 
Day 15 
CT scan or MRI of chest, abdomen/pelvis, 
and brain (only if positive during screening) 
Every 8 weeks (±7 days) from C1D1 through Week 24, then every 12 weeks (±7 days) 
Nivolumab (480 mg infusion Q4W) 
X 
 
 
X 
 
Xt 
 
 
 
 
 
Binimetinib dispensing plus diary (15 mg 
tablets BID; total dose based on cohort) 
X 
 
 
X 
 
X 
 
 
 
 
 
Assess binimetinib compliance 
 
 
 
X 
 
X 
 
X 
 
 
 
Adverse events 
Assess continuously 
X 
Xv 
Concomitant medications/therapies 
Assess continuously 
X 
X 
Survival Follow up 
 
 
 
 
 
 
 
 
Xu 
Xu 
Xu 
Abbreviations: BID=twice daily; BNP=brain natriuretic peptide; CA 19-9=cancer antigen 19-9; CEA=carcinoembryonic antigen; CT=computed tomography; 
ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; IV=intravenous; MRI=magnetic resonance imaging; MUGA=multigated 
acquisition; PK=pharmacokinetic; PS=performance status; Q4W=every 4 weeks. 
a Within 2 weeks of coming off study and before the 30-day safety follow up. 
b Document subsequent anticancer therapy and progressive disease after subsequent anticancer therapy. 
c Optical coherence tomography (OCT) and fluorescein angiography performed for any non-vascular/vascular abnormality, respectively. Visual field testing will only be 
performed when clinically indicated. 
d Performed at C4D1 and then Q8W thereafter (i.e., C6D1, C8D1, C10D1, etc.).  
e Only required if there was a clinically significant abnormality noted at the End of Treatment Visit. 
f Performed at C3D1 and then Q8W thereafter (i.e., C5D1, C7D1, etc.). 
g Performed at C5D1 and then Q12W thereafter (i.e., C8D1, C11D1, etc.). 
h Electrocardiograms should be performed prior to PK and biomarker blood collection. 
i Triplicate 12-lead ECG performed pre-binimetinib administration (within 5-10 mins total time).  
j Single 12-lead ECG performed 1 hour (± 15 min) after binimetinib administration.  
k Performed pre-binimetinib administration and at 1 hour (± 15 min) after binimetinib administration.  
l Performed predose (all study drugs).  
m For women of childbearing potential only: If not performed within 24 hours prior to Day 1 dosing, perform a predose serum pregnancy test.  
n Serum or urine.  
o If creatine kinase ≥ 3 × upper limit of normal (ULN), follow with isoenzymes serum creatinine and myoglobin in blood or urine weekly and troponin in blood as applicable.  
p Performed locally; however, if abnormal, send to the central lab. 
q To be collected 1.5 hours (± 15 minutes) post-binimetinib dose. 
r To be collected pre-binimetinib dose. 
s Collected only through Cycle 5.  
t Administered at C3D1 and Q4W thereafter (i.e., C4D1, C5D1, etc.). 

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u Patients to be contacted via telephone every 12 weeks ± 2 weeks after treatment discontinuation until the End of Study (see Section 4.3) or until withdrawal of consent for such 
follow up, lost to follow up, or death. 
v Only SAEs will be assessed. 

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Table 13: 
Schedule of Events: Phase 1b Arm 1B (Nivolumab + Ipilimumab + Binimetinib) 
Procedure/ Assessment 
(± 3-day window for all visits except for 
C1D1 [no window] and 100-day follow up 
[± 7 days] and 150-day follow-up [+7days]) 
Treatment Phase 
Follow-up Phase 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of 
Treatmenta 
30-Day 
Follow 
upb 
100-Day 
Follow upb 
150-Day 
Follow upb 
Day 1 Day 15 Day 22 
Day 1 
Day 15 
Day 1 
Day 15 
Verify inclusion/exclusion criteria pre-
treatment 
X 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Physical examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
ECOG PS 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Ophthalmic examinationc 
 
 
 
X 
 
Xd 
 
X 
Xe 
 
 
Dermatologic examination 
X 
 
 
 
 
Xf 
 
X 
X 
 
 
ECHO/MUGA 
 
 
 
X 
 
Xg 
 
X 
 
 
 
Triplicate 12-lead ECGh 
Xi 
 
 
 
 
 
 
 
 
 
 
Single 12-lead ECGh 
Xj 
 
 
Xk 
 
Xl 
 
X 
 
 
 
Pregnancy test 
Xm 
 
 
Xn 
 
Xn 
 
Xn 
Xn 
 
 
Hematology 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
Clinical chemistry incl. BNP and 
troponin I 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Coagulation 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Cardiac/muscle enzymeso 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Thyroid panel 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Urinalysisp 
X 
 
 
X 
 
X 
 
 
 
 
 
PK blood sample 
Xq 
Xq,r 
 
 
Xr 
 
Xr,s 
 
 
 
 
Tumor biopsy (optional)  
 
 
 
X 
 
 
 
X 
 
 
 
Blood sample (if optional biopsy 
performed) 
 
 
 
X 
 
 
 
X 
 
 
 
Blood sample for biomarkers 
X 
 
 
X 
 
X 
 
X 
 
 
 
Blood sample for tumor markers (CEA, 
CA19-9) 
X 
 
 
X 
 
X 
 
X 
 
 
 
Blood sample for genomic profiling 
X 
 
 
 
 
 
 
 
 
 
 
CT scan or MRI of chest, 
abdomen/pelvis, and brain (only if 
positive during screening) 
Every 8 weeks (±7 days) from C1D1 through Week 24, then every 12 weeks (±7 days) 

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Procedure/ Assessment 
(± 3-day window for all visits except for 
C1D1 [no window] and 100-day follow up 
[± 7 days] and 150-day follow-up [+7days]) 
Treatment Phase 
Follow-up Phase 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of 
Treatmenta 
30-Day 
Follow 
upb 
100-Day 
Follow upb 
150-Day 
Follow upb 
Day 1 Day 15 Day 22 
Day 1 
Day 15 
Day 1 
Day 15 
Nivolumab (480 mg infusion Q4W)  
X 
 
 
X 
 
Xt 
 
 
 
 
 
Binimetinib dispensing plus diary (15 mg 
tablets BID; total dose based on cohort) 
X 
 
 
X 
 
X 
 
 
 
 
 
Assess binimetinib compliance 
 
 
 
X 
 
X 
 
X 
 
 
 
Ipilimumab (1 mg/kg Q8W) 
X 
 
 
 
 
Xu 
 
 
 
 
 
Adverse events 
Assess continuously 
X 
Xw 
Concomitant medications/therapies 
Assess continuously 
X 
X 
Survival Follow up 
 
 
 
 
 
 
 
 
Xv 
Xv 
Xv 
Abbreviations: BID=twice daily; BNP=brain natriuretic peptide; CA 19-9=cancer antigen 19-9; CEA=carcinoembryonic antigen; CT=computed tomography; 
ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; IV=intravenous; MRI=magnetic resonance imaging; MUGA=multigated 
acquisition; PK=pharmacokinetic; PS=performance status; Q4W=every 4 weeks; Q8W=every 8 weeks. 
a Within 2 weeks of coming off study and before the 30-day safety follow up. 
b Document subsequent anticancer therapy and progressive disease after subsequent anticancer therapy. 
c Optical coherence tomography (OCT) and fluorescein angiography performed for any non-vascular/vascular abnormality, respectively. Visual field testing will only be 
performed when clinically indicated. 
d Performed at C4D1 and then Q8W thereafter (i.e., C6D1, C8D1, C10D1, etc.).  
e Only required if there was a clinically significant abnormality noted at the End of Treatment Visit. 
f Performed at C3D1 and then Q8W thereafter (i.e., C5D1, C7D1, etc.). 
g Performed at C5D1 and then Q12W thereafter (i.e., C8D1, C11D1, etc.). 
h Electrocardiograms should be performed prior to PK and biomarker blood collection. 
i Triplicate 12-lead ECG performed pre-binimetinib administration (within 5-10 mins total time). 
j Single 12-lead ECG performed 1 hour (± 15 min) after binimetinib administration.  
k Performed pre-binimetinib administration and at 1 hour (± 15 min) after binimetinib administration. 
l Performed predose (all study drugs).  
m For women of childbearing potential only: If not performed within 24 hours prior to Day 1 dosing, perform a predose serum pregnancy test. 
n Serum or urine.  
o If creatine kinase ≥ 3 x upper limit of normal (ULN), follow with isoenzymes serum creatinine and myoglobin in blood or urine weekly and troponin in blood   as applicable.  
p Performed locally; however, if abnormal, send to the central lab.  
q To be collected 1.5 hours (± 15 minutes) post-binimetinib dose and before the beginning of the ipilimumab infusion on C1D1. 
r To be collected pre-binimetinib dose. 
s Collected only through Cycle 5. 
t Administered at C3D1 and Q4W thereafter (i.e., C4D1, C5D1,C6D1, etc.). 
u Administered at C3D1 and Q8W thereafter (i.e., C5D1, C7D1, C9D1, etc.). 

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v Patients to be contacted via telephone every 12 weeks ± 2 weeks after treatment discontinuation until the End of Study (see Section 4.3) or until withdrawal of consent for such 
follow up, lost to follow up, or death 
w Only SAEs will be assessed. 
 

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Table 14: 
Schedule of Events: Phase 2 Arm 2A (Nivolumab + Binimetinib) 
Procedure/ Assessment 
(± 3-day window for all visits except for C1D1 [no 
window] and 100-day follow up [± 7 days] and  
150-day follow-up [+7days]) 
Treatment Phase 
Follow-up Phase 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of 
Treatmenta 
30-Day 
Follow 
upb 
100-Day 
Follow 
upb  
150-Day 
Follow 
upb 
Day 1 Day 15 Day 22 
Day 1 
Day 15 
Day 1 
Day 15 
Verify inclusion/exclusion criteria pre-treatment 
X 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Physical examination 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
ECOG PS 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Ophthalmic examinationc 
 
 
 
X 
 
Xd 
 
X 
Xe 
 
 
Dermatologic examination 
X 
 
 
 
 
Xf 
 
X 
X 
 
 
ECHO/MUGA 
 
 
 
X 
 
Xg 
 
X 
 
 
 
Triplicate 12-lead ECGh 
Xi 
 
 
 
 
 
 
 
 
 
 
Single 12-lead ECGh 
Xj 
 
 
Xk 
 
Xl 
 
X 
 
 
 
Pregnancy test 
Xm 
 
 
Xn 
 
Xn 
 
Xn 
Xn 
 
 
Hematology 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
Clinical chemistry incl. BNP and troponin I 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Coagulation 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Cardiac/muscle enzymeso 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Thyroid panel 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Urinalysisp 
X 
 
 
X 
 
X 
 
 
 
 
 
PK blood sample 
Xq 
Xq,r 
 
 
Xr 
 
Xr,s 
 
 
 
 
Tumor biopsy (optional) 
 
 
 
X 
 
 
 
X 
 
 
 
Blood sample (if optional biopsy performed)  
 
 
 
X 
 
 
 
X 
 
 
 
Blood sample for biomarkers 
X 
 
 
X 
 
X 
 
X 
 
 
 
Blood sample for tumor markers 
X 
 
 
X 
 
X 
 
X 
 
 
 
Blood sample for genomic profiling 
X 
 
 
 
 
 
 
 
 
 
 
CT scan or MRI of chest, abdomen/pelvis, and 
brain (only if positive during screening) 
Every 8 weeks (±7 days) from C1D1 through Week 24, then every 12 weeks (±7 days) 

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Procedure/ Assessment 
(± 3-day window for all visits except for C1D1 [no 
window] and 100-day follow up [± 7 days] and  
150-day follow-up [+7days]) 
Treatment Phase 
Follow-up Phase 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of 
Treatmenta 
30-Day 
Follow 
upb 
100-Day 
Follow 
upb  
150-Day 
Follow 
upb 
Day 1 Day 15 Day 22 
Day 1 
Day 15 
Day 1 
Day 15 
Nivolumab (480 mg infusion) 
X 
 
 
X 
 
Xt 
 
 
 
 
 
Binimetinib dispensing plus diary (15 mg 
tablets BID at the RP2D) 
X 
 
 
X 
 
X 
 
 
 
 
 
Assess binimetinib compliance 
 
 
 
X 
 
X 
 
X 
 
 
 
Adverse events 
Assess continuously 
X 
Xv 
Concomitant medications/therapies 
Assess continuously 
X 
X 
Survival Follow up 
 
 
 
 
 
 
 
 
Xu 
Xu 
Xu 
Abbreviations: BID=twice daily; BNP=brain natriuretic peptide; CA 19-9=cancer antigen 19-9; CEA=carcinoembryonic antigen; CT=computed tomography; 
ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; IV=intravenous; MRI=magnetic resonance imaging; MUGA=multigated 
acquisition; PK=pharmacokinetic; PS=performance status; Q4W=every 4 weeks; RP2D=recommended Phase 2 dose. 
a Within 2 weeks of coming off study and before the 30-day safety follow up. 
b Document subsequent anticancer therapy and progressive disease after subsequent anticancer therapy. 
c Optical coherence tomography (OCT) and fluorescein angiography performed for any non-vascular/vascular abnormality, respectively. Visual field testing will only be 
performed when clinically indicated. 
d Performed at C4D1 and then Q8W thereafter (i.e., C6D1, C8D1, C10D1, etc.).  
e Only required if there was a clinically significant abnormality noted at the End of Treatment Visit. 
f Performed at C3D1 and then Q8W thereafter (i.e., C5D1, C7D1, etc.). 
g Performed at C5D1 and then Q12W thereafter (i.e., C8D1, C11D1, etc.). 
h Electrocardiograms should be performed prior to PK and biomarker blood collection. 
i Triplicate 12-lead ECG performed pre-binimetinib administration (within 5-10 mins total time).  
j Single 12-lead ECG performed 1 hours (± 15 min) after binimetinib administration.  
k Performed pre-binimetinib administration and at 1 hour (± 15 min) after binimetinib administration.  
l Performed predose (all study drugs).  
m For women of childbearing potential only: If not performed within 24 hours prior to Day 1 dosing, perform a predose serum pregnancy test.  
n Serum or urine.  
o If creatine kinase ≥ 3 x upper limit of normal (ULN), follow with isoenzymes serum creatinine and myoglobin in blood or urine weekly and troponin in blood as applicable.  
p Performed locally; however, if abnormal, send to the central lab.  
q To be collected 1.5 hours (± 15 minutes) post-binimetinib dose  
r To be collected pre-binimetinib dose. 
s Collected only through Cycle 5. 
t Administered at C3D1 and Q4W thereafter (i.e., C4D1, C5D1, C6D1, etc.).  
u Patients to be contacted via telephone every 12 weeks ± 2 weeks after treatment discontinuation until the End of Study (see Section 4.3) or until withdrawal of consent for such 
follow up, lost to follow up, or death. 
v Only SAEs will be assessed. 

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Table 15: 
Schedule of Events: Phase 2 Arm 2B (Nivolumab + Ipilimumab + Binimetinib) 
Procedure/ Assessment 
(± 3-day window for all visits except for C1D1 [no 
window] and 100-day follow up [± 7 days] and 150-
day follow-up [+7days]) 
Treatment Phase 
Follow-up Phase 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of 
Treatmenta 
30-Day 
Follow 
upb 
100-Day 
Follow 
Upb 
150-Day 
Follow 
Upb 
Day 1 Day 15 Day 22 
Day 1 Day 15 
Day 1 
Day 15 
Verify inclusion/exclusion criteria pre-treatment 
X 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Physical examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
ECOG PS 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Ophthalmic examinationc 
 
 
 
X 
 
Xd 
 
X 
Xe 
 
 
Dermatologic examination 
X 
 
 
 
 
Xf 
 
X 
X 
 
 
ECHO/MUGA 
 
 
 
X 
 
Xg 
 
X 
 
 
 
Triplicate 12-lead ECGh 
Xi 
 
 
 
 
 
 
 
 
 
 
Single 12-lead ECGh 
Xj 
 
 
Xk 
 
Xl 
 
X 
 
 
 
Pregnancy test 
Xm 
 
 
Xn 
 
Xn 
 
Xn 
Xn 
 
 
Hematology 
X 
X 
X 
X 
 
X 
 
X 
X 
 
 
Clinical chemistry incl. BNP and troponin I 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Coagulation 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Cardiac/muscle enzymeso 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Thyroid panel 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Urinalysisp 
X 
 
 
X 
 
X 
 
 
 
 
 
PK blood sample 
Xq 
Xq,r 
 
 
Xr 
 
Xr,s 
 
 
 
 
Tumor biopsy (optional) 
 
 
 
X 
 
 
 
X 
 
 
 
Blood sample (if optional biopsy performed) 
 
 
 
X 
 
 
 
X 
 
 
 
Blood sample for biomarkers 
X 
 
 
X 
 
X 
 
X 
 
 
 
Blood sample for tumor markers (CEA and CA 
19-9) 
X 
 
 
X 
 
X 
 
X 
 
 
 
Blood sample for genomic profiling 
X 
 
 
 
 
 
 
 
 
 
 
CT scan or MRI of chest, abdomen/pelvis, and 
brain (only if positive during screening) 
Every 8 weeks (±7 days) from C1D1 through Week 24, then every 12 weeks (±7 days) 
Nivolumab (480 mg infusion Q4W) 
X 
 
 
X 
 
Xt 
 
 
 
 
 

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Procedure/ Assessment 
(± 3-day window for all visits except for C1D1 [no 
window] and 100-day follow up [± 7 days] and 150-
day follow-up [+7days]) 
Treatment Phase 
Follow-up Phase 
Cycle 1 
Cycle 2 
Subsequent Cycles 
End of 
Treatmenta 
30-Day 
Follow 
upb 
100-Day 
Follow 
Upb 
150-Day 
Follow 
Upb 
Day 1 Day 15 Day 22 
Day 1 Day 15 
Day 1 
Day 15 
Binimetinib dispensing plus diary (15 mg 
tablets BID at the RP2D) 
X 
 
 
X 
 
X 
 
 
 
 
 
Assess binimetinib compliance 
 
 
 
X 
 
X 
 
X 
 
 
 
Ipilimumab (1 mg/kg Q8W) 
X 
 
 
 
 
Xu 
 
 
 
 
 
Adverse events 
Assess continuously 
X 
Xw 
Concomitant medications/therapies 
Assess continuously 
X 
X 
Survival Follow up 
 
 
 
 
 
 
 
 
Xv 
Xv 
Xv 
Abbreviations: BID=twice daily; BNP=brain natriuretic peptide; CA 19-9=cancer antigen 19-9; CEA=carcinoembryonic antigen; CT=computed tomography; 
ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; IV=intravenous; MRI=magnetic resonance imaging; MUGA=multigated 
acquisition; PK=pharmacokinetic; PS=performance status; Q4W=every 4 weeks; Q8W=every 8 weeks; RP2D=recommended Phase 2 dose. 
a Within 2 weeks of coming off study and before the 30-day safety follow up. 
b Document subsequent anticancer therapy and progressive disease after subsequent anticancer therapy. 
c Optical coherence tomography (OCT) and fluorescein angiography performed for any non-vascular/vascular abnormality, respectively. Visual field testing will only be 
performed when clinically indicated. 
d Performed at C4D1 and then (Q8W thereafter (i.e., C6D1, C8D1, C10D1, etc.).  
e Only required if there was a clinically significant abnormality noted at the End of Treatment Visit. 
f Performed at C3D1 and then Q8W thereafter (i.e., C5D1, C7D1, etc.). 
g Performed at C5D1 and then Q12W thereafter (i.e., C8D1, C11D1, etc.). 
h Electrocardiograms should be performed prior to PK and biomarker blood collection. 
i Triplicate 12-lead ECG performed pre-binimetinib administration (within 5-10 minutes total time).  
j Single 12-lead ECG performed 1 hour (± 15 min) after binimetinib administration.  
k Performed pre-binimetinib administration and at 1 hours (± 15 min) after binimetinib administration.  
l Performed predose (all study drugs).  
m For women of childbearing potential only: If not performed within 24 hours prior to Day 1 dosing, perform a predose serum pregnancy test.  
n Serum or urine.  
o If creatine kinase ≥ 3 x upper limit of normal (ULN), follow with isoenzymes serum creatinine and myoglobin in blood or urine weekly and troponin in blood as applicable.  
p Performed locally; however, if abnormal, send to the central lab.  
q To be collected 1.5 hours (± 15 minutes) post-binimetinib dose and before the beginning of the ipilimumab infusion on C1D1. To be collected pre-binimetinib dose. 
r To be collected pre-binimetinib dose. 
s Collected only through Cycle 5. 
t Administered at C3D1 and Q4W thereafter (i.e., C4D1, C5D1, C6D1, etc.).  
u Administered at C3D1 and Q8W thereafter (i.e., C5D1, C7D1, C9D1, etc.). 
v Patients to be contacted via telephone every 12 weeks ± 2 weeks after treatment discontinuation until the End of Study (see Section 4.3) or until withdrawal of consent for such 
follow up, lost to follow up, or death. 
w Only SAEs will be assessed. 

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8.1 
Prescreening (All Arms and Phases) 
Patient may undergo molecular prescreening at any time prior to randomization based on 
eligibility criteria described in Section 5.2.1.  
 
Obtain written informed consent for molecular testing 
 
Verify all prescreening inclusion/exclusion criteria 
 
Manually assign a patient study number 
 
If tumor has previously been determined to be MSS and RAS mutant by local assay, confirm 
testing was done using PCR, IHC or NGS 
 
Obtain and send archival or fresh tumor specimen to the central laboratory, as soon as 
possible following the signing of the Prescreening informed consent for confirmation of MSS 
and RAS status (see Section 7.1.1). If an adequate archival tumor sample (tumor block or 
minimum of 6 slides; optimally up to 15 slides) is not available, a tumor biopsy is required. If 
a patient’s archival specimen was collected >1 year prior to prescreening, collection of a 
fresh biopsy is recommended, if feasible. The same tumor sample will be used for the RAS 
and MSI testing. If the central laboratory determines that the sample is inadequate for 
analysis, a second sample may be submitted. 
 
If a fresh biopsy is collected, collect a blood sample at the time of biopsy 
8.2 
Screening (All Arms and Phases) 
All screening procedures to determine eligibility for study participation must be performed 
within specific time windows before the first dose of study treatment. Eligibility is determined 
using results of screening assessments performed before the first dose of study treatment and up 
to and including Day 1. Patients may be re-screened once at the discretion of the Investigator 
and/or individual assessments may be repeated, as appropriate. If a particular assessment is 
repeated, the results obtained closest to the first dose of study treatment should be used to assess 
eligibility. 
At the site, the Investigator will maintain a log for all screened patients (including patients who 
fail screening after providing written informed consent) and all enrolled patients. If the patient 
has not been molecularly prescreened, obtain written informed consent for molecular testing. 
Screening:  Within 28 days prior to Day 1 
 
Obtain Screening informed consent (must be obtained prior to performance of any study-
specific tests or evaluations that are not considered SOC) 
 
Confirm MSS and RAS status using a central laboratory if not performed previously 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
 
Versi o n 4. 0 
1 3 1  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
 
C ollect 2 bl o o d sa m ples ( u p t o 1 0 m L eac h) f or bi o mar ker a nal yses 
 
Rec or d de m o gra p hic i nf or mati o n (a ge, race, et h nicit y). 
 
Rec or d c urre nt a n d p ast me dical hist or y  
 
D oc u me nt ca n cer di a g n osis a n d e xte nt of disease 
 
D oc u me nt pri or s yste mic ca ncer t hera pies, ra diati o n, s ur ger y  
 
Rec or d all me di cati o ns/tr eat me nts t hat were a d mi nistere d/c o n d ucte d wit hi n 2 8 da ys pri or t o 
Da y 1 
 
O btai n f ull o p ht hal mic e x a mi nati o n 
 
O btai n f ull der mat ol o gic e x a mi nati o n 
 
O btai n uri ne sa m ple f or uri nal ysis 
 
C T or M RI of c hest, a b d o me n/ pel vis, a n d brai n ( o nl y i n patie nts wit h a hist or y of 
as y m pt o matic brai n metastases 
 
C o m plete t u m or b ur de n assess me nts acc or di n g t o R E CI S T 
 
 
Verif y all Scree ni n g i ncl usi o n/e x cl usi o n criteria  
Scree ni n g:  Wit hi n 1 4 d a ys pri or t o D a y 1 
 
Meas ure b o d y wei g ht a n d hei g ht 
 
Assess vital si g ns ( bl o o d press ure, p ulse, a n d te m p erat ur e)  
 
 C o m plete p h ysical e x a mi nati o n  
 
Assess E C O G P S 
 
Perf or m E C H O/ M U G A s ca n  
 
Si n gle E C G 
 
C ollecti o n of bl o o d sa m ples f or t he f oll o wi n g:  
o  He mat ol o g y, c o a g ulati o n, c he mistr y i n cl u di n g brai n natri uretic pe pti de ( B N P) a n d 
tr o p o ni n I  
o  S er u m pre g na n c y test (fe males of c hil d beari n g p ot e ntial o nl y)  
o  L H, F S H a n d/ or estra di ol ( o nl y f or fe m ales w h o are p ost- me n o pa usal a n d fe males 
s ur gi call y sterile b y o o p h orect o m y al o ne)  
o  He patitis B s urface a nti ge n 
o  He patitis C a nti b o d y 
o  H I V, w here a p plica ble 
C CI

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
 
Versi o n 4. 0 
1 3 2  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
o  C R P  
o  C ar diac/ m uscle e nz y mes 
o  T h yr oi d p a nel 
 
Verif y all Scree ni n g i ncl usi o n/e x cl usi o n criteria 
 
P h ase 2 o nl y:  Re gister patie nt i n I W R S f or ra n d o mizati o n 
8. 3  
P h ase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u m a b + bi ni meti ni b): C ycle 1 
8. 3. 1  P h ase 1 b Ar m 1 A a n d P h ase 2 Ar m 2 A ( ni v ol u m a b + bi ni meti ni b): C ycle 1 D a y 1 
N ote: Critic al pr oce d ures a n d ac tivities t h at occ ur cl osely t o get her ar o u n d t he ti me of st u dy dr u g 
a d mi nistr ati o n o n Cycle 1 D ay 1 are re prese nte d i n  Fi g ure 3  i n or der t o assist wit h t he ti mi n g of 
e ac h activit y. T he fi g ure d oes n ot i ncl u de all re q uire d pr oce d ures a n d a ctivities occ urri n g o n 
Cycle 1 D ay 1. 
 
V erif y all Scree ni n g i ncl usi o n/e x cl usi o n criteria pretreat me nt 
 
Meas ure b o d y wei g ht 
 
Assess vital si g ns ( bl o o d press ure, p ulse, a n d te m p erat ur e)  
 
C o m plete p h ysical e x a mi nati o n  
 
Assess E C O G P S 
 
O btai n f ull der mat ol o gic e x a mi nati o n 
 
Tri plicate 1 2-l ea d E C G p erf or me d pre- bi ni meti ni b a d mi nistrati o n ( wit hi n 5- 1 0 mi n utes t otal 
ti me), t he n a si n gl e E C G 1 h o ur ( ± 1 5 mi n utes) aft er bi ni meti ni b a d mi nistrati o n  
 
C ollecti o n of  bl o o d sa m ples f or t he f oll o wi n g: 
o  He mat ol o g y, c o a g ulati o n, c he mistr y i n cl u di n g B N P a n d tr o p o ni n I  
o  If n ot perf or me d wit hi n 2 4 h o urs pri or t o Da y 1 d osi n g, pre d os e ser u m pre g na nc y test 
(fe males of c hil d beari n g p ote ntial o nl y)  
o  C ar diac/ m uscle e nz y mes 
o  T h yr oi d p a nel 
o  B i o mar ker a nal ysis 
 
 
 
O btai n uri ne sa m pl e f or uri nal ysis 
 
C T or M RI of c hest, a b d o me n/ pel vis, a n d brai n ( o nl y if p ositi ve d uri n g scree ni n g)  
 
A d mi nister bi ni meti ni b  
C CI

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 
Administer nivolumab 
 
Collect a PK blood sample 1.5 hours (± 15 minutes) post binimetinib dosing 
 
Dispense a 4-week supply of binimetinib along with a monthly diary. Review dosing 
instructions with patient. 
 
Assess AEs 
 
Assess concomitant medications/therapies 
Figure 3: 
Arm 1A/Arm 2A: Timing of ECGs and Blood Collections in Relation to Study 
Drug Administration on Cycle 1 Day 1 
 
 
8.3.2 Phase 1b Arm 1A and Phase 2 Arm 2A (nivolumab + binimetinib): Cycle 1 Day 15 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Collection of blood samples for the following: 
o Hematology, chemistry including BNP and troponin I  
o Cardiac/muscle enzymes 
o PK analysis (collected prior to morning dose of binimetinib) 
 
Administer binimetinib 
 
Collect a PK blood sample 1.5 hours (± 15 minutes) post binimetinib dosing 
 
Assess AEs 
 
Assess concomitant medications/therapies 

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8.3.3 Phase 1b Arm 1A and Phase 2 Arm 2A (nivolumab + binimetinib): Cycle 1 Day 22 
 
Collection of blood samples for the following: 
o Hematology 
o Cardiac/muscle enzymes 
 
Assess AEs 
 
Assess concomitant medications/therapies 
8.4 
Phase 1b Arm 1A and Phase 2 Arm 2A (nivolumab + binimetinib): Cycle 2 
8.4.1 Phase 1b Arm 1A and Phase 2 Arm 2A (nivolumab + binimetinib): Cycle 2 Day 1 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Obtain full ophthalmic examination 
 
Perform ECHO/MUGA scan 
 
Single 12-lead ECG performed pre-binimetinib administration, then 1 hour (± 15 minutes) 
after binimetinib administration  
 
Collection of blood samples for the following: 
o Hematology, coagulation, chemistry including BNP and troponin I  
o Serum (or urine) pregnancy test (females of childbearing potential only)  
o Cardiac/muscle enzymes 
o Thyroid panel 
o Biomarker analysis  
 
Obtain urine sample for urinalysis 
 
Perform optional tumor biopsy and if performed, collect a blood sample at the time of biopsy 
 
Administer binimetinib 
 
Administer nivolumab 
 
Assess binimetinib compliance and dispense a 4-week supply along with a monthly diary. 
Review dosing instructions with patient. 
 
Assess AEs 
 
Assess concomitant medications/therapies 

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8.4.2 Phase 1b Arm 1A and Phase 2 Arm 2A (nivolumab + binimetinib): Cycle 2 Day 15 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Collection of blood samples for the following: 
o Cardiac/muscle enzymes 
o PK analysis (collected prior to morning dose of binimetinib) 
 
Assess AEs 
 
Assess concomitant medications/therapies 
8.5 
Phase 1b Arm 1A and Phase 2 Arm 2A (nivolumab + binimetinib): Subsequent 
Cycles 
8.5.1 Phase 1b Arm 1A and Phase 2 Arm 2A (nivolumab + binimetinib): Subsequent 
Cycles Day 1 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Cycle 3 Day 1, Cycle 5 Day 1 and Cycle 7 Day 1 and then Q12W: (±7 days): CT or MRI 
of chest, abdomen/pelvis, and brain (only if positive during screening) 
 
Cycle 3 Day 1: Obtain full dermatologic examination - performed Q8W thereafter (i.e., 
C5D1, C7D1, etc.) 
 
Cycle 4 Day 1: Obtain full ophthalmic examination - performed Q8W thereafter (i.e., C6D1, 
C8D1, etc.).  
 
Cycle 5 Day 1 and then Q12W: Perform ECHO/MUGA scan 
 
Single 12-lead ECG performed predose (all study drugs) 
 
Collection of blood samples for the following: 
o Hematology, coagulation, chemistry including BNP and troponin I  
o Serum (or urine) pregnancy test (females of childbearing potential only)  
o Cardiac/muscle enzymes 
o Thyroid panel 
o Biomarker analysis 
 
Obtain urine sample for urinalysis 
 
Administer binimetinib 

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Administer nivolumab – then Q4W thereafter 
 
Assess binimetinib compliance and dispense a 4-week supply along with a monthly diary. 
Review dosing instructions with patient. 
 
Assess AEs 
 
Assess concomitant medications/therapies 
8.5.2 Phase 1b Arm 1A and Phase 2 Arm 2A (nivolumab + binimetinib): Subsequent 
Cycles Day 15 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Cycles 3 through 5: Collect blood samples for PK analysis prior to morning dose of 
binimetinib 
 
Assess AEs 
 
Assess concomitant medications/therapies 
8.6 
Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Cycle 1 
8.6.1 Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Cycle 1 Day 1 
Note: Critical procedures and activities that occur closely together around the time of study drug 
administration on Cycle 1 Day 1 are represented in Figure 4 in order to assist with the timing of 
each activity. The figure does not include all required procedures and activities occurring on 
Cycle 1 Day 1. 
 
Verify all Screening inclusion/exclusion criteria pretreatment 
 
Phase 2 only: Register patient in IWRS for randomization 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Obtain full ophthalmic examination 
 
Obtain full dermatologic examination 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
 
Versi o n 4. 0 
1 3 7  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
 
Tri plicate 1 2-l ea d E C G p erf or me d pre- bi ni meti ni b a d mi nistrati o n ( wit hi n 5- 1 0 mi n utes t otal 
ti me), t he n a si n gl e E C G 1 h o ur ( ± 1 5 mi n utes) aft er bi ni meti ni b a d mi nistrati o n 
 
C ollec ti o n of bl o o d sa m ples f or t he f oll o wi n g: 
o  He mat ol o g y, c o a g ulati o n, c he mistr y i n cl u di n g B N P a n d tr o p o ni n I  
o  If n ot perf or me d wit hi n 2 4 h o urs pri or t o Da y 1 d osi n g, pre d os e ser u m pre g na nc y test 
(fe males of c hil d beari n g p ote ntial o nl y)  
o  C ar diac/ m uscle e nz y mes 
o  T h yr oi d p a nel 
o  B i o mar ker a nal ysis 
 
 
 
O btai n uri ne sa m ple f or uri nal ysis 
 
C T or M RI of c hest, a b d o me n/ pel vis, a n d brai n ( o nl y if p ositi ve d uri n g scree ni n g)  
 
A d mi nister bi ni meti ni b  
 
A d mi nister ni v ol u ma b  
 
C ollect a P K bl o o d sa m ple 1. 5 h o urs ( ± 1 5 mi n utes) p ost bi ni meti ni b d osi n g 
 
A d mi nister i pili m u ma b a fter P K bl o o d sa m ple is c ollecte d 
 
Dis pe nse a 4- wee k s u p pl y of bi ni meti ni b al o n g wit h a m o nt hl y diar y. Re vie w d osi n g 
i nstr ucti o ns wit h patient.  
 
Assess A Es 
 
Assess c o nc o mita nt me di cati o ns/t hera pies 
C CI

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Figure 4: 
Arm 1B/Arm 2B: Timing of ECGs and Blood Collections in Relation to Study 
Drug Administration on Cycle 1 Day 1 
 
 
8.6.2 Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Cycle 1 Day 15 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Collection of blood samples for the following: 
o Hematology, coagulation, chemistry including BNP and troponin I  
o Cardiac/muscle enzymes 
o PK analysis (collected prior to morning dose of binimetinib) 
 
Administer binimetinib 
 
Collect a PK blood sample 1.5 hours (± 15 minutes) post binimetinib dosing 
 
Assess AEs 
 
Assess concomitant medications/therapies 
8.6.3 Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Cycle 1 Day 22 
 
Collection of blood samples for the following: 

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o Hematology 
o Cardiac/muscle enzymes 
 
Assess AEs 
 
Assess concomitant medications/therapies 
8.7 
Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Cycle 2 
8.7.1 Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Cycle 2 Day 1 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Obtain full ophthalmic examination 
 
Perform ECHO/MUGA scan 
 
Single 12-lead ECG performed pre-binimetinib administration, then 1 hour (± 15 minutes) 
after binimetinib administration 
 
Collection of blood samples for the following: 
o Hematology, coagulation, chemistry including BNP and troponin I  
o Serum (or urine) pregnancy test (females of childbearing potential only)  
o Cardiac/muscle enzymes 
o Thyroid panel 
o Biomarker analysis 
 
Obtain urine sample for urinalysis 
 
Perform optional tumor biopsy and if performed, collect a blood sample at the time of biopsy 
 
Administer binimetinib 
 
Administer nivolumab 
 
Assess binimetinib compliance and dispense a 4-week supply along with a monthly diary. 
Review dosing instructions with patient. 
 
Assess AEs 
 
Assess concomitant medications/therapies 

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8.7.2 Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Cycle 2 Day 15 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Collection of blood samples for the following: 
o Cardiac/muscle enzymes 
o PK analysis (collected prior to morning dose of binimetinib) 
 
Assess AEs 
 
Assess concomitant medications/therapies 
8.8 
Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Subsequent Cycles 
8.8.1 Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Subsequent Cycles Day 1 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Cycle 3 Day 1, Cycle 5 Day 1 and Cycle 7 Day 1 and then Q12W: (±7 days): CT or MRI 
of chest, abdomen/pelvis, and brain (only if positive during screening) 
 
Cycle 4 Day 1: Obtain full ophthalmic examination - performed Q8W thereafter (i.e., C6D1, 
C8D1, etc.)  
 
Obtain full dermatologic examination - performed Q8W thereafter 
 
Perform ECHO/MUGA scan then Q12W thereafter 
 
Single 12-lead ECG performed predose (all study drugs) 
 
Collection of blood samples for the following: 
o Hematology, coagulation, chemistry including BNP and troponin I 
o Serum (or urine) pregnancy test (females of childbearing potential only)  
o Cardiac/muscle enzymes 
o Thyroid panel 

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o Biomarker analysis 
 
Obtain urine sample for urinalysis 
 
Administer binimetinib 
 
Administer nivolumab  
 
Administer ipilimumab - administered Q8W thereafter 
 
Assess binimetinib compliance and dispense a 4-week supply along with a monthly diary. 
Review dosing instructions with patient. 
 
Assess AEs 
 
Assess concomitant medications/therapies 
8.8.2 Phase 1b Arm 1B and Phase 2 Arm 2B (nivolumab + binimetinib + ipilimumab): 
Subsequent Cycles Day 15 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Cycles 3 through 5: Collect blood samples for PK analysis prior to morning dose of 
binimetinib 
 
Assess AEs 
 
Assess concomitant medications/therapies 
8.9 
Follow-up Visits (All Arms and Phases) 
8.9.1 End of Treatment Visit 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Obtain full ophthalmic examination 
 
Obtain full dermatologic examination 
 
Perform ECHO/MUGA scan 
 
Single 12-lead ECG  
 
Collection of blood samples for the following: 

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o Hematology, coagulation, chemistry including BNP and troponin I  
o Serum (or urine) pregnancy test (females of childbearing potential only)  
o Cardiac/muscle enzymes 
o Thyroid panel 
o Biomarker analysis 
 
Perform optional tumor biopsy and if performed, collect a blood sample at the time of biopsy 
 
Assess binimetinib compliance  
 
Assess AEs 
 
Assess concomitant medications/therapies 
8.9.2 30-Day Safety Follow-up Visit 
All patients will return for a 30-Day Safety Follow-up Visit approximately 30 days (± 3 days) 
after the last dose of study drug. Information related to AEs (including concomitant medication 
taken for ongoing AEs) and ongoing antineoplastic treatments will be collected (see 
Section 10.9). 
 
Measure body weight 
 
Assess vital signs (blood pressure, pulse, and temperature) 
 
Complete physical examination  
 
Assess ECOG PS 
 
Obtain full dermatologic examination 
 
Collection of blood samples for the following: 
o Hematology, coagulation, chemistry including BNP and troponin I  
o Serum (or urine) pregnancy test (females of childbearing potential only)  
o Thyroid panel 
 
Assess AEs 
 
Assess concomitant medications/therapies 
 
If applicable, document subsequent anticancer therapy and progressive disease after 
subsequent anticancer therapy 
8.9.3 100-Day Safety Follow-Up Visit 
All patients will return for a 100-Day Safety Follow-Up visit which occurs 100 days (± 7 days) 
after last dose of study drug. Information related to AEs and SAEs (including concomitant 

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medication taken for ongoing AEs/SAEs) and ongoing antineoplastic treatments will be collected 
(see Section 10.9). 
 
Assess all AEs and SAEs 
 
Assess concomitant medications/therapies administered for all AEs and SAEs 
 
If applicable, document subsequent anticancer therapy and progressive disease after 
subsequent anticancer therapy  
8.9.4 150-Day Safety Follow-Up Assessment (Phone Call) 
All patients will be contacted via telephone 150 days (+ 7 days) after last dose of study drug to 
obtain information on SAEs (including concomitant medications taken for ongoing SAEs) and 
survival as available. Ongoing antineoplastic treatments will be collected if available (see 
Section 10.9). 
8.9.5 Tumor Assessment Follow-up Visits 
All tumor assessments should be performed every 8 weeks (±7 days) from C1D1 through Week 
24, then every 12 weeks (±7 days) thereafter until disease progression, withdrawal of consent, 
initiation of subsequent anticancer therapy, patient is lost to follow-up, death or defined end of 
study (Section 4.3). 
 
CT or MRI of chest, abdomen/pelvis, and brain (only if positive during screening). 
8.9.6 Survival Follow-up 
Contact patients or medical caregiver via telephone every 12 weeks ± 2 weeks after treatment 
discontinuation for survival status until the End of Study (see Section 4.3) or until withdrawal of 
consent for such follow up, lost to follow up, or death. 
 
If applicable, document subsequent anticancer therapy and progressive disease after 
subsequent anticancer therapy. 
8.10 Collection of Data for Ongoing Patients Following Database Lock 
If the primary objective of the study has been met or the Sponsor decides to stop the study early, 
the database may be locked for the purpose of analyzing and reporting data. Patients may 
continue to receive study treatment per protocol beyond database lock if the Investigator and the 
Sponsor agree that patients’ best interests are served by continuing to receive study treatment.  
In such cases, appropriate safety information will continue to be captured per protocol and 
submitted to the Sponsor. The information to be collected may include treatment-related AEs and 
SAEs, laboratory results of special interest, study drug administration, patient status and date and 
reason(s) for study withdrawal. 

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9.0 STUDY DISCONTINUATION 
9.1 
Termination of the Study by the Sponsor 
This study may be discontinued at any time due to safety concerns, failure to meet expected 
enrollment goals, administrative reasons or at the discretion of the Sponsor. Should the study be 
terminated prematurely, the Sponsor will provide written notification to all Investigators and 
regulatory authorities and will specify the reason(s) for early termination. The Investigator must 
inform the Institutional Review Board (IRB) promptly and provide the reason(s) for the 
termination. 
9.2 
Treatment Discontinuation for Individual Patients 
Patients may withdraw their consent to participate in the study at any time for any reason without 
prejudice to their future medical care by the physician or at the institution. Upon withdrawal of 
consent, patients should be asked if they are willing to be contacted by telephone for monitoring 
of survival. If a patient withdraws consent, the date, stated reason for and level of consent 
withdrawal should be documented. Patient data collected up to the date of consent withdrawal 
will be included in the analyses. Any blood or tissue samples collected up to the date of 
withdrawal of consent will be analyzed. 
Wherever possible, the tests and evaluations listed for the End of Treatment visit should be 
carried out and an effort should be made to continue follow-up. The Sponsor should be notified 
of all study withdrawals through the designated eCRFs in a timely manner. 
Patients meeting any of the following criteria must discontinue study drug treatment: 
 
Withdrawal of consent (no further participation)  
 
Patient decision to discontinue study treatment (but request agreement to return for end of 
treatment assessments, safety follow-up assessments and/or survival follow-up) 
 
Unacceptable AEs or failure to tolerate study drug 
 
Dose interruption of > 28 consecutive days in administration of binimetinib or > 6 weeks in 
administration of nivolumab or > 18 weeks in administration of ipilimumab, unless judged 
by the Investigator and the Sponsor’s Medical Monitor or designee to be in the best interest 
of the patient to continue treatment 
 
Changes in the patient’s condition or development of an intercurrent illness which renders the 
patient unacceptable for further treatment in the judgment of the Investigator 
 
Disease progression as defined by RECIST, v1.1 (continuation of treatment beyond 
progression permitted in special circumstances as defined in Section 4.2)  

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 
Clinical progression, per the discretion of the Investigator 
 
Receipt of non-protocol-specified anticancer therapy for study indication (chemotherapy, 
biological therapy or radiation therapy that includes > 30% of the bone marrow reserve) 
 
Patient becomes pregnant or begins breastfeeding 
 
Significant protocol deviation that, in the opinion of the Investigator and/or Sponsor, renders 
the patient unsuitable for further study drug administration 
 
Lost to follow-up 
 
Death 
 
Termination of the study by the Sponsor (described in Section 9.1). 
Patients meeting any of the following criteria may, at the discretion of the Investigator, be 
discontinued from study drug treatment: 
 
Is found not to have met eligibility criteria; the patient would be discontinued if the 
investigator determines that the patient would not benefit from participation in the study due 
to eligibility deviation. 
 
Is noncompliant with study procedures or study drug administration in the opinion of the 
investigator (see Section 6.7). 
9.3 
Study Discontinuation for Individual Patients 
The patient may be considered discontinued from the study for the following reasons: 
 
Withdrawal of consent for survival follow-up 
 
Lost to follow-up 
 
Death 
 
Termination of the study by the Sponsor (described in Section 9.1). 
9.4 
Replacement of Patients 
In Phase 1b of the study, patients who terminate participation in the study for any reason other 
than an AE or abnormal laboratory value unrelated to disease, disease progression, intercurrent 
illness or concomitant medications/therapies before completing at least 75% dose intensity 
(administered dose in mg/planned dose in mg) of the binimetinib doses in Cycle 1 will be 
considered ineligible for the safety assessment required for MTD determination.  
In the Phase 2 part of the study, randomized patients who discontinue prior to study completion 
will not be replaced. 

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10.0 SAFETY MONITORING: DEFINITIONS AND REPORTING 
10.1 Adverse Event 
An AE is defined as any untoward medical occurrence, including the exacerbation of a 
pre-existing condition, in a patient administered an investigational (medicinal) product 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 investigational product, whether or not considered related 
to the investigational product. 
10.2 Immune-Mediated Adverse Events 
Every AE must be assessed by the investigator with regard to whether it is considered immune-
mediated. Immune-mediated AEs are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (e.g., infection or tumor 
progression) have been ruled out and that require the use of corticosteroids. Immune-mediated 
AEs can include events with an alternate etiology which were exacerbated by the induction of 
autoimmunity. For events which are potentially immune-mediated, additional information will be 
collected on the eCRF. 
10.3 Events Related to Progression of Disease 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors) will be designated as progression 
of disease in the eCRF and should not be reported as an AE or SAE unless a causal relationship 
to study drug is suspected.   
10.4 Clinical Laboratory Abnormalities 
An abnormal laboratory value that is not associated with an already reported AE is to be 
recorded as an AE only if an action on the study drug is made as a result of the abnormality, if 
intervention for management of the abnormality is required, or at the discretion of the 
Investigator. 
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or baseline, or per Investigator discretion.  
10.5 Overdose 
An overdose of study drug (whether symptomatic or asymptomatic) will be reported as an AE. 

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10.6 Assessment of Severity 
The severity rating of an AE refers to its intensity. The severity of each AE will be determined 
by the Investigator using the NCI CTCAE v4.03. For any term that is not specifically listed in 
the CTCAE scale, severity should be assigned a Grade of 1 through 5 using the following 
CTCAE guidelines: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Fatal  
10.7 Assessment of Causality 
An assessment of causal relationship of each study drug to each AE must be performed by the 
Investigator. Medical judgment should be used to determine the cause of the AE, considering all 
relevant factors such as (but not limited to) the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the study 
medication and de-challenge or re-challenge. 
Yes (possibly, probably or definitely related): there is a reasonable possibility that the study drug 
caused the event; one or more of the following criteria apply: 
 
The event follows a reasonable temporal sequence from administration of study drug. 
 
The event could not be reasonably attributed to the known characteristics of the patient’s 
clinical state, environmental or toxic factors or other modes of therapy administered to the 
patient. 
 
The event follows a known pattern of response to study drug. 
 
The event disappears or decreases on cessation or reduction in dose of the study drug. 
(It should be noted that in some situations an AE will not disappear or decrease in intensity 
upon discontinuation of study drug despite other clear indications of relatedness).  

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 
The event reappears or worsens when the study drug is re-administered. 
No (unlikely, probably not related or definitely not related): there is no reasonable possibility 
that the study drug caused the event; one or more of the following criteria apply: 
 
The event does not follow a reasonable temporal sequence from administration of study drug. 
 
The event could be reasonably attributed to the known characteristics of the patient’s clinical 
state, concurrent illness, environment or toxic factors or other modes of therapy administered 
to the patient. 
 
The event does not follow a known pattern of response to study drug. 
 
The event does not disappear or decrease on cessation or reduction in dose of the study drug, 
and it does not reappear or worsen when the study drug is re-administered. 
10.8 Assessment of Seriousness 
An AE is considered “serious” if it results in any of the following outcomes: 
 
Results in death. 
Note: Death is an outcome of an SAE and not an SAE in itself. Death should only be 
reported as an SAE term when no additional information is known about a fatal 
event. When death is an outcome, the event(s) resulting in death should be reported 
(e.g., “pulmonary embolism” with a fatal outcome) and assigned severity Grade 5. 
 
Is immediately life-threatening (its occurrence places the patient at immediate risk of death. 
It does not include an event that, had it occurred in a more severe form, might have caused 
death) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
Note: Hospitalization includes any hospital admission, even if for less than 
24 hours. The following do not meet hospitalization serious criteria:  
 A visit to the emergency room, or outpatient observation that does not result in 
admission 
 Elective surgery, planned prior to signing consent 
 Routine health assessment requiring admission  
 
Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
 
Is a congenital anomaly/birth defect. 

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 
Based upon appropriate medical judgment, represents an important medical event that may 
jeopardize the patient or may require intervention to prevent one of the outcomes described 
above. 
10.9 Reporting of Serious and Nonserious Adverse Events 
All AEs, serious and nonserious (including the exacerbation of a pre-existing condition) and 
regardless of causality to study drug, will be fully recorded on the appropriate eCRF. For each 
AE, the Investigator must provide its duration (start and end dates or ongoing), severity 
(intensity), assessment of causality, whether specific action or therapy was required, and whether 
action was taken with regard to study drug treatment. 
Any AE that occurs from the signing of the ICF until the first dose of study drug is to be 
recorded on the AE eCRF page only if the event was related to a study procedure. All other 
AEs/findings prior to the first dose of study drug should be recorded on the medical history 
eCRF. All AEs occurring from the first dose of study drug until 100 days after the last dose of 
study drug must be recorded on the AE eCRF, regardless of causal relationship to the 
investigational product. After 100 days, SAEs only are to be reported until 150 days after the last 
dose of study drug, regardless of causal relationship to investigational product. SAEs occurring 
greater than 150 days after the last dose of study drug should be reported only if considered 
related to investigational product. 
In addition to recording SAEs on the AE eCRF, all SAEs must be reported to the Sponsor within 
24 hours of the Investigator’s knowledge by faxing the completed SAE form to the Sponsor at 
the number provided on the SAE form or fax cover sheet. If new information becomes available 
for a previously reported SAE, a follow-up SAE report should be sent within 24 hours.  
Investigators must follow patients with AEs/SAEs until the event has resolved, the condition has 
stabilized, withdrawal of consent, the patient is lost to follow up, or death OR until 150 days 
after the last dose of study drug, whichever occurs first. Ongoing treatment-related SAEs may be 
followed beyond this time period if clinically indicated.  
10.10 Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Suspected unexpected serious adverse reactions (SUSARs) will be collected and reported by the 
Sponsor and/or designee to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in participating 
countries. 

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10.11 Pregnancy or Drug Exposure during Pregnancy 
If a patient becomes pregnant during the study, administration of study drug is to be discontinued 
immediately. 
Pregnancies (both those of female patients and female partners of male patients) must be 
reported to the Sponsor or designee within 24 hours of the Investigator’s knowledge using the 
Investigational Product Pregnancy Report. All pregnancies will be followed through to outcome 
and the outcome must be reported to the Sponsor or designee using the Investigational Product 
Pregnancy Outcome Report.  
Pregnancies themselves are not considered AEs or SAEs. However, any AEs or SAEs occurring 
during pregnancy are to be reported following AE and SAE reporting guidelines. 

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11.0 STATISTICAL METHODS 
11.1 Sample Size 
For the dose-finding period of this study (Phase 1b), the primary objective is to determine the 
RP2D of binimetinib in combination with nivolumab with or without ipilimumab. The total 
number of patients enrolled in the dose-finding period will depend on the number of dose levels 
tested and the number of patients treated in each cohort before the RP2D has been determined. 
Approximately 90 patients are planned. A maximum of approximately 42 patients will be 
enrolled in Phase 1b and a minimum of approximately 48 patients will be enrolled in Phase 2. 
In Phase 1b, a maximum of approximately 21 patients will be treated in each arm, with a target 
of 9 patients at the MTD. In the Phase 2 period of the study, a minimum of approximately 
24 patients will be treated in each arm. Randomization into Phase 2 will continue until at least 
33 patients have received the doublet and the triplet, respectively, at the RP2D (Phase 1b and 
Phase 2 combined). 
The primary analysis of the response rate and efficacy endpoints will include all Phase 2 patients 
plus those treated at the same dose/schedule in Phase 1b; thus, it is expected that a minimum of 
33 patients in each arm will be available for the primary efficacy evaluation.   
In the doublet arm, a response rate of 5% or less will be considered unacceptably low. Hence, in, 
the null hypothesis that the response rate is at most 5% will be tested against the alternative 
hypothesis that the response rate is greater than 5%. The targeted response rate is 20%.  With 
these assumptions, and a two-tailed alpha = 0.10 significance level, 33 patients will provide 
approximately 86% power. 
In the triplet arm, a response rate of 10% or less will be considered unacceptably low. Hence, the 
null hypothesis that the response rate is at most 10% will be tested against the alternative 
hypothesis that the response rate is greater than 10%. The targeted response rate is 30%.  With 
these assumptions, and a two-tailed alpha = 0.10 significance level, 33 patients will provide 
approximately 91% power 
The study is not adequately powered to compare the response rate between treatment arms; these 
comparisons will be descriptive only. 

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11.2 Analysis Sets 
11.2.1 Full Analysis Set 
The Full Analysis Set (FAS) will consist of all patients who receive at least one dose of study 
drug. 
11.2.2 Safety Set 
The Safety Set (SS) will consist of all patients who receive at least one dose of study drug.   
11.2.3 Dose-Determining Set 
The Dose-Determining Set (DDS) includes all patients from Phase 1b who either experience a 
DLT or receive at least 75% of the planned binimetinib dose intensity during the first cycle of 
treatment. 
Patients in the DDS who do not experience DLT during the first cycle will be considered to have 
sufficient safety evaluations if they have been observed for ≥ 28 days following the first dose and 
are considered by both the Sponsor and Investigators to have enough safety data to conclude that 
a DLT did not occur. 
11.2.4 Per Protocol Set 
The Per-Protocol Set (PPS) will consist of all patients in the FAS who are sufficiently compliant 
with the protocol requirements. A precise definition of the criteria required for inclusion in the 
PPS will be provided in the statistical analysis plan (SAP). 
11.2.5 Pharmacokinetic Set 
The PK Analysis Set (PAS) will consist of all patients who receive at least one dose of 
binimetinib and have at least one evaluable bioanalytical result. 
11.3 Statistical Analyses and Methods 
11.3.1 General Considerations 
A detailed SAP will be prepared by the Sponsor or designee. This plan may modify the statistical 
methods outlined in the protocol; however, any major modifications of the primary endpoint or 
key secondary endpoint definition or analysis will also be described in a protocol amendment. 
Data analyses from this study will be performed by the Sponsor or designee.  
11.3.2 Patient Characteristics 
The following baseline patient characteristics will be summarized descriptively by treatment 
group: ECOG PS, demographics (age, gender and race); prior anticancer agents (chemotherapy, 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
 
Versi o n 4. 0 
1 5 3  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
bi ol o gics, tar gete d s mall m olec ules); pri or c h e m ot hera p y; best r es p o nse t o pri or c he m ot hera p y; 
pri or ra di ot hera p y, pri or s ur ger y; me dical hist or y; c o nc o mita nt me dicati o n usa ge; vari o us ge n es’ 
m utati o n stat us. 
1 1. 3. 3  Effic ac y A n al yses 
U nless ot her wise state d, effic ac y a n al ys es will be c o n d ucte d usi n g t he F A S. A s u p p orti ve 
a nal ysis of t he pri mar y efficac y e n d p oi nt fr o m P hase 2 will be c o n d ucte d usi n g t he P P S. 
A d diti o nal details f or met h o d ol o g y f or e n d p oi nts n ot liste d bel o w will be pr o vi de d i n t he S A P. 
1 1. 3. 3. 1  
O bjecti ve R es p o nse R ate 
T he o verall best res p o nse (i.e., C R or partial res p o nse [ P R ]) as assesse d b y t he I n v esti gat or per 
R E CI S T v 1. 1 will be det er mi ne d f or eac h p atie nt. T he O R R will be calc ulate d wit hi n eac h 
treat me nt ar m, w h ere O R R is defi ne d as t he n u m b er of patie nts a c hie vi n g a n o verall best 
res p o nse of C R or P R di vi de d b y t he t otal n u m ber of patie nts i n t hat treat me nt ar m. T he O R R 
wit h e x act ( Cl o p per- Pears o n) 9 5 % c o nfi de n ce i nter vals ( CIs) will be pr o vi d e d. 
B ot h c o nfir me d a n d u nc o nfir me d O R R will be s u m marize d , b ut t he pri mar y a n al ysis will be 
base d o n c o nfir me d res p o nses.   
A si m ilar a nal ysis will be pr o vi de d f or t he rate of C R. 
 
 
1 1. 3. 4  S afet y A n al yses 
Descri pti ve statistics will be use d t o s u m m arize safet y d ata. A Es, E C G a n d la b orat or y dat a will 
be re vie we d a n d s u m mariz e d o n a n o n g oi n g basis d uri n g t h e st u d y. All A E, E C G a n d safet y 
la b orat or y a b n or malities of p ote ntial cli nical c o ncer n will be descri be d. Safet y d ata will be 
prese nte d i n ta b ular a n d/ or gra p hic al f or mat a n d s u m marize d descri pti vel y b y d ose gr o u p, ti me, 
a n d c o h ort w h ere a p pr o priate. A bs ol ute val ue data a n d c ha n ge fr o m bas eli ne data will be 
s u m marize d as a p pr o priate. 
All A Es will be c o de d b y b o d y s yste m usi n g t he Me dical Dicti o nar y f or R e g ul at or y Acti vities 
( Me d D R A ®), a n d s u m m ar y ta bles f or all A Es will be ge n erate d. I n ci de nce rates will be 
s u m marize d f or eac h preferre d ter m a n d b o d y s yst e m. A d diti o nal s u m mar y ta bles will be 
ge n erat e d f or t he f oll o wi n g s u bsets of patie nts: patie nts wit h S A Es, patie nts wit h st u d y dr u g 
relate d A Es, p atie nts w h o die d, a n d patie nts w h o disc o nti n ue d d ue t o A Es. Se verit y of e ve nts 
will als o be s u m marize d. 
C CI

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I nc. 
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
 
Versi o n 4. 0 
1 5 4  
C o nfi de ntial 
0 2 Marc h 2 0 1 8 
1 1. 3. 5  P h ar m a c o ki netic A n al ysis 
N o n-c o m part me nt al p har mac o ki netic para meters will n ot be esti mate d d ue t o s pars e sa m pli n g i n 
t his trial. P har mac o ki netic para m eters will be det er mi ne d f or bi ni meti ni b a n d/ or A R 0 0 4 2 6 0 3 2 
usi n g a m o del- b ase d a p pr oac h t o deter mi ne a p pr o priate m o del- bas e d P K para meters a n d t heir 
res pecti ve v aria bilit y, if dee me d a p pr o priate. P K data ma y be a nal yze d i n at least 2 wa ys: 
 
Data fr o m t his st u d y will  be a nal yz e d al o ne base d o n t he pre vi o usl y d escri b e d p o p ulati o n P K 
m o del. T he str uct ur e of t he m o del will re mai n si milar b ut para meters (fi x e d a n d ra n d o m 
effects) will be esti mate d base d o n t he c urre nt p o p ulati o n. 
 
If nee d e d, pri or k n o wl e d ge fr o m ot her st u dies wit h i nte nsi ve sa m pli n g ma y be i ntr o d uce d i n 
t he a nal ysis b y eit her fi xi n g t he p o p ulati o n para meters t o t he val ue esti mate d pre vi o usl y or 
b y a d di n g d ata fr o m t he pre vi o us st u dies t o t he dataset t o esti mate p o p ulati o n para meters a n d 
deri ve E m pirical Ba y es Esti mates of P K para met ers f or p atie nts i n t his st u d y. 
Details of t hese a n al yses a n d of t he i nc or p orati o n of pri or i nf or mati o n will be pr o vi de d i n a 
s pecific sta n dal o n e m o deli n g pla n. A nal ysis will be pr o vi de d i n a s pecific re p ort as a p pr o priate. 
 
P K e x p os ure  will be deri ve d fr o m t he p o p ul ati o n P K m o del i n or der 
t o o btai n act ual dail y e x p os ure. 
 
 
1 1. 4  O p er ati n g C h ar acteristics 
D ose-es calati o n a n d de-escalati o n decisi o ns will be base d o n t he met h o d ol o g y o utli ne d i n t he 
m T PI- 2 p a per ( G u o et al. 2 0 1 7). T he d ose le vels i n Ar m 1A are ra n k e d bas e d o n d ose i nte nsit y, 
as o utli ne d i n  Ta ble 1 6  ( hi g her ra n ks i m pl y hi g h er d ose i nte nsit y). 
C CI
C CI

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Table 16: 
Dose Levels 
Arm 
Dose Level 
(*Starting 
Dose Level) 
Binimetinib 
Nivolumab 
Ipilimumab 
1A 
(Doublet) 
4* 
45 mg BID  
480 mg Q4W 
N/A 
3 
45 mg BID 3W on / 1W off  
2 
30 mg BID 
1 
30 mg BID 3W on / 1W off 
1B 
(Triplet)a 
4 
45 mg BID  
480 mg Q4W 
1 mg/kg Q8W 
3 
45 mg BID 3W on / 1W off  
2 
30 mg BID 
1 
30 mg BID 3W on / 1W off 
a The starting Dose Level of Arm 1B (Triplet) will be the RP2D of binimetinib from Arm 1A. If tolerated, the RP2D of 
binimetinib from Arm 1A will be considered the RP2D for Arm 1B. If not tolerated, any dose level below the RP2D for Arm 
1B may be explored. 
 
Modifying the mTPI-2 to allow for a maximum of 9 patients at a dose level modifies the 
operating characteristics of the standard mTPI-2. Results of simulations based on these 
modifications are provided below for various true DLT rates. 
Simulations are generated with the following additional assumptions: Max sample size of 21, 
target probability of DLT = 30%, equivalence interval = (25%, 35%), cohort size = 3, number of 
simulations per scenario = 1000. 

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Table 17: 
Dose-limiting Toxicities Probability Scenarios 
Dose Level 
Rank based on 
dose intensity 
1 
2 
3 
4 
Binimetinib 
dose/schedule 
30 mg BID Q3/4w 
30 mg BID 
45 mg BID Q3/4w 
45 mg BID 
Scenario 1 
True DLT rate 
10% 
15% 
20% 
35% 
Probability selected 
as MTD* 
.005 
.097 
.165 
.732 
Average total 
sample size 
11.5 
% of patients 
experiencing a DLT 
30.1% 
Scenario 2 
True DLT rate 
5% 
10% 
20% 
25% 
Probability selected 
as MTD* 
.004 
.039 
.074 
.882 
Average total 
sample size 
10.2 
% of patients 
experiencing a DLT 
23.1% 
*In cases where rows do not add up to 100%, the model concluded that no dose level was acceptable. 

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12.0 DATA RECORDING, RETENTION AND MONITORING 
12.1 Data Management 
Data will be collected using an electronic data capture system (EDC) at the clinical site. The 
Investigator or designee will record data specified in the protocol using eCRFs. Changes or 
corrections to eCRFs will be made by the Investigator or an authorized member of the study staff 
according to the policies and procedures at the site. 
It is the Investigator’s responsibility to ensure eCRFs are complete and accurate. Following 
review and approval, the Investigator will electronically sign and date the pages. This signature 
certifies that the Investigator has thoroughly reviewed and confirmed all data on the eCRF. 
A portable document format (PDF) file of the eCRFs will be provided to the site after all data 
have been monitored and reconciled. An electronic copy will be archived at the site. 
12.2 Data Monitoring 
This study will be closely monitored by representatives of the Sponsor throughout its duration. 
Monitoring will include personal visits with the Investigator and study staff as well as 
appropriate communications by telephone, fax, mail, email or use of the EDC system, if 
applicable. It is the monitor’s responsibility to inspect eCRFs at regular intervals throughout the 
study to verify the completeness, accuracy and consistency of the data and to confirm adherence 
to the study protocol and to Good Clinical Practice (GCP) guidelines. The Investigator agrees to 
cooperate with the monitor to ensure that any problems detected during the course of this study 
are resolved promptly. The Investigator and site will permit study-related monitoring, audits, EC 
review and regulatory inspection, including direct access to source documents. 
It is understood that study monitors and any other personnel authorized by the Sponsor may 
contact and visit the Investigator and will be permitted to inspect all study records (including 
eCRFs and other pertinent data) on request, provided that patient confidentiality is maintained 
and that the inspection is conducted in accordance with local regulations. 
Every effort will be made to maintain the anonymity and confidentiality of patients during this 
study. However, because of the experimental nature of this treatment, the Investigator agrees to 
allow representatives of the Sponsor, the development partner of the Sponsor, as well as 
authorized representatives of regulatory authorities to inspect the facilities used in the conduct of 
this study and to inspect, for purposes of verification, the hospital or clinic records of all patients 
enrolled in the study. 

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12.3 Quality Control and Quality Assurance 
Quality control procedures will be conducted according to the Sponsor’s internal procedures. 
The study site may be audited by a quality assurance representative of the Sponsor. All necessary 
data and documents will be made available for inspection. 

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13.0 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
13.1 Good Clinical Practice 
The study will be performed in accordance with the protocol, guidelines for GCP established by 
the International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) and applicable local regulatory requirements and laws 
and in accordance with European Clinical Trials Directive. 
13.2 Ethics Committee Approval 
The Investigator must inform and obtain approval from the EC for the conduct of the study at 
named sites, the protocol, informed consent documents and any other written information that 
will be provided to the patients and any advertisements that will be used. Written approval must 
be obtained prior to recruitment of patients into the study and shipment of study drug. 
Proposed amendments to the protocol and aforementioned documents must be submitted to the 
Sponsor for review and approval, then to the EC. Amendments may be implemented only after a 
copy of the approval letter from the EC has been transmitted to the Sponsor. Amendments that 
are intended to eliminate an apparent immediate hazard to patients may be implemented prior to 
receiving Sponsor or EC approval. However, in this case, approval must be obtained as soon as 
possible after implementation. 
Per GCP guidelines, the Investigator will be responsible for ensuring that an annual update is 
provided to the EC to facilitate continuing review of the study and that the EC is informed about 
the end of the study. Copies of the update, subsequent approvals and final letter must be sent to 
the Sponsor. 
13.3 Regulatory Authority Approval 
The study will be performed in accordance with the requirements of each country’s regulatory 
authorities (e.g., FDA, European Medicines Agency (EMA) and Health Canada) and will also 
meet all of the requirements of ICH GCP guidance. Amendments to the protocol will be 
submitted to the relevant authorities (e.g., FDA, EMA or Health Canada) for approval prior to 
implementation in accordance with applicable regulations. 
13.4 Other Required Approvals 
In addition to EC and regulatory authority approval, all other required approvals (e.g., approval 
from the local research and development board or scientific committee) will be obtained prior to 
recruitment of patients into the study and shipment of study drug. 

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13.5 Informed Consent 
Informed consent is a process that is initiated prior to the patient’s agreeing to participate in the 
study and continues throughout the patient’s study participation. It is the Investigator’s 
responsibility (or designee) to obtain written informed consent from each patient after adequate 
explanation of the aims, methods, anticipated benefits and potential hazards of the study and 
before any study procedures are initiated. Each patient should be given a copy of the informed 
consent document and associated materials. The original copy of the signed and dated informed 
consent document must be retained at the site and is subject to inspection by representatives of 
the Sponsor or regulatory authorities. If any amendments occur throughout the course of the 
study that affect the ICF (i.e., when new study procedures or assessments have been added), all 
active patients should be reconsented using the same process for the initial consent. 
13.6 Patient Confidentiality 
The Investigator must ensure that the patient’s privacy is maintained. On the eCRF or other 
documents submitted to the Sponsor, patients will be identified by a patient number only. 
Documents that are not submitted to the Sponsor (e.g., signed informed consent documents) 
should be kept in a confidential file by the Principal Investigator. 
The Investigator shall permit authorized representatives of the Sponsor, regulatory authorities 
and ethics committees to review the portion of the patient’s medical record that is directly related 
to the study. As part of the required content of informed consent documents, the patient must be 
informed that his/her records will be reviewed in this manner. 
13.7 Disclosure of Information 
Information concerning the study, patent applications, processes, scientific data or other pertinent 
information is confidential and remains the property of the Sponsor. The Principal Investigator 
may use this information for the purposes of the study only. 
It is understood by the Principal Investigator that the Sponsor will use information obtained in 
this clinical study in connection with the clinical development program, and therefore may 
disclose it as required to other clinical investigators and to regulatory authorities. In order to 
allow the use of the information derived from this clinical study, the Principal Investigator 
understands that he/she has an obligation to provide complete test results and all data obtained 
during this study to the Sponsor. 
Verbal or written discussion of results prior to study completion and full reporting should only 
be undertaken with written consent from the Sponsor. 

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13.8 Publication of Study Data 
The conditions regulating dissemination of the information derived from this study are described 
in the Clinical Trial Agreement. 

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14.0 ADHERENCE TO THE PROTOCOL 
Investigators must apply due diligence to avoid protocol deviations, and the Sponsor (and 
designee[s]) will not pre-authorize deviations. If the Investigator believes a change to the 
protocol would improve the conduct of the study, this must be considered for implementation in 
a protocol amendment. Protocol deviations will be recorded. 
14.1 Amendments to the Protocol 
Only the Sponsor may modify the protocol. The only exception is when the Investigator 
considers that a patient’s safety is compromised without immediate action. In these 
circumstances, immediate approval of the chairman of the EC must be sought, and the 
Investigator should inform the Sponsor and the full EC within 5 working days after the 
emergency occurred. All amendments that have an impact on patient risk or the study objectives 
or require revision of the informed consent document must receive approval from the EC prior to 
implementation. 
 

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APPENDICES 

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APPENDIX 1: 
RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
BINIMETINIB-INDUCED DIARRHEA 
Proactively Investigate for Occurrence of Diarrhea and Educate Patient: 
1. Remind patients at each visit to contact the Investigator immediately upon the first sign of 
loose stool or symptoms of abdominal pain. Additionally, at each study visit, each patient 
should be asked regarding occurrence of diarrhea or diarrhea-related symptoms. If the patient 
has had symptoms, the patient should be asked regarding the actions taken for these 
symptoms and re-instruct if indicated. 
2. Patients should be instructed on dietary modification and early warning signs of diarrhea and 
potentially life-threatening illnesses (e.g., severe cramping might be a sign of severe 
diarrhea; fever with diarrhea might be a sign of infection; fever and dizziness on standing 
might be a sign of shock).  
3. Patients should be educated about what to report to the Investigator (i.e., number of stools, 
stool composition, stool volume). 
Anti-diarrhea Therapy: 
In order to effectively manage diarrhea and mitigate the escalation in severity or duration of 
diarrhea, patient education as outlined above, as well as proper management of diarrhea is 
important.  
Management of diarrhea should be instituted at the first sign of abdominal cramping, loose stools 
or overt diarrhea. All concomitant therapies /used for treatment of diarrhea must be recorded on 
the eCRF. It is recommended that patients be provided loperamide tablets and be instructed on 
the use of loperamide on the first day of binimetinib dosing. In addition to the binimetinib-
induced diarrhea dosing guidelines provided in Section 6.4.2 of the protocol, these instructions 
should be provided at each visit and the site should ensure that the patient understood the 
instructions.  
See Section 6.4.2 in the protocol to explain the frequency of diarrhea and its relationship to NCI 
CTCAE v.4.03 grading and to determine if diarrhea is complicated or uncomplicated. 

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Rule out Other or Concomitant Causes: 
These may include: 
 
Infection with Candida, Salmonella, Clostridium difficile, Campylobacter. Giardia, 
Entamoeba or Cryptosporidium species, which can lead to severe infections in 
immunosuppressed patients. 
 
Medication-induced diarrhea. 
 
Malabsorption/lactose intolerance. 
 
Fecal impaction, partial bowel obstruction. 
For Uncomplicated Grade 1/2 Diarrhea: 
 
Stop all lactose-containing products and alcohol, and eat frequent small meals that include 
bananas, rice, applesauce or toast. 
 
Stop laxatives, bulk fiber (e.g., Metamucil®), and stool softeners (e.g., docusate sodium, 
Colace®). 
 
Stop high-osmolar food supplements (e.g., Ensure® Plus, Jevity® Plus [with fiber]). 
 
Drink 8 to 10 large glasses of clear liquids per day (e.g., water, Pedialyte®, Gatorade®, broth). 
 
Consider administration of a standard dose of loperamide: initial administration 4 mg, then 
2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool. 
 
Discontinue loperamide after 12-hours diarrhea-free (Grade 0) interval. 
 
Consider temporary interruption of binimetinib until resolved to Grade ≤ 1. Re-treatment 
may then be resumed at current dose level. 
 
If uncomplicated Grade 1 to Grade 2 diarrhea persists for more than 24 hours, escalate to 
high-dose loperamide: 2 mg every 2 hours (maximum of 16 mg/day) or after each unformed 
stool. 
Note: Oral antibiotics may be started as prophylaxis for infections under the discretion of the 
physician. 
 
If uncomplicated Grade 1 to Grade 2 diarrhea persists after 48 hours of treatment with 
loperamide, discontinue loperamide and begin a second-line agent which can be an opiate 
(opium tincture or paregoric), octreotide acetate or steroid (budesonide). 
For Complicated Grade 1/2 Diarrhea or Any Grade 3/4 Diarrhea: 
 
The patient must call the Investigator immediately. 

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 
Temporarily interrupt binimetinib treatment until resolved to Grade ≤ 1. Restart binimetinib 
at a reduced dose level. 
 
If loperamide has not been intitiated, initiate loperamide immediately. Initial administration 4 
mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool. 
 
Administer IV fluids and electrolytes as needed. In case of severe hydration, replace 
loperamide with octreotide acetate. 
 
Monitor/continue IV fluids and antibiotics as needed. Intervention should be continued until 
the patient is diarrhea-free for at least 24 hours. 
 
Hospitalization may need to be considered. 
 

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APPENDIX 2: 
RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
BINIMETINIB-INDUCED CUTANEOUS REACTIONS 
Clinical judgment and experience of the treating physician should guide the management plan of 
each patient. In addition to the binimetinib-induced cutaneous reaction dosing guidelines 
provided in Section 6.4.2 of the protocol, these instructions should be provided at each visit and 
the site should ensure that the patient understood the instructions.  
The Initial Rash Treatment Regimen may be initiated as prophylactic treatment 24 hours prior to 
the first treatment, or later as needed to treat mild rash (CTCAE Grade 1). 
Initial Rash Treatment Regimen: 
 
Application of topical agents to the most commonly affected skin areas such as face, scalp, 
neck, upper chest and upper back. Topical agents include the following: 
o Non-oily sunscreen (PABA-free, SPF ≥ 30, UVA/UVB protection); 
o Topical steroids, preferably mometasone cream (e.g., Elocon®); 
o Topical erythromycin (e.g., Eryaknen®); 
o Topical pimocrolimus. 
Note: Topical agents should be applied on a daily basis starting on Day 1 of study treatment or 
24 hours prior to first treatment, and more often as needed. 
 
Possibly oral doxycycline (100 mg daily) for the first 2 to 3 weeks of study drug 
administration. 
Other effective medications are antihistamines, other topical corticosteroids, other topical 
antibiotics and low-dose systemic corticosteroids. 
The treatment algorithm based on CTCAE grade is as follows: 
Mild Rash (CTCAE Grade 1) Treatment Regimen: 
 
Initiate Initial Rash Treatment Regimen, if not already started. 
 
Use of topical corticosteroid (e.g., mometasone cream) and/or topical antibiotic (e.g., 
erythromycin 2%) is recommended. 
 
The patient should be reassessed within a maximum of 2 weeks, or as per Investigator 
opinion. 

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Moderate Rash (CTCAE Grade 2) Treatment Regimen: 
 
Use of topical erythromycin or clindamycin (1%) plus topical mometasone or topical 
pimecrolimus (1% cream) plus oral antibiotics, such as lymecycline (408 mg QD), 
doxycycline (100 mg BID) or minocycline (50 to 100 mg BID). 
 
Although there has been no evidence of phototoxicity or photosensitivity in patients treated 
with binimetinib, doxycycline (or minocycline as second line) should be used with thorough 
UV protection (i.e., avoidance of direct exposure to sunlight, use of sunscreen and 
sunglasses, etc.). 
 
Use of acitretin is not recommended. 
Severe Rash (CTCAE Grade 3-4) Treatment Regimen: 
CTCAE Grade 3: 
 
In addition to the interventions recommended for moderate rash, consider oral prednisolone 
at a dose of 0.5 mg/kg. Upon improvement, taper the dose in a stepwise manner (25 mg for 7 
days, subsequently decreasing the dose by 5 mg/day every day). 
 
Alternatively, in addition to the interventions recommended for moderate rash, consider oral 
isotretinoin (low dose, i.e., 0.3 to 0.5 mg/kg) (Lacouture et al. 2011). 
 
Use of acitretin is not recommended. 
CTCAE Grade 4 Treatment Regimen: 
 
Immediately discontinue the patient from study drug and treat the patient with oral or topical 
medications (see recommendation CTCAE Grade 3). 
Symptomatic Treatment Regimen: 
It is strongly recommended that patients who develop rash/skin toxicities receive symptomatic 
treatment: 
 
For pruritic lesions: use cool compresses and oral antihistamine agents. 
 
For fissuring: use Monsel’s solution, silver nitrate or zinc oxide cream. If not sufficient, use 
mild corticosteroid ointments or ointments containing a combination of corticosteroid and 
antibiotic such as Fucicort®. 
 
For desquamation: use emollients that are mild pH 5/neutral (recommended to contain 10% 
urea). 

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 
For paronychia: use antiseptic bath and local potent corticosteroids, use oral antibiotics, and, 
if no improvement is seen, refer to a dermatologist or surgeon. 
 
For infected lesions: obtain bacterial and fungal cultures and treat with topical or systemic 
antibiotics, if indicated, based on sensitivity of culture. 
References: 
Lacouture ME, Anadkat MJ, Bensadoun RJ et al. Clinical practice guidelines for the prevention 
and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer 
2011;19:1079–95. 

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APPENDIX 3: 
RECOMMENDED GUIDELINES FOR THE MANAGEMENT OF 
BINIMETINIB-ASSOCIATED INTERSTITIAL LUNG DISEASE 
Clinical judgment and experience of the treating physician should guide the management plan of 
each patient. In addition to the binimetinib-associated interstitial lung disease (ILD) dosing 
guidelines provided in Section 6.4.2 of the protocol, these instructions should be provided at 
each visit and the site should ensure that the patient understood the instructions.  
Drug-associated ILD or pneumonitis is a clinical diagnosis based on clinical signs and 
symptoms, radiological changes, pulmonary function tests (PFT) and exclusion of other possible 
etiologies of parenchymal lung disease. The most common symptoms of ILD are nonspecific and 
include dyspnea, dry cough, fever, fatigue, hypoxia, and occasional hemoptysis. The CTCAE 
v.4.03 criteria for ILD (pneumonitis) are provided below. 
CTCAE v. 4.03 Criteria for Pneumonitis 
 
Grade 
Adverse Event 
1 
2 
3 
4 
5 
Pneumonitis 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated 
Symptomatic; 
medical 
intervention 
indicated; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self care 
ADL; oxygen 
indicated 
Life-threatening 
respiratory 
compromise; 
urgent 
intervention 
indicated (e.g., 
tracheotomy or 
intubation) 
Death 
Definition: A disorder characterized by inflammation or diffusely affecting the lung parenchyma. 
 
All patients should be instructed to immediately report new or worsening respiratory symptoms. 
Diagnostic procedures include PFT and high-resolution CT scans. The principal management of 
ILD consists of drug interruption and/or dose reduction and treatment with steroids as specified 
below. Empirical antibiotics directed at likely pathogens should also be considered while the 
results of diagnostic procedures and cultures are pending.  
 
Prednisolone 40 mg oral, daily 
o Reduce dose by 10 mg every 2 weeks × 2 (until dose reduced to 20 mg oral, daily) 
o Reduce dose by 5 mg weekly × 4 weeks 
 
Combine with empirical antimicrobial therapy while awaiting results of diagnostic 
procedures 

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References: 
Shah R. Tyrosine kinase inhibitor-induced interstitial lung disease: Clinical features, diagnostic 
challenges, and therapeutic dilemmas. Drug Saf 2016;39:1073-1091. 

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APPENDIX 4: 
RECOMMENDED MANAGEMENT ALGORITHMS FOR 
GASTROINTESTINAL, RENAL, PULMONARY, HEPATIC, 
ENDOCRINOPATHY, SKIN, AND NEUROLOGIC ADVERSE 
EVENTS FROM NIVOLUMAB OR IPILIMUMAB TREATMENT 
 
Figure A: 
GI Adverse Event Management Algorithm 
 
 

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Figure B: 
Renal Adverse Event Management Algorithm 
 
 

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Figure C: 
Pulmonary Adverse Event Management Algorithm 
 
 

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Figure D: 
Hepatic Adverse Event Management Algorithm 
 
 

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Figure E: 
Endocrinopathy Management Algorithm 
 
 

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Figure F: 
Skin Adverse Event Management Algorithm 
 
 

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Figure G: 
Neurological Adverse Event Management Algorithm 
 
 

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APPENDIX 5: 
SNELLEN EQUIVALENCE (VISUAL ACUITY CONVERSION 
CHART) 
 
References: 
Holladay JT. Visual acuity measurements. J Cataract Refract Surg. 2004;30:287-90. 
 

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APPENDIX 6: 
LIST OF CONCOMITANT MEDICATIONS 
Table A: 
P-gp and BCRP Inhibitors/Inducers to Be Used with Caution 
Transporter 
Gene 
Inhibitor 1 
Inducer 2 
P-gp 
ABCB1 
Alogliptin, amiodarone, azithromycin, 
captopril, carvedilol, clarithromycin, 
conivaptan, cyclosporine, daclatasvir, 
diltiazem, dronedarone, eliglustat, 
erythromycin, felodipine, flibanserin, 
fluvoxamine, indinavir, indinavir and 
ritonavir, itraconazole, ivacaftor, 
ketoconazole, lapatinib, lopinavir and 
ritonavir, nelfinavir, paroxetine, 
propafenone, quercetin, quinidine, quinine, 
ranolazine, rifampin, ritonavir, rolapitant, 
saquinavir and ritonavir, simeprevir, St. 
John’s Wort, suvorexant, telaprevir, 
ticagrelor, tipranavir and ritonavir, 
velpatasvir, verapamil, vorapaxar 
Avasimibe, 
carbamazepine, danshen 
(Salvia miltiorrhiza), 
efavirenz, phenytoin, 
rifampin, St. John’s wort, 
tipranavir/ritonavir 
BCRP 
ABCG2 
Cyclosporine, elacridar (GF120918), 
eltrombopag, gefitinib 
Not known 
Based on University of Washington Database (https://didb.druginteractioninfo.org/resources/list-of-substrates-inhibitors-and-
inducers/?Oid=1130) and the FDA draft guidance for drug-drug interaction studies 
(https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf) 
1 Inhibitors listed for P-gp are those that showed > 25% increase in digoxin or fexofenadine area under the 
concentration-time curve (AUC). 
2 Inducers listed for P-gp are those that showed > 20% decrease in digoxin or fexofenadine AUC. 
 
Table B: 
List of Inhibitors and Inducers of UGT1A1 to Be Used with Caution 
Inhibitors of UGT1A1 
Inducers of UGT1A1 
Atazanavir, erlotinib, flunitrazepam, gemfibrozil, 
indinavir, ketoconazole, nilotinib, pazopanib, 
propofol, regorafenib, sorafenib 
Carbamazepine, nicotine, rifampicin, testosterone 
propionate 
 

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APPENDIX 7: 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST), VERSION 1.1 
1.0 
MEASURABILITY OF TUMOR AT BASELINE 
1.1 
Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
1.1.1 Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm); 
 
10 mm caliper measurement by clinical examination (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable); 
 
20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed. 
1.1.2 Non-Measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
1.1.3 Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 

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 
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 
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 mestastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable. 
1.2 
Specifications by Methods of Measurements 
1.2.1 Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 4 weeks before the beginning of the treatment. 
1.2.2 Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin 
lesions, documentation by colour photography including a ruler to estimate the size of the lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical examination and 

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imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm 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. 
MRI is also acceptable in certain situations (e.g., for body scans).  
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials were recurrence following complete response or 
surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response. Because tumor markers are disease specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain).When effusions are known to be a 
potential adverse effect of treatment (e.g., with certain taxane compounds of angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for response 

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or stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
2.0 
TUMOR RESPONSE EVALUATION 
2.1 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion (as detailed above).  
2.2 
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved, a maximum of two and 
four lesions respectively will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.  
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. As previously noted, pathological nodes which 
are defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the 
baseline sum. The short axis of the node is the diameter normally used by radiologists to judge if 
a node is involved by solid tumor. Nodal size is normally reported as two dimensions in the 
plane in which the image is obtained (for CT scan this is almost always the axial plane; for MRI 
the plane of acquisition may be axial, saggital, or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm X 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm 
should be recorded as the node measurement. All other pathological nodes (those with short axis 
≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that have a short axis 
< 10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 

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included in the sum, then as previously noted, only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
2.3 
Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
2.3.1 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. The appearance of one or more new lesions is also considered 
progression. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.3.2 Special Notes on the Assessment of Target Lesions 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. Case report 
forms (CRFs) or other data collection methods may therefore be designed to have target nodal 

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lesions recorded in a separate section where, in order to qualify for CR, each node must achieve 
a short axis < 10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to 
be included in the sum of target lesion. 
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small to 
measure’. When this occurs it is important that a value be recorded on the CRF. If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible, therefore providing this default value will prevent false responses 
or progressions based upon measurement error. If the radiologist is able to provide an actual 
measurement, that should be recorded, even if below 5 mm. 
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 truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2.3.3 Evaluation of Non-Target Lesion 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the 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). 

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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. The 
appearance of one or more new lesions is also considered progression. 
2.3.4 Special Notes on Assessment of Progression of Non-Target Disease 
The concept of progression of non-target disease requires additional explanations as follows: 
When the patient also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease 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. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.  
When the patient has only non-measurable disease. This circumstance arises in some phase III 
trials when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as previously noted, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified, a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease: i.e., an 
increase in tumor burden representing an additional 73% increase in ‘volume’ (which is 
equivalent to a 20% increase in diameter in a measurable lesion). Examples include an increase 
in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to 
widespread, or may be described in protocols as ‘sufficient to require a change in therapy’. If 
‘unequivocal progression’ is seen, the patient should be considered to have had overall PD at that 
point. While it would be ideal to have objective criteria to apply to non-measurable disease, the 
very nature of that disease makes it impossible to do so, therefore the increase must be 
substantial. 
2.3.5 New Lesions 
The appearance of new malignant lesions denotes disease progression. There are no specific 
criteria for the identification of new radiographic lesions; however, the finding of a new lesion 

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should be unequivocal: i.e., not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor. This is 
particularly important when the patient’s baseline lesions show partial or complete response. 
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 scan 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan.  
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 imagine 
can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. A ‘positive’ FDG-PET scan lesion is one which is FDG avid with 
an uptake greater than twice that of the surrounding tissue on the attenuation corrected 
image. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that time (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. 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a 

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response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may 
also require confirmatory measurement. Specifically, in non-randomised trials where response is 
the primary endpoint, confirmation of PR or CR is needed to deem either one the ‘best overall 
response’.  
2.4.1 Time Point Response 
It is assumed that at each protocol specified time point, a response assessment occurs. Table C 
provides a summary of the overall response status calculation at each time point for patients who 
have measurable disease at baseline. 
Table C: 
Time Point Response: Patients with Target (± Non-Target) Disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, NE=inevaluable 
When patients have non-measurable (therefore non-target) disease only, Table D is to be used. 

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Table D: 
Time Point Response: Patients with Non-Target Disease Only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised. 
2.4.2 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 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.  
2.4.3 Best Overall Response: All Time Points 
The best overall response is determined once all the data for the patient is known.  
Best response is defined as the best response across all time points (for example, a patient who 
has SD at first assessment, PR at second assessment, and PD on last assessment has a best 
overall response of PR). When SD is believed to be the best response, it must also meet the 
protocol specified minimum time from baseline. If the minimum time is not met when SD is 
otherwise the best time point response, the patient’s best response depends on the subsequent 
assessments. For example, a patient who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same patient lost to follow-
up after the first SD assessment would be considered inevaluable.  
2.4.4 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 the increase in size of the nodes. As noted earlier, this means that patients with CR may 
not have total sum of ‘zero’ on the CRF. 

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

Bi ni meti ni b ( M E K i n hi bit or) 
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Bi ni meti ni b ( M E K i n hi bit or) 
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C CI

Bi ni meti ni b ( M E K i n hi bit or) 
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Bi ni meti ni b ( M E K i n hi bit or) 
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REFERENCES 
Angelova M, Charoentong P, Hackl H, et al. Characterization of the immunophenotypes and 
antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets 
for immunotherapy. Genome Biol. 2015;16:64. 
Amado RG, Wolf M, Peeters M, et al. Wild-Type KRAS is required for panitumumab efficacy in 
patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26(10):1626-34.  
Atkins D, Breuckmann A, Schmahl GE, et al. MHC class I antigen processing pathway defects, 
ras mutations and disease stage in colorectal carcinoma. Int J Cancer. 2004;109(2):265-73. 
Avastin PI at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125085s267lbl.pdf 
accessed 18 May 2017. 
Bendell JC, Bang Y-J, Chee CE, et al. A phase Ib study of safety and clinical activity of 
atezolizumab (A) and cobimetinib (C) in patients (pts) with metastatic colorectal cancer 
(mCRC). J Clin Oncol 2018; 36: (suppl 4S; abstr 560). 
Bendell JC, Kim TW, Goh BC, et al. Clinical activity and safety of cobimetinib and 
atezolizumab in colorectal cancer. J Clin Oncol 2016; 34: (suppl; abstr 3502). 
Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with 
and without cetuximab in the first-line treatment of metastatic colorectal cancer J Clin Oncol. 
2009;27:663-71. 
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous 
non–small-cell lung cancer. N Engl J Med 2015; 373:1627-39. 
Boland PM, Ma WW. Immunotherapy for colorectal cancer. Cancers 2017;9(5):E50. 
Brahmer JR, Drake CG, Wollner I, et al: Phase I study of single-agent anti–programmed death-1 
(MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and 
immunologic correlates. J Clin Oncol.2010; 28:3167-75. 
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell 
non–small-cell lung cancer. N Engl J Med 2015;373:123-35. 
Brea EJ, Oh CY, Manchado E, et al. Kinase Regulation of Human MHC Class I Molecule 
Expression on Cancer Cells. Cancer Immunol Res. 2016;4(11):936-47. 
Brock EJ, Ji K, Reiners JJ, et al. How to target activated Ras proteins: Direct inhibition vs. 
induced mislocalization. Mini Reviews in Medicinal Chemistry. 2016; 16(5), 358–69. 
Cancer Genome Atlas Network: Comprehensive molecular characterization of human colon and 
rectal cancer. Nature. 2012;487: 330–7. 
Chirica M, Le Bourhis L, Lehmann-Che J, et al. Phenotypic analysis of T cells infiltrating colon 
cancers: Correlations with oncogenic status. Oncoimmunology 2015;4(8): e1016698-2-12. 

Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-162-202 
 
 
Version 4.0 
199 
 
Confidential 
02 March 2018 
Clinical Trials Facilitation Group Guidelines 2014. Recommendations related to contraception 
and pregnancy testing in clinical trials. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf   Accessed 12 
July 2017. 
Cusimano A, Fodera D, D’Alessandro N, et al. Potentiation of the antitumor effects of both 
selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors in human hepatic cancer cells by 
inhibition of the MEK/ERK pathway. Cancer Biol Ther. 2007;6(9):1457-64. 
Diaz LA, Uram JN, Wang H, et al. Programmed death-1 blockade in mismatch repair deficient 
cancer independent of tumor histology. J Clin Oncol 2016; 34: (suppl; abstr 3003).arch on 
Cancer; 2010. Available from: http://globocan.iarc.fr  Accessed on 30 June 2017. 
Douillard JY, Siena S, Cassidy J, et al. Randomized, Phase III trial of panitumumab with 
infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-
line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME 
Study. J Clin Oncol. 2010; 28(31):4697-705. 
Douillard JY, Oliner KS, Siena S, et al. Panitumumab–FOLFOX4 treatment and RAS mutations 
in colorectal cancer. N Engl J Med 2013;369:1023-34. 
Douillard JY, Siena S, Cassidy J, et al. Final results from PRIME: randomized phase III study of 
panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Annal 
Oncol. 2014;25:1346-55. 
Ebert Peter JR, Cheung J, Yang Y, et al. MAP Kinase Inhibition Promotes T Cell and Anti-tumor 
Activity in Combination with PD-L1 Checkpoint Blockade. Immunity. 2016.44:609-21. 
Erbitux PI at https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125084s242lbl.pdf 
accessed 18 May 2017. 
Giannakis M, Mu JJ, Shukla SA, et al. Genomic correlates of immune-cell infiltrates in 
colorectal cancer. Cell Reports 2016;15:857-65. 
Glimelius B, Lahn M. Window-of-opportunity trials to evaluate clinical activity of new 
molecular entities in oncology. Annals Oncol. 2011; 22:1717–25. 
Grothey A and Goldberg RM. A review of oxaliplatin and its clinical use in colorectal cancer. 
Expert Opin Pharmacother. 2004; 5(10):2159-70. 
Guo W, Wang SJ, Yang S, et al. A Bayesian interval dose-finding design addressingOckham's 
razor: mTPI-2. Contemp Clin Trials 2017;58:23-33. 
Hellmann MD, Gettinger SN, Goldman JW, et al. CheckMate 012: Safety and efficacy of first-
line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol. 
2016; 34: suppl; abstr 3001. 

Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-162-202 
 
 
Version 4.0 
200 
 
Confidential 
02 March 2018 
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with 
metastatic melanoma; N Engl J Med. 2010;363(8):711-23. 
Hoeflich KP, Merchant M, Orr C, et al. Intermittent administration of MEK inhibitor GDC-0973 
plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition. Cancer 
Res. 2012; 72:210-19. 
Hugo W, Shi H, Sun L, et al. Non-genomic and immune evolution of melanoma acquiring 
MAPKi resistance.  Cell 2015;162:1271-85. 
Infante JR, Fecher LA, Falchook GS, et al. Safety, pharmacokinetic, pharmacodynamic, and 
efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet 
Oncol. 2012. 13:773-81. 
Ipilimumab Investigator’s Brochure Version 19. Mar-2015. DCN: 930017531. 
Irving BA, Cheung J, Yang Y, et al. MAP kinase inhibitors stimulate T cell and anti-tumor 
activity in combination with blockade of the PD-L1/PD-1 interaction. J Immunother Cancer 
2013;1(Suppl 1):P79. 
Lal N, Beggs AD, Willcox BE, et al. An immunogenomic stratification of colorectal cancer: 
Implications for development of targeted immunotherapy. OncoImmunology. 2015; 4:e976052. 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Overall survival results from a phase III trial of 
nivolumab combined with ipilimumab in treatment-naive patients with advanced melanoma 
(CheckMate 067). 2017 AACR Annual Meeting. Abstract CT075.  
Le DT, Uram JN, Wang H, et al. Programmed death-1 blockade in mismatch repair deficient 
colorectal cancer. J Clin Oncol 2016;34:suppl; abstr 103. 
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with mismatch-repair deficiency. 
New Engl J Med. 2015; 372:2509-20. 
Lea IA, Jackson MA, Li X et al. Genetic pathways and mutation profiles of human cancers: site- 
and exposure-specific patterns. Carcinogenesis 2007; 28:1851-8. 
Liu L, Mayes PA, Eastman S, et al. The BRAF and MEK inhibitors dabrafenib and trametinib: 
Effects on immune function and in combination with immunomodulatory antibodies targeting 
PD-1, PD-L1, and CTLA-4. Clin Cancer Res 2015; 21(7):1639-1651. 
Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite 
instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discovery 
2015;5:43-51. 
Loi S, Dushyanthen S, Beavis PA, et al. RAS/MAPK activation is associated with reduced 
tumor-infiltrating lymphocytes in triple-negative breast cancer: Therapeutic Cooperation 
Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors. Clin Cancer Res. 
2016;22(6):1499-509. 

Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-162-202 
 
 
Version 4.0 
201 
 
Confidential 
02 March 2018 
Martín-Algarra S, Haanen JB, Horak C, et al. Safety of reduced infusion times for nivolumab 
plus ipilimumab (N + I) and nivolumab alone (N) in advanced melanoma. Ann Oncol 2016; 27 
(suppl_6): 1125. 
Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory 
metastatic colorectal cancer. N Engl J Med. 2015; 372(20):1909-19. 
Mimura K, Kua LF, Shiraishi K, et al. Inhibition of mitogen-activated protein kinase pathway 
can induce upregulation of human leukocyte antigen class I without PD-L1-upregulation in 
contract to interferon-Ɣ treatment. Cancer Sci. 2014; 105(10):1236-44. 
Momtaz P, Park V, Panageas KS, et al. Safety of infusing ipilimumab over 30 minutes. J Clin 
Oncol 2015; 33(30); 3454-8. 
National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology – 
Colon Cancer. Version 2.2017. Available at 
https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed 12 July 2017. 
Nivolumab Investigator’s Brochure Version 15, June 2016 
Ohrling K, Edler D, Hallstrom M, et al. Mismatch repair protein expression is an independent 
prognostic factor in sporadic colorectal cancer. Acta Oncol. 2010; 49(6):797-804. 
Opdivo PI at https://packageinserts.bms.com/pi/pi_opdivo.pdf accessed 19 July 2017 
O’Toole A, Michielsen AJ, Nolan B, et al. Tumour microenvironment of both early- and late-
stage colorectal cancer is equally immunosuppressive. Br J Cancer 2014;111:927-32. 
Ott PA, Hodi SF, Kaufman HL, et al. Combination immunotherapy: a road map. J Immunother 
Cancer. 2017;5(16):1-15. 
Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab + ipilimumab in treatment of patients 
with metastatic colorectal cancer with and without high microstallite instability (MSI-H): 
CheckMate-142 interim results. J Clin Oncol. 2016;34: (suppl; abstr 3501). 
Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with 
fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line 
treatment in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:4706-13. 
Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in 
untreated melanoma. N Engl J Med. 2015; 372:2006-17. 
Reardon DA, Sampson JH, Sahebjam S, et al. Safety and activity of nivolumab (nivo) 
monotherapy and nivo in combination with ipilimumab (ipi) in recurrent glioblastoma (GBM): 
updated results from checkmate-143. J Clin Oncol. 2016; 34:suppl; abstr 2014. 

Bi ni meti ni b ( M E K i n hi bit or) 
Arra y Bi o P har ma I n c.  
Cli nical St u d y A R R A Y- 1 6 2 -2 0 2  
 
 
Versi o n 4. 0 
2 0 2  
 
C o nfi de ntial 
0 2 Marc h 2 0 1 8  
Ri ne hart J, A djei A A, L o R uss o P M, et al. M ultice nter P hase II st u d y of t h e oral M E K i n hi bit or, 
CI - 1 0 4 0, i n p atie nts wit h a d va nce d n o n-s mall-cell l u n g, breast, c ol o n, a n d pa ncreatic ca ncer. J 
Cli n O nc ol. 2 0 0 4; 2 2: 4 4 5 6 - 6 2. 
R o bert C, T h o mas L, B o n dare n k o I, et al. I pili m u ma b pl us dacar bazi ne f or pre vi o usl y u ntr eate d 
metastatic m elan o ma. N E n gl J Me d. 2 0 1 1; 3 6 4( 2 6): 2 5 1 7- 2 6. 
Sal m o n H, I d o ya ga J, Ra h ma n A, et al. E x pa nsi o n a n d acti vati o n of C D 1 0 3 + de n dritic cell 
pr o ge nit ors at t he t u m or site e n ha nces t u m or res p o nses t o t hera pe utic P D- L 1 a n d B R A F 
in hi biti o n. I m m u nit y . 2 0 1 6; 4 4: 9 2 4- 3 8. 
Sa matar A A a n d P o uli ka k os PI. Tar geti n g R A S- E R K si g nalli n g i n ca ncer: pr o mises a n d 
c halle n ges. N at Re v Dr u g Disc o v. 2 0 1 4; 1 3: 9 2 8- 4 2. 
Sc ha de n d orf D, Lar ki n J, P ost o w M, et al. Efficac y a n d s afet y o utc o m es i n patie nts wit h 
a d va nce d mela n o ma ( M E L) w h o disc o nti n ue d treat me nt wit h ni v ol u ma b ( NI V O) pl us 
i pili m u ma b (I PI) d ue t o t o xicit y. Prese nt e d at t he 1 6t h W orl d C o n gress o n Ca ncers of t h e 
S ki n/ 1 2t h C o n gress of t he E ur o pea n Ass ociati o n of Der mat o- O nc ol o g y, A u g ust 3 1 – Se pte m ber 3, 
2 0 1 6, Vie n na, A ustria. 
Sc hirr i pa M, Cre m oli ni C, L o u pa kis F, et al. R ole of N R A S  m utati o ns as pr o g n ostic a n d 
pr e dicti ve mar kers i n metastatic c ol orect al ca n cer. I nt J Ca ncer. 2 0 1 5; 1 3 6: 8 3 – 9 0.  
Seli ger B, H ar ders C, L o h ma n n S, et al. D o w n-re g ulati o n of t he M H C cl ass I a nti ge n- pr o cessi n g 
mac hi ner y after o n c o ge ni c tra nsf or m ati o n of m uri ne fi br o blasts. E ur J I m m u n ol. 1 9 9 8; 2 8( 1): 1 2 2-
3 3.  
 
 
S har ma  P a n d Allis o n J P. I m m u ne c hec k p oi nt tar geti n g i n ca ncer t hera p y: t o war d c o m bi nati o n 
strate gies wit h c urati ve p ote ntial. Cell. 2 0 1 5; 1 6 1: 2 0 5- 1 4 
S he n g H, Willia ms C S, S ha o J, et al. I n d ucti o n of c ycl o o x y ge nas e- 2 b y acti vate d Ha-ras 
o nc o ge ne i n r at- 1 fi br o bl asts a n d t he r ole of mit o ge n-acti vat e d pr otei n ki nase pat h wa y. J Bi ol 
C he m. 1 9 9 8 ; 2 7 3 : 2 2 1 2 0- 2 7. 
Sie gel R L, Mill er K D, a n d J e mal A. Ca ncer Statistics, 2 0 1 5. C A Ca ncer J Cli n. 2 0 1 5; 6 5: 5- 2 9. 
S mit h J C, Br o o ks L. K R A S m utati o ns are ass ociate d wit h i nferi or cli nical o utc o me i n patie nts 
wit h metastatic c ol orect al ca ncer, b ut are n ot pre di cti ve f or be n efit wit h ce dira ni b. E ur J Ca ncer. 
2 0 1 3; 4 9( 1 0): 2 4 2 4 – 2 4 3 2.  
S oric h MJ , Wiese M D, R o wla n d A, et al. E xte n de d R A S  m utati o ns a n d a nti- E G F R m o n ocl o nal 
anti b o d y s ur vi val b e nefit i n metastatic c ol orect al ca ncer: a meta-a nal ysis of ra n d o mize d, 
c o ntr olle d trials. A n n O n c ol. 2 0 1 5; 2 6( 1): 1 3- 2 1.  
C CI

Binimetinib (MEK inhibitor) 
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Clinical Study ARRAY-162-202 
 
 
Version 4.0 
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Confidential 
02 March 2018 
Stivarga PI at https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203085s001lbl.pdf 
accessed 18 May 2017. 
Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse 
sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004; 
22(2):229-37. 
Urner-Bloch U, Urner M, Stieger P, et al. Transient MEK inhibitor-associated retinopathy in 
metastatic melanoma. Annals Oncol 2014;25:1437-41. 
Urner-Bloch U, Urner M, Jaberg-Bentele N, et al. MEK inhibitor-associated retinopathy 
(MEKAR) in metastatic melanoma: Long-term ophthalmic effects. Eur J Cancer 2016;65:130-8. 
Van Cutsem E Lenz HJ, Kohne CH, et al. Fluorouracil, leucovorin, and irinotecan plus 
cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 2015;33(7)692-700. 
Van Cutsem E, Cervantes A, Nordlinger B, et al. Metastatic colorectal cancer: ESMO clinical 
practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:1386-1422. 
Wang D, Mann JR, DuBoise RN. The role of prostaglandins and other eicosanoids in the 
gastrointestinal tract. Gastroenterology 2005;128(5):1445-61. 
Wang X, Feng Y, Bajaj G, et al. Quantitative characterization of the exposure-response 
relationship for cancer immunotherapy: A case study of nivolumab in patients with advanced 
melanoma. CPT Pharmacometrics Syst Pharmacol. 2017; 6(1):40-8. 
WHO Fact Sheet at http://www.who.int/mediacentre/factsheets/fs297/en/  Accessed 11 July 
2017. 
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;15:7412-20. 
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. 
N Engl J Med. 2013; 369:122-33. 
Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Updated results from a phase III trial of 
nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naïve patients (pts) with 
advanced melanoma (MEL) (CheckMate 067). J Clin Oncol. 2016; 34: suppl; abstr 9505. 
Xiao Y and Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly 
good candidate for checkpoint blockade immunotherapy. Cancer Discover 2015; 5:16-18. 
Yervoy PI at http://packageinserts.bms.com/pi/pi_yervoy.pdf accessed 19 July 2017 
Yokota T, Ura T, Shibata N, et al. BRAF mutation is a powerful prognostic factor in advanced 
and recurrent colorectal cancer. Br J Cancer 2011;104(5):856-62. 
Zaltrap PI at https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125418s000lbl.pdf 
accessed 18 May 2017. 

Binimetinib (MEK inhibitor) 
Array BioPharma Inc. 
Clinical Study ARRAY-162-202 
 
 
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Zelenay S, van der Veen AG, Bottcher JP, et al. Cyclo-oxygenase-dependent tumor growth 
thorough evasion of immunity. Cell 2015;162(6):1257-70.