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

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

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.As of Amendment 09 (29 Mar 2024), participants with advanced ccRCC will transition from MK-3795 to belzutifan (MK-6482) in combination with nivolumab or belzutifan alone.

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Kidney Cancer; Renal Cell Carcinoma; Clear Cell Renal Cell Carcinoma; ccRCC; RCC
• Intervention / Treatment: Drug: MK-3795; Drug: Nivolumab; Drug: Cabozantinib; Drug: Bezlutifan

Detailed Description

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. As of Amendment 09 (29 Mar 2024), participants with advanced ccRCC will transition from MK-3795 to belzutifan in combination with nivolumab or belzutifan alone.

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.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cancer Center
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale School of Medicine
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami - Sylvester Comprehensive Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Winship Cancer Institue
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Simon Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland - Greenebaum Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital - Cancer Center
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deconess Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • New York
    • New York, New York, United States, 10019-1147
      • Mount Sinai Heath System
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburg Medical Center
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • The West Clinic
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Medical Center
  • Texas
    • Dallas, Texas, United States, 75239
      • UT Southwestern Medical Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute
    • Seattle, Washington, United States, 98109
      • University of Washington
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

PART 1

• Has locally advanced or metastatic clear cell renal cell carcinoma (ccRCC) and has progressed during treatment with at least one prior therapeutic regimen
• Has a life expectancy of ≥ 3 months
• Has adequate organ function
• 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 human immunodeficiency virus (HIV) infection
• 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

• Has gastrointestinal (GI) disorders
• Has any history of congenital long QT syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 3: MK-3795 + Cabozantinib; 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; Oral administration; Other Names: PT2385, PT-2385, HIF-2a, MK-3795; Drug: Cabozantinib; Oral administration; Other Names: Cabometyx
Experimental: Part 1: MK-3795; Participants with advanced ccRCC receive MK-3795 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-3795. 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; Oral administration; Other Names: PT2385, PT-2385, HIF-2a, MK-3795
Experimental: Part 2: MK-3795 + Nivolumab + Belzutifan; 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 ~1 year (12 cycles; each cycle length = 28 days) or until unequivocal progression or treatment discontinuation, whichever occurs later. As per Amendment 09 (29 March 2024), participants will not receive MK-3795. Participants receive nivolumab 240mg by IV infusion over ~60 minutes every 2 weeks in combination with belzutifan 120 mg once daily (QD) for up to ~1 year (12 cycles; each cycle length = 28 days) or until unequivocal progression or treatment discontinuation, whichever occurs later. If participants experience an adverse event, then nivolumab will be discontinued and participants will continue to receive belzutifan 120 mg QD alone for up to ~1 year (12 cycles; each cycle length = 28 days) or until unequivocal progression or treatment discontinuation, whichever occurs later.	Drug: MK-3795; Oral administration; Other Names: PT2385, PT-2385, HIF-2a, MK-3795; Drug: Nivolumab; IV infusion; Other Names: Opdivo; Drug: Bezlutifan; Oral administration; Other Names: MK-6482

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Courtney KD, Infante JR, Lam ET, Figlin RA, Rini BI, Brugarolas J, Zojwalla NJ, Lowe AM, Wang K, Wallace EM, Josey JA, Choueiri TK. Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2alpha Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol. 2018 Mar 20;36(9):867-874. doi: 10.1200/JCO.2017.74.2627. Epub 2017 Dec 19.

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2014
• Primary Completion (Actual): January 31, 2017
• Study Completion (Estimated): November 30, 2024

Study Registration Dates

• First Submitted: November 14, 2014
• First Submitted That Met QC Criteria: November 18, 2014
• First Posted (Estimated): November 19, 2014

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: 3795-001; PT2385-101 (Other Identifier: Peloton Study ID); MK-3795-001 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf