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.
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.
