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Clinical Trial Results:
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

Summary
EudraCT number	2017-003464-12
Trial protocol	GB ES NL BE
Global end of trial date	25 Feb 2021

Results information
Results version number	v1(current)
This version publication date	12 Feb 2022
First version publication date	12 Feb 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ARRAY-162-202

ISRCTN number

US NCT number

NCT03271047

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, United States

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Jul 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 Feb 2021

Was the trial ended prematurely?

Main objective of the trial

Phase 1b: 1. Determine the MTD and RP2D of binimetinib administered in combination with nivolumab 2. Determine the MTD and RP2D of binimetinib administered in combination with nivolumab plus ipilimumab Phase 2: Assess the preliminary antitumor activity of the treatment combinations based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Oct 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

5 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 10

Country: Number of subjects enrolled

Netherlands: 10

Country: Number of subjects enrolled

Spain: 27

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

United States: 19

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

This study included 2 phases: Phase 1b and Phase 2. The recommended dose for Phase 2 (RP2D) of binimetinib was determined in Phase 1b (dose finding phase). Total 75 subjects were enrolled in 22 sites in 5 countries. Study started from 18 October 2017 and completed on 25 February 2021.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1b: Nivolumab+Binimetinib

Arm description

Subjects with previously treated microsatellite-stable (MSS) metastatic colorectal cancer with rat sarcoma virus (RAS) mutation received binimetinib at a starting dose of 45 milligrams (mg) tablet orally twice daily (BID) along with 480 mg intravenous (IV) dose of nivolumab every 4 weeks in each 28 day treatment cycle. Binimetinib dose modification to intermitted dosing (3 weeks on treatment and 1 week off treatment) with 45 mg dose or dose reduction to 30 mg BID or 30 mg intermittent dosing based on investigator’s decision as per its tolerability among subjects. Subjects then followed up for safety for around 150 days.

Arm type

Experimental

Investigational medicinal product name

Binimetinib and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Intravenous use, Oral use

Dosage and administration details

Subjects received binimetinib at a starting dose of 45 mg tablet orally BID along with nivolumab 480 mg IV every 4 weeks in each 28 day treatment cycle.

Phase 1b: Nivolumab+Ipilimumab+Binimetinib

Arm description

Subjects with previously treated MSS metastatic colorectal cancer with RAS mutation received binimetinib at a starting dose of 45 mg tablet BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle. Ipilimumab was administered at the dose of 1 milligram per kilogram (mg/kg) IV every 8 weeks after completion of nivolumab infusion. Binimetinib dose modification to intermitted dosing (3 weeks on treatment and 1 week off treatment) with 45 mg dose or dose reduction to 30 mg BID or 30 mg intermittent dosing based on investigator’s decision as per its tolerability among subjects. Subjects then followed up for safety for around 150 days.

Arm type

Experimental

Investigational medicinal product name

Binimetinib, Nivolumab and Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Subjects received binimetinib at a starting dose of 45 mg tablet BID along with nivolumab 480 mg IV dose every 4 weeks in each 28 day treatment cycle. Ipilimumab was administered at the dose of 1 mg/kg IV every 8 weeks after completion of nivolumab infusion.

Phase 2: Nivolumab+Binimetinib

Arm description

Subjects with previously treated MSS metastatic colorectal cancer with RAS mutation received 45 mg binimetinib tablet orally BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle, until disease progression, unacceptable toxicity, withdrawal of informed consent, initiation of subsequent anticancer therapy, lost to follow-up or death. Subjects then followed up for safety for around 150 days.

Arm type

Experimental

Investigational medicinal product name

Binimetinib and Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Subjects received 45 mg binimetinib tablet orally BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle.

Phase 2: Nivolumab+Ipilimumab+Binimetinib

Arm description

Subjects with previously treated MSS metastatic colorectal cancer with RAS mutation received 45 mg binimetinib tablet orally BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle. Ipilimumab was administered at the dose of 1 mg/kg IV every 8 weeks after completion of nivolumab infusion until disease progression, unacceptable toxicity, withdrawal of informed consent, initiation of subsequent anticancer therapy, lost to follow-up or death. Subjects then followed up for safety for around 150 days.

Arm type

Experimental

Investigational medicinal product name

Binimetinib, Nivolumab and Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Injection

Routes of administration

Oral use, Intravenous use

Dosage and administration details

Subjects received binimetinib 45 mg tablet orally BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle. Ipilimumab was administered at the dose of 1 mg/kg IV every 8 weeks after completion of nivolumab infusion.

Number of subjects in period 1	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Started	10	11	27	27
Completed	0	0	0	0
Not completed	10	11	27	27
Consent withdrawn by subject	-	2	5	-
Death	8	8	20	21
Unspecified	-	-	-	1
Lost to follow-up	1	-	2	1
Completed follow-up per protocol	1	1	-	4

Baseline characteristics

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Reporting group title

Phase 1b: Nivolumab+Binimetinib

Reporting group description

Reporting group title

Phase 1b: Nivolumab+Ipilimumab+Binimetinib

Reporting group description

Reporting group title

Phase 2: Nivolumab+Binimetinib

Reporting group description

Reporting group title

Phase 2: Nivolumab+Ipilimumab+Binimetinib

Reporting group description

Subjects with previously treated MSS metastatic colorectal cancer with RAS mutation received 45 mg binimetinib tablet orally BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle. Ipilimumab was administered at the dose of 1 mg/kg IV every 8 weeks after completion of nivolumab infusion until disease progression, unacceptable toxicity, withdrawal of informed consent, initiation of subsequent anticancer therapy, lost to follow-up or death. Subjects then followed up for safety for around 150 days.

Reporting group values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib	Total
Number of subjects	10	11	27	27	75
Age Categorical
Units: Subjects
18-64 years	5	9	19	20	53
65-84 years	5	2	8	7	22
Sex: Female, Male
Units: Subjects
Female	2	4	11	10	27
Male	8	7	16	17	48
Race (NIH/OMB)
Units: Subjects
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
Unknown or Not Reported	0	0	0	0	0
Others	0	0	4	3	7
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	1	0	1
Not Hispanic or Latino	10	11	21	23	65
Unknown	0	0	1	0	1
Not Reported	0	0	4	4	8

End points

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Reporting group title

Phase 1b: Nivolumab+Binimetinib

Reporting group description

Reporting group title

Phase 1b: Nivolumab+Ipilimumab+Binimetinib

Reporting group description

Reporting group title

Phase 2: Nivolumab+Binimetinib

Reporting group description

Reporting group title

Phase 2: Nivolumab+Ipilimumab+Binimetinib

Reporting group description

Subjects with previously treated MSS metastatic colorectal cancer with RAS mutation received 45 mg binimetinib tablet orally BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle. Ipilimumab was administered at the dose of 1 mg/kg IV every 8 weeks after completion of nivolumab infusion until disease progression, unacceptable toxicity, withdrawal of informed consent, initiation of subsequent anticancer therapy, lost to follow-up or death. Subjects then followed up for safety for around 150 days.

Primary: Phase 2: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

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End point title

Phase 2: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 ^[1] ^[2]

End point description

ORR:percentage of subjects who achieved best overall response(BOR) of complete response(CR)/partial response(PR) determined by investigator per RECISTv1.1.CR:disappearance of target and non-target lesions and normalization of tumour markers. Pathological lymph nodes must have short axis measures less than (<)10 millimeter(mm). PR: >=30%decrease in 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: >=20%increase in sum of diameters of target lesions, taking as reference smallest sum on study. In addition to relative increase of 20%, sum must demonstrate absolute increase of >=5mm. Appearance of one/more new lesions considered progression. All subjects randomized to study treatment in Phase 2. -99999, 99999=Lower, upper limit of 95%confidence interval(CI) not estimable,as there were no subjects with event in this reporting group.

End point type

Primary

End point timeframe

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)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was summarized for Phase 2: Nivolumab+Binimetinib and Phase 2: Nivolumab+Ipilimumab+Binimetinib reporting arms only.

End point values	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	27	27
Units: Percentage of subjects
number (confidence interval 95%)	0.0 (-99999 to 99999)	7.4 (0.9 to 24.3)

No statistical analyses for this end point

Primary: Phase 1b: Number of Subjects With Dose-Limiting Toxicities (DLT)

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End point title

Phase 1b: Number of Subjects With Dose-Limiting Toxicities (DLT) ^[3] ^[4]

End point description

DLT:AE/abnormal laboratory assessed unrelated-disease,disease progression,intercurrent illness/concomitant medication/therapies resulting inability tolerate 75%dose intensity in Cycle(C)1.Total bilirubin(TBL)grade(G)>=3(>3.0*upper limit of normal[ULN)]);AST/ALT>5-8*ULN>5days(D),>8*ULN,>3*ULN concurrent TBL>2*ULN;G>=3 serum creatinine,CK elevation,ECG QTcF prolonged,G3 troponin,electrolyte>72hours(hrs),G3/4 amylase/lipase.G4ANC,platelet count(PC)>7D;G3/4PC,other AE except lymphopenia.G>=3retinopathy,other disorder>21D;G2uveitis/eye pain/blurred vision/decreased visual acuity;G4 other disorder.Decrease LVEF>10% G>=3cardiac disorders.G3/4hypertension.G3fatigue>=7D,hypersensitivity,infusion reaction,fever>=72hrs/haemodynamic compromise,endocrinopathy.G>=2interstitial lung disease/pneumonitis;G3bronchospasm.G3/4rash,hand foot skin reaction,photosensitivity.G3colitis;G3/4diarrhea,nausea/vomiting.NeurologicG3.Other haematologic/nonhaematolic G>=3AE.Dose determining set was analysed.

End point type

Primary

End point timeframe

Cycle 1: Day 1 up to Day 28

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be reported for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for Phase 1b: Nivolumab+Binimetinib and Phase 1b: Nivolumab+Ipilimumab+Binimetinib reporting arms only.

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	9	11
Units: Subjects	1	2

No statistical analyses for this end point

Secondary: Phase 1b: Objective Response Rate (ORR) per RECIST v1.1

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End point title

Phase 1b: Objective Response Rate (ORR) per RECIST v1.1 ^[5]

End point description

ORR: percentage of subjects who achieved a BOR of CR or PR as determined by investigator per RECIST v1.1. As per RECIST v1.1, CR: disappearance of target and non-target lesions and normalization of tumour markers. Pathological lymph nodes must have short axis measures <10 mm. PR: >=30% decrease in the sum of measures (longest diameter for tumour 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: >=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. All subjects who received at least 1 dose of any study treatment in Phase 1b. -99999 and 99999=Lower and upper limit of 95%CI not estimable, as there were no subjects who had event in this reporting group.

End point type

Secondary

End point timeframe

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)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for Phase 1b: Nivolumab+Binimetinib and Phase 1b: Nivolumab+Ipilimumab+Binimetinib reporting arms only.

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	10	11
Units: Percentage of subjects
number (confidence interval 95%)	0.0 (-99999 to 99999)	0.0 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) as per RECIST v1.1

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End point title

Duration of Response (DOR) as per RECIST v1.1

End point description

DOR:time between date of first documented confirmed response(PR/CR)and date of first documented progression/death due to any cause. CR:disappearance of target and non-target lesions and normalization of tumour markers. Pathological lymph nodes short axis measures <10mm. PR:>=30% decrease in sum of measures(tumour lesions-longest diameter and nodes-short axis)of target lesions, taking as reference baseline sum of diameters. PD: >=20% increase in sum of diameters of measured lesions taking as references smallest sum of diameters recorded on study(including baseline),absolute increase of >=5mm/appearance of at least 1new lesion. Unequivocal progression of existing non-target lesions. FAS:all subjects who received at least 1dose of any study drug in Phase1b and all subjects randomized to study treatment in Phase2.‘Number of subjects analysed’:signifies number of subjects who achieved an objective response.No subjects had event in Phase1b and Nivolumab and Binimetinib group of Phase2.

End point type

Secondary

End point timeframe

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)

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	0 ^[6]	0 ^[7]	0 ^[8]	2
Units: Months
median (confidence interval 95%)	( to )	( to )	( to )	11.4 (7.5 to 15.2)

Notes
[6] - No subjects had event in Phase 1b: Nivolumab+ Binimetinib.
[7] - No subjects had event in Phase 1b: Nivolumab+Ipilimumab+Binimetinib.
[8] - No subjects had event in Phase 2: Nivolumab+Binimetinib.

No statistical analyses for this end point

Secondary: Percentage of Subjects With Complete Response as per RECIST v1.1

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End point title

Percentage of Subjects With Complete Response as per RECIST v1.1

End point description

Complete response as per RECIST v1.1 was defined as disappearance of target and non-target lesions and normalization of tumour markers. Pathological lymph nodes must have short axis measures <10 mm. Full analysis set (FAS) included all subjects who received at least 1 dose of any study drug in Phase 1b and all subjects randomized to study treatment in Phase 2.

End point type

Secondary

End point timeframe

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)

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	10	11	27	27
Units: Percentage of subjects	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03

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End point title

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

End point description

AE:any untoward medical occurrence in a subject 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 30days after last dose or before start of new anticancer therapy minus 1day, whichever occurred first. TEAE graded by CTCAE grade 4.03: G3:severe/medically significant but not immediately life-threatening/hospitalization/prolongation of existing hospitalization indicated/disabling/limiting self-care activities of daily living(ADL); G4:life-threatening consequence/urgent intervention indicated. In this endpoint, number of subjects with ‘all grades’ and ‘G3/4’ were reported. Safety set: all subjects who received at least 1 dose of study drug.

End point type

Secondary

End point timeframe

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)

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	10	11	27	27
Units: Subjects
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

No statistical analyses for this end point

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03: Haematology and Coagulation

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End point title

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

End point description

Haematology parameters: Haemoglobin (Hb) graded high, Hb 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: 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. Safety set included of all subjects who received at least 1 dose of study drug. Here “n”: subjects evaluable for this endpoint for specified rows. Baseline=BL, Postbaseline=PBL, Missing=M. '99999' signifies data not available as none of the subjects were evaluable for specified categories.

End point type

Secondary

End point timeframe

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)

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	10	11	27	27
Units: Subjects
Haemoglobin-Low G:G0(BL) to G0(PBL) n=7,6,13,16	3	3	4	5
Haemoglobin-Low G:G0(BL) to G1(PBL) n=7,6,13,16	2	2	6	10
Haemoglobin-Low G:G0(BL) to G2(PBL) n=7,6,13,16	2	1	2	1
Haemoglobin-Low G:G0(BL) to G3(PBL) n=7,6,13,16	0	0	1	0
Haemoglobin-Low G:G1(BL) to G0(PBL) n=3,5,10,6	0	0	1	0
Haemoglobin-Low G:G1(BL) to G1(PBL) n=3,5,10,6	1	4	4	4
Haemoglobin-Low G:G1(BL) to G2(PBL) n=3,5,10,6	2	0	3	1
Haemoglobin-Low G:G1(BL) to G3(PBL) n=3,5,10,6	0	1	1	1
Haemoglobin-Low G:G1(BL) to M(PBL) n=3,5,10,6	0	0	1	0
Haemoglobin-Low G:G2(BL) to G2(PBL) n=0,0,4,5	99999	99999	3	5
Haemoglobin-Low G:G2(BL) to G3(PBL) n=0,0,4,5	99999	99999	1	0
Haemoglobin-High G:G0(BL) to G0(BL) n=10,11,27,27	10	11	26	26
Haemoglobin-High G:G0(BL) to G1(PBL) n=10,11,27,27	0	0	0	1
Haemoglobin-High G:G0(BL) to M(PBL) n=10,11,27,27	0	0	1	0
Lymphocytes–Low G:G0(BL) to G0(PBL) n=7,9,21,22	6	7	11	11
Lymphocytes–Low G:G0(BL) to G1(PBL) n=7,9,21,22	0	0	2	4
Lymphocytes–Low G:G0(BL) to G2(PBL) n=7,9,21,22	0	2	4	6
Lymphocytes–Low G:G0(BL) to G3(PBL) n=7,9,21,22	1	0	3	1
Lymphocytes–Low G:G0(BL) to M (PBL) n=7,9,21,22	0	0	1	0
Lymphocytes–Low G:G1(BL) to G0(PBL) n=0,1,2,1	99999	0	0	1
Lymphocytes–Low G:G1 (BL) to G2 (PBL) n=0,1,2,1	99999	1	1	0
Lymphocytes–Low G:G1(BL) to G3(PBL )n=0,1,2,1	99999	0	1	0
Lymphocytes–Low G:G2(BL) to G0(PBL) n=2,0,3,4	0	99999	1	0
Lymphocytes–Low G:G2(BL) to G2(PBL) n=2,0,3,4	1	99999	1	2
Lymphocytes–Low G:G2(BL) to G3(PBL) n=2,0,3,4	1	99999	1	2
Lymphocytes–Low G:G3(BL) to G0(PBL) n=1,1,1,0	0	0	1	99999
Lymphocytes–Low G:G3(BL) to G2(PBL) n=1,1,1,0	0	1	0	99999
Lymphocytes–Low G:G3(BL) to G3(PBL) n=1,1,1,0	1	0	0	99999
Lymphocytes-High: G0(BL) to G0(PBL) n=10,11,27,27	9	11	25	26
Lymphocytes-High: G0(BL) to G2(PBL) n=10,11,27,27	1	0	1	1
Lymphocytes-High: G0(BL) to M(PBL) n=10,11,27,27	0	0	1	0
Neutrophils-Low G: G0(BL) to G0(PBL) n=10,11,25,27	9	11	23	26
Neutrophils-Low G: G0(BL) to G1(PBL) n=10,11,25,27	0	0	1	1
Neutrophils-Low G: G0(BL) to G2(PBL) n=10,11,25,27	1	0	0	0
Neutrophils-Low G: G0(BL) to M(PBL) n=10,11,25,27	0	0	1	0
Neutrophils-Low G: G1(BL) to G0(PBL) n=0,0,2,0	99999	99999	1	99999
Neutrophils-Low G: G1(BL) to G3(PBL) n=0,0,2,0	99999	99999	1	99999
Platelet count-Low G:G0(BL)toG0(PBL)n=10,10,26,26	8	9	21	22
Platelet count-Low G:G0(BL)toG1(PBL)n=10,10,26,26	2	1	3	4
Platelet count-Low G:G0(BL)toM(PBL)n=10,10,26,26	0	0	2	0
Platelet count-Low G: G1(BL) to G0(PBL) n=0,1,1,1	99999	1	0	0
Platelet count-Low G: G1(BL) to G1(PBL) n=0,1,1,1	99999	0	1	1
WBC-Low: G0(BL) to G0(PBL) n=10,11,26,26	9	11	21	24
WBC-Low: G0(BL) to G1(PBL) n=10,11,26,26	0	0	2	0
WBC-Low: G0(BL) to G2(PBL) n=10,11,26,26	1	0	1	2
WBC-Low: G0(BL) to G4(PBL) n=10,11,26,26	0	0	1	0
WBC-Low: G0(BL) to M(PBL) n=10,11,26,26	0	0	1	0
WBC-Low: G1(BL) to G1(PBL) n=0,0,1,1	99999	99999	1	0
WBC-Low: G1(BL) to G2(PBL) n=0,0,1,1	99999	99999	0	1
WBC-High: G0(BL) to G0(PBL) n=10,11,27,27	10	11	26	27
WBC-High: G0(BL) to M(PBL) n=10,11,27,27	0	0	1	0
aPTT-High: G0(BL) to G0(PBL) n=10,10,24,24	6	8	16	17
aPTT-High: G0(BL) to G1(PBL) n=10,10,24,24	3	2	6	6
aPTT-High: G0(BL) to G2(PBL) n=10,10,24,24	1	0	2	1
aPTT-High: G1(BL) to G0(PBL) n=0,1,3,2	99999	0	0	1
aPTT-High: G1(BL) to G1(PBL) n=0,1,3,2	99999	1	1	1
aPTT-High: G1(BL) to G3(PBL) n=0,1,3,2	99999	0	1	0
aPTT-High: G1(BL) to M(PBL) n=0,1,3,2	99999	0	1	0
aPTT-High: M(BL) to G0(PBL) n=0,0,0,1	99999	99999	99999	1
INR-High: G0(BL) to G0(PBL) n=9,8,20,17	5	6	16	13
INR-High: G0(BL) to G1(PBL) n=9,8,20,17	4	2	4	4
INR-High: G1(BL) to G0(PBL) n=1,2,7,9	0	1	1	1
INR-High: G1(BL) to G1(PBL) n=1,2,7,9	1	1	5	8
INR-High: G1(BL) to M(PBL) n=1,2,7,9	0	0	1	0
INR-High: G2(BL) to G2(PBL) n=0,1,0,0	99999	1	99999	99999
INR-High: M(BL) to G0(PBL) n=0,0,0,1	99999	99999	99999	1

No statistical analyses for this end point

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Haematology and Coagulation

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End point title

Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Haematology and Coagulation

End point description

Haematology parameters: Basophils, Eosinophils, Haematocrit, Monocytes, Red blood cells(RBC). Coagulation parameters: Prothrombin Time(PT). 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 endpoint. Categories with at least 1 non-zero data values are reported. Safety set included of all subjects who received at least 1 dose of study drug. Here “n”: subjects evaluable for this endpoint for specified rows. Baseline=BL, Postbaseline=PBL. '99999' signifies data not available as none of the subjects were evaluable for specified categories.

End point type

Secondary

End point timeframe

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)

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	10	11	27	27
Units: Subjects
Basophils: Normal(BL)to Low(PBL)n=10,11,27,27	0	0	1	0
Basophils: Normal(BL) to Normal(PBL) n=10,11,27,27	10	11	25	27
Basophils: Normal(BL) to Missing(PBL)n=10,11,27,27	0	0	1	0
Eosinophils: Normal(BL) to Low(PBL) n=9,11,27,27	0	0	0	1
Eosinophils: Normal(BL)to Normal(PBL)n=9,11,27,27	7	11	25	20
Eosinophils: Normal(BL) to High(PBL) n=9,11,27,27	2	0	1	6
Eosinophils:Normal(BL) to Missing(PBL)n=9,11,27,27	0	0	1	0
Eosinophils: High(BL) to Normal(PBL) n=1,0,0,0	1	99999	99999	99999
Haematocrit: Low(BL) to Low(PBL) n=2,2,10,9	2	1	8	9
Haematocrit: Low(BL) to Normal(PBL) n=2,2,10,9	0	1	1	0
Haematocrit: Low(BL) to Missing(PBL) n=2,2,10,9	0	0	1	0
Haematocrit: Normal(BL) to Low(PBL) n=8,9,17,18	5	4	13	12
Haematocrit: Normal(BL) to Normal(PBL) n=8,9,17,18	3	4	4	6
Haematocrit:Normal(BL) to High&Low(PBL)n=8,9,17,18	0	1	0	0
Monocytes: Normal(BL) to Low(PBL) n=10,11,27,26	1	0	1	0
Monocytes: Normal(BL) to Normal(PBL) n=10,11,27,26	9	7	19	20
Monocytes: Normal(BL) to High(PBL) n=10,11,27,26	0	4	6	6
Monocytes: Normal(BL)to Missing(PBL)n=10,11,27,26	0	0	1	0
Monocytes: High(BL) to Normal(PBL) n=0,0,0,1	99999	99999	99999	1
RBC: Low(BL) to Low(PBL) n=1,2,14,7	1	1	13	6
RBC: Low(BL) to Normal(PBL) n=1,2,14,7	0	1	1	1
RBC: Normal(BL) to Low(PBL) n=8,9,13,19	6	5	8	10
RBC: Normal(BL) to Normal(PBL) n=8,9,13,19	2	4	3	9
RBC: Normal(BL) to High(PBL) n=8,9,13,19	0	0	1	0
RBC: Normal(BL) to Missing(PBL) n=8,9,13,19	0	0	1	0
RBC: High(BL) to Low(PBL) n=1,0,0,1	0	99999	99999	1
RBC: High(BL) to Normal(PBL) n=1,0,0,1	1	99999	99999	0
PT: Normal(BL) to Normal(PBL) n=7,7,19,17	3	3	8	8
PT: Normal(BL) to High(PBL) n=7,7,19,17	4	4	11	9
PT: High (BL) to Normal(PBL) n=3,4,8,9	0	1	0	0
PT: High(BL) to High(PBL) n=3,4,8,9	3	3	7	9
PT: High(BL) to Missing(PBL) n=3,4,8,9	0	0	1	0
PT: Missing(BL) to High(PBL) n=0,0,0,1	99999	99999	99999	1

No statistical analyses for this end point

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on CTCAE v4.03: Chemistry

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End point title

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

End point description

Abnormalities: Albumin-graded low(L), Alkaline phosphatase(ALP)-graded high(H), Alanine aminotransferase(ALT)-H, Aspartate aminotransferase(AST)-H, Bilirubin-H, Amylase-H, Creatinine-H, Corrected calcium-H, Creatine Kinase-H, Glucose-H, Glucose-L, Lipase-H, Magnesium-H, Magnesium-L, Potassium-H, Potassium-L, Sodium-H and Sodium-L. Abnormalities graded by CTCAE v4.03 G1=mild;G2=moderate;G 3/4=severe/life-threatening. A G0 was assigned for all non-missing values not graded as 1 or higher. If value graded >=1 but falls within normal range, grade was reset to 0. Categories with at least 1 non-zero data values are reported. Safety set-all subjects received at least 1 dose of study drug. Here “n”- subjects evaluable for this endpoint for specified rows. Baseline=BL, Postbaseline=PBL, Missing=M. 99999=data not available as none of the subjects were evaluable for specified categories.

End point type

Secondary

End point timeframe

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)

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	10	11	27	27
Units: Subjects
ALT-High: G0(BL) to G0(PBL) n=8,10,20,21	5	5	12	12
ALT-High: G0(BL) to G1(PBL) n=8,10,20,21	3	5	7	5
ALT-High: G0(BL) to G2(PBL) n=8,10,20,21	0	0	1	1
ALT-High: G0(BL) to G3(PBL) n=8,10,20,21	0	0	0	3
ALT-High: G1(BL) to G0(PBL) n=1,1,5,5	0	0	1	0
ALT-High: G1(BL) to G1(PBL) n=1,1,5,5	1	1	3	2
ALT-High: G1(BL) to G2(PBL) n=1,1,5,5	0	0	1	2
ALT-High: G1(BL) to G3(PBL) n=1,1,5,5	0	0	0	1
ALT-High: G2(BL) to G2(PBL) n=1,0,1,1	1	99999	1	0
ALT-High: G2(BL) to G3(PBL) n=1,0,1,1	0	99999	0	1
ALT-High: G3(BL) to Missing(PBL) n=0,0,1,0	99999	99999	1	99999
AST-High: G0(BL) to G0(PBL) n=8,7,21,22	3	2	8	5
AST-High: G0(BL) to G1(PBL) n=8,7,21,22	5	4	11	13
AST-High: G0(BL) to G2(PBL) n=8,7,21,22	0	1	2	2
AST-High: G0(BL) to G3(PBL) n=8,7,21,22	0	0	0	2
AST-High: G1(BL) to G1(PBL) n=2,4,5,5	2	4	3	1
AST-High: G1(BL) to G2(PBL) n=2,4,5,5	0	0	1	3
AST-High: G1(BL) to G3(PBL) n=2,4,5,5	0	0	1	1
AST-High: G2(BL) to Missing(PBL) n=0,0,1,0	99999	99999	1	99999
Albumin-Low: G0(BL) to G0(PBL) n=10,8,25,26	4	2	8	8
Albumin-Low: G0(BL) to G1(PBL) n=10,8,25,26	3	2	9	11
Albumin-Low: G0(BL) to G2(PBL) n=10,8,25,26	3	4	7	6
Albumin-Low: G0(BL) to G3(PBL) n=10,8,25,26	0	0	0	1
Albumin-Low: G0(BL) to Missing(PBL) n=10,8,25,26	0	0	1	0
Albumin-Low: G1(BL) to G1(PBL) n=0,2,2,1	99999	0	0	1
Albumin-Low: G1(BL) to G2(PBL) n=0,2,2,1	99999	2	2	0
Albumin-Low: G2(BL) to G2(PBL) n=0,1,0,0	99999	1	99999	99999
ALP-High: G0(BL) to G0(PBL) n=5,4,15,12	2	2	7	6
ALP-High: G0(BL) to G1(PBL) n=5,4,15,12	3	1	8	5
ALP-High: G0(BL) to G2(PBL) n=5,4,15,12	0	1	0	1
ALP-High: G1(BL) to G1(PBL) n=4,4,9,11	1	0	5	7
ALP-High: G1(BL) to G2(PBL) n=4,4,9,11	2	4	3	3
ALP-High: G1(BL) to G3(PBL) n=4,4,9,11	1	0	1	1
ALP-High: G2(BL) to G2(PBL) n=1,1,2,2	0	1	0	0
ALP-High: G2(BL) to G3(PBL) n=1,1,2,2	1	0	2	2
ALP-High: G3(BL) to G3(PBL) n=0,2,1,2	99999	2	0	2
ALP-High: G3(BL) to Missing(PBL) n=0,2,1,2	99999	0	1	0
Amylase-High: G0(Bl) to G0(PBL) n=9,11,27,26	8	7	18	20
Amylase-High: G0(BL) to G1(PBL) n=9,11,27,26	1	2	5	2
Amylase-High: G0(BL) to G2(PBL) n=9,11,27,26	0	0	1	2
Amylase-High: G0(BL) to G3(PBL) n=9,11,27,26	0	1	2	2
Amylase-High: G0(BL) to Missing(PBL) n=9,11,27,26	0	1	1	0
Amylase-High: G1(BL) to G2(PBL) n=1,0,0,0	1	99999	99999	99999
Amylase-High: G2(BL) to G4(PBL) n=0,0,0,1	99999	99999	99999	1
Bilirubin-High: G0(BL) to G0(PBL) n=10,10,26,27	10	9	25	24
Bilirubin-High: G0(BL) to G1(PBL) n=10,10,26,27	0	0	1	2
Bilirubin-High: G0(BL) to G2(PBL) n=10,10,26,27	0	1	0	1
Bilirubin-High: G1(BL) to G2(PBL) n=0,1,0,0	99999	1	99999	99999
Bilirubin-High: G4(BL) to Missing(PBL) n=0,0,1,0	99999	99999	1	99999
Corrected calcium-Low:G0(BL)toG0(PBL)n=10,11,27,26	7	11	24	25
Corrected calcium-Low:G0(BL)toG1(PBL)n=10,11,27,26	3	0	2	1
Corrected calcium-Low: G0(BL)toM(PBL)n=10,11,27,26	0	0	1	0
Corrected calcium-Low:G1(BL)to G0(PBL)n=0,0,0,1	99999	99999	99999	1
Correctedcalcium-High:G0(BL)toG0(PBL)n=10,11,27,26	10	11	25	25
Correctedcalcium-High:G0(BL)toG1(PBL)n=10,11,27,26	0	0	1	1
Correctedcalcium-High: G0(BL)toM(PBL)n=10,11,27,26	0	0	1	0
Corrected calcium-High:G1(BL)toG0(PBL)n=0,0,0,1	99999	99999	99999	1
Creatine kinase-High: G0(BL)toG0(PBL)n=9,10,27,23	1	3	3	7
Creatine kinase-High:G0(BL)toG1(PBL)n=9,10,27,23	3	4	11	7
Creatine kinase-High:G0(BL)toG2(PBL)n=9,10,27,23	4	2	6	8
Creatine kinase-High: G0(BL)toG3(PBL)n=9,10,27,23	1	1	5	1
Creatine kinase-High: G0(BL)toG4(PBL)n=9,10,27,23	0	0	1	0
Creatine kinase-High: G0(BL)toM(PBL)n=9,10,27,23	0	0	1	0
Creatine kinase-High:G1(BL)toG2(PBL)n=1,1,0,3	0	1	99999	1
Creatine kinase-High:G1(BL)toG3(PBL)n=1,1,0,3	1	0	99999	1
Creatine kinase-High: G1(BL)toG4(PBL)n=1,1,0,3	0	0	99999	1
Creatine kinase-High: M(BL)toG1(PBL)n=0,0,0,1	99999	99999	99999	1
Creatinine-High: G0(BL) to G0(PBL) n=10,11,27,27	1	2	6	7
Creatinine-High: G0(BL) to G1(PBL) n=10,11,27,27	7	7	14	18
Creatinine-High: G0(BL) to G2(PBL) n=10,11,27,27	2	2	5	2
Creatinine-High: G0(BL) to G4(PBL) n=10,11,27,27	0	0	1	0
Creatinine-High: G0(BL) to M(PBL) n=10,11,27,27	0	0	1	0
Glucose-Low: G0(BL) to G0(PBL) n=10,11,26,26	10	10	23	26
Glucose-Low: G0(BL) to G1(PBL) n=10,11,26,26	0	1	1	0
Glucose-Low: G0(BL) to G2(PBL) n=10,11,26,26	0	0	1	0
Glucose-Low: G0(BL) to M(PBL) n=10,11,26,26	0	0	1	0
Glucose-Low: G1(BL) to G0(PBL) n=0,0,1,1	99999	99999	0	1
Glucose-Low: G1(BL) to G1(PBL) n=0,0,1,1	99999	99999	1	0
Glucose-High: G0(BL) to G0(PBL) n=9,10,24,21	7	6	18	14
Glucose-High: G0(BL) to G1(PBL) n=9,10,24,21	0	1	1	1
Glucose-High: G0(BL) to G2(PBL) n=9,10,24,21	1	1	0	1
Glucose-High: G0(BL) to M(PBL) n=9,10,24,21	1	2	5	5
Glucose-High: G1(BL) to G0(PBL) n=0,0,1,1	99999	99999	1	0
Glucose-High: G1(BL) to G2(PBL) n=0,0,1,1	99999	99999	0	1
Glucose-High: G3(BL) to G2(PBL) n=0,0,1,2	99999	99999	1	0
Glucose-High: G3(BL) to G3(PBL) n=0,0,1,2	99999	99999	0	1
Glucose-High: G3(BL) to M(PBL) n=0,0,1,2	99999	99999	0	1
Glucose-High: M(BL) to G0(PBL) n=1,1,1,3	0	0	0	1
Glucose-High: M(BL) to G3(PBL) n=1,1,1,3	0	0	1	0
Glucose-High: M(BL) to M(PBL) n=1,1,1,3	1	1	0	2
Lipase-High: G0(BL) to G0(PBL) n=9,10,25,23	5	6	17	15
Lipase-High: G0(BL) to G1(PBL) n=9,10,25,23	2	2	2	4
Lipase-High: G0(BL) to G2(PBL) n=9,10,25,23	1	1	1	0
Lipase-High: G0(BL) to G3(PBL) n=9,10,25,23	1	0	4	3
Lipase-High: G0(BL) to G4(PBL) n=9,10,25,23	0	0	0	1
Lipase-High: G0(BL) to M(PBL) n=9,10,25,23	0	1	1	0
Lipase-High: G1(BL) to G0(PBL) n=1,1,2,3	1	0	1	0
Lipase-High: G1(BL) to G1(PBL) n=1,1,2,3	0	1	1	2
Lipase-High: G1(BL) to G3(PBL) n=1,1,2,3	0	0	0	1
Lipase-High: G4(BL) to G4(PBL) n=0,0,0,1	99999	99999	99999	1
Magnesium-Low: G0(BL) to G0(PBL) n=9,11,26,27	8	10	22	24
Magnesium-Low: G0(BL) to G1(PBL) n=9,11,26,27	1	1	3	2
Magnesium-Low: G0(BL) to G2(PBL) n=9,11,26,27	0	0	0	1
Magnesium-Low: G0(BL) to M(PBL) n=9,11,26,27	0	0	1	0
Magnesium-Low: G1(BL) to G2(PBL) n=1,0,0,0	1	99999	99999	99999
Magnesium-Low: G2(BL) toG3(PBL) n=0,0,1,0	99999	99999	1	99999
Magnesium-High: G0(BL) to G0(PBL) n=10,11,27,27	10	11	26	27
Magnesium-High: G0(BL) to M(PBL) n=10,11,27,27	0	0	1	0
Potassium-Low: G0(BL) to G0(PBL) n=10,11,26,27	7	9	20	23
Potassium-Low: G0(BL) to G1(PBL) n=10,11,26,27	3	2	3	4
Potassium-Low: G0(BL) to G3(PBL) n=10,11,26,27	0	0	1	0
Potassium-Low: G0(BL) to G4(PBL) n=10,11,26,27	0	0	1	0
Potassium-Low: G0(BL) to M(PBBL) n=10,11,26,27	0	0	1	0
Potassium-Low: G3(BL) to G3 (PBL) n=0,0,1,0	99999	99999	1	99999
Potassium-High: G0(BL) to G0(PBL) n=10,11,26,27	9	10	23	23
Potassium-High: G0(BL) toG1(PBL) n=10,11,26,27	1	1	2	4
Potassium-High: G0(BL) to M(PBL) n=10,11,26,27	0	0	1	0
Potassium-High: G1(BL) to G0(PBL) n=0,0,1,0	99999	99999	1	99999
Sodium-Low: G0(BL) to G0(PBL) n=10,10,25,27	8	7	19	23
Sodium-Low: G0(BL) to G1(PBL) n=10,10,25,27	1	3	3	1
Sodium-Low: G0(BL) to G3(PBL) n=10,10,25,27	0	0	1	2
Sodium-Low: G0(BL) to G4(PBL) n=10,10,25,27	0	0	2	1
Sodium-Low: G1(BL) to G1(PBL) n=0,0,2,0	99999	99999	1	99999
Sodium-Low: G1(BL) to M(PBL) n=0,0,2,0	99999	99999	1	99999
Sodium-Low: G3(BL) to G3(PBL) n=0,1,0,0	99999	1	99999	99999
Sodium-High: G0(BL) to G0(PBL) n=10,11,27,27	10	11	23	22
Sodium-High: G0(BL) to G1(PBL) n=10,11,27,27	0	0	3	5
Sodium-High: G0(BL) to M(PBL) n=10,11,27,27	0	0	1	0

No statistical analyses for this end point

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Chemistry and Thyroid Function

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End point title

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

End point description

Chemistry laboratory parameters:Blood urea nitrogen (BUN), Protein, Chloride, Cancer antigen19-9 (CA19-9), Brain natriuretic peptide(BNP), Bicarbonate, 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 endpoint. Categories with at least 1 non-zero data values are reported. Safety set:all subjects who received at least 1 dose of study drug. ‘n’=subjects evaluable for this endpoint for specified rows. Baseline=BL, Postbaseline=PBL, Missing=M. ‘99999’=data not available as none of the subjects were evaluable for specified categories.

End point type

Secondary

End point timeframe

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)

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	10	11	27	27
Units: Subjects
BNP: Normal(BL) to Normal(PBL) n=9,9,27,25	8	6	24	22
BNP: Normal(BL) to High(PBL) n=9,9,27,25	1	3	2	3
BNP: Normal(BL) to Missing(PBL) n=9,9,27,25	0	0	1	0
BNP: High(BL) to Normal(PBL) n=1,2,0,2	0	2	99999	0
BNP: High(BL) to High(PBL) n=1,2,0,2	1	0	99999	2
BUN: Normal(BL) to Normal(PBL) n=7,9,25,21	4	3	15	14
BUN: Normal(BL) to High(PBL) n=7,9,25,21	3	5	9	7
BUN: Normal(BL) to Missing(PBL) n=7,9,25,21	0	1	1	0
BUN: High(BL) to Normal(PBL) n=3,2,2,6	0	0	2	3
BUN: High(BL) to High(PBL) n=3,2,2,6	3	2	0	3
Bicarbonate: Low(BL) to Normal(PBL) n=0,2,1,3	99999	1	0	3
Bicarbonate: Low(BL) to High(PBL) n=0,2,1,3	99999	1	1	0
Bicarbonate: Normal(BL) to Low(PBL) n=10,9,26,24	2	1	6	9
Bicarbonate:Normal(BL)to Normal(PBL)n=10,9,26,24	7	6	18	11
Bicarbonate: Normal(BL) to High(PBL) n=10,9,26,24	1	2	1	3
Bicarbonate:Normal(BL)toHigh&Low(PBL)n=10,9,26,24	0	0	0	1
Bicarbonate:Normal(BL)to Missing(PBL)n=10,9,26,24	0	0	1	0
CA19-9: Normal(BL) to Normal(PBL) n=3,4,8,9	3	3	6	7
CA19-9: Normal(BL) to High(PBL) n=3,4,8,9	0	0	2	1
CA19-9: Normal(BL) to Missing(PBL) n=3,4,8,9	0	1	0	1
CA19-9: High(BL) to Normal(PBL) n=7,7,19,18	0	0	1	1
CA19-9: High(BL) to High(PBL) n=7,7,19,18	7	6	16	16
CA19-9: High(BL) to Missing(PBL) n=7,7,19,18	0	1	2	1
CEA: Normal(BL) to Normal(PBL) n=1,0,3,6	1	99999	1	3
CEA: Normal(BL) to High(PBL) n=1,0,3,6	0	99999	2	2
CEA: Normal(BL) to Missing(PBL) n=1,0,3,6	0	99999	0	1
CEA: High(BL) to Normal(PBL) n=9,11,24,21	0	0	1	0
CEA: High(BL) to High(PBL) n=9,11,24,21	9	9	20	20
CEA: High(BL) to Missing(PBL) n=9,11,24,21	0	2	3	1
Chloride: Low(BL) to Low(PBL) n=0,1,2,1	99999	1	1	1
Chloride: Low(BL) to Missing(PBL) n=0,1,2,1	99999	0	1	0
Chloride: Normal(BL) to Low(PBL) n=10,10,25,26	2	2	8	3
Chloride: Normal(BL) to Normal(PBL) n=10,10,25,26	8	7	15	22
Chloride: Normal(BL) to High(PBL) n=10,10,25,26	0	0	2	1
Chloride:Normal(BL)to High&Low(PBL)n=10,10,25,26	0	1	0	0
T3: Low(BL) to Low(PBL) n=0,0,1,2	99999	99999	0	1
T3: Low(BL) to Missing(PBL) n=0,0,1,2	99999	99999	1	1
T3: Normal(BL) to Low(PBL) n=10,11,26,23	3	5	8	7
T3: Normal(BL) to Normal(PBL) n=10,11,26,23	7	5	15	15
T3:Normal(BL) to High&Low(PBL)n=10,11,26,23	0	0	1	0
T3: Normal(BL) to Missing(PBL) n=10,11,26,23	0	1	2	1
T3: High(BL) to High(PBL) n=0,0,0,2	99999	99999	99999	2
T4: Low(BL) to Low(PBL) n=0,1,0,1	99999	0	99999	1
T4: Low(BL) to Normal(PBL) n=0,1,0,1	99999	1	99999	0
T4: Normal(BL) to Low(PBL) n=10,10,26,24	0	1	2	3
T4: Normal(BL) to Normal(PBL)n=10,10,26,24	10	8	17	17
T4: Normal(BL) to High(PBL) n=10,10,26,24	0	0	3	1
T4:Normal(BL)to High&Low(PBL)n=10,10,26,24	0	0	1	1
T4: Normal(BL) to Missing(PBL) n=10,10,26,24	0	1	3	2
T4: High(BL) to Low(PBL) n=0,0,1,2	99999	99999	0	1
T4: High(BL) to Nomal(PBL) n=0,0,1,2	99999	99999	1	1
LDH: Low(BL) to Low(PBL) n=1,0,0,0	1	99999	99999	99999
LDH: Normal(BL) to Normal(PBL) n=6,5,20,15	1	1	6	5
LDH: Normal(BL) to High(PBL) n=6,5,20,15	5	4	14	10
LDH: High(BL) to Normal(PBL) n=3,6,7,12	0	0	0	1
LDH: High(BL) to High(PBL) n=3,6,7,12	3	6	6	11
LDH: High(BL) to Missing(PBL) n=3,6,7,12	0	0	1	0
Protein: Low(BL) to Low(PBL) n=0,1,0,0	99999	1	99999	99999
Protein: Normal(BL) to Low(PBL) n=10,10,27,27	5	6	11	11
Protein: Normal(BL) to Normal(PBL) n=10,10,27,27	5	4	12	14
Protein: Normal(BL) to High(PBL) n=10,10,27,27	0	0	0	2
Protein:Normal(BL)to High&Low(PBL)n=10,10,27,27	0	0	3	0
Protein: Normal(BL) to Missing(PBL) n=10,10,27,27	0	0	1	0
TSH: Low(BL) to Low(PBL) n=0,0,0,1	99999	99999	99999	1
TSH: Normal(BL) to Low(PBL) n=9,7,24,26	0	0	2	3
TSH: Normal(BL) to Normal(PBL) n=9,7,24,26	8	7	14	20
TSH: Normal(BL) to High(PBL) n=9,7,24,26	1	0	3	1
TSH:Normal(BL)to High&Low(PBL)n=9,7,24,26	0	0	2	0
TSH: Normal(BL) to Missing(PBL) n=9,7,24,26	0	0	3	2
TSH: High(BL) to Normal(PBL) n=1,4,3,0	0	2	2	99999
TSH: High(BL) to High(PBL) n=1,4,3,0	1	1	1	99999
TSH: High(BL) to Missing(PBL) n=1,4,3,0	0	1	0	99999
Troponin I: Normal(BL) to Normal(PBL)n=0,2,26,26	99999	2	11	10
Troponin I: Normal(BL) to High(PBL)n=0,2,26,26	99999	0	1	2
Troponin I: Normal(BL) to Missing(PBL) n=0,2,26,26	99999	0	14	14
Troponin I: Missing(BL)to Normal(PBL)n=5,3,0,1	4	3	99999	1
Troponin I: Missing(BL) to High(PBL) n=5,3,0,1	1	0	99999	0
Uric acid: Low(BL) to Low(PBL) n=0,1,1,3	99999	0	0	2
Uric acid: Low(BL) to Normal(PBL) n=0,1,1,3	99999	1	0	1
Uric acid: Low(BL) to Missing(PBL) n=0,1,1,3	99999	0	1	0
Uric acid: Normal(BL) to Low(PBL) n=9,9,23,21	1	2	4	4
Uric acid: Normal(BL) to Normal(PBL)n=9,9,23,21	8	5	15	16
Uric acid: Normal(BL) to High(PBL) n=9,9,23,21	0	2	4	1
Uric acid: High(BL) to Normal(PBL) n=1,1,3,3	0	0	1	0
Uric acid: High(BL) to High(PBL) n=1,1,3,3	1	1	2	3

No statistical analyses for this end point

Secondary: Number of Subjects With Abnormal Hepatic Laboratory Values

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End point title

Number of Subjects With Abnormal Hepatic Laboratory Values

End point description

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. Safety set: all subjects who received at least 1 dose of study drug. ‘n’=subjects evaluable for this endpoint for specified rows.

End point type

Secondary

End point timeframe

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)

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	10	11	27	27
Units: Subjects
ALT: >3 ULN n=9,11,25,26	0	0	2	7
ALT: >5 ULN n=10,11,26,27	0	0	0	5
ALT: >8 ULN n=10,11,26,27	0	0	0	1
AST: >3 ULN n=10,11,26,27	0	1	4	8
AST: >5 ULN n=10,11,26,27	0	0	1	3
AST: >8 ULN n=10,11,26,27	0	0	1	1
ALT or AST: >3 ULN n=9,11,25,26	0	1	3	7
ALT or AST: >5 ULN n=10,11,26,27	0	0	1	4
ALT or AST: >8 ULN n=10,11,26,27	0	0	1	1
Total bilirubin: >1.5 ULN n=9,11,26,26	0	2	0	1
Alkaline phosphatase: >2 ULN n=8,6,22,22	3	3	4	8
Alkaline phosphatase: >3 ULN n=10,8,24,24	4	4	2	4

No statistical analyses for this end point

Secondary: Concentration Versus Time Summary of Plasma Concentration of Binimetinib

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End point title

Concentration Versus Time Summary of Plasma Concentration of Binimetinib

End point description

The pharmacokinetic analysis set included of all subjects who received at least 1 dose of binimetinib and have at least 1 evaluable bioanalytical result. Here, ‘n’ signifies subjects evaluable for this endpoint for specified rows. ‘99999’= geometric mean and geometric coefficient of variation were not estimable as concentration was below the limit of quantification. ‘9999’=data not available as none of the subjects were evaluable for specified categories.

End point type

Secondary

End point timeframe

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

End point values	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib
Number of subjects analysed	10	11	26	27
Units: nanogram per milliliter
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1: 1.5 hours post dose n=10,11,21,23	228 ± 152.2	163 ± 129.6	261 ± 90.9	217 ± 134.5
Cycle 1 Day 15: pre dose n=4,5,12,8	135 ± 60.9	125 ± 103.9	77 ± 141.2	81.8 ± 143.6
Cycle 1 Day 15: 1.5 hours post dose n=4,8,15,18	542 ± 57.6	414 ± 24.5	294 ± 84.4	324 ± 83.3
Cycle 2 Day 15: pre dose n=4,2,7,7	108 ± 52.9	99999 ± 99999	88.5 ± 111.3	120 ± 77.7
Cycle 3 Day 15: pre dose n=3,2,1,3	140 ± 42.0	99999 ± 99999	99999 ± 99999	89.2 ± 183.4
Cycle 4 Day 15: pre dose n=2,1,1,1	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999
Cycle 5 Day 15: pre dose n=1,0,1,1	99999 ± 99999	9999 ± 9999	99999 ± 99999	99999 ± 99999

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All-Cause Mortality:Treatment start upto 150days(D) after last dose(Phase1b:max upto 13months[m] approx,Phase2: max upto 30m approx);TEAEs (serious/other AEs):Treatment start upto 30D after last dose(Phase1b:max upto 9m approx.;Phase2:max upto 26m approx)

Adverse event reporting additional description

Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event. Safety set was evaluated. Both TEAE and treatment-related AEs were monitored.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Phase 1b: Nivolumab+Binimetinib

Reporting group description

Subjects with previously treated MSS metastatic colorectal cancer with RAS mutation received binimetinib at a starting dose of 45 mg tablet orally BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle. Binimetinib dose modification to intermitted dosing (3 weeks on treatment and 1 week off treatment) with 45 mg dose or dose reduction to 30 mg BID or 30 mg intermittent dosing based on investigator’s decision as per its tolerability among subjects. Subjects then followed up for safety for around 150 days.

Reporting group title

Phase 1b: Nivolumab+Ipilimumab+Binimetinib

Reporting group description

Subjects with previously treated MSS metastatic colorectal cancer with RAS mutation received binimetinib at a starting dose of 45 mg tablet BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle. Ipilimumab was administered at the dose of 1 mg/kg IV every 8 weeks after completion of nivolumab infusion. Binimetinib dose modification to intermitted dosing (3 weeks on treatment and 1 week off treatment) with 45 mg dose or dose reduction to 30 mg BID or 30 mg intermittent dosing based on investigator’s decision as per its tolerability among subjects. Subjects then followed up for safety for around 150 days.

Reporting group title

Phase 2: Nivolumab+Ipilimumab+Binimetinib

Reporting group description

Subjects with previously treated MSS metastatic colorectal cancer with RAS mutation received 45 mg binimetinib tablet orally BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle. Ipilimumab was administered at the dose of 1 mg/kg IV every 8 weeks after completion of nivolumab infusion until disease progression, unacceptable toxicity, withdrawal of informal consent, initiation of subsequent anticancer therapy, lost to follow-up or death. Subjects then followed up for safety for around 150 days.

Reporting group title

Phase 2: Nivolumab+Binimetinib

Reporting group description

Subjects with previously treated MSS metastatic colorectal cancer with RAS mutation received 45 mg binimetinib tablet orally BID along with 480 mg IV dose of nivolumab every 4 weeks in each 28 day treatment cycle, until disease progression, unacceptable toxicity, withdrawal of informal consent, initiation of subsequent anticancer therapy, lost to follow-up or death. Subjects then followed up for safety for around 150 days.

Serious adverse events	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 10 (50.00%)	6 / 11 (54.55%)	11 / 27 (40.74%)	12 / 27 (44.44%)
number of deaths (all causes)	8	8	21	20
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Superior vena cava syndrome
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Localised oedema
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumonitis
subjects affected / exposed	0 / 10 (0.00%)	2 / 11 (18.18%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocarditis
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Intestinal obstruction
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin reaction
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal colic
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephritis
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypophysitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Candida infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Infected seroma
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periorbital cellulitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 27 (3.70%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	1 / 27 (3.70%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase 1b: Nivolumab+Binimetinib	Phase 1b: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Ipilimumab+Binimetinib	Phase 2: Nivolumab+Binimetinib
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 10 (100.00%)	11 / 11 (100.00%)	27 / 27 (100.00%)	27 / 27 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	2	0	0	2
Basal cell carcinoma
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Cancer pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	4 / 27 (14.81%)	3 / 27 (11.11%)
occurrences all number	0	1	4	4
Hypotension
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	5 / 10 (50.00%)	5 / 11 (45.45%)	11 / 27 (40.74%)	8 / 27 (29.63%)
occurrences all number	7	8	19	14
Fatigue
subjects affected / exposed	4 / 10 (40.00%)	6 / 11 (54.55%)	11 / 27 (40.74%)	11 / 27 (40.74%)
occurrences all number	7	8	20	18
Pyrexia
subjects affected / exposed	3 / 10 (30.00%)	3 / 11 (27.27%)	14 / 27 (51.85%)	8 / 27 (29.63%)
occurrences all number	4	5	17	19
Face oedema
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	4 / 27 (14.81%)
occurrences all number	0	1	0	5
Chills
subjects affected / exposed	1 / 10 (10.00%)	1 / 11 (9.09%)	4 / 27 (14.81%)	4 / 27 (14.81%)
occurrences all number	1	1	6	4
Asthenia
subjects affected / exposed	3 / 10 (30.00%)	1 / 11 (9.09%)	9 / 27 (33.33%)	7 / 27 (25.93%)
occurrences all number	5	2	17	18
Localised oedema
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	3 / 27 (11.11%)	0 / 27 (0.00%)
occurrences all number	0	0	3	0
Influenza like illness
subjects affected / exposed	0 / 10 (0.00%)	2 / 11 (18.18%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	2	0	0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Pruritus genital
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Scrotal oedema
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	2	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 10 (20.00%)	3 / 11 (27.27%)	6 / 27 (22.22%)	6 / 27 (22.22%)
occurrences all number	3	3	6	11
Dyspnoea
subjects affected / exposed	0 / 10 (0.00%)	4 / 11 (36.36%)	4 / 27 (14.81%)	4 / 27 (14.81%)
occurrences all number	0	6	8	6
Pneumonitis
subjects affected / exposed	0 / 10 (0.00%)	2 / 11 (18.18%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	4	0	0
Dysphonia
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	3 / 27 (11.11%)
occurrences all number	0	0	0	4
Productive cough
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	1	7	0
Epistaxis
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Rales
subjects affected / exposed	0 / 10 (0.00%)	2 / 11 (18.18%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	2	0	0
Wheezing
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	2
Dyspnoea exertional
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Nasal congestion
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Confusional state
subjects affected / exposed	0 / 10 (0.00%)	2 / 11 (18.18%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	2	0	0
Insomnia
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	5 / 10 (50.00%)	3 / 11 (27.27%)	13 / 27 (48.15%)	14 / 27 (51.85%)
occurrences all number	19	13	40	40
Ejection fraction decreased
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	7 / 27 (25.93%)	4 / 27 (14.81%)
occurrences all number	1	0	12	4
Alanine aminotransferase increased
subjects affected / exposed	0 / 10 (0.00%)	2 / 11 (18.18%)	8 / 27 (29.63%)	2 / 27 (7.41%)
occurrences all number	0	2	23	2
Aspartate aminotransferase increased
subjects affected / exposed	0 / 10 (0.00%)	3 / 11 (27.27%)	9 / 27 (33.33%)	2 / 27 (7.41%)
occurrences all number	0	3	21	3
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	5 / 27 (18.52%)	0 / 27 (0.00%)
occurrences all number	1	0	6	0
Amylase increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	3 / 27 (11.11%)	3 / 27 (11.11%)
occurrences all number	0	0	10	3
Blood bilirubin increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	2 / 27 (7.41%)
occurrences all number	0	0	2	3
Lipase increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	2 / 27 (7.41%)
occurrences all number	0	0	11	2
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	5	0
Troponin T increased
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	3 / 27 (11.11%)	0 / 27 (0.00%)
occurrences all number	0	0	3	0
Platelet count decreased
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	2
Weight decreased
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Troponin I increased
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Electrocardiogram abnormal
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Intraocular pressure increased
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Prothrombin time prolonged
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	2	0	0
Abdominal injury
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Scratch
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Laceration
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Skin abrasion
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	2	0	0	0
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	2
Ventricular hypokinesia
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Nervous system disorders
Dysgeusia
subjects affected / exposed	1 / 10 (10.00%)	2 / 11 (18.18%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	1	2	2	0
Dizziness
subjects affected / exposed	0 / 10 (0.00%)	2 / 11 (18.18%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	2	0	2
Neuropathy peripheral
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Syncope
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Headache
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	4 / 27 (14.81%)	7 / 27 (25.93%)
occurrences all number	0	1	6	15
Leukopenia
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Thrombocytopenia
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Eye disorders
Visual impairment
subjects affected / exposed	2 / 10 (20.00%)	1 / 11 (9.09%)	3 / 27 (11.11%)	0 / 27 (0.00%)
occurrences all number	3	1	4	0
Periorbital oedema
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	3 / 27 (11.11%)
occurrences all number	2	0	0	3
Vision blurred
subjects affected / exposed	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	1	0	0
Macular oedema
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	2
Subretinal fluid
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	2
Eyelid oedema
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Photopsia
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Retinopathy
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Eye oedema
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Dry age-related macular degeneration
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Vitreous detachment
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	6 / 10 (60.00%)	4 / 11 (36.36%)	15 / 27 (55.56%)	13 / 27 (48.15%)
occurrences all number	21	7	36	31
Nausea
subjects affected / exposed	5 / 10 (50.00%)	2 / 11 (18.18%)	11 / 27 (40.74%)	12 / 27 (44.44%)
occurrences all number	8	3	12	13
Abdominal pain
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	5 / 27 (18.52%)	5 / 27 (18.52%)
occurrences all number	1	0	5	5
Constipation
subjects affected / exposed	2 / 10 (20.00%)	3 / 11 (27.27%)	6 / 27 (22.22%)	9 / 27 (33.33%)
occurrences all number	2	4	6	10
Vomiting
subjects affected / exposed	2 / 10 (20.00%)	8 / 11 (72.73%)	10 / 27 (37.04%)	7 / 27 (25.93%)
occurrences all number	9	10	16	7
Abdominal distension
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	3 / 27 (11.11%)	3 / 27 (11.11%)
occurrences all number	0	1	3	3
Stomatitis
subjects affected / exposed	1 / 10 (10.00%)	2 / 11 (18.18%)	3 / 27 (11.11%)	3 / 27 (11.11%)
occurrences all number	3	2	6	9
Dry mouth
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	5 / 27 (18.52%)	3 / 27 (11.11%)
occurrences all number	0	1	5	3
Dyspepsia
subjects affected / exposed	1 / 10 (10.00%)	1 / 11 (9.09%)	3 / 27 (11.11%)	0 / 27 (0.00%)
occurrences all number	1	1	3	0
Abdominal discomfort
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	1	2	0
Ascites
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	4 / 27 (14.81%)
occurrences all number	0	0	0	6
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	5 / 27 (18.52%)	0 / 27 (0.00%)
occurrences all number	1	0	5	0
Abdominal pain upper
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	1	2	0
Abdominal pain lower
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Haemorrhoids
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Pancreatitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	3	0
Proctalgia
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	2
Lower gastrointestinal haemorrhage
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Glossitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Colitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	3	0	0
Mesenteric arterial occlusion
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Small intestinal obstruction
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	2	0	0	0
Skin and subcutaneous tissue disorders
Dermatitis acneiform
subjects affected / exposed	7 / 10 (70.00%)	6 / 11 (54.55%)	12 / 27 (44.44%)	13 / 27 (48.15%)
occurrences all number	15	15	25	22
Pruritus
subjects affected / exposed	0 / 10 (0.00%)	3 / 11 (27.27%)	7 / 27 (25.93%)	5 / 27 (18.52%)
occurrences all number	0	4	9	5
Rash
subjects affected / exposed	3 / 10 (30.00%)	1 / 11 (9.09%)	14 / 27 (51.85%)	8 / 27 (29.63%)
occurrences all number	5	4	32	13
Dry skin
subjects affected / exposed	1 / 10 (10.00%)	2 / 11 (18.18%)	5 / 27 (18.52%)	2 / 27 (7.41%)
occurrences all number	1	2	6	5
Rash maculo-papular
subjects affected / exposed	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	3 / 27 (11.11%)
occurrences all number	1	6	0	3
Pruritus generalised
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	1	2	0
Erythema
subjects affected / exposed	1 / 10 (10.00%)	1 / 11 (9.09%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	3	1	2	0
Alopecia
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	2 / 27 (7.41%)
occurrences all number	0	0	2	2
Rash macular
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	4
Rash papular
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Rash pruritic
subjects affected / exposed	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	2	0	0	0
Acne
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Dermatitis
subjects affected / exposed	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	19	1	0	0
Hyperhidrosis
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	2
Dermatitis exfoliative generalised
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	2	0	0
Ecchymosis
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Exfoliative rash
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	3	0	0
Skin fissures
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	2	0	0	0
Rash erythematous
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Petechiae
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Skin hyperpigmentation
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Skin lesion
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Skin reaction
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	2	0	0
Urticaria
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	1	0	0	2
Proteinuria
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Chromaturia
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Renal colic
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	1	0	0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	0 / 10 (0.00%)	2 / 11 (18.18%)	0 / 27 (0.00%)	3 / 27 (11.11%)
occurrences all number	0	2	0	3
Back pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	4 / 27 (14.81%)	5 / 27 (18.52%)
occurrences all number	0	0	4	11
Arthralgia
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	1	0	2	0
Neck pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	2	3	0
Muscular weakness
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Pain in extremity
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Infections and infestations
Paronychia
subjects affected / exposed	1 / 10 (10.00%)	1 / 11 (9.09%)	3 / 27 (11.11%)	3 / 27 (11.11%)
occurrences all number	1	1	4	9
Rash pustular
subjects affected / exposed	1 / 10 (10.00%)	1 / 11 (9.09%)	3 / 27 (11.11%)	2 / 27 (7.41%)
occurrences all number	1	1	6	7
Urinary tract infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	1	0	2
Bronchitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Folliculitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	6	0
Oral herpes
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Conjunctivitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0
Pneumonia
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	2	0	0	0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 10 (20.00%)	3 / 11 (27.27%)	6 / 27 (22.22%)	13 / 27 (48.15%)
occurrences all number	2	3	6	13
Hypokalaemia
subjects affected / exposed	2 / 10 (20.00%)	1 / 11 (9.09%)	2 / 27 (7.41%)	3 / 27 (11.11%)
occurrences all number	5	1	2	5
Hypomagnesaemia
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	1	0	5	0
Dehydration
subjects affected / exposed	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	2	2	0	0
Hyperglycaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	0	2	0
Hypoalbuminaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	2
Hyponatraemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	2 / 27 (7.41%)	0 / 27 (0.00%)
occurrences all number	0	6	4	0
Hypocalcaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	0	1	0	0
Hypophosphataemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	2 / 27 (7.41%)
occurrences all number	0	0	0	3
Hyperuricaemia
subjects affected / exposed	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 27 (0.00%)	0 / 27 (0.00%)
occurrences all number	1	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

02 Mar 2018

(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.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 2: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

Primary: Phase 2: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

Primary: Phase 1b: Number of Subjects With Dose-Limiting Toxicities (DLT)

Primary: Phase 1b: Number of Subjects With Dose-Limiting Toxicities (DLT)

Secondary: Phase 1b: Objective Response Rate (ORR) per RECIST v1.1

Secondary: Phase 1b: Objective Response Rate (ORR) per RECIST v1.1

Secondary: Duration of Response (DOR) as per RECIST v1.1

Secondary: Duration of Response (DOR) as per RECIST v1.1

Secondary: Percentage of Subjects With Complete Response as per RECIST v1.1

Secondary: Percentage of Subjects With Complete Response as per RECIST v1.1

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAE) Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03: Haematology and Coagulation

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03: Haematology and Coagulation

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Haematology and Coagulation

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Haematology and Coagulation

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on CTCAE v4.03: Chemistry

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on CTCAE v4.03: Chemistry

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Chemistry and Thyroid Function

Secondary: Number of Subjects With Shift From Baseline in Laboratory Parameter Values Based on Normal Range: Chemistry and Thyroid Function

Secondary: Number of Subjects With Abnormal Hepatic Laboratory Values

Secondary: Number of Subjects With Abnormal Hepatic Laboratory Values

Secondary: Concentration Versus Time Summary of Plasma Concentration of Binimetinib

Secondary: Concentration Versus Time Summary of Plasma Concentration of Binimetinib

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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