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

Renal Cell Carcinoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02293980
• Other study ID #: 3795-001
• Secondary ID: PT2385-101MK-379
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: November 25, 2014
• Est. completion date: November 30, 2026

Study information

• Verified date: May 2024
• Source: Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 110
• Est. completion date: November 30, 2026
• Est. primary completion date: January 31, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• ccRCC
• Clear Cell Renal Cell Carcinoma
• Kidney Cancer
• Kidney Neoplasms
• RCC
• Renal Cell Carcinoma

Intervention

Drug:
• MK-3795
Oral administration
• Nivolumab
IV infusion
• Cabozantinib
Oral administration
• Bezlutifan
Oral administration

Locations

Country	Name	City	State
United States	Emory University Winship Cancer Institue	Atlanta	Georgia
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	University of Maryland - Greenebaum Cancer Center	Baltimore	Maryland
United States	Beth Israel Deconess Medical Center	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital - Cancer Center	Boston	Massachusetts
United States	Rush University Medical Center	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	The Ohio State University	Columbus	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Virginia Cancer Specialists	Fairfax	Virginia
United States	The West Clinic	Germantown	Tennessee
United States	Indiana University Simon Cancer Center	Indianapolis	Indiana
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of Miami - Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Tennessee Oncology	Nashville	Tennessee
United States	Vanderbilt Medical Center	Nashville	Tennessee
United States	Yale School of Medicine	New Haven	Connecticut
United States	Mount Sinai Heath System	New York	New York
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	University of Pittsburg Medical Center	Pittsburgh	Pennsylvania
United States	Swedish Cancer Institute	Seattle	Washington
United States	University of Washington	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	Terminal half-life (t½?z) of Study Treatment	Blood samples will be collected at designated timepoints for the determination of (t½?z). (t½?z) 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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Merck Clinical Trials Information