Clinical trial NCT02972034: Study of MK-8353 in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Malignancies (MK-8353-013)
Official title: A Phase Ib Study to Evaluate the Safety and Tolerability of MK-8353 in Combination With Pembrolizumab in Patients With Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Neoplasms
Colorectal Cancer
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2016-11-23
Enrollment: 111
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to 27 months
measure: Number of Participants Who Discontinued Study Drug Due to an Adverse Event (AE)
timeFrame: Up to 24 months
measure: Number of Participants Who Experienced Dose-Limiting Toxicity (DLT)
timeFrame: Cycle 1 (Arms A, B & C: Up to 21 days)
Secondary outcomes:
measure: Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by the Investigator
timeFrame: Up to 24 months
measure: Percent Change in Cancer Antigen 125 (CA-125)
timeFrame: Cycle 1-8 Day 1, and end of treatment/ safety follow-up (30 days after the last dose). Each cycle was 21 days.
measure: Percent Change in Carcinoembryonic Antigen (CEA)
timeFrame: Cycle 1-9 Day 1, and end of treatment/ safety follow-up (30 days after the last dose). Each cycle was 21 days
measure: Percent Change in Carbohydrate Antigen (CA19-9)
timeFrame: Cycle 1-7 Day 1, and end of treatment/ safety follow-up (30 days after the last dose). Each cycle was 21 days.
Other outcomes:
Locations:
city: Grand Rapids
country: United States
facility: Call for Information (Investigational Site 0002)
state: Michigan
city: Nashville
country: United States
facility: Call for Information (Investigational Site 0001)
state: Tennessee
city: Kirkland
country: Canada
facility: Merck Canada
state: Quebec
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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 Oct;42(5):581-589. doi: 10.1007/s10637-024-01461-z. Epub 2024 Sep 14.