A Phase 1 Study to Evaluate the Safety, Tolerability and Efficacy of MK-8353 Combination Therapies in Subjects With Advanced Solid Tumors

Recruitment & Eligibility

Status: Pending

Sex: Not specified

Target Recruitment: 24

Inclusion Criteria

1. Be willing and able to provide written informed consent for the trial.
2. Have one of the following pathologically/histologically confirmed cancer types to be
eligible for each study arm:;a. Arm A: metastatic CRC with a KRAS mutation in their tumor sample,
progressed during or within 6 months of the last dose of a prior chemotherapy,
and FOLFIRI treatment is indicated in the opinion of the investigator;;•* Subjects must agree to provide archival tumor tissue sample or newly
obtained tumor biopsy sample if archived tissue is unavailable for
analysis of KRAS mutation to determine eligibility.;b. Arms B & C: any advanced solid tumor (metastatic or locally advanced
disease) that has failed to respond to curative therapy, progressed despite
curative therapy, or for which curative therapy is not available.;•* For Arm C: a subset of subjects enrolled at the maximum tolerated
dose (MTD) must have either NRAS/BRAF mutant melanoma or
KRAS mutant NSCLC. In this subset, subjects must agree to provide
archival tumor tissue sample or newly obtained tumor biopsy sample if
archived tissue is unavailable for analysis of KRAS/NRAS/BRAF
mutation to determine eligibility.;3. Have at least one measurable lesion, as defined by Response Evaluation Criteria in
Solid Tumors (RECIST v1.1). If the subject has received radiation therapy, at least
one measurable lesion must be outside the area of radiation, or at least one
measurable lesion must be progressing inside the area of radiation.;4. Be able to swallow, retain, and absorb oral medications and oral nutrition.;5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.;6. Demonstrate adequate organ function as defined by the following table, all screening
labs should be performed within one-two weeks of treatment initiation. Be able to adhere to dose and visit schedules.;8. Each female subject of childbearing potential must have a negative urine or serum
pregnancy test. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required. The serum pregnancy test must be negative
for the subject to be eligible.;9. Each female subject who is not free from menses for >2 years, post hysterectomy /
oophorectomy, or surgically sterilized, must be willing to use either 2 adequate
barrier methods or a barrier method plus a hormonal method of contraception to
prevent pregnancy or to abstain from heterosexual activity throughout the study,
starting with Visit 1 through 90 days after the last dose of study therapy. Approved
contraceptive methods include, for example: intra uterine device, diaphragm with
spermicide, cervical cap with spermicide, male condoms, or female condom with
spermicide. Spermicides alone are not an acceptable method of contraception.
Each male subject must agree to use an adequate method of contraception or abstain
from heterosexual intercourse with a partner who could become pregnant starting
with the first dose of study drug through 90 days after the last dose of study therapy.

Exclusion Criteria

• Has unstable or progressing central nervous system (CNS) metastasis. Subjects with known CNS metastasis may be included if the subject is asymptomatic for 1 month with no requirement for steroids or antiseizure medications.
• Has active gastrointestinal disease or a disorder or a history of surgery that significantly alters gastrointestinal motility or absorption in the opinion of the investigator.
• Has received ERK inhibitors for the disease under study.
• For Arm A: The subject has a known dihydropyrimindine dehydrogenase (DPD) deficiency or known UGT1A1*28 polymorphism.
• For Arm C:
- The subject has received prior therapy with an anti-PD-1 or anti PD-L1 antibody.
- The subject has an active autoimmune disease or a documented history of autoimmune disease, except vitiligo or resolved childhood asthma/atopy
- The subject is on chronic systemic steroid therapy or on any other form of immunosuppressive medication.
• Has a known hypersensitivity to MK-8353, irinotecan (Arm A), leucovorin (Arm A), 5-FU (Arm A), MK-8669 (Arm B), MK-3475 or any other mAb (Arm C) or their components.
• Has received any treatment more recently than the indicated washout period prior to the start of treatment with MK-8353 combinations, or must continue to receive any treatment listed in the exclusion medication list during the current trial.
• Has clinically relevant cardiovascular, hepatic, neurologic, endocrine, or other major systemic diseases that would make implementation of the protocol difficult.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>The goal of this study is to evaluate the safety, tolerability and PK<br /><br>parameters of MK-8353 in combination with three different anti-cancer agents (3<br /><br>arms of combinations). The dose escalation and confirmation of the MTD will be<br /><br>done using a design based on Toxicity Probability Interval (TPI) for each arm<br /><br>of this study.</p><br>

Secondary Outcome Measures