Metastatic Colorectal Cancer
Conditions
Keywords
CRC, MSS, non-MSI-H, PD-1, anti-PD-1, anti PD-1, MEK, MEK inhibitor
Brief summary
The purpose of this study is to determine safety and tolerability and to establish a preliminary recommended Phase 2 dose (RP2D) for the following combinations: pembrolizumab plus binimetinib (Cohort A), pembrolizumab plus mFOLFOX7 (oxaliplatin 85 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2) (Cohort B), pembrolizumab plus mFOLFOX7 and binimetinib (Cohort C), pembrolizumab plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\]400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) (Cohort D), and pembrolizumab plus FOLFIRI and binimetinib (Cohort E).
Interventions
BIOLOGICALPembrolizumab
200 mg Pembrolizumab solution for IV infusion Q3W
DRUGBinimetinib
tablet orally BID at 30 or 45 mg depending upon DLT profile
DRUGOxaliplatin
85 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 cocktail. Dose may be de-escalated to 70 mg/m\^2 if the standard dose of mFOLFOX7 is deemed too toxic per mTPI, based upon occurrence of DLTs.
DRUGLeucovorin
400 mg/m\^2 as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation.
DRUG5-Fluorouracil [5-FU]
2400 mg/m\^2 over 46-48 hours as IV infusion. Administered Q2W as part of mFOLFOX7 or FOLFIRI cocktail, depending upon allocation. Dose may be de-escalated to 2000 mg/m\^2 if the standard dose of mFOLFOX7 or FOLFIRI is deemed too toxic per mTPI, based upon occurrence of DLTs.
DRUGIrinotecan
180 mg/m\^2 as IV infusion. Administered Q2W as part of FOLFIRI cocktail. Dose may be de-escalated to 150 mg/m\^2 if the standard dose of FOLFIRI is deemed too toxic per mTPI, based upon occurrence of DLTs.
Sponsors
Array BioPharma
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 18 years of age * Has a histologically-confirmed, unresectable or metastatic (Stage IV American Joint Committee on Cancer \[AJCC seventh edition\]) colorectal cancer (CRC) * Has a locally determined non microsatellite instability high/ proficient mismatch repair (non-MSI-H/pMMR) tumor status * Has at least 1 radiologically measurable lesion as defined by RECIST 1.1 * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Has a life expectancy of at least 3 months * Has the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption. * Has adequate organ function * Male participants must agree to use contraception during the treatment period and for ≥180 days, after the last dose of study treatment and refrain from donating sperm during this period. Male participants with pregnant partners must agree to use a condom * Female participants eligible to participate if not pregnant, not breastfeeding, and is not a woman of childbearing potential (WOCBP) or is a WOCBP who agrees to follow contraceptive guidance during the treatment period and for ≥180 days after the last dose of study treatment * Participants for Cohort A: * Has been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin * Participants for Cohorts B and C: * Must not have received prior systemic chemotherapy for Stage IV CRC * Participants for Cohorts D and E: * Must have been previously treated with 1 line of therapy including a fluoropyrimidine plus an oxaliplatin-based regimen * Participants for Cohorts A, C, and E: * Have a 12-lead electrocardiogram (ECG) and echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed by the investigator or other qualified person to evaluate cardiac function prior to enrollment in the study
Exclusion criteria
* Is currently participating and receiving study therapy in a study of an investigational agent or has participated and received study therapy in a study of an investigational agent or has used an investigational device within 28 days of administration of MK-3475 * Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (prior to the first dose of study therapy, or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Gr 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier * Has history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years * Has clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis * Has a known hypersensitivity, intolerability or contraindication to any component of study treatment, including premedication * Has any active infection requiring systemic therapy * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has received prior therapy with compounds targeting programmed death (PD)-1, PD-L1, PD-L2, or a mitogen-activated protein kinase (MAPK) pathway inhibitor * Has an autoimmune disease that has required systemic treatment in the past 2 years with use of disease modifying agents, corticosteroids, or immunosuppressive drugs * Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization * Has known history of human immunodeficiency virus (HIV) infection * Has a known history of Hepatitis B * Has received live vaccine within 30 days of the planned start of study therapy * Has undergone major surgery and has not recovered adequately from any toxicity and/or complications from the intervention prior to starting study therapy * Has baseline peripheral neuropathy/paresthesia * Has any medical, psychiatric, cognitive, or other conditions that may compromise the participant's ability to understand the participant information, give informed consent, comply with the study protocol, or complete the study. * Has symptomatic congestive heart failure (CHF) * Has a history of acute or chronic pancreatitis * Has existing uncontrolled arterial hypertension (systolic blood pressure \[SBP\] ≥150 mmHg or diastolic blood pressure \[DBP\] ≥100 mmHg) despite appropriate medical therapy * Has a history of thromboembolic or cerebrovascular events within 6 months prior to registration * Has neuromuscular disorders associated with an elevated creatine kinase * A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment * Potential Participants for Cohorts A, C or E who are to Receive Binimetinib: * Has a history of, or current, retinal vein occlusion (RVO) or current risk factors for RVO * Has retinal degenerative disease * Potential Participants for Cohorts A, C, D or E: * Has a known history of Gilbert's Syndrome * Potential Participants for Cohorts D or E: * Has a previous treatment with irinotecan * Has plans to use, or is using, any herbal medications/supplements or any medications or foods that are strong inhibitors or inducers of cytochrome P450 3A 4/5 ≤1 week prior to the start of study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT) | Up to approximately first 28 days of treatment | The occurrence of any of the following toxicities during Part 1 of the study (the first 21 days for Cohort A, first 28 days for Cohorts B,C, D, & E), if possibly, probably or definitely related to study treatment, was considered a DLT: Grade (Gr) 4 non hematologic toxicity, Gr 4 hematologic toxicity lasting \>7 days, Gr 3 thrombocytopenia, Any non-hematologic AE ≥Gr 3 in severity, Any Gr 3 or Gr 4 non-hematologic laboratory value, Febrile neutropenia Gr 3 or Gr 4, Any prolonged delay in initiating study therapy due to a treatment-related AE that started during the DLT period, Any treatment-related toxicity that causes the participant to discontinue treatment during the DLT period, Missing \>25% of binimetinib doses as a result of drug-related AE(s), Gr 5 toxicity, Cardiac disorders and vascular disorders, Eye disorders (Retinopathy or retinal detachment Gr ≥ 3). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | Up to Approximately 64 months | ORR was determined in all participants and was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). The percentage of participants who experienced CR or PR is presented. Per Protocol, analysis was per cohort. |
Countries
Canada, United States
Participant flow
Pre-assignment details
A total of 161 participants were screened, 116 participants were allocated, and 114 received at least 1 dose of study treatment across 14 study sites in 2 countries. This study included 2 parts: Part 1 was a dose finding phase and Part 2 was a dose confirmation phase to further examine safety and explore efficacy. Cohorts A, C, and E did not proceed to Part 2.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Part 1: Pembrolizumab +Binimetinib 30 mg Participants in Cohort A received pembrolizumab (200 mg) intravenous (IV) every 3 weeks (Q3W) plus binimetinib orally at of 30 mg twice a day (BID) until disease progression or discontinuation. | 6 |
| Cohort A Part 1: Pembrolizumab +Binimetinib 45 mg Participants in Cohort A will receive pembrolizumab (200 mg) IV Q3W plus binimetinib orally at 45 mg BID (Dose Level 2 \[DL2\]) until disease progression or discontinuation. | 16 |
| Cohort B Part 1: Pembrolizumab + mFOLFOX7 Participants in Cohort B received pembrolizumab (200 mg) IV Q3W plus mFOLFOX7 (oxaliplatin 85 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2 over 46-48 hours) IV Q2W until disease progression or discontinuation. | 15 |
| Cohort B Part 2: Pembrolizumab + mFOLFOX7 During Part 2, participants in Cohort B received pembrolizumab (200 mg) IV Q3W plus mFOLFOX7 (oxaliplatin 85mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2 over 46-48 hours) IV Q2W until disease progression or discontinuation. | 16 |
| Cohort C Part 1: Pembrolizumab + mFOLFOX7 + Binimetinib 30 mg Participants in Cohort C received pembrolizumab 200 mg IV Q3W plus mFOLFOX7 (oxaliplatin 85mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; fluorouracil \[5-FU\] 2400 mg/m\^2 over 46-48 hours) IV Q2W in combination with binimetinib orally at a starting dose of 30 mg BID until disease progression or discontinuation. | 11 |
| Cohort D Part 1: Pembrolizumab + FOLFIRI Participants in Cohort D received a standard dose (DL1) of pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) IV Q2W until disease progression or discontinuation. | 16 |
| Cohort D Part 2: Pembrolizumab + FOLFIRI During Part 2, participants in Cohort D received pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) until disease progression or discontinuation. | 16 |
| Cohort E Part 1: Pembrolizumab + FOLFIRI + Binimetinib 30 mg Participants in Cohort E received pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) Q2W in combination with binimetinib orally at a starting dose of 30 mg BID until disease progression or discontinuation. | 9 |
| Cohort E Part 1: MK-3475 200 mg Q3W + FOLFIRI Q2W + Binimetinib 45 mg BID During Part 2, participants in Cohort E received pembrolizumab 200 mg IV Q3W plus FOLFIRI (irinotecan 180 mg/m\^2; leucovorin \[calcium folinate\] 400 mg/m\^2; 5-FU 2400 mg/m\^2 over 46-48 hours) Q2W plus binimetinib orally at the starting dose of 45 mg BID until disease progression or discontinuation. | 11 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 5 | 16 | 13 | 11 | 9 | 12 | 11 | 6 | 7 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
| Overall Study | Sponsor Decision | 1 | 0 | 2 | 3 | 2 | 3 | 3 | 3 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 2 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort A Part 1: Pembrolizumab +Binimetinib 30 mg | Cohort A Part 1: Pembrolizumab +Binimetinib 45 mg | Cohort B Part 1: Pembrolizumab + mFOLFOX7 | Cohort B Part 2: Pembrolizumab + mFOLFOX7 | Cohort C Part 1: Pembrolizumab + mFOLFOX7 + Binimetinib 30 mg | Cohort D Part 1: Pembrolizumab + FOLFIRI | Cohort D Part 2: Pembrolizumab + FOLFIRI | Cohort E Part 1: Pembrolizumab + FOLFIRI + Binimetinib 30 mg | Cohort E Part 1: MK-3475 200 mg Q3W + FOLFIRI Q2W + Binimetinib 45 mg BID | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 55.0 Years STANDARD_DEVIATION 9.3 | 59.4 Years STANDARD_DEVIATION 11.3 | 55.5 Years STANDARD_DEVIATION 11.6 | 50.3 Years STANDARD_DEVIATION 12 | 54.8 Years STANDARD_DEVIATION 14.1 | 56.3 Years STANDARD_DEVIATION 11.7 | 52.5 Years STANDARD_DEVIATION 13.8 | 57.9 Years STANDARD_DEVIATION 11.4 | 48.2 Years STANDARD_DEVIATION 10.4 | 54.4 Years STANDARD_DEVIATION 12.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 15 Participants | 13 Participants | 15 Participants | 9 Participants | 13 Participants | 16 Participants | 8 Participants | 10 Participants | 105 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 15 Participants | 11 Participants | 15 Participants | 9 Participants | 14 Participants | 13 Participants | 8 Participants | 10 Participants | 99 Participants |
| Sex: Female, Male Female | 1 Participants | 11 Participants | 7 Participants | 3 Participants | 3 Participants | 11 Participants | 5 Participants | 5 Participants | 4 Participants | 50 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 8 Participants | 13 Participants | 8 Participants | 5 Participants | 11 Participants | 4 Participants | 7 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 6 | 16 / 16 | 13 / 15 | 12 / 16 | 9 / 11 | 13 / 16 | 11 / 16 | 6 / 9 | 7 / 11 |
| other Total, other adverse events | 6 / 6 | 14 / 14 | 15 / 15 | 16 / 16 | 11 / 11 | 16 / 16 | 16 / 16 | 9 / 9 | 11 / 11 |
| serious Total, serious adverse events | 1 / 6 | 7 / 14 | 5 / 15 | 8 / 16 | 7 / 11 | 6 / 16 | 2 / 16 | 5 / 9 | 7 / 11 |
Outcome results
Primary
Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT)
The occurrence of any of the following toxicities during Part 1 of the study (the first 21 days for Cohort A, first 28 days for Cohorts B,C, D, & E), if possibly, probably or definitely related to study treatment, was considered a DLT: Grade (Gr) 4 non hematologic toxicity, Gr 4 hematologic toxicity lasting \>7 days, Gr 3 thrombocytopenia, Any non-hematologic AE ≥Gr 3 in severity, Any Gr 3 or Gr 4 non-hematologic laboratory value, Febrile neutropenia Gr 3 or Gr 4, Any prolonged delay in initiating study therapy due to a treatment-related AE that started during the DLT period, Any treatment-related toxicity that causes the participant to discontinue treatment during the DLT period, Missing \>25% of binimetinib doses as a result of drug-related AE(s), Gr 5 toxicity, Cardiac disorders and vascular disorders, Eye disorders (Retinopathy or retinal detachment Gr ≥ 3).
Time frame: Up to approximately first 28 days of treatment
Population: Population based on all participants who received treatment and that were DLT Evaluable in Part 1 of study. These populations included all allocated participants in Part 1 who received at least 1 dose of study intervention according to the study intervention they received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A Part 1: Pembrolizumab +Binimetinib 30 mg | Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT) | 16.7 Percetange of Participants |
| Cohort A Part 1: Pembrolizumab +Binimetinib 45 mg | Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT) | 0.0 Percetange of Participants |
| Cohort B Part 1: Pembrolizumab + mFOLFOX7 | Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT) | 0.0 Percetange of Participants |
| Cohort C Part 1: Pembrolizumab + mFOLFOX7 + Binimetinib 30 mg | Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT) | 27.3 Percetange of Participants |
| Cohort D Part 1: Pembrolizumab + FOLFIRI | Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT) | 7.1 Percetange of Participants |
| Cohort E Part 1: Pembrolizumab + FOLFIRI + Binimetinib 30 mg | Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT) | 33.3 Percetange of Participants |
| Cohort E Part 1: MK-3475 200 mg Q3W + FOLFIRI Q2W + Binimetinib 45 mg BID | Percentage of Participants Who Experienced Dose-Limiting Toxicity (DLT) | 45.5 Percetange of Participants |
Secondary
Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
ORR was determined in all participants and was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR). The percentage of participants who experienced CR or PR is presented. Per Protocol, analysis was per cohort.
Time frame: Up to Approximately 64 months
Population: The analysis population consisted of all evaluable participants for each cohort with a baseline scan with measurable disease by investigator assessment who received at least 1 dose of study treatment. Per protocol, the populations were analyzed by cohort and treatment combination (irrespective of dose); therefore, data by individual dose were not analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort A Part 1: Pembrolizumab +Binimetinib 30 mg | Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | 0.0 Percentage of participants |
| Cohort A Part 1: Pembrolizumab +Binimetinib 45 mg | Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | 61.3 Percentage of participants |
| Cohort B Part 1: Pembrolizumab + mFOLFOX7 | Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | 27.3 Percentage of participants |
| Cohort C Part 1: Pembrolizumab + mFOLFOX7 + Binimetinib 30 mg | Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | 25.0 Percentage of participants |
| Cohort D Part 1: Pembrolizumab + FOLFIRI | Objective Response Rate (ORR) Per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | 20.0 Percentage of participants |