Clinical trial NCT02293980: A Phase 1, Dose-Escalation Trial of PT2385 Tablets In Patients With Advanced Clear Cell Renal Cell Carcinoma (MK-3795-001)
Official title: A Phase 1, Multiple-Dose, Dose-Escalation Trial of PT2385 Tablets, a HIF-2α Inhibitor, in Patients With Advanced Clear Cell Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: ccRCC
RCC
Kidney Cancer
Clear Cell Renal Cell Carcinoma
Renal Cell Carcinoma
Lead sponsor: Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2014-11-19
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: Part 1: 3 Weeks, Part 2: 4 Weeks, Part 3: 4 Weeks
measure: Recommended Phase 2 Dose (RP2D)
timeFrame: Part 1: 3 Weeks; Part 2: 4 Weeks, Part 3: 4 Weeks
Secondary outcomes:
measure: Number of Participants Who Experience an Adverse Event (AE)
timeFrame: Up to approximately 9 years
measure: Best Response (BOR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)
timeFrame: Up to approximately 1 year
measure: Objective Response Rate (ORR) per RECIST 1.1
timeFrame: Up to approximately 1 year
measure: Progression-Free Survival (PFS) per RECIST 1.1
timeFrame: Up to approximately 9 years
measure: Duration of Response (DOR) per RECIST 1.1
timeFrame: Up to approximately 1 year
measure: Clinical Benefit Rate (CBR) per RECIST 1.1
timeFrame: Up to approximately 1 year
measure: Maximum concentration (Cmax) of Study Treatment
timeFrame: At designated timepoints (up to 106 days)
measure: Time to Maximum Concentration (Tmax) of Study Treatment
timeFrame: At designated timepoints (up to 106 days)
measure: Terminal half-life (t½λz) of Study Treatment
timeFrame: At designated timepoints (up to 106 days)
measure: Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of Study Treatment
timeFrame: At designated timepoints (up to 106 days)
measure: Area Under the Concentration-Time Curve From 0 to Inf Extrapolated (AUC0-inf Extrap) of Study Treatment
timeFrame: At designated timepoints (up to 106 days)
measure: Area Under the Concentration-Time Curve From 0 to 12 Hours (AUC0-12) of Study Treatment
timeFrame: At designated timepoints (up to 106 days)
measure: Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) of Study Treatment
timeFrame: At designated timepoints (up to 106 days)
measure: Apparent Volume of Distribution (Vz/F) of Study Treatment
timeFrame: At designated timepoints (up to 106 days)
measure: Apparent Clearance (CL/F) of Study Treatment
timeFrame: At designated timepoints (up to 106 days)
measure: Accumulation Ratio (RAC)
timeFrame: At designated timepoints (up to 106 days)
measure: Mean Plasma Concentration of Erythropoietin (EPO) Level
timeFrame: At designated timepoints (up to 106 days)
measure: Mean Plasma Concentration of Plasminogen Activator Inhibitor 1 (PAI-1) Level
timeFrame: At designated timepoints (up to 106 days)
measure: Mean Plasma Concentration of Insulin Growth Factor Binding Protein 3 (IGFBP3) Level
timeFrame: At designated timepoints (up to 106 days)
measure: Mean Plasma Concentration of Vascular Endothelial Growth Factor A (VEGFa) Level
timeFrame: At designated timepoints (up to 106 days)
measure: Percent Change from Baseline in the EPO Level
timeFrame: Baseline and up to approximately Week 16
measure: Percent Change from Baseline in the PAI-1 Level
timeFrame: Baseline and up to approximately Week 16
measure: Percent Change from Baseline in the IGFBP3 Level
timeFrame: Baseline and up to approximately Week 16
measure: Percent Change from Baseline in the VEGFa
timeFrame: Baseline and up to approximately Week 16
measure: Antitumor Activity
timeFrame: Baseline, at Week 6 and every 9 Weeks thereafter up to approximately 1 year
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Miami
country: United States
facility: University of Miami - Sylvester Comprehensive Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University Winship Cancer Institue
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Simon Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland - Greenebaum Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital - Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: New York
country: United States
facility: Mount Sinai Heath System
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburg Medical Center
state: Pennsylvania
city: Germantown
country: United States
facility: The West Clinic
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Medical Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.