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

• ClinicalTrials.gov Identifier: NCT02972034
• Recruitment Status: Active, not recruiting
• First Posted: November 23, 2016
• Last Update Posted: December 17, 2020
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Neoplasms; Colorectal Cancer	Drug: MK-8353; Biological: Pembrolizumab	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 182 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib Study to Evaluate the Safety and Tolerability of MK-8353 in Combination With Pembrolizumab in Patients With Advanced Malignancies
• Actual Study Start Date: January 13, 2017
• Estimated Primary Completion Date: September 30, 2022
• Estimated Study Completion Date: September 30, 2022

Arms and Interventions

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.	Drug: MK-8353; PO capsule; Biological: Pembrolizumab; IV infusion; Other Name: MK-3475
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.	Drug: MK-8353; PO capsule; Biological: Pembrolizumab; IV infusion; Other Name: MK-3475
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.	Drug: MK-8353; PO capsule; Biological: Pembrolizumab; IV infusion; Other Name: MK-3475
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.	Drug: MK-8353; PO capsule; Biological: Pembrolizumab; IV infusion; Other Name: MK-3475

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as Assessed by the Investigator [ Time Frame: Up to 24 months ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Michigan

Call for Information (Investigational Site 0002)

Grand Rapids, Michigan, United States, 49546

United States, Tennessee

Call for Information (Investigational Site 0001)

Nashville, Tennessee, United States, 37203

Canada, Quebec

Merck Canada

Kirkland, Quebec, Canada, H9H 4M7

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

More Information

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02972034
• Other Study ID Numbers: 8353-013; 2016-003478-42 ( EudraCT Number ); MK-8353-013 ( Other Identifier: Merck Protocol Number )
• First Posted: November 23, 2016
• Last Update Posted: December 17, 2020
• Last Verified: December 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents