A Study of MK-6598 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Advanced Solid Tumors (MK-6598-001)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety and establish a preliminary recommended Phase 2 dose (RP2D) of MK-6598 administered as monotherapy and in combination with pembrolizumab (MK-3475) in adult participants with advanced or metastatic solid tumors.

Official Title
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A Phase 1, Open-label, Multicenter Study to Assess Safety, Tolerability, PK, and Efficacy of MK-6598 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced Solid Tumors

Conditions
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Advanced or Metastatic Solid Tumors

Intervention / Treatment
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* Drug: MK-6598
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and has received, or been intolerant to, all treatment known to confer clinical benefit. Has measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by the local site investigator/radiology. Has one or more discrete malignant lesions that are amenable to a minimum of 2 separate biopsies. Has a baseline tumor sample that can be submitted for analysis. Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART). A participant assigned male sex at birth who receives MK-6598 must agree to use contraception and should refrain from donating sperm during the specified period(s) of at least 102 days after study interventions. A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding and at least 1 of the following: not a participant of childbearing potential (POCBP) or a POCBP who agrees to follow the contraceptive guidance during the treatment period and for up to 120 days after study intervention. Exclusion Criteria: Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention or has not recovered to CTCAE Version 5.0 Grade 1 or better from any AEs that were due to cancer therapeutics administered more than 4 weeks earlier (this includes participants with previous immunomodulatory therapy with residual immune-related AEs). Known additional malignancy that is progressing or has required active treatment within 2 years. Clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis. A severe hypersensitivity (≥Grade 3) reaction to treatment with a monoclonal antibody/components of the study intervention. Active infection requiring therapy. History of interstitial lung disease. History of (noninfectious) pneumonitis that required steroids or current pneumonitis. Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed. Has known hepatitis B or C infections or known to be positive for hepatitis B surface antigen (HBsAg)/hepatitis B virus (HBV) deoxyribonucleic acid (DNA) or hepatitis C antibody or ribonucleic acid (RNA). Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. Received prior radiotherapy within 2 weeks of start of study intervention, has radiation-related toxicities requiring corticosteroids, or had a history of radiation pneumonitis. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137), and was discontinued from that treatment due to a ≥Grade 3 immune-related AE (irAE). Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the start of study treatment. Has had an allogeneic tissue/solid organ transplant in the last 5 years or has evidence of graft-versus-host disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-6598<br>Participants will receive MK-6598 daily (QD) at escalating dose levels from 50-500 mg for up to a total of 35 cycles (up to approximately 24 months). | Drug: MK-6598<br>* Oral tablet<br>|
| Experimental: MK-6598 + Pembrolizumab<br>Participants will receive MK-6598 QD at escalating dose levels from 50-500, plus pembrolizumab 200 mg once every 21-day cycle for up to 35 cycles (up to approximately 24 months). | Drug: MK-6598<br>* Oral tablet<br>Biological: Pembrolizumab<br>* Intravenous (IV) infusion<br>* Other names: Keytruda®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with a Dose-Limiting Toxicity (DLT) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) Version 5.0 | DLT is defined as any of the following toxicities, unless assessed by the investigator to be clearly due to the underlying disease or extraneous causes: Grade (Gr) 4 nonhematologic toxicity (not laboratory); Gr 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia; Gr 4 thrombocytopenia of any duration; Gr 3 thrombocytopenia associated with clinically significant bleeding; Gr 4 anemia regardless of duration; Nonhematologic AE Gr ≥3 in severity, with exceptions; Any Gr 3 or 4 nonhematologic lab abnormality if clinically significant medical intervention is required, or if leads to hospitalization, persists for >72 hours or results in drug-induced liver injury with exceptions; Gr 3 or 4 febrile neutropenia; Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity; Treatment-related toxicity resulting in study treatment discontinuation during Cycle 1 (C1); Missing >25% of MK-6598 doses as a result of treatment-related AE during C1; Gr 5 toxicity. | Up to approximately 21 days | 
| Number of Participants Who Experience At Least One 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 experienced an AE will be reported. | Up to approximately 27 months | 
| Number of Participants Who Discontinue Study Treatment Due to an 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 study treatment due to an AE will be reported. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) of MK-6598 | Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine AUC. | Days 1, 8, and 15 of Cycle 1: predose, postdose at 30 minutes (min), 45 min, 60 min, 2 hours (hrs), 6 hrs; Days 2 and 9 of Cycle 1: predose; Day 1 of Cycles 2, 5, 10, 15, 20, 25, 30, and 35: predose | 
| Minimum Serum Concentration (Cmin) of MK-6598 | Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmin | Days 1, 8, and 15 of Cycle 1: predose, postdose at 30 min, 45 min, 60 min, 2 hrs, 6 hrs; Days 2 and 9 of Cycle 1: predose; Day 1 of Cycles 2, 5, 10, 15, 20, 25, 30, and 35: predose | 
| Maximum Serum Concentration (Cmax) of MK-6598 | Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax. | Days 1, 8, and 15 of Cycle 1: predose, postdose at 30 min, 45 min, 60 min, 2 hrs, 6 hrs; Days 2 and 9 of Cycle 1: predose; Day 1 of Cycles 2, 5, 10, 15, 20, 25, 30, and 35: predose | 
| Tumor Phenylpyruvate Concentrations | Blood samples pre-dose and at multiple timepoints post-dose will be used to determine tumor phenylpyruvate concentrations. | Days 1, 8, and 15 of Cycle 1: predose, postdose at 30 min, 45 min, 60 min, 2 hrs, 6 hrs; Days 2 and 9 of Cycle 1: predose; Day 1 of Cycles 2, 5, 10, 15, 20, 25, 30, and 35: predose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Programmed Cell Death-1 (PD1, PD-1), Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)