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

Phase 2

Completed

Conditions: MSS
RAS-mutant Colorectal Cancer

Interventions: Drug: binimetinib
Drug: nivolumab
Drug: ipilimumab

Registration Number: NCT03271047

Lead Sponsor: Pfizer

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 75

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase 1b / Arm 1A	nivolumab	binimetinib + nivolumab
Phase 2 / Arm 2A	nivolumab	binimetinib + nivolumab
Phase 2 / Arm 2A	binimetinib	binimetinib + nivolumab
Phase 1b / Arm 1A	binimetinib	binimetinib + nivolumab
Phase 1b / Arm 1B	binimetinib	binimetinib + nivolumab + ipilimumab
Phase 1b / Arm 1B	nivolumab	binimetinib + nivolumab + ipilimumab
Phase 1b / Arm 1B	ipilimumab	binimetinib + nivolumab + ipilimumab
Phase 2 / Arm 2B	binimetinib	binimetinib + nivolumab + ipilimumab
Phase 2 / Arm 2B	ipilimumab	binimetinib + nivolumab + ipilimumab
Phase 2 / Arm 2B	nivolumab	binimetinib + nivolumab + ipilimumab

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (49): UCLA Hematology/Oncology
🇺🇸
Los Angeles, California, United States
UCLA Hematology/Oncology - Santa Monica
🇺🇸
Santa Monica, California, United States
Christiana Care Health Services, Helen F. Graham Cancer Center Pharmacy, Suite 3200
🇺🇸
Newark, Delaware, United States
Christiana Care Health Services, Helen F. Graham Cancer Center
🇺🇸
Newark, Delaware, United States
Christiana Care Oncology Hematology, Helen F Graham Cancer Center, Suite 2400
🇺🇸
Newark, Delaware, United States
Medical Oncology Hematology Consultants, PA, Helen F. Graham Cancer Center
🇺🇸
Newark, Delaware, United States
Christiana Care Health Services, Christiana Hospital
🇺🇸
Newark, Delaware, United States
Georgetown University Medical Center Department of Pharmacy, Research
🇺🇸
Washington, District of Columbia, United States
Georgetown University Medical Center
🇺🇸
Washington, District of Columbia, United States
Hematology Oncology Associates of the Treasure Coast
🇺🇸
Port Saint Lucie, Florida, United States
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UCLA Hematology/Oncology
🇺🇸Los Angeles, California, United States