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

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

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.

Study Overview

• Status: Terminated
• Conditions: Neoplasms; Colorectal Cancer
• Intervention / Treatment: Biological: Pembrolizumab; Drug: MK-8353

• Study Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Kirkland, Quebec, Canada, H9H 4M7
      • Merck Canada
• United States
  • Michigan
    • Grand Rapids, Michigan, United States, 49546
      • Call for Information (Investigational Site 0002)
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Call for Information (Investigational Site 0001)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A: MK-8353 BID Continuous+Pembro; 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.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; Drug: MK-8353; PO capsule
Experimental: B: MK-8353 QD Continuous+Pembro; 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.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; Drug: MK-8353; PO capsule
Experimental: C: MK-8353 QD 1 Week On/1 Week Off+Pembro; 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.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; Drug: MK-8353; PO capsule
Experimental: D: MK-8353 QD Run-in→MK-8353 QD Continuous+Pembro; 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.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; Drug: MK-8353; PO capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced an Adverse Event (AE)	Number of participants who experienced an AE was defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study treatment	Up to 27 months
Number of Participants Who Discontinued Study Drug Due to 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 who discontinued treatment due to an AE was assessed.	Up to 24 months
Number of Participants Who Experienced Dose-Limiting Toxicity (DLT)	DLT was defined as a treatment-related adverse event (AE) including the following: Grade (Gr) 4 nonhematologic toxicity (not laboratory), Gr 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia or Gr 4 thrombocytopenia of any duration or Gr 3 thrombocytopenia associated with clinically significant bleeding, Gr 3 non-hematological AE with the exception of fatigue lasting >3 days despite optimal supportive care, any Gr 3 or Gr 4 nonhematologic laboratory value if medical intervention is required to treat the subject, or abnormality leads to hospitalization or abnormality persists for >1 week, Gr 3 or Gr 4 febrile neutropenia, prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity, any treatment-related toxicity that causes the subject to discontinue treatment during Cycle 1, missing >25% of MK-8353 doses as a result of drug-related AE(s) during the first cycle, Gr 5 toxicity.	Cycle 1 (Arms A, B & C: Up to 21 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	ORR was defined as the percentage of the participants in the analysis population who have 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, taking as reference the baseline sum diameters). The ORR per RECIST 1.1 as assessed by Investigator was presented.	Up to 24 months
Percent Change in Cancer Antigen 125 (CA-125)	CA-125 was the tumour biomarker used to test cancer. Disease progression is indicated by CA-125 tumor marker elevation.	Cycle 1-8 Day 1, and end of treatment/ safety follow-up (30 days after the last dose). Each cycle was 21 days.
Percent Change in Carcinoembryonic Antigen (CEA)	CEA was the tumour biomarker used to test cancer. Disease progression is indicated by CEA tumor marker elevation.	Cycle 1-9 Day 1, and end of treatment/ safety follow-up (30 days after the last dose). Each cycle was 21 days
Percent Change in Carbohydrate Antigen (CA19-9)	CA19-9 was the tumour biomarker used to test cancer. Disease progression is indicated by CA19-9 tumor marker elevation	Cycle 1-7 Day 1, and end of treatment/ safety follow-up (30 days after the last dose). Each cycle was 21 days.

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Lakhani NJ, Burris H 3rd, Miller WH Jr, Huang M, Chen LC, Siu LL. A phase 1b study of the ERK inhibitor MK-8353 plus pembrolizumab in patients with advanced solid tumors. Invest New Drugs. 2024 Sep 14. doi: 10.1007/s10637-024-01461-z. Online ahead of print.

Helpful Links

• Merck Oncology Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2017
• Primary Completion (Actual): December 2, 2022
• Study Completion (Actual): December 2, 2022

Study Registration Dates

• First Submitted: November 21, 2016
• First Submitted That Met QC Criteria: November 21, 2016
• First Posted (Estimated): November 23, 2016

Study Record Updates

• Last Update Posted (Actual): November 21, 2024
• Last Update Submitted That Met QC Criteria: November 13, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Neoplasms; Colorectal Neoplasms; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pembrolizumab
• Other Study ID Numbers: 8353-013; MK-8353-013 (Other Identifier: Merck Protocol Number); 2016-003478-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No