Safety and Efficacy of Vicriviroc (MK-7690) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Microsatellite Stable (MSS) Colorectal Cancer (CRC) (MK-7690-046)

Study Overview
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Brief Summary
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This trial will evaluate the safety and efficacy of vicriviroc (MK-7690) at 2 dose levels in combination with pembrolizumab (MK-3475) in participants with advanced/metastatic microsatellite stable (MSS) colorectal cancer (CRC).

Official Title
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A Phase 2 Trial to Evaluate the Safety and Efficacy of Vicriviroc (MK-7690) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Microsatellite Stable (MSS) Colorectal Cancer (CRC)

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: Vicriviroc
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a histologically proven locally advanced unresectable or metastatic CRC. Have locally confirmed MSS CRC. Have been previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan, and have received, been intolerant to, or been ineligible for all treatment known to confer clinical benefit. Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days of starting study intervention. Male participants must agree to use contraception and refrain from donating sperm for at least 120 days after the last dose of study intervention. Female participants must be not pregnant and not breastfeeding. Further, a female participant must either not be a woman of childbearing potential (WOCBP) or, if a WOCBP, agree to use contraception during the treatment period and for at least 120 days after the last dose of study intervention. Have adequate organ function. Exclusion Criteria: Have a known additional malignancy that is progressing or has required active treatment within the past 2 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Have severe hypersensitivity reaction to treatment with any monoclonal antibody or components of the study interventions. Have an active autoimmune disease requiring systemic treatment in the past 2 years, except vitiligo or resolved childhood asthma/atopy. Have a history of vasculitis. Have an active infection requiring systemic therapy. Have symptomatic ascites or pleural effusion. Have interstitial lung disease requiring oral or IV glucocorticoids. Have a history of pneumonitis (noninfectious) that required steroids, or has current pneumonitis. Have a known history of human immunodeficiency virus (HIV) infection. Have a known history of hepatitis B or known active hepatitis C virus infection. Have a known history of active tuberculosis (TB; Bacillus tuberculosis). Have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, make administration of the study interventions hazardous, or make it difficult to monitor adverse events. Have a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with study requirements. Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 120 days after the last dose of study intervention. Are a WOCBP who has a positive urine pregnancy test within 72 hours before randomization or treatment allocation. Have undergone major surgery and have not recovered adequately from any toxicity and/or complications from the intervention before starting study intervention. Have a seizure disorder requiring ongoing antiseizure therapy or with any condition that, in the judgment of the investigator, is likely to increase the risk of seizure (e.g., CNS malignancy or toxoplasmosis). Have known gastrointestinal (GI) disease such as esophageal, gastric, or duodenal ulceration or inflammatory bowel disease, or history of GI surgery. Are using any drug (therapeutic or recreational), or withdrawal thereof, that poses an increased risk of convulsions. Have had an allogeneic tissue/solid organ transplant. Have received prior therapy with vicriviroc or other CCR5 antagonist (e.g., maraviroc) or have received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent. Have been treated with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137). Have received prior systemic anticancer therapy, including investigational agents, or has used an investigational device within 28 days before the first dose of study intervention. Have received prior radiotherapy (not to target lesions) within 2 weeks of start of study intervention. Are expected to require any other form of antineoplastic therapy while on study. Have a diagnosis of immunodeficiency, is receiving chronic systemic steroid therapy in excess of replacement doses (prednisone ≤10 mg/day is acceptable), or is taking any other form of immunosuppressive medication within 7 days before the first dose of the study intervention. Have received a live-virus vaccine within 30 days before the first dose of the study intervention. Are currently participating in or have participated in a study of an investigational agent, or have used an investigational device within 28 days before the first dose of study intervention.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vicriviroc QD at Dose Level 1 (150 mg) + Pembrolizumab (200 mg)<br>Participants receive vicriviroc 150 mg tablets per os (PO) every day (QD) of each 21-day cycle up to 35 cycles and pembrolizumab 200 mg as a 30-minute intravenous (IV) infusion on Day 1 of each 21 day cycle up to 35 cycles (cycle length: 21 days). | Drug: Vicriviroc<br>* Vicriviroc tablets administered orally, QD at dose level 1 or 2.<br>* Other names: MK-7690;Biological: Pembrolizumab<br>* Pembrolizumab administered by IV infusion at 200 mg every 3 weeks (Q3W), given on cycle day 1.<br>* Other names: MK-3475;|
| Experimental: Vicriviroc QD at Dose Level 2 (250 mg) + Pembrolizumab (200 mg)<br>Participants receive vicriviroc 250 mg tablets PO QD of each 21-day cycle up to 35 cycles and pembrolizumab 200 mg as a 30-minute IV infusion on Day 1 of each 21 day cycle up to 35 cycles (cycle length: 21 days). | Drug: Vicriviroc<br>* Vicriviroc tablets administered orally, QD at dose level 1 or 2.<br>* Other names: MK-7690;Biological: Pembrolizumab<br>* Pembrolizumab administered by IV infusion at 200 mg every 3 weeks (Q3W), given on cycle day 1.<br>* Other names: MK-3475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) | Objective response rate (ORR) was defined as the percentage of participants who experienced a 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) and was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by the investigator. ORR was estimated and analyzed using Clopper-Pearson interval. | Up to  32 months | 
| Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) | DLTs were assessed during the first cycle (21 days) & were defined as: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia, Gr 4 thrombocytopenia of any duration, Gr 3 thrombocytopenia associated with bleeding; nonhematologic adverse event (AE) ≥ Gr 3 (with exceptions); Gr 3 or 4 nonhematologic lab abnormality (if medical intervention was required, lead to hospitalization, or persisted for >72 hours); Gr 3 or 4 febrile neutropenia; inability to receive ≥75% of the planned vicriviroc dose because of drug-related tolerability; drug-related toxicity that caused a >2 week delay in Cycle 2 initiation; elevated aspartate aminotransferase or alanine aminotransferase lab value that is >3× upper limit of normal (ULN) & an elevated total bilirubin value >2× ULN & an alkaline phosphatase value <2× ULN, in which no alternative reasons were found. | Up to Day 21 of Cycle 1 (each cycle is 21 days) | 
| Number of Participants Who Experienced an Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants with at least one AE was assessed. | Up to  28 months | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants who discontinued treatment due to an AE was assessed | Up to  25 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria in Solid Tumors 1.1 for Immune-based Therapeutics (iRECIST) | An objective response rate was defined as the percentage of participants who experienced an immune-based complete response (iCR: disappearance of all target lesions) or immune-based partial response (iPR: at least a 30% decrease in the sum of diameters of target lesions). The percentage of participants who experienced an iCR or iPR using immune-based therapeutics Response Evaluation Criteria in Solid Tumors (iRECIST) per investigator was presented. ORR was estimated and analyzed using Clopper-Pearson interval. | Up to  32 months | 
| Progression-Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) | PFS was defined as the time from the first dose of study treatment to the date of the first documentation of disease progression, as determined by investigator per RECIST 1.1 or death due to any cause (whichever occurred first). Disease progression was defined as at least 20 percent (%) increase (including an absolute increase of at least 5 millimeter [mm]) in the sum of diameter of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method. | Up to  32 months | 
| PFS Based on Modified Response Evaluation Criteria in Solid Tumors 1.1 for Immune-based Therapeutics (iRECIST) | PFS was defined as the time from the first dose of study treatment to the date of the first documentation of disease progression, as determined by investigator per modified iRECIST or death due to any cause (whichever occurred first). Disease progression was defined as at least 20 percent (%) increase (including an absolute increase of at least 5 millimeter [mm]) in the sum of diameter of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. PFS was estimated and analyzed using Kaplan-Meier method. | Up to  32 months | 
| Overall Survival (OS) | OS is defined as the time from the first dose of study treatment until death from any cause. | Up to  32 months | 
| Plasma Area Under the Concentration Time-Curve From 0 to 8 Hours (AUC 0-8hrs) of Vicriviroc | Plasma vicriviroc concentration was quantified for each arm to determine AUC 0-8hrs, defined as the area under the concentration vs. time curve for vicriviroc from 0 to 8 hours. | Pre-dose, 1, 2, 4, and 8 hours after vicriviroc administration on Cycle 1 (each cycle= 21-days) Day 1, Cycle 2 Day 1. | 
| Maximum Observed Plasma Concentration (Cmax) of Vicriviroc | Plasma vicriviroc concentration was quantified for each arm to determine Cmax, defined as the maximum observed concentration of vicriviroc in plasma. | Pre-dose, 1, 2, 4, and 8 hours after vicriviroc administration on Cycle 1 (each cycle= 21-days) Day 1, Cycle 2 Day 1. | 
| Trough Plasma Concentration (Ctrough) of Vicriviroc | Plasma vicriviroc concentration was quantified for each arm to determine Ctrough, defined as the minimum plasma concentration of vicriviroc observed after administration and just before the subsequent dose. | Pre-dose, and 1, 2, 4, and 8 hours after vicriviroc administration on Cycle 1 (each cycle= 21-days) Day 1; Cycle 3 Day 21. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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programmed cell death 1 (PD-1, PD1 ), programmed cell death ligand 1 (PD-L1, PDL1), microsatellite stable (MSS) colorectal cancer (CRC), chemokine receptor type 5 (CCR5)