Study of MK-0472 in Participants With Advanced/Metastatic Solid Tumors (MK-0472-001)

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy, safety, and tolerability of MK-0472 administered as monotherapy and in combination with pembrolizumab (MK-3475) in participants with histologically or cytologically confirmed diagnosis of advanced/metastatic solid tumors. There is no primary hypothesis to be tested for this study.

Official Title
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A Phase 1/1b Open-label, Multicenter Clinical Study of MK-0472 as Monotherapy and Combination Therapy in Participants With Advanced/Metastatic Solid Tumors.

Conditions
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Metastatic Solid Tumors, Advanced Solid Tumors

Intervention / Treatment
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* Drug: MK-0472
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The main inclusion criteria include but are not limited to the following: Histologically or cytologically confirmed advanced/metastatic solid tumor by pathology report with oncogenic receptor tyrosine kinase (RTK) pathway alterations confirmed by a historical report or local testing and have received, or been intolerant to, all available treatment known to confer clinical benefit Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening Participants with human immunodeficiency virus (HIV) infection must have well controlled HIV on stable (>4 weeks) antiretroviral therapy (ART) Exclusion Criteria: The main exclusion criteria include but are not limited to the following: Has not recovered to common terminology criteria for adverse events (CTCAE) Grade 1 or better from any adverse events that were due to cancer therapeutics administered more than 4 weeks earlier. Participants receiving ongoing replacement hormone therapy for endocrine immune-related AEs will not be excluded from participation in this study Has history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years History of hyperparathyroidism or hypercalcemia Has one or more of the following ophthalmological findings/conditions: a) Intraocular pressure >21 mm Hg and/or any diagnosis of glaucoma b) Diagnosis of central serous retinopathy, retinal vein occlusion, or retinal artery occlusion and c) Diagnosis of retinal degenerative disease Has clinically significant cardiovascular disease Bullous exfoliative skin disorders of any grade Known hypersensitivity to MK-0472 or pembrolizumab, or any of their excipients Received therapy with a proton-pump inhibitor or an H2 histamine blocker receptor antagonist within 7 days before the first scheduled day of study dosing Has discontinued prior therapy with an anti-programmed cell death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-programmed death-ligand 2 (PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor due to an adverse event Received prior systemic anticancer therapy including investigational agents within 4 weeks before first dose Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication Has known additional malignancy that is progressing or has required active treatment within the past 2 years Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable for at least 4 weeks as confirmed by repeat imaging performed during the study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention Has active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy Has history of pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Has active infection requiring systemic therapy Has history of allogeneic tissue/solid organ transplant Have not adequately recovered from major surgery or have ongoing surgical complications

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-0472<br>Participants receive MK-0472 capsule up to 300 mg orally once daily (QD) until disease progression or withdrawal/discontinuation. | Drug: MK-0472<br>* Oral Administration<br>|
| Experimental: MK-0472 + Pembrolizumab<br>Participants receive MK-0472 capsule up to 300 mg orally QD until disease progression or withdrawal/discontinuation plus pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles (up to approximately 2 years). | Drug: MK-0472<br>* Oral Administration<br>Biological: Pembrolizumab<br>* 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 Who Experience a Dose Limiting Toxicity (DLT) as Assessed Using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | DLT will be defined as any drug-related AE observed during the DLT evaluation period (e.g. Cycle 1) that results in a change to a given dose or a delay in initiating the next cycle. | At the end of Cycle 1 (each cycle is 21 days) | 
| Number of Participants Who Experience One or More Adverse Events (AEs) | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who experience one or more AE's will be reported. | Up to approximately 56 months | 
| Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The number of participants who discontinue study treatment due to an AE will be reported. | Up to approximately 56 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration Time-curve From Time 0 to the Last Quantifiable Concentration (AUC0-t) of MK-0472 | Blood samples will be collected at specified intervals for the determination of AUC0-t. AUC0-t is defined as the area under concentration-time curve from 0 to last quantifiable concentration. | Cycle 1 Day 1; Cycle 2 Day 1: Predose and 1, 2, 4, and 8 hours postdose; Cycles 1, 2: Days 2, 15: Predose (Each cycle length = 21 days) | 
| Lowest Plasma Concentration (Ctrough) of MK-0472 | Blood samples will be collected at specified intervals for the determination of Ctrough. Ctrough is defined as the lowest concentration of MK-0472 reached before the next dose is administered. | Cycles 2-6, and every third cycle up to Cycle 81: Day 1: Predose (Each cycle length = 21 days) | 
| Maximum Serum Concentration (Cmax) of MK-0472 | Blood samples will be collected at specified intervals for the determination of Cmax. Cmax is defined as the maximum concentration of MK-0472 reached. | Cycle 1 Day 1; Cycle 2 Day 1: 1, 2, 4, and 8 hours postdose (Each cycle length = 21 days) | 

 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 Death-Ligand 1 (PDL1, PD-L1), Src Homology-2 Domain Containing Protein Tyrosine Phosphatase-2 (SHP-2)