Study of MK-8353 in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Malignancies (MK-8353-013)

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability and preliminary efficacy of MK-8353 when administered in combination with pembrolizumab (MK-3475). There are two parts in this study: Part 1 will be dose escalation and confirmation, and Part 2 will be a cohort expansion. In Part 1, the recommended phase II dose (RP2D) of MK-8353 in combination with a fixed dose of pembrolizumab in participants with advanced malignancies will be identified and confirmed. Participants will be initially enrolled to receive MK-8353 at 350 mg twice a day (BID) in combination with pembrolizumab at a fixed dose of 200 mg on Day 1 of each 3-week cycle (Q3W) for up to 24 months of treatment. In Part 2, participants with advanced colorectal cancer (CRC) that is microsatellite stable (i.e., non-microsatellite instability-high/deficient mismatch repair [non-MSI-H/dMMR]) who received at least one and up to five prior lines of therapy will be enrolled at the RP2D in the expansion cohort to further evaluate safety and efficacy. The protocol has been amended to lower the starting doses of MK-8353 in combination with pembrolizumab. In addition, 3 arms have been added: one in which MK-8353 will be administered continuously once a day (QD) in combination with pembrolizumab, one optional arm in which MK-8353 will be administered 1 week on/1 week off QD in combination with pembrolizumab and one optional arm in which participants undergo a MK-8353 QD run-in period prior to starting combination therapy with pembrolizumab.

Official Title
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A Phase Ib Study to Evaluate the Safety and Tolerability of MK-8353 in Combination With Pembrolizumab in Patients With Advanced Malignancies

Conditions
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Neoplasms, Colorectal Cancer

Intervention / Treatment
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* Drug: MK-8353
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1: Has a histologically- or cytologically-documented, locally-advanced or metastatic solid malignancy and has received ≥1 and <6 prior line of cancer treatment regimen(s). Part 2: Has a histologically-confirmed adenocarcinoma originating from the colon or rectum (Stage 4 American Joint Committee on Cancer [AJCC] 7th edition) that is microsatellite stable (i.e., non-MSI-H/dMMR). Appendiceal cancer is included AND Has experienced disease progression or was intolerant to at least 1 and up to 5 systemic chemotherapy regimen(s) for metastatic CRC that must have included fluroropyrimidines and irinotecan or oxaliplatin, ± anti-vascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor (EGFR)(if indicated by RAS mutational status). Provides an archival or newly obtained tumor tissue sample and blood samples for biomarker analysis. Has ≥1 measurable lesion as defined by RECIST 1.1 on imaging studies. Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. Has adequate organ function Female participants of childbearing potential who are willing to use either 2 adequate barrier methods, or to abstain from heterosexual activity throughout the study. Male participants of childbearing potential must agree to use an adequate method of contraception. Exclusion Criteria: Has disease that is suitable for local treatment administered with curative intent. Part 1: Has received prior therapy with cancer vaccines, or compounds targeting PD-1 (including Merck pembrolizumab [MK-3475]), programmed cell death ligand 1 (PD-L1), PD-L2, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), or Mitogen-activated protein kinase (MAPK)/Extracellular signal-regulated Kinase (MEK). Part 2: Has received prior therapy with cancer vaccines, or compounds targeting PD-1 (including Merck pembrolizumab [MK-3475]), PD-L1, PD-L2, CTLA-4, lymphocyte-activation gene 3 (LAG-3), CD-137, OX-40 (tumor necrosis factor receptor superfamily, member 4 [TNFRSF4], also known as CD134), cluster of differentiation 40 (CD-40), glucocorticoid-induced TNFR-related protein (GITR), serine/threonine-protein kinase B-Raf (BRAF), MEK or other molecules in the MAPK pathway. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of study drug. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Has had a prior anticancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or has not recovered (i.e. ≤ Grade 1 or at Baseline) from adverse events (AEs) due to agents administered more than 4 weeks earlier. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 14 days prior to study Day 1 or who has not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to a previously administered agent. Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors within 4 weeks prior to study Day 1. Has a known additional malignancy that is progressing or requires active treatment. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Has a history of interstitial lung disease. Has an active infection requiring systemic therapy. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study. Has a known history of Human Immunodeficiency Virus (HIV). Has known active Hepatitis B or Hepatitis C. Has received a live-virus vaccination within 30 days of planned treatment start. Has had an allogenic tissue/solid organ transplant.

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: MK-8353 BID Continuous+Pembro<br>Participants receive MK-8353 orally (PO) two times each day (BID) on Days 1 through 21 of each 21-day cycle PLUS pembrolizumab (pembro) 200 mg intravenously (IV) on Day 1 of each 21-day cycle for up to 35 cycles. | Drug: MK-8353<br>* PO capsule<br>Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;|
| Experimental: B: MK-8353 QD Continuous+Pembro<br>Participants receive MK-8353 PO once each day (QD) on Days 1 through 21 of each 21-day cycle PLUS pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles. | Drug: MK-8353<br>* PO capsule<br>Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;|
| Experimental: C: MK-8353 QD 1 Week On/1 Week Off+Pembro<br>Optional Arm: Participants receive MK-8353 PO QD on Days 1 to 7, Days 15 to 21 and Days 29 to 35 PLUS pembrolizumab 200 mg IV on Day 1 and Day 22 of each 42-day period (based on 2 cycles of 21 days) for up to 35 cycles. | Drug: MK-8353<br>* PO capsule<br>Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;|
| Experimental: D: MK-8353 QD Run-in→MK-8353 QD Continuous+Pembro<br>Optional Arm: Participants undergo an MK-8353 PO QD run-in period from Day -14 to Day -1 prior to Cycle 1 during which they receive MK-8353 PO QD. After the run-in period, participants receive MK-8353 PO QD on Days 1 through 21 of each 21-day cycle PLUS pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 36 cycles. | Drug: MK-8353<br>* PO capsule<br>Biological: Pembrolizumab<br>* IV infusion<br>* Other names: MK-3475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experience an Adverse Event (AE) |  | Up to 27 months | 
| Percentage of Participants Who Discontinue Study Drug Due to an AE |  | Up to 24 months | 
| Percentage of Participants Who Experience a Dose-limiting Toxicity (DLT) |  | During Cycle 1 (Arms A, B & C: Up to 21 days; Arm D: Up to 35 days) | 

Secondary 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) as Assessed by the Investigator |  | Up to 24 months |