CompletedNCT03271047Updated Jan 4, 2022Results posted

Study of Binimetinib + Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Microsatellite-stable (MSS) Metastatic Colorectal Cancer With RAS Mutation

A Phase 2 interventional study of binimetinib and nivolumab in MSS and RAS-mutant Colorectal Cancer, sponsored by Pfizer. Completed at 50 sites in 5 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2022-01-04.

Sponsored by Pfizer · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 75
Allocation: Non-randomized
Ages: 18 Years and older
Sex: All

Study summary

This is a multicenter, open-label, Phase 1B/2 study to evaluate the safety and assess the preliminary anti-tumor activity of binimetinib administered in combination with nivolumab or nivolumab + ipilimumab in adult patients with advanced metastatic colorectal cancer (mCRC) with microsatellite stable (MSS) disease and presence of a RAS mutation that have received at least one prior line of therapy and no more than 2 prior lines of therapy. The study contains a Phase 1b period to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and schedule of binimetinib followed by a randomized Phase 2 period to assess the efficacy of the combinations.

Conditions studied

MSS
RAS-mutant Colorectal Cancer

Browse trials for

Neoplasms 9,610

Keywords

cancer

In context

Neoplasms

9,610 studies on the registry are indexed under Neoplasms; 2,508 are open to participants now.

This study's enrollment of 75 is above the median of 50 across 7,429 interventional studies indexed under Neoplasms.

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Lead sponsor

Pfizer is the lead sponsor of 3,323 studies on the registry; 145 are open to participants now.

Of its 597 completed or terminated interventional studies of FDA-regulated products, 391 (65%) have results posted.

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Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Eligibility criteria

Key Inclusion Criteria

Measurable, histologically/cytologically confirmed metastatic colorectal cancer (mCRC).
Able to provide a sufficient amount of representative tumor specimen for central laboratory testing of RAS mutation status and microsatellite stable (MSS).
- If a fresh tissue sample is provided, a blood sample is required.
Metastatic colorectal cancer (mCRC) categorized as microsatellite stable (MSS) by polymerase chain reaction (PCR) per local assay at any time prior to Screening or by the central laboratory.
RAS mutation per local assay at any time prior to Screening or by the central laboratory.
Have received at least 1 prior line of therapy and meets at least one of the following criteria:
- were unable to tolerate the prior first-line regimen
- experienced disease progression during or after prior first-line regimen for metastatic disease
- progressed during or within 3 months of completing adjuvant chemotherapy. Note: Generally, treatments that are separated by an event of progression are considered different regimens.
Have received no more than 2 prior lines of therapy (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.
Adequate bone marrow, cardiac, kidney and liver function
Able to take oral medications
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of child-bearing potential
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

Key Exclusion Criteria

Prior treatment with any MEK inhibitor, 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.
Any untreated central nervous system (CNS) lesion.
Patients with an active, known or suspected autoimmune disease. 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.
Known history of retinal vein occlusion (RVO).
Known history of Gilbert's syndrome.
Pregnant or breastfeeding females.
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:
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.
Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
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).
History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
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.
Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection, and/or detectable virus.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Non-randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 75 participants (actual)

Study arms

Experimental
Phase 1b / Arm 1A
binimetinib + nivolumab
Drug: binimetinib · Drug: nivolumab
Experimental
Phase 1b / Arm 1B
binimetinib + nivolumab + ipilimumab
Drug: binimetinib · Drug: nivolumab · Drug: ipilimumab
Experimental
Phase 2 / Arm 2A
binimetinib + nivolumab
Drug: binimetinib · Drug: nivolumab
Experimental
Phase 2 / Arm 2B
binimetinib + nivolumab + ipilimumab
Drug: binimetinib · Drug: nivolumab · Drug: ipilimumab

Interventions

Drugbinimetinib
Orally, twice daily.
Drugnivolumab
Intravenously (IV) every 4 weeks (Q4W)
Drugipilimumab
intravenously (IV) every 8 weeks (Q8W)

What researchers measure

Primary outcomes

Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLT)
DLT:Adverse event(AE)/abnormal laboratory assessed unrelated-disease,disease progression,intercurrent illness/concomitant medication/therapies resulting inability tolerate 75% dose intensity in Cycle 1.Total bilirubin(TBL)grade(G)\>=3 (\>3.0\*upper limit of normal\[ULN)\]);AST/ALT\>5-8\*ULN\>5 days,\>8\*ULN,\>3\*ULN concurrent TBL\>2\*ULN;G\>=3 serum creatinine,CK elevation,ECG QTcF prolonged,G3 troponin,electrolyte\>72 hours,G3/4 amylase/lipase.G4 ANC,platelet count\>7 days;G3/4 platelet count,other AE except lymphopenia.G\>=3 retinopathy,other disorder\>21 days;G2 uveitis/eye pain/blurred vision/decreased visual acuity;G4 other disorder.Decrease LVEF\>10% G\>=3 cardiac disorders.G3/4 hypertension.G3 fatigue\>=7 days,hypersensitivity,infusion reaction,fever\>=72 hours/hemodynamic compromise,endocrinopathy.G\>=2 interstitial lung disease/pneumonitis;G3 bronchospasm.G3/4 rash,hand foot skin reaction,photosensitivity.G3 colitis;G3/4 diarrhea,nausea/vomiting.Neurologic G3.Other hematologic/nonhematolic G\>=3 AE.
Time frame: Cycle 1: Day 1 up to Day 28
Phase 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1
ORR was defined as the percentage of participants who achieved a best overall response (BOR) of complete response (CR) or partial response (PR) as determined by investigator per RECIST v1.1. As per RECIST v1.1, CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures less than (\<)10 millimeter (mm). PR was defined as at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-progressive disease (PD). PD was defined as at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to 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 was considered progression.
Time frame: From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 2: maximum up to 26 months approximately)

Secondary outcomes

Phase 1b: Objective Response Rate (ORR) Per RECIST v1.1
ORR was defined as the percentage of participants who achieved a BOR of CR or PR as determined by investigator per RECIST v1.1. As per RECIST v1.1, CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures \<10 mm. PR was defined as at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non-target lesions must be non-PD. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum 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 was also considered progression.
Time frame: From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately)
Duration of Response (DOR) as Per RECIST v1.1
DOR was defined as the time between the date of the first documented confirmed response (PR or CR) and the date of the first documented progression or death due to any cause. As per RECIST v1.1: CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes short axis measures \<10 mm. PR was defined as at least 30% decrease in sum of measures (tumor lesions- longest diameter and nodes- short axis) of target lesions, taking as reference baseline sum of diameters. PD was defined as at least 20% increase in sum of diameters of measured lesions taking as references smallest sum of diameters recorded on study (including baseline) and an absolute increase of \>=5 mm or appearance of at least 1 new lesion. Unequivocal progression of existing non-target lesions.
Time frame: From date of first documented CR/PR to date of first documented PD, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately, Phase 2: maximum up to 26 months approximately)
Percentage of Participants With Complete Response as Per RECIST v1.1
Complete response as per RECIST v1.1 was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures \<10 mm.
Time frame: From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately and Phase 2: maximum up to 26 months approximately)
Number of Participants With Treatment-Emergent Adverse Events (TEAE) Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03
AE: any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE: AE resulting in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs: events between first dose of study drug and up to 30 days after last dose or before start of new anticancer therapy minus 1 day, whichever occurred first. TEAE graded by CTCAE grade 4.03: Grade 3: severe/medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care activities of daily living (ADL); Grade 4: life-threatening consequence, urgent intervention indicated. In this outcome measure, number of participants with 'all grades' and 'Grade 3/4' were reported.
Time frame: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (Phase 1b: maximum up to 9 months approximately and Phase 2: maximum up to 26 months approximately)
Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03: Hematology and Coagulation
Hematological parameters included: Hemoglobin graded high, Hemoglobin graded low, Platelets count graded low, White Blood Cell (WBC) graded high, WBC graded low, Neutrophils graded low, Lymphocytes graded high, Lymphocytes graded low. Coagulation parameters included: International Normalized Ratio (INR) graded high, Activated Partial Thromboplastin Time (aPTT) graded high. Test abnormalities were graded by CTCAE v4.03 as Grade 1=mild; Grade 2=moderate; Grade 3/Grade 4=severe/life-threatening. A grade 0 was assigned for all non-missing values not graded as 1 or higher. If value was graded \>=1 but falls within the normal range, the grade was reset to 0. Categories with at least 1 non-zero data values are reported.
Time frame: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Hematology and Coagulation
Hematology parameters: Basophils, Eosinophils, Hematocrit, Monocytes, Red blood cells (RBC). Coagulation parameters: Prothrombin Time. Laboratory values were as per laboratory normal ranges. Values above range were reported as high and values below range as low. Laboratory parameters were graded based on laboratory normal ranges as low, normal, high and missing are reported in this outcome measure. Categories with at least 1 non-zero data values are reported.
Time frame: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on CTCAE v4.03: Chemistry
Abnormalities: Albumin graded low, Alkaline phosphatase (ALP) graded high, Alanine aminotransferase (ALT) graded high, Aspartate aminotransferase (AST) graded high, Bilirubin graded high, Amylase graded high, Creatinine graded high, Corrected calcium graded high, Creatine Kinase (CK) graded high, Glucose graded high, Glucose graded low, Lipase graded high, Magnesium graded high, Magnesium graded low, Potassium graded high, Potassium graded low, Sodium graded high and Sodium graded low. Test abnormalities were graded by CTCAE v4.03 as Grade 1=mild; Grade 2=moderate; Grade 3/Grade 4=severe/life-threatening. A grade 0 was assigned for all non-missing values not graded as 1 or higher. If value was graded \>=1 but falls within the normal range, the grade was reset to 0. Categories with at least 1 non-zero data values are reported.
Time frame: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Chemistry and Thyroid Function
Chemistry laboratory parameters: Blood urea nitrogen (BUN), Total protein, Chloride, Cancer antigen 19-9 (CA 19-9), Brain natriuretic peptide (BNP), Bicarbonate, Direct bilirubin, Carcinoembryonic antigen (CEA), Lactate dehydrogenase (LDH), Uric acid, Troponin I. Thyroid panel laboratory parameters: Thyroid-stimulating hormone (TSH), Free triiodothyronine (T3), Free thyroxine (T4). Laboratory values were as per laboratory normal ranges. Values above range were reported as high and values below range as low. Shift in chemistry and thyroid panel severity from baseline grade low, normal, high and missing to the post baseline grades as low, normal, high and missing are reported in this outcome measure. Categories with at least 1 non-zero data values are reported.
Time frame: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
Number of Participants With Abnormal Hepatic Laboratory Values
Criteria for abnormal hepatic laboratory parameters: Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT): \>3\* upper limit of normal (ULN), \>5\*ULN, \>8\*ULN, \>10\*ULN, \>20\*ULN; Total bilirubin (TBL) \>1.5\*ULN, \>2\*ULN; Alkaline phosphatase (ALP) \>2\*ULN, \>3\*ULN. Categories with at least 1 non-zero data values are reported.
Time frame: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
Concentration Versus Time Summary of Plasma Concentration of Binimetinib
Time frame: 1.5 hours post dose of binimetinib on Day 1, 15 of Cycle 1; pre dose of binimetinib on Day 15 of Cycle 1, 2, 3, 4, 5

Results

Posted Nov 2, 2021

Participant flow

Phase 1b: Dose Finding Period

Participant flow — Phase 1b: Dose Finding Period
Milestone	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib
Started	10	11
Completed	0	0
Not completed	10	11
Withdrew: Death	8	8
Withdrew: Lost to follow-up	1	0
Withdrew: Withdrawal by subject	0	2
Withdrew: Completed follow-up per protocol	1	1

Randomized Phase 2 Period

Participant flow — Randomized Phase 2 Period
Milestone	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Started	27	27
Completed	0	0
Not completed	27	27
Withdrew: Other	0	1
Withdrew: Death	20	21
Withdrew: Lost to follow-up	2	1
Withdrew: Withdrawal by subject	5	0
Withdrew: Completed follow-up per protocol	0	4

Outcome measures

PrimaryPhase 1b: Number of Participants With Dose-Limiting Toxicities (DLT)

DLT:Adverse event(AE)/abnormal laboratory assessed unrelated-disease,disease progression,intercurrent illness/concomitant medication/therapies resulting inability tolerate 75% dose intensity in Cycle 1.Total bilirubin(TBL)grade(G)\>=3 (\>3.0\*upper limit of normal\[ULN)\]);AST/ALT\>5-8\*ULN\>5 days,\>8\*ULN,\>3\*ULN concurrent TBL\>2\*ULN;G\>=3 serum creatinine,CK elevation,ECG QTcF prolonged,G3 troponin,electrolyte\>72 hours,G3/4 amylase/lipase.G4 ANC,platelet count\>7 days;G3/4 platelet count,other AE except lymphopenia.G\>=3 retinopathy,other disorder\>21 days;G2 uveitis/eye pain/blurred vision/decreased visual acuity;G4 other disorder.Decrease LVEF\>10% G\>=3 cardiac disorders.G3/4 hypertension.G3 fatigue\>=7 days,hypersensitivity,infusion reaction,fever\>=72 hours/hemodynamic compromise,endocrinopathy.G\>=2 interstitial lung disease/pneumonitis;G3 bronchospasm.G3/4 rash,hand foot skin reaction,photosensitivity.G3 colitis;G3/4 diarrhea,nausea/vomiting.Neurologic G3.Other hematologic/nonhematolic G\>=3 AE.

Time frame:: Cycle 1: Day 1 up to Day 28
Reported as:: Count of participants · Participants

Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLT)
Participants	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib
Phase 1b: Number of Participants With Dose-Limiting Toxicities (DLT)	1	2

PrimaryPhase 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

ORR was defined as the percentage of participants who achieved a best overall response (BOR) of complete response (CR) or partial response (PR) as determined by investigator per RECIST v1.1. As per RECIST v1.1, CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures less than (\<)10 millimeter (mm). PR was defined as at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference baseline sum of diameters. Non-target lesions must be non-progressive disease (PD). PD was defined as at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to 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 was considered progression.

Time frame:: From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 2: maximum up to 26 months approximately)
Reported as:: Number · Percentage of participants

Phase 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1
Percentage of participants	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Phase 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1	0.0 (NA to NA)	7.4 (0.9 to 24.3)

SecondaryPhase 1b: Objective Response Rate (ORR) Per RECIST v1.1

ORR was defined as the percentage of participants who achieved a BOR of CR or PR as determined by investigator per RECIST v1.1. As per RECIST v1.1, CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures \<10 mm. PR was defined as at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non-target lesions must be non-PD. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum 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 was also considered progression.

Time frame:: From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately)
Reported as:: Number · Percentage of participants

Phase 1b: Objective Response Rate (ORR) Per RECIST v1.1
Percentage of participants	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib
Phase 1b: Objective Response Rate (ORR) Per RECIST v1.1	0.0 (NA to NA)	0.0 (NA to NA)

SecondaryDuration of Response (DOR) as Per RECIST v1.1

DOR was defined as the time between the date of the first documented confirmed response (PR or CR) and the date of the first documented progression or death due to any cause. As per RECIST v1.1: CR was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes short axis measures \<10 mm. PR was defined as at least 30% decrease in sum of measures (tumor lesions- longest diameter and nodes- short axis) of target lesions, taking as reference baseline sum of diameters. PD was defined as at least 20% increase in sum of diameters of measured lesions taking as references smallest sum of diameters recorded on study (including baseline) and an absolute increase of \>=5 mm or appearance of at least 1 new lesion. Unequivocal progression of existing non-target lesions.

Time frame:: From date of first documented CR/PR to date of first documented PD, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately, Phase 2: maximum up to 26 months approximately)
Reported as:: Median · Months

Duration of Response (DOR) as Per RECIST v1.1
Months	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Duration of Response (DOR) as Per RECIST v1.1	—	—	—	11.4 (7.5 to 15.2)

SecondaryPercentage of Participants With Complete Response as Per RECIST v1.1

Complete response as per RECIST v1.1 was defined as disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures \<10 mm.

Time frame:: From start of the treatment until disease progression, death or initiation of new anticancer therapy, whichever occurred first (Phase 1b: maximum up to 9 months approximately and Phase 2: maximum up to 26 months approximately)
Reported as:: Number · Percentage of participants

Percentage of Participants With Complete Response as Per RECIST v1.1
Percentage of participants	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Percentage of Participants With Complete Response as Per RECIST v1.1	0	0	0	0

SecondaryNumber of Participants With Treatment-Emergent Adverse Events (TEAE) Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03

AE: any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE: AE resulting in any of following outcomes/deemed significant for any other reason: death; initial /prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs: events between first dose of study drug and up to 30 days after last dose or before start of new anticancer therapy minus 1 day, whichever occurred first. TEAE graded by CTCAE grade 4.03: Grade 3: severe/medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care activities of daily living (ADL); Grade 4: life-threatening consequence, urgent intervention indicated. In this outcome measure, number of participants with 'all grades' and 'Grade 3/4' were reported.

Time frame:: From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (Phase 1b: maximum up to 9 months approximately and Phase 2: maximum up to 26 months approximately)
Reported as:: Count of participants · Participants

Number of Participants With Treatment-Emergent Adverse Events (TEAE) Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03
Participants	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Treatment emergent AEs- All grades	10	11	27	27
Treatment emergent SAEs- All grades	5	6	12	11
Treatment emergent AEs- Grade 3/4	6	8	19	21
Treatment emergent SAEs- Grade 3/4	5	6	11	10

SecondaryNumber of Participants With Shift From Baseline in Laboratory Parameter Values Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03: Hematology and Coagulation

Hematological parameters included: Hemoglobin graded high, Hemoglobin graded low, Platelets count graded low, White Blood Cell (WBC) graded high, WBC graded low, Neutrophils graded low, Lymphocytes graded high, Lymphocytes graded low. Coagulation parameters included: International Normalized Ratio (INR) graded high, Activated Partial Thromboplastin Time (aPTT) graded high. Test abnormalities were graded by CTCAE v4.03 as Grade 1=mild; Grade 2=moderate; Grade 3/Grade 4=severe/life-threatening. A grade 0 was assigned for all non-missing values not graded as 1 or higher. If value was graded \>=1 but falls within the normal range, the grade was reset to 0. Categories with at least 1 non-zero data values are reported.

Time frame:: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
Reported as:: Count of participants · Participants

Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03: Hematology and Coagulation
Participants	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Hemoglobin- CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	3	3	4	5
Hemoglobin- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	2	2	6	10
Hemoglobin- CTCAE Graded Low: Grade 0 (at baseline) to Grade 2 (at post baseline)	2	1	2	1
Hemoglobin- CTCAE Graded Low: Grade 0 (at baseline) to Grade 3 (at post baseline)	0	0	1	0
Hemoglobin- CTCAE Graded Low: Grade 1 (at baseline) to Grade 0 (at post baseline)	0	0	1	0
Hemoglobin- CTCAE Graded Low: Grade 1 (at baseline) to Grade 1 (at post baseline)	1	4	4	4
Hemoglobin- CTCAE Graded Low: Grade 1 (at baseline) to Grade 2 (at post baseline)	2	0	3	1
Hemoglobin- CTCAE Graded Low: Grade 1 (at baseline) to Grade 3 (at post baseline)	0	1	1	1
Hemoglobin- CTCAE Graded Low: Grade 1 (at baseline) to Missing (at post baseline)	0	0	1	0
Hemoglobin- CTCAE Graded Low: Grade 2 (at baseline) to Grade 2 (at post baseline)	—	—	3	5
Hemoglobin- CTCAE Graded Low: Grade 2 (at baseline) to Grade 3 (at post baseline)	—	—	1	0
Hemoglobin- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	10	11	26	26
Hemoglobin- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	0	0	0	1
Hemoglobin- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Lymphocytes - CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	6	7	11	11
Lymphocytes- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	0	0	2	4
Lymphocytes- CTCAE Graded Low: Grade 0 (at baseline) to Grade 2 (at post baseline)	0	2	4	6
Lymphocytes- CTCAE Graded Low: Grade 0 (at baseline) to Grade 3 (at post baseline)	1	0	3	1
Lymphocytes- CTCAE Graded Low: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Lymphocytes- CTCAE Graded Low: Grade 1 (at baseline) to Grade 0 (at post baseline)	—	0	0	1
Lymphocytes- CTCAE Graded Low: Grade 1 (at baseline) to Grade 2 (at post baseline)	—	1	1	0
Lymphocytes- CTCAE Graded Low: Grade 1 (at baseline) to Grade 3 (at post baseline)	—	0	1	0
Lymphocytes- CTCAE Graded Low: Grade 2 (at baseline) to Grade 0 (at post baseline)	0	—	1	0
Lymphocytes- CTCAE Graded Low: Grade 2 (at baseline) to Grade 2 (at post baseline)	1	—	1	2
Lymphocytes- CTCAE Graded Low: Grade 2 (at baseline) to Grade 3 (at post baseline)	1	—	1	2
Lymphocytes- CTCAE Graded Low: Grade 3 (at baseline) to Grade 0 (at post baseline)	0	0	1	—
Lymphocytes- CTCAE Graded Low: Grade 3 (at baseline) to Grade 2 (at post baseline)	0	1	0	—
Lymphocytes- CTCAE Graded Low: Grade 3 (at baseline) to Grade 3 (at post baseline)	1	0	0	—
Lymphocytes- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	9	11	25	26
Lymphocytes- CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	1	0	1	1
Lymphocytes- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Neutrophils- CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	9	11	23	26
Neutrophils- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	0	0	1	1
Neutrophils- CTCAE Graded Low: Grade 0 (at baseline) to Grade 2 (at post baseline)	1	0	0	0
Neutrophils- CTCAE Graded Low: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Neutrophils- CTCAE Graded Low: Grade 1 (at baseline) to Grade 0 (at post baseline)	—	—	1	—
Neutrophils- CTCAE Graded Low: Grade 1 (at baseline) to Grade 3 (at post baseline)	—	—	1	—
Platelets- CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	8	9	21	22
Platelets- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	2	1	3	4
Platelets- CTCAE Graded Low: Grade 0 (at baseline) to Missing (at post baseline)	0	0	2	0
Platelets- CTCAE Graded Low: Grade 1 (at baseline) to Grade 0 (at post baseline)	—	1	0	0
Platelets- CTCAE Graded Low: Grade 1 (at baseline) to Grade 1 (at post baseline)	—	0	1	1
WBC- CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	9	11	21	24
WBC- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	0	0	2	0
WBC- CTCAE Graded Low: Grade 0 (at baseline) to Grade 2 (at post baseline)	1	0	1	2
WBC- CTCAE Graded Low: Grade 0 (at baseline) to Grade 4 (at post baseline)	0	0	1	0
WBC- CTCAE Graded Low: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
WBC- CTCAE Graded Low: Grade 1 (at baseline) to Grade 1 (at post baseline)	—	—	1	0
WBC- CTCAE Graded Low: Grade 1 (at baseline) to Grade 2 (at post baseline)	—	—	0	1
WBC- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	10	11	26	27
WBC- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
aPTT- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	6	8	16	17
aPTT- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	3	2	6	6
aPTT- CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	1	0	2	1
aPTT- CTCAE Graded High: Grade 1 (at baseline) to Grade 0 (at post baseline)	—	0	0	1
aPTT- CTCAE Graded High: Grade 1 (at baseline) to Grade 1 (at post baseline)	—	1	1	1
aPTT- CTCAE Graded High: Grade 1 (at baseline) to Grade 3 (at post baseline)	—	0	1	0
aPTT- CTCAE Graded High: Grade 1 (at baseline) to Missing (at post baseline)	—	0	1	0
aPTT- CTCAE Graded High: Missing (at baseline) to Grade 0 (at post baseline)	—	—	—	1
INR- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	5	6	16	13
INR- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	4	2	4	4
INR- CTCAE Graded High: Grade 1 (at baseline) to Grade 0 (at post baseline)	0	1	1	1
INR- CTCAE Graded High: Grade 1 (at baseline) to Grade 1 (at post baseline)	1	1	5	8
INR- CTCAE Graded High: Grade 1 (at baseline) to Missing (at post baseline)	0	0	1	0
INR- CTCAE Graded High: Grade 2 (at baseline) to Grade 2 (at post baseline)	—	1	—	—
INR- CTCAE Graded High: Missing (at baseline) to Grade 0 (at post baseline)	—	—	—	1

SecondaryNumber of Participants With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Hematology and Coagulation

Hematology parameters: Basophils, Eosinophils, Hematocrit, Monocytes, Red blood cells (RBC). Coagulation parameters: Prothrombin Time. Laboratory values were as per laboratory normal ranges. Values above range were reported as high and values below range as low. Laboratory parameters were graded based on laboratory normal ranges as low, normal, high and missing are reported in this outcome measure. Categories with at least 1 non-zero data values are reported.

Time frame:: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
Reported as:: Count of participants · Participants

Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Hematology and Coagulation
Participants	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Basophils: Normal (at baseline) to Low (at post baseline)	0	0	1	0
Basophils: Normal (at baseline) to Normal (at post baseline)	10	11	25	27
Basophils: Normal (at baseline) to Missing (at post baseline)	0	0	1	0
Eosinophils: Normal (at baseline) to Low (at post baseline)	0	0	0	1
Eosinophils: Normal (at baseline) to Normal (at post baseline)	7	11	25	20
Eosinophils: Normal (at baseline) to High (at post baseline)	2	0	1	6
Eosinophils: Normal (at baseline) to Missing (at post baseline)	0	0	1	0
Eosinophils: High (at baseline) to Normal (at post baseline)	1	—	—	—
Hematocrit: Low (at baseline) to Low (at post baseline)	2	1	8	9
Hematocrit: Low (at baseline) to Normal (at post baseline)	0	1	1	0
Hematocrit: Low (at baseline) to Missing (at post baseline)	0	0	1	0
Hematocrit: Normal (at baseline) to Low (at post baseline)	5	4	13	12
Hematocrit: Normal (at baseline) to Normal (at post baseline)	3	4	4	6
Hematocrit: Normal (at baseline) to High & Low (at post baseline)	0	1	0	0
Monocytes: Normal (at baseline) to Low (at post baseline)	1	0	1	0
Monocytes: Normal (at baseline) to Normal (at post baseline)	9	7	19	20
Monocytes: Normal (at baseline) to High (at post baseline)	0	4	6	6
Monocytes: Normal (at baseline) to Missing (at post baseline)	0	0	1	0
Monocytes: High (at baseline) to Normal (at post baseline)	—	—	—	1
RBC: Low (at baseline) to Low (at post baseline)	1	1	13	6
RBC: Low (at baseline) to Normal (at post baseline)	0	1	1	1
RBC: Normal (at baseline) to Low (at post baseline)	6	5	8	10
RBC: Normal (at baseline) to Normal (at post baseline)	2	4	3	9
RBC: Normal (at baseline) to High (at post baseline)	0	0	1	0
RBC: Normal (at baseline) to Missing (at post baseline)	0	0	1	0
RBC: High (at baseline) to Low (at post baseline)	0	—	—	1
RBC: High (at baseline) to Normal (at post baseline)	1	—	—	0
Prothrombin Time: Normal (at baseline) to Normal (at post baseline)	3	3	8	8
Prothrombin Time: Normal (at baseline) to High (at post baseline)	4	4	11	9
Prothrombin Time: High (at baseline) to Normal (at post baseline)	0	1	0	0
Prothrombin Time: High (at baseline) to High (at post baseline)	3	3	7	9
Prothrombin Time: High (at baseline) to Missing (at post baseline)	0	0	1	0
Prothrombin Time: Missing (at baseline) to High (at post baseline)	—	—	—	1

SecondaryNumber of Participants With Shift From Baseline in Laboratory Parameter Values Based on CTCAE v4.03: Chemistry

Abnormalities: Albumin graded low, Alkaline phosphatase (ALP) graded high, Alanine aminotransferase (ALT) graded high, Aspartate aminotransferase (AST) graded high, Bilirubin graded high, Amylase graded high, Creatinine graded high, Corrected calcium graded high, Creatine Kinase (CK) graded high, Glucose graded high, Glucose graded low, Lipase graded high, Magnesium graded high, Magnesium graded low, Potassium graded high, Potassium graded low, Sodium graded high and Sodium graded low. Test abnormalities were graded by CTCAE v4.03 as Grade 1=mild; Grade 2=moderate; Grade 3/Grade 4=severe/life-threatening. A grade 0 was assigned for all non-missing values not graded as 1 or higher. If value was graded \>=1 but falls within the normal range, the grade was reset to 0. Categories with at least 1 non-zero data values are reported.

Time frame:: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
Reported as:: Count of participants · Participants

Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on CTCAE v4.03: Chemistry
Participants	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
ALT- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	5	5	12	12
ALT- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	3	5	7	5
ALT- CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	0	0	1	1
ALT- CTCAE Graded High: Grade 0 (at baseline) to Grade 3 (at post baseline)	0	0	0	3
ALT- CTCAE Graded High: Grade 1 (at baseline) to Grade 0 (at post baseline)	0	0	1	0
ALT- CTCAE Graded High: Grade 1 (at baseline) to Grade 1 (at post baseline)	1	1	3	2
ALT- CTCAE Graded High: Grade 1 (at baseline) to Grade 2 (at post baseline)	0	0	1	2
ALT- CTCAE Graded High: Grade 1 (at baseline) to Grade 3 (at post baseline)	0	0	0	1
ALT- CTCAE Graded High: Grade 2 (at baseline) to Grade 2 (at post baseline)	1	—	1	0
ALT- CTCAE Graded High: Grade 2 (at baseline) to Grade 3 (at post baseline)	0	—	0	1
ALT- CTCAE Graded High: Grade 3 (at baseline) to Missing (at post baseline)	—	—	1	—
AST- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	3	2	8	5
AST- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	5	4	11	13
AST- CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	0	1	2	2
AST- CTCAE Graded High: Grade 0 (at baseline) to Grade 3 (at post baseline)	0	0	0	2
AST- CTCAE Graded High: Grade 1 (at baseline) to Grade 1 (at post baseline)	2	4	3	1
AST- CTCAE Graded High: Grade 1 (at baseline) to Grade 2 (at post baseline)	0	0	1	3
AST- CTCAE Graded High: Grade 1 (at baseline) to Grade 3 (at post baseline)	0	0	1	1
AST- CTCAE Graded High: Grade 2 (at baseline) to Missing (at post baseline)	—	—	1	—
Albumin- CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	4	2	8	8
Albumin- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	3	2	9	11
Albumin- CTCAE Graded Low: Grade 0 (at baseline) to Grade 2 (at post baseline)	3	4	7	6
Albumin- CTCAE Graded Low: Grade 0 (at baseline) to Grade 3 (at post baseline)	0	0	0	1
Albumin- CTCAE Graded Low: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Albumin- CTCAE Graded Low: Grade 1 (at baseline) to Grade 1 (at post baseline)	—	0	0	1
Albumin- CTCAE Graded Low: Grade 1 (at baseline) to Grade 2 (at post baseline)	—	2	2	0
Albumin- CTCAE Graded Low: Grade 2 (at baseline) to Grade 2 (at post baseline)	—	1	—	—
Alkaline phosphatase- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	2	2	7	6
Alkaline phosphatase- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	3	1	8	5
Alkaline phosphatase- CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	0	1	0	1
Alkaline phosphatase- CTCAE Graded High: Grade 1 (at baseline) to Grade 1 (at post baseline)	1	0	5	7
Alkaline phosphatase- CTCAE Graded High: Grade 1 (at baseline) to Grade 2 (at post baseline)	2	4	3	3
Alkaline phosphatase- CTCAE Graded High: Grade 1 (at baseline) to Grade 3 (at post baseline)	1	0	1	1
Alkaline phosphatase- CTCAE Graded High: Grade 2 (at baseline) to Grade 2 (at post baseline)	0	1	0	0
Alkaline phosphatase- CTCAE Graded High: Grade 2 (at baseline) to Grade 3 (at post baseline)	1	0	2	2
Alkaline phosphatase- CTCAE Graded High: Grade 3 (at baseline) to Grade 3 (at post baseline)	—	2	0	2
Alkaline phosphatase- CTCAE Graded High: Grade 3 (at baseline) to Missing (at post baseline)	0	0	1	0
Amylase- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	8	7	18	20
Amylase- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	1	2	5	2
Amylase- CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	0	0	1	2
Amylase- CTCAE Graded High: Grade 0 (at baseline) to Grade 3 (at post baseline)	0	1	2	2
Amylase- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	1	1	0
Amylase- CTCAE Graded High: Grade 1 (at baseline) to Grade 2 (at post baseline)	1	—	—	—
Amylase- CTCAE Graded High: Grade 2 (at baseline) to Grade 4 (at post baseline)	—	—	—	1
Bilirubin- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	10	9	25	24
Bilirubin- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	0	0	1	2
Bilirubin- CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	0	1	0	1
Bilirubin- CTCAE Graded High: Grade 1 (at baseline) to Grade 2 (at post baseline)	—	1	—	—
Bilirubin- CTCAE Graded High: Grade 4 (at baseline) to Missing (at post baseline)	—	—	1	—
Corrected Calcium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	7	11	24	25
Corrected Calcium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	3	0	2	1
Corrected Calcium- CTCAE Graded Low: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Corrected Calcium- CTCAE Graded Low: Grade 1 (at baseline) to Grade 0 (at post baseline)	—	—	—	1
Corrected Calcium- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	10	11	25	25
Corrected Calcium- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	0	0	1	1
Corrected Calcium- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Corrected Calcium- CTCAE Graded High: Grade 1 (at baseline) to Grade 0 (at post baseline)	—	—	—	1
Creatine kinase- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	1	3	3	7
Creatine kinase- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	3	4	11	7
Creatine kinase- CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	4	2	6	8
Creatine kinase- CTCAE Graded High: Grade 0 (at baseline) to Grade 3 (at post baseline)	1	1	5	1
Creatine kinase- CTCAE Graded High: Grade 0 (at baseline) to Grade 4 (at post baseline)	0	0	1	0
Creatine kinase- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Creatine kinase- CTCAE Graded High: Grade 1 (at baseline) to Grade 2 (at post baseline)	0	1	—	1
Creatine kinase- CTCAE Graded High: Grade 1 (at baseline) to Grade 3 (at post baseline)	1	0	—	1
Creatine kinase- CTCAE Graded High: Grade 1 (at baseline) to Grade 4 (at post baseline)	0	0	—	1
Creatine kinase - CTCAE Graded High: Missing (at baseline) to Grade 1 (at post baseline)	—	—	—	1
Creatinine- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	1	2	6	7
Creatinine- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	7	7	14	18
Creatinine- CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	2	2	5	2
Creatinine- CTCAE Graded High: Grade 0 (at baseline) to Grade 4 (at post baseline)	0	0	1	0
Creatinine- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Glucose- CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	10	10	23	26
Glucose- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	0	1	1	0
Glucose- CTCAE Graded Low: Grade 0 (at baseline) to Grade 2 (at post baseline)	0	0	1	0
Glucose- CTCAE Graded Low: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Glucose- CTCAE Graded Low: Grade 1 (at baseline) to Grade 0 (at post baseline)	—	—	0	1
Glucose- CTCAE Graded Low: Grade 1 (at baseline) to Grade 1 (at post baseline)	—	—	1	0
Glucose- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	7	6	18	14
Glucose- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	0	1	1	1
Glucose - CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	1	1	0	1
Glucose- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	1	2	5	5
Glucose- CTCAE Graded High: Grade 1 (at baseline) to Grade 0 (at post baseline)	—	—	1	0
Glucose - CTCAE Graded High: Grade 1 (at baseline) to Grade 2 (at post baseline)	—	—	0	1
Glucose- CTCAE Graded High: Grade 3 (at baseline) to Grade 2 (at post baseline)	—	—	1	0
Glucose- CTCAE Graded High: Grade 3 (at baseline) to Grade 3 (at post baseline)	—	—	0	1
Glucose- CTCAE Graded High: Grade 3 (at baseline) to Missing (at post baseline)	—	—	0	1
Glucose- CTCAE Graded High: Missing (at baseline) to Grade 0 (at post baseline)	0	0	0	1
Glucose- CTCAE Graded High: Missing (at baseline) to Grade 3 (at post baseline)	0	0	1	0
Glucose- CTCAE Graded High: Missing (at baseline) to Missing (at post baseline)	1	1	0	2
Lipase- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	5	6	17	15
Lipase- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	2	2	2	4
Lipase- CTCAE Graded High: Grade 0 (at baseline) to Grade 2 (at post baseline)	1	1	1	0
Lipase- CTCAE Graded High: Grade 0 (at baseline) to Grade 3 (at post baseline)	1	0	4	3
Lipase- CTCAE Graded High: Grade 0 (at baseline) to Grade 4 (at post baseline)	0	0	0	1
Lipase- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	1	1	0
Lipase- CTCAE Graded High: Grade 1 (at baseline) to Grade 0 (at post baseline)	1	0	1	0
Lipase- CTCAE Graded High: Grade 1 (at baseline) to Grade 1 (at post baseline)	0	1	1	2
Lipase- CTCAE Graded High: Grade 1 (at baseline) to Grade 3 (at post baseline)	0	0	0	1
Lipase- CTCAE Graded High: Grade 4 (at baseline) to Grade 4 (at post baseline)	—	—	—	1
Magnesium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	8	10	22	24
Magnesium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	1	1	3	2
Magnesium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 2 (at post baseline)	0	0	0	1
Magnesium- CTCAE Graded Low: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Magnesium- CTCAE Graded Low: Grade 1 (at baseline) to Grade 2 (at post baseline)	1	—	—	—
Magnesium- CTCAE Graded Low: Grade 2 (at baseline) to Grade 3 (at post baseline)	—	—	1	—
Magnesium- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	10	11	26	27
Magnesium- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Potassium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	7	9	20	23
Potassium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	3	2	3	4
Potassium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 3 (at post baseline)	0	0	1	0
Potassium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 4 (at post baseline)	0	0	1	0
Potassium- CTCAE Graded Low: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Potassium- CTCAE Graded Low: Grade 3 (at baseline) to Grade 3 (at post baseline)	—	—	1	—
Potassium- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	9	10	23	23
Potassium- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	1	1	2	4
Potassium- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0
Potassium- CTCAE Graded High: Grade 1 (at baseline) to Grade 0 (at post baseline)	—	—	1	—
Sodium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 0 (at post baseline)	9	7	19	23
Sodium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 1 (at post baseline)	1	3	3	1
Sodium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 3 (at post baseline)	0	0	1	2
Sodium- CTCAE Graded Low: Grade 0 (at baseline) to Grade 4 (at post baseline)	0	0	2	1
Sodium- CTCAE Graded Low: Grade 1 (at baseline) to Grade 1 (at post baseline)	—	—	1	—
Sodium- CTCAE Graded Low: Grade 1 (at baseline) to Missing (at post baseline)	—	—	1	—
Sodium- CTCAE Graded Low: Grade 3 (at baseline) to Grade 3 (at post baseline)	—	1	—	—
Sodium- CTCAE Graded High: Grade 0 (at baseline) to Grade 0 (at post baseline)	10	11	23	22
Sodium- CTCAE Graded High: Grade 0 (at baseline) to Grade 1 (at post baseline)	0	0	3	5
Sodium- CTCAE Graded High: Grade 0 (at baseline) to Missing (at post baseline)	0	0	1	0

SecondaryNumber of Participants With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Chemistry and Thyroid Function

Chemistry laboratory parameters: Blood urea nitrogen (BUN), Total protein, Chloride, Cancer antigen 19-9 (CA 19-9), Brain natriuretic peptide (BNP), Bicarbonate, Direct bilirubin, Carcinoembryonic antigen (CEA), Lactate dehydrogenase (LDH), Uric acid, Troponin I. Thyroid panel laboratory parameters: Thyroid-stimulating hormone (TSH), Free triiodothyronine (T3), Free thyroxine (T4). Laboratory values were as per laboratory normal ranges. Values above range were reported as high and values below range as low. Shift in chemistry and thyroid panel severity from baseline grade low, normal, high and missing to the post baseline grades as low, normal, high and missing are reported in this outcome measure. Categories with at least 1 non-zero data values are reported.

Time frame:: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
Reported as:: Count of participants · Participants

Number of Participants With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Chemistry and Thyroid Function
Participants	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
BNP: Normal (at baseline) to Normal (at post baseline)	8	6	24	22
BNP: Normal (at baseline) to High (at post baseline)	1	3	2	3
BNP: Normal (at baseline) to Missing (at post baseline)	0	0	1	0
BNP: High (at baseline) to Normal (at post baseline)	0	2	—	0
BNP: High (at baseline) to High (at post baseline)	1	0	—	2
BUN: Normal (at baseline) to Normal (at post baseline)	4	3	15	14
BUN (mmol/L): Normal (at baseline) to High (at post baseline)	3	5	9	7
BUN: Normal (at baseline) to Missing (at post baseline)	0	1	1	0
BUN: High (at baseline) to Normal (at post baseline)	0	0	2	3
BUN: High (at baseline) to High (at post baseline)	3	2	0	3
Bicarbonate: Low (at baseline) to Normal (at post baseline)	—	1	0	3
Bicarbonate: Low (at baseline) to High (at post baseline)	—	1	1	0
Bicarbonate: Normal (at baseline) to Low (at post baseline)	2	1	6	9
Bicarbonate: Normal (at baseline) to Normal (at post baseline)	7	6	18	11
Bicarbonate: Normal (at baseline) to High (at post baseline)	1	2	1	3
Bicarbonate: Normal (at baseline) to High and Low (at post baseline)	0	0	0	1
Bicarbonate: Normal (at baseline) to Missing (at post baseline)	0	0	1	0
CA 19-9: Normal (at baseline) to Normal (at post baseline)	3	3	6	7
CA 19-9: Normal (at baseline) to High (at post baseline)	0	0	2	1
CA 19-9: Normal (at baseline) to Missing (at post baseline)	0	1	0	1
CA 19-9: High (at baseline) to Normal (at post baseline)	0	0	1	1
CA 19-9: High (at baseline) to High (at post baseline)	7	6	16	16
CA 19-9: High (at baseline) to Missing (at post baseline)	0	1	2	1
CEA: Normal (at baseline) to Normal (at post baseline)	1	—	1	3
CEA: Normal (at baseline) to High (at post baseline)	0	—	2	2
CEA: Normal (at baseline) to Missing (at post baseline)	0	—	0	1
CEA: High (at baseline) to Normal (at post baseline)	0	0	1	0
CEA: High (at baseline) to High (at post baseline)	9	9	20	20
CEA: High (at baseline) to Missing (at post baseline)	0	2	3	1
Chloride: Low (at baseline) to Low (at post baseline)	—	1	1	1
Chloride: Low (at baseline) to Missing (at post baseline)	—	0	1	0
Chloride: Normal (at baseline) to Low (at post baseline)	2	2	8	3
Chloride: Normal (at baseline) to Normal (at post baseline)	8	7	15	22
Chloride: Normal (at baseline) to High (at post baseline)	0	0	2	1
Chloride: Normal (at baseline) to High & Low (at post baseline)	0	1	0	0
Free T3: Low (at baseline) to Low (at post baseline)	—	—	0	1
Free T3: Low (at baseline) to Missing (at post baseline)	—	—	1	1
Free T3: Normal (at baseline) to Low (at post baseline)	3	5	8	7
Free T3: Normal (at baseline) to Normal (at post baseline)	7	5	15	15
Free T3: Normal (at baseline) to High and Low (at post baseline)	0	0	1	0
Free T3: Normal (at baseline) to Missing (at post baseline)	0	1	2	1
Free T3: High (at baseline) to High (at post baseline)	—	—	—	2
Free T4: Low (at baseline) to Low (at post baseline)	—	0	—	1
Free T4: Low (at baseline) to Normal (at post baseline)	—	1	—	0
Free T4: Normal (at baseline) to Low (at post baseline)	0	1	2	3
Free T4: Normal (at baseline) to Normal (at post baseline)	10	8	17	17
Free T4: Normal (at baseline) to High (at post baseline)	0	0	3	1
Free T4: Normal (at baseline) to High and Low (at post baseline)	0	0	1	1
Free T4: Normal (at baseline) to Missing (at post baseline)	0	1	3	2
Free T4: High (at baseline) to Low (at post baseline)	—	—	0	1
Free T4: High (at baseline) to Normal (at post baseline)	—	—	1	1
LDH: Low (at baseline) to Low (at post baseline)	1	—	—	—
LDH: Normal (at baseline) to Normal (at post baseline)	1	1	6	5
LDH: Normal (at baseline) to High (at post baseline)	5	4	14	10
LDH: High (at baseline) to Normal (at post baseline)	0	0	0	1
LDH: High (at baseline) to High (at post baseline)	3	6	6	11
LDH: High (at baseline) to Missing (at post baseline)	0	0	1	0
Protein: Low (at baseline) to Low (at post baseline)	—	1	—	—
Protein: Normal (at baseline) to Low (at post baseline)	5	6	11	11
Protein: Normal (at baseline) to Normal (at post baseline)	5	4	12	14
Protein: Normal (at baseline) to High (at post baseline)	0	0	0	2
Protein: Normal (at baseline) to High and Low (at post baseline)	0	0	3	0
Protein: Normal (at baseline) to Missing (at post baseline)	0	0	1	0
TSH: Low (at baseline) to Low (at post baseline)	—	—	—	1
TSH: Normal (at baseline) to Low (at post baseline)	0	0	2	3
TSH: Normal (at baseline) to Normal (at post baseline)	8	7	14	20
TSH: Normal (at baseline) to High (at post baseline)	1	0	3	1
TSH: Normal (at baseline) to High and Low (at post baseline)	0	0	2	0
TSH: Normal (at baseline) to Missing (at post baseline)	0	0	3	2
TSH: High (at baseline) to Normal (at post baseline)	0	2	2	—
TSH: High (at baseline) to High (at post baseline)	1	1	1	—
TSH: High (at baseline) to Missing (at post baseline)	0	1	0	—
Troponin I: Normal (at baseline) to Normal (at post baseline)	—	2	11	10
Troponin I: Normal (at baseline) to High (at post baseline)	—	0	1	2
Troponin I: Normal (at baseline) to Missing (at post baseline)	—	0	14	14
Troponin I: Missing (at baseline) to Normal (at post baseline)	4	3	—	1
Troponin I: Missing (at baseline) to High (at post baseline)	1	0	—	0
Uric acid: Low (at baseline) to Low (at post baseline)	—	0	0	2
Uric acid: Low (at baseline) to Normal (at post baseline)	—	1	0	1
Uric acid: Low (at baseline) to Missing (at post baseline)	—	0	1	0
Uric acid: Normal (at baseline) to Low (at post baseline)	1	2	4	4
Uric acid: Normal (at baseline) to Normal (at post baseline)	8	5	15	16
Uric acid: Normal (at baseline) to High (at post baseline)	0	2	4	1
Uric acid: High (at baseline) to Normal (at post baseline)	0	0	1	0
Uric acid: High (at baseline) to High (at post baseline)	1	1	2	3

SecondaryNumber of Participants With Abnormal Hepatic Laboratory Values

Criteria for abnormal hepatic laboratory parameters: Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT): \>3\* upper limit of normal (ULN), \>5\*ULN, \>8\*ULN, \>10\*ULN, \>20\*ULN; Total bilirubin (TBL) \>1.5\*ULN, \>2\*ULN; Alkaline phosphatase (ALP) \>2\*ULN, \>3\*ULN. Categories with at least 1 non-zero data values are reported.

Time frame:: Phase 1b: Baseline up to 30 days after last dose (maximum up to 9 months approximately), Phase 2: Baseline up to 30 days after last dose (maximum up to 26 months approximately)
Reported as:: Count of participants · Participants

Number of Participants With Abnormal Hepatic Laboratory Values
Participants	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
ALT: >3 ULN	0	0	2	7
ALT: >5 ULN	0	0	0	5
ALT: >8 ULN	0	0	0	1
AST: >3 ULN	0	1	4	8
AST: >5 ULN	0	0	1	3
AST: >8 ULN	0	0	1	1
ALT or AST: >3 ULN	0	1	3	7
ALT or AST: >5 ULN	0	0	1	4
ALT or AST: >8 ULN	0	0	1	1
Total bilirubin: >1.5 ULN	0	2	0	1
Alkaline phosphatase: >2 ULN	3	3	4	8
Alkaline phosphatase: >3 ULN	4	4	2	4

SecondaryConcentration Versus Time Summary of Plasma Concentration of Binimetinib

Time frame:: 1.5 hours post dose of binimetinib on Day 1, 15 of Cycle 1; pre dose of binimetinib on Day 15 of Cycle 1, 2, 3, 4, 5
Reported as:: Geometric mean · nanogram per milliliter

Concentration Versus Time Summary of Plasma Concentration of Binimetinib
nanogram per milliliter	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Cycle 1 Day 1: 1.5 Hours post dose	228 ± 152.2	163 ± 129.6	261 ± 90.9	217 ± 134.5
Cycle 1 Day 15: pre dose	135 ± 60.9	125 ± 103.9	77.0 ± 141.2	81.8 ± 143.6
Cycle 1 Day 15: 1.5 Hours post dose	542 ± 57.6	414 ± 24.5	294 ± 84.4	324 ± 83.3
Cycle 2 Day 15: pre dose	108 ± 52.9	NA ± NA	88.5 ± 111.3	120 ± 77.7
Cycle 3 Day 15: pre dose	140 ± 42.0	NA ± NA	NA ± NA	89.2 ± 183.4
Cycle 4 Day 15: pre dose	NA ± NA	NA ± NA	NA ± NA	NA ± NA
Cycle 5 Day 15: pre dose	NA ± NA	—	NA ± NA	NA ± NA

Adverse events

Collected over All-Cause Mortality: From start of the treatment up to 150 days after last dose (Phase 1b: maximum up to 13 months approximately and Phase 2: maximum up to 30 months approximately); TEAEs (including serious and other AEs): From start of the treatment up to 30 days after last dose (Phase 1b: maximum up to 9 months approximately and Phase 2: maximum up to 26 months approximately). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Phase 1b: Nivolumab+Binimetinib	8/10 (80%)	5/10 (50%)	10/10 (100%)
Phase 1b: Nivolumab+Ipilimumab+Binimetinib	8/11 (72.7%)	6/11 (54.5%)	11/11 (100%)
Phase 2: Nivolumab+Binimetinib	20/27 (74.1%)	12/27 (44.4%)	27/27 (100%)
Phase 2: Nivolumab+Ipilimumab+Binimetinib	21/27 (77.8%)	11/27 (40.7%)	27/27 (100%)

Most frequent serious events

Showing 10 of 55

Most frequent serious events
Event	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
PneumonitisRespiratory, thoracic and mediastinal disorders	0/10	2/11	0/27	0/27
Acute coronary syndromeCardiac disorders	1/10	0/11	0/27	0/27
Small intestinal obstructionGastrointestinal disorders	1/10	0/11	0/27	0/27
PyrexiaGeneral disorders	1/10	0/11	1/27	1/27
PneumoniaInfections and infestations	1/10	0/11	0/27	2/27
Tumour associated feverNeoplasms benign, malignant and unspecified (incl cysts and polyps)	1/10	0/11	0/27	0/27
HypoxiaRespiratory, thoracic and mediastinal disorders	1/10	0/11	0/27	0/27
Dermatitis acneiformSkin and subcutaneous tissue disorders	1/10	0/11	0/27	0/27
MyocarditisCardiac disorders	0/10	1/11	1/27	0/27
ColitisGastrointestinal disorders	0/10	1/11	0/27	0/27

Most frequent other events

Showing 10 of 148

Most frequent other events
Event	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
VomitingGastrointestinal disorders	2/10	8/11	7/27	10/27
Dermatitis acneiformSkin and subcutaneous tissue disorders	7/10	6/11	13/27	12/27
DiarrhoeaGastrointestinal disorders	6/10	4/11	13/27	15/27
FatigueGeneral disorders	4/10	6/11	11/27	11/27
PyrexiaGeneral disorders	3/10	3/11	8/27	14/27
Blood creatine phosphokinase increasedInvestigations	5/10	3/11	14/27	13/27
RashSkin and subcutaneous tissue disorders	3/10	1/11	8/27	14/27
NauseaGastrointestinal disorders	5/10	2/11	12/27	11/27
Oedema peripheralGeneral disorders	5/10	5/11	8/27	11/27
Decreased appetiteMetabolism and nutrition disorders	2/10	3/11	13/27	6/27

Baseline characteristics

Full Analysis Set (FAS) included all participants who received at least 1 dose of any study drug in Phase 1b and all participants randomized to study treatment in Phase 2.

Age, Categorical
Age, Categorical(Participants)	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib	Total
<=18 years	0	0	0	0	0
Between 18 and 65 years	5	9	19	20	53
>=65 years	5	2	8	7	22

Sex: Female, Male
Sex: Female, Male(Participants)	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib	Total
Female	2	4	11	10	27
Male	8	7	16	17	48

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib	Total
Hispanic or Latino	0	0	1	0	1
Not Hispanic or Latino	10	11	21	23	65
Unknown or Not Reported	0	0	5	4	9

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib	Total
American Indian or Alaska Native	0	0	0	0	0
Asian	0	0	1	0	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	1	0	1	1	3
White	9	11	21	23	64
More than one race	0	0	0	0	0
Unknown or Not Reported	0	0	4	3	7

Study locations

50 sites

UCLA Hematology/Oncology
Los Angeles, California 90095, United States
UCLA Hematology/Oncology - Santa Monica
Santa Monica, California 90404, United States
Christiana Care Health Services, Helen F. Graham Cancer Center Pharmacy, Suite 3200
Newark, Delaware 19713, United States
Christiana Care Health Services, Helen F. Graham Cancer Center
Newark, Delaware 19713, United States
Christiana Care Oncology Hematology, Helen F Graham Cancer Center, Suite 2400
Newark, Delaware 19713, United States
Medical Oncology Hematology Consultants, PA, Helen F. Graham Cancer Center
Newark, Delaware 19713, United States
Christiana Care Health Services, Christiana Hospital
Newark, Delaware 19718, United States
Georgetown University Medical Center Department of Pharmacy, Research
Washington D.C., District of Columbia 20007, United States
Georgetown University Medical Center
Washington D.C., District of Columbia 20007, United States
Hematology Oncology Associates of the Treasure Coast
Port Saint Lucie, Florida 34952, United States
Indiana CTSI Clinical Research Center (ICRC)
Indianapolis, Indiana 46202, United States
Indiana University Health Hospital
Indianapolis, Indiana 46202, United States
Indiana University Health Melvin and Bren Simon Cancer Center
Indianapolis, Indiana 46202, United States
Investigational Drug Services IUHSCC
Indianapolis, Indiana 46202, United States
Sidney &Lois Eskenazi Hospital
Indianapolis, Indiana 46202, United States
Spring Mill Medical Center
Indianapolis, Indiana 46290, United States
Siteman Cancer Center - Barnes St. Peters
City of Saint Peters, Missouri 63376, United States
Siteman Cancer Center - West County
Creve Coeur, Missouri 63141, United States
Siteman Cancer Center - North County
Florissant, Missouri 63031, United States
Center for Outpatient Health (Dermatology Clinic)
St Louis, Missouri 63108, United States
Center for Outpatient Health (Ophthalmology Clinic)
St Louis, Missouri 63108, United States
Barnes-Jewish Hospital
St Louis, Missouri 63110, United States
Washington University School of Medicine
St Louis, Missouri 63110, United States
Siteman Cancer Center - South County
St Louis, Missouri 63129, United States
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania 19104, United States
Investigational Drug Service of the University of Pennsylvania
Philadelphia, Pennsylvania 19104, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania 19111, United States
Sarah Cannon Research Institute
Chattanooga, Tennessee 37404, United States
SCRI Tennessee Oncology Chattanooga
Chattanooga, Tennessee 37404, United States
Tennessee Oncology, PLLC
Cleveland, Tennessee 37311, United States
Tennessee Oncology NASH - SCRI - PPDS
Nashville, Tennessee 37203, United States
The Sarah Cannon Research Institute.
Nashville, Tennessee 37203, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas 77030, United States
UZ Leuven - Dermatology
Leuven, 3000, Belgium
UZ Leuven - Ophthalmology
Leuven, 3000, Belgium
UZ Leuven
Leuven, 3000, Belgium
The Netherlands Cancer Institute Antoni Van Leeuwenhoek
Amsterdam, North Holland 1066 CX, Netherlands
OLVG locatie Oost
Amsterdam, North Holland 1091 AC, Netherlands
Amsterdam Medical Center (AMC)
Amsterdam, North Holland 1105 AZ, Netherlands
Hospital Universitario Vall d'Hebron
Barcelona, 08035, Spain
Hospital Universitario Vall d'Hebrón - PPDS
Barcelona, 08035, Spain
Hospital General Universitario Gregorio Marañon
Madrid, 28007, Spain
Clinica Rementeria
Madrid, 28010, Spain
Hospital Universitario 12 Octubre
Madrid, 28041, Spain
Hospital HM Universitario Sanchinarro, CIOCC
Madrid, 28050, Spain
Royal Marsden Hospital - London
London, London, CITY of SW3 6JJ, United Kingdom
Churchill Hospital
Oxford, Oxfordshire OX3 7LE, United Kingdom
Royal Marsden Hospital NHS Foundation Trust
Surrey, Sutton SM2 5PT, United Kingdom
Royal Marsden Hospital NHS Foundation Trust
London, SW3 6JJ, United Kingdom
Royal Marsden Hospital -Fulham Road
London, SW36JJ, United Kingdom

References and documents

Publications

Elez E, Cubillo A, Alfonso PG, Middleton MR, Chau I, Alkuzweny B, Alcasid A, Zhang X, Van Cutsem E. Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study. BMC Cancer. 2024 Apr 11;24(1):446. doi: 10.1186/s12885-024-12153-5. PubMed 38600471 ↗

Study documents

Study protocol · Mar 2, 2018
Statistical analysis plan · Oct 9, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Data sharing details ↗ · www.pfizer.com

Timeline

Tracking since Sep 25, 2026

ElapsedEstimatedEstimated, not yet reachedSimilar studies: half by the dot; the band is the middle halfHalf of similar studies reached it by the dot; the band is the middle half, from a quarter to three quarters

Ran from Oct 2017 to primary completion in Oct 2020, 35 months.

Results were first posted in Nov 2021, 1 year after primary completion.

Of 162 industry-sponsored phase 2 interventional studies under Neoplasms, half reached primary completion within 46 months of starting (the median), counting those still running; a quarter within 32 and three quarters within 72. This study's 35 months is below that.

Counting every sponsor, half of 554 studies reached it within 52 months; a quarter within 33 and three quarters within 88.

Neoplasms covers many different conditions, not one, so the studies compared here vary widely. Read these figures as a rough guide.

How these figures are worked out, and which studies are left out of them.

Registered: Aug 31, 2017
First posted: Sep 1, 2017
StartActual: Oct 18, 2017
Primary completionActual: Oct 13, 2020
CompletionActual: Feb 25, 2021
Results first posted: Nov 2, 2021
Last update: Jan 4, 2022

What these dates mean

Start.: When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.: When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.: When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.: Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.

No changes since tracking began. The registry record was last updated on Jan 4, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03271047
Lead sponsor: Pfizer
Collaborators: Bristol-Myers Squibb
Responsible party: Sponsor
First posted: Sep 1, 2017
Start date: Oct 18, 2017
Primary completion: Oct 13, 2020
Completion: Feb 25, 2021
Results posted: Nov 2, 2021
Last update: Jan 4, 2022

Study contacts

Pfizer CT.gov Call Center

study director · Pfizer

Oversight

Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Dec 2021. You cannot join it, but the record below documents what was studied.

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Discussion

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