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NCT Number: NCT02293980

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

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.

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Key information

Conditions

ccRCC Adenocarcinoma Carcinoma Carcinoma, Renal Cell Clear Cell Renal Cell Carcinoma Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Kidney Cancer Kidney Diseases Kidney Neoplasms Male Urogenital Diseases Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Glandular and Epithelial RCC Renal Cell Carcinoma Urogenital Diseases Urogenital Neoplasms Urologic Diseases Urologic Neoplasms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Cedars-Sinai Medical Center, Los Angeles, California, United States

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

MK-3795

Drug

Oral administration

Other names: PT2385, PT-2385, HIF-2a, MK-3795

Nivolumab

Drug

IV infusion

Other names: Opdivo

Cabozantinib

Drug

Oral administration

Other names: Cabometyx

Bezlutifan

Drug

Oral administration

Other names: MK-6482

Primary outcomes

  1. Maximum Tolerated Dose (MTD)

    Time frame: Part 1: 3 Weeks, Part 2: 4 Weeks, Part 3: 4 Weeks

    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.

  2. Recommended Phase 2 Dose (RP2D)

    Time frame: Part 1: 3 Weeks; Part 2: 4 Weeks, Part 3: 4 Weeks

    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.

Secondary outcomes

  1. Number of Participants Who Experience an Adverse Event (AE)

    Time frame: Up to approximately 9 years

    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.

  2. Best Response (BOR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1)

    Time frame: Up to approximately 1 year

    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.

  3. Objective Response Rate (ORR) per RECIST 1.1

    Time frame: Up to approximately 1 year

    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.

  4. Progression-Free Survival (PFS) per RECIST 1.1

    Time frame: Up to approximately 9 years

    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.

  5. Duration of Response (DOR) per RECIST 1.1

    Time frame: Up to approximately 1 year

    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.

  6. Clinical Benefit Rate (CBR) per RECIST 1.1

    Time frame: Up to approximately 1 year

    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.]).

  7. Maximum concentration (Cmax) of Study Treatment

    Time frame: At designated timepoints (up to 106 days)

    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.

  8. Time to Maximum Concentration (Tmax) of Study Treatment

    Time frame: At designated timepoints (up to 106 days)

    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.

  9. Terminal half-life (t½λz) of Study Treatment

    Time frame: At designated timepoints (up to 106 days)

    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.

  10. Area Under the Concentration-Time Curve From 0 to Infinity (AUC0-inf) of Study Treatment

    Time frame: At designated timepoints (up to 106 days)

    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.

  11. Area Under the Concentration-Time Curve From 0 to Inf Extrapolated (AUC0-inf Extrap) of Study Treatment

    Time frame: At designated timepoints (up to 106 days)

    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.

  12. Area Under the Concentration-Time Curve From 0 to 12 Hours (AUC0-12) of Study Treatment

    Time frame: At designated timepoints (up to 106 days)

    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.

  13. Area Under the Plasma Concentration-time Curve From Time 0 to Last (AUC0-last) of Study Treatment

    Time frame: At designated timepoints (up to 106 days)

    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.

  14. Apparent Volume of Distribution (Vz/F) of Study Treatment

    Time frame: At designated timepoints (up to 106 days)

    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.

  15. Apparent Clearance (CL/F) of Study Treatment

    Time frame: At designated timepoints (up to 106 days)

    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.

  16. Accumulation Ratio (RAC)

    Time frame: At designated timepoints (up to 106 days)

    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.

  17. Mean Plasma Concentration of Erythropoietin (EPO) Level

    Time frame: At designated timepoints (up to 106 days)

    Blood samples will be collected at designated timepoints to measure EPO level. The mean concentration of EPO level will be reported.

  18. Mean Plasma Concentration of Plasminogen Activator Inhibitor 1 (PAI-1) Level

    Time frame: At designated timepoints (up to 106 days)

    Blood samples will be collected at designated timepoints to measure PAI-1 level. The mean concentration of PAI-1 level will be reported.

  19. Mean Plasma Concentration of Insulin Growth Factor Binding Protein 3 (IGFBP3) Level

    Time frame: At designated timepoints (up to 106 days)

    Blood samples will be collected at designated timepoints to measure IGFBP3 level. The mean concentration of IGFBP3 level will be reported.

  20. Mean Plasma Concentration of Vascular Endothelial Growth Factor A (VEGFa) Level

    Time frame: At designated timepoints (up to 106 days)

    Blood samples will be collected at designated timepoints to measure VEGFa level. The mean concentration of VEGFa level will be reported.

  21. Percent Change from Baseline in the EPO Level

    Time frame: Baseline and up to approximately Week 16

    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.

  22. Percent Change from Baseline in the PAI-1 Level

    Time frame: Baseline and up to approximately Week 16

    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.

  23. Percent Change from Baseline in the IGFBP3 Level

    Time frame: Baseline and up to approximately Week 16

    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.

  24. Percent Change from Baseline in the VEGFa

    Time frame: Baseline and up to approximately Week 16

    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.

  25. Antitumor Activity

    Time frame: Baseline, at Week 6 and every 9 Weeks thereafter up to approximately 1 year

    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.

Sponsors and collaborators

Lead sponsor

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

Industry

Registry information

Official study 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

Important dates

Study start
2014
Primary completion
2017
Study completion
2026
First posted
Nov 19, 2014
Registry last updated
Jun 17, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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