A Phase 1, Dose-Escalation Trial of PT2385 Tablets In Patients With Advanced Clear Cell Renal Cell Carcinoma (MK-3795-001)

Study Overview
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Brief Summary
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PART 1: The primary objective of this study is to identify the maximum tolerated dose (MTD) of MK-3795, formerly called PT2385 and/or the recommended Phase 2 dose (RP2D) of MK-3795 in patients with advanced clear cell renal cell carcinoma (ccRCC). PART 2: The primary objective of this study is to identify the MTD of MK-3795 up to the RP2D, in combination with nivolumab, in patients with advanced ccRCC. PART 3: The primary objective of this study is to identify the MTD of MK-3795 up to the RP2D, in combination with cabozantinib tablets, in patients with advanced ccRCC.

Detailed Description
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PART 1: This is a Phase 1, multiple-dose, dose-escalation trial of MK-3795, where patients with advanced ccRCC will be assigned to sequential dose cohorts. Patient safety will be monitored with frequent physical examinations, vital sign measurements, electrocardiograms (ECGs), and hematology and chemistry laboratory studies, and by recording all adverse events (AEs). Blood will be obtained for analysis of the concentration of MK-3795 and to assess biomarkers. PART 2: This is a Phase 1 trial of MK-3795 in combination with nivolumab, where patients with advanced ccRCC will be assigned to dose cohorts. Patient safety will be monitored with frequent physical examinations, vital sign measurements, ECGs, and hematology and chemistry laboratory studies, and by recording all AEs. Blood will be obtained for analysis of the concentration of MK-3795 and to assess biomarkers. PART 3: This is a Phase 1 trial of MK-3795 in combination with cabozantinib tablets, where patients with advanced ccRCC will be assigned to dose cohorts. Patient safety will be monitored with frequent physical examinations, vital sign measurements, ECGs, and hematology and chemistry laboratory studies, and by recording all AEs. Blood will be obtained for analysis of the concentration of MK-3795 and cabozantinb and to assess biomarkers.

Official Title
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A Phase 1, Multiple-Dose, Dose-Escalation Trial of PT2385 Tablets, a HIF-2α Inhibitor, in Patients With Advanced Clear Cell Renal Cell Carcinoma

Conditions
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ccRCC, RCC, Kidney Cancer, Clear Cell Renal Cell Carcinoma, Renal Cell Carcinoma

Intervention / Treatment
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* Drug: MK-3795
* Drug: Nivolumab
* Drug: Cabozantinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria PART 1 Has locally advanced or metastatic ccRCC and has progressed during treatment with at least one prior therapeutic regimen Is of age ≥ 18 years Has a life expectancy of ≥ 3 months Has adequate organ function If a female patient, must be surgically sterile, post-menopausal, or must agree to use physician-approved method of birth control during the study and for a minimum of 30 days after the last study drug administration, or if a male patient with a female partner, must agree to use physician-approved method of birth control during the study and for a minimum of 30 days after the last study drug administration Able to swallow oral medications PART 2 - In addition to PART 1 Received no more than three prior systemic treatment regimens in the advanced or metastatic setting Must have received at least one but not more than two prior anti-angiogenic therapy regimens PART 3 - In addition to PART 1 • Must have received at least one vascular endothelial growth factor receptor (VEGFR) targeting tyrosine kinase inhibitor Exclusion Criteria PART 1 Has a history of untreated brain metastasis or history of leptomeningeal disease or spinal cord compression Has failed to recover from the reversible effects of prior anticancer therapy Has uncontrolled or poorly controlled hypertension Is receiving warfarin anticoagulant therapy or expected to require warfarin Has had any major cardiovascular event within 6 months prior to study drug administration Has any other clinically significant cardiac, respiratory, or other medical or psychiatric condition that might interfere with participation in the trial or interfere with the interpretation of trial results Has had major surgery within 4 weeks before first study drug administration Has known HIV Has an active infection requiring systemic treatment Is participating in another therapeutic clinical trial PART 2 - In addition to PART 1 Has received prior immunotherapy Has any active or recent history of a known or suspected autoimmune disease PART 3 - In addition to PART 1 Gastrointestinal (GI) disorders Any history of congenital long QT syndrome

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: MK-3475<br>Participants with advanced ccRCC receive MK-3475 at an initial dose level of 100mg orally, twice daily (BID) up to approximately 3 weeks. Dose levels will be escalated to identify the maximum tolerated dose (MTD) and/or Recommended Phase 2 Dose (RP2D) for MK-3475. Each escalated dose will be continued for up to approximately 3 weeks before escalating a dose again until a dose limiting toxicity (DLT) is experienced. Thereafter, participants receive RP2D dose of MK-3795 for up to 2 cycles (each cycle length = 28 days) for up to approximately 1 year. Participants may continue to receive MK-3795 beyond 1 year at the discretion of the Sponsor. | Drug: MK-3795<br>* Oral administration<br>* Other names: PT2385, PT-2385, HIF-2a, MK-3795;|
| Experimental: Part 2: MK-3795 + Nivolumab<br>Participants with advanced ccRCC in the expansion phase receive the RP2D of MK-3795 orally in combination with nivolumab 240mg by IV infusion over  60 minutes every 2 weeks for up to approximately 1 year (12 cycles; each cycle length = 28 days) or until unequivocal progression or treatment discontinuation, whichever occurs later. | Drug: MK-3795<br>* Oral administration<br>* Other names: PT2385, PT-2385, HIF-2a, MK-3795;Drug: Nivolumab<br>* IV infusion<br>* Other names: Opdivo;|
| Experimental: Part 3: MK-3795 + Cabozantinib<br>Participants with advanced ccRCC in the expansion phase receive the RP2D of MK-3795 in combination with cabozantinib 20mg up to 60mg orally QD for up to approximately 1 year (12 cycles; each cycle length = 28 days) or until unequivocal progression or treatment discontinuation, whichever occurs later. | Drug: MK-3795<br>* Oral administration<br>* Other names: PT2385, PT-2385, HIF-2a, MK-3795;Drug: Cabozantinib<br>* Oral administration<br>* Other names: Cabometyx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | MTD of MK-3795 will be determined. MTD will be defined as the dose level at which 2 or more participants experience a dose limiting toxicity (DLT) which will be deemed intolerable and the dose level below will be declared the MTD. | Part 1: 3 Weeks, Part 2: 4 Weeks, Part 3: 4 Weeks | 
| Recommended Phase 2 Dose (RP2D) | The RP2D of MK-3795 will be determined. The RP2D will be determined based on the MTD (or the optimal biological dose (OBD) if the MTD is not identified), the overall safety profile with continued treatment, and pharmacokinetic (PK) profile. | Part 1: 3 Weeks; Part 2: 4 Weeks, Part 3: 4 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experience an Adverse Event (AE) | An AE is defined as any untoward medical occurrence in a participant administered a study treatment which did not necessarily have to have a causal relationship with this treatment. An AE could be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The number of participants who experience an AE will be presented. | Up to approximately 9 years | 
| Best Response (BOR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | BOR is the best tumor response recorded up until documentation of progression of disease (PD) or death from any cause, or until the patient withdraws consent. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. | Up to approximately 1 year | 
| Objective Response Rate (ORR) per RECIST 1.1 | ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience a CR or PR based on RECIST 1.1 will be presented. | Up to approximately 1 year | 
| Progression-Free Survival (PFS) per RECIST 1.1 | PFS is defined as the time from the first dose of MK-3795 to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. | Up to approximately 9 years | 
| Duration of Response (DOR) per RECIST 1.1 | For participants who demonstrate a confirmed Complete Response (CR: Disappearance of all target lesions) or confirmed Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The median DOR will be presented. | Up to approximately 1 year | 
| Clinical Benefit Rate (CBR) per RECIST 1.1 | CBR is defined as the percentage of participants who achieve clinical benefit. Clinical benefit is defined as a best response of CR (Disappearance of all target lesions), PR (At least a 30% decrease in the sum of diameters of target lesions) or stable disease (SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD.]). | Up to approximately 1 year | 
| Maximum concentration (Cmax) of Study Treatment | Blood samples will be collected at designated timepoints for the determination of Cmax. Cmax was defined as the maximum concentration of study treatment is reached. | At designated timepoints (up to 106 days) | 
| Time to Maximum Concentration (Tmax) of Study Treatment | Blood samples will be collected at designated timepoints the determination of Tmax. Tmax is defined as the time to the maximum concentration of study treatment reached. | At designated timepoints (up to 106 days) | 
| Terminal half-life (t½λz) of Study Treatment | Blood samples will be collected at designated timepoints for the determination of (t½λz). (t½λz) is defined as the time required for the plasma concentration of study drug to decrease 50% in the final stage of its elimination. | At designated timepoints (up to 106 days) | 
| Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of Study Treatment | Blood samples will be collected at designated timepoints for the determination of AUC0-inf. AUC0-inf is the area under the serum concentration-time curve from time zero to infinity. | At designated timepoints (up to 106 days) | 
| Area Under the Concentration-Time Curve From 0 to Inf Extrapolated (AUC0-inf Extrap) of Study Treatment | Blood samples were collected at designated timepoints for the determination of AUC0-inf extrapolated. AUC0-inf extrapolated is a measure of mean concentration in serum from time zero to infinity. | At designated timepoints (up to 106 days) | 
| Area Under the Concentration-Time Curve From 0 to 12 Hours (AUC0-12) of Study Treatment | Blood samples were collected at designated timepoints for the determination of AUC0-12. AUC0-12 is a measure of mean concentration in serum from time zero to 12 hours. | At designated timepoints (up to 106 days) | 
| Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) of Study Treatment | Blood samples were collected at designated timepoints for the determination of AUC0-last. AUC0-last is a measure of mean concentration in serum from time zero to last measurable concentration. | At designated timepoints (up to 106 days) | 
| Apparent Volume of Distribution (Vz/F) of Study Treatment | Blood samples were collected at designated timepoints for the determination of Vz/F. Vz/F is a the volume of study drug that would need to be uniformly distributed to produce desired serum concentration. F is the fraction of the dose absorbed. | At designated timepoints (up to 106 days) | 
| Apparent Clearance (CL/F) of Study Treatment | Blood samples were collected at designated timepoints for the determination of CL/F. CL/F is a the volume of plasma from which study drug was eliminated per unit time. F is the fraction of the dose absorbed. | At designated timepoints (up to 106 days) | 
| Accumulation Ratio (RAC) | Blood samples were collected at designated timepoints for the determination of RAC. RAC is calculated as AUC0-12 at steady state divided by AUC0-12 after first dose. | At designated timepoints (up to 106 days) | 
| Mean Plasma Concentration of Erythropoietin (EPO) Level | Blood samples will be collected at designated timepoints to measure EPO level. The mean concentration of EPO level will be reported. | At designated timepoints (up to 106 days) | 
| Mean Plasma Concentration of Plasminogen Activator Inhibitor 1 (PAI-1) Level | Blood samples will be collected at designated timepoints to measure PAI-1 level. The mean concentration of PAI-1 level will be reported. | At designated timepoints (up to 106 days) | 
| Mean Plasma Concentration of Insulin Growth Factor Binding Protein 3 (IGFBP3) Level | Blood samples will be collected at designated timepoints to measure IGFBP3 level. The mean concentration of IGFBP3 level will be reported. | At designated timepoints (up to 106 days) | 
| Mean Plasma Concentration of Vascular Endothelial Growth Factor A (VEGFa) Level | Blood samples will be collected at designated timepoints to measure VEGFa level. The mean concentration of VEGFa level will be reported. | At designated timepoints (up to 106 days) | 
| Percent Change from Baseline in the EPO Level | Blood samples will be collected at designated timepoints to measure EPO level. The percent change from baseline in EPO level up to approximately Week 16 will be reported. | Baseline and up to approximately Week 16 | 
| Percent Change from Baseline in the PAI-1 Level | Blood samples will be collected at designated timepoints to measure PAI-1 level. The percent change from baseline in PAI-1 level up to approximately Week 16 will be reported. | Baseline and up to approximately Week 16 | 
| Percent Change from Baseline in the IGFBP3 Level | Blood samples will be collected at designated timepoints to measure IGFBP3 level. The percent change from baseline in IGFBP3 level up to approximately Week 16 will be reported. | Baseline and up to approximately Week 16 | 
| Percent Change from Baseline in the VEGFa | Blood samples will be collected at designated timepoints to measure VEGFa level. The percent change from baseline in VEGFa level up to approximately Week 16 will be reported. | Baseline and up to approximately Week 16 | 
| Antitumor Activity | Antitumor activity will be assessed by non-contrast or contrast computerized tomography (CT) or magnetic resonance imaging (MRI) at baseline, during Week 6, and every 9 weeks thereafter up to approximately 1 year. | Baseline, at Week 6 and every 9 Weeks thereafter up to approximately 1 year |