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

Sponsor
Peloton Therapeutics, Inc. (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02293980
Collaborator
(none)
110
Enrollment
25
Locations
3
Arms
108.2
Anticipated Duration (Months)
4.4
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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.

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.

Condition or Disease Intervention/Treatment Phase
Phase 1

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.

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 Design

Study Type:
Interventional
Actual Enrollment :
110 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Nov 25, 2014
Actual Primary Completion Date :
Jan 31, 2017
Anticipated Study Completion Date :
Nov 30, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part 1: MK-3475

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
Oral administration
Other Names:
  • PT2385, PT-2385, HIF-2a, MK-3795

    		•
    Experimental: Part 2: MK-3795 + Nivolumab

    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
    Oral administration
    Other Names:
  • PT2385, PT-2385, HIF-2a, MK-3795

    • Drug: Nivolumab
    IV infusion
    Other Names:
  • Opdivo

    		•
    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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Maximum Tolerated Dose (MTD) [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) [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 Outcome Measures

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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Cedars-Sinai Medical Center Los Angeles California United States 90048
    2 University of Colorado Cancer Center Aurora Colorado United States 80045
    3 Yale School of Medicine New Haven Connecticut United States 06510
    4 University of Miami - Sylvester Comprehensive Cancer Center Miami Florida United States 33136
    5 Emory University Winship Cancer Institue Atlanta Georgia United States 30322
    6 Rush University Medical Center Chicago Illinois United States 60612
    7 Indiana University Simon Cancer Center Indianapolis Indiana United States 46202
    8 University of Maryland - Greenebaum Cancer Center Baltimore Maryland United States 21201
    9 Massachusetts General Hospital - Cancer Center Boston Massachusetts United States 02114
    10 Beth Israel Deconess Medical Center Boston Massachusetts United States 02215
    11 Dana-Farber Cancer Institute Boston Massachusetts United States 02215
    12 Barbara Ann Karmanos Cancer Institute Detroit Michigan United States 48201
    13 Mount Sinai Heath System New York New York United States 10019-1147
    14 Cleveland Clinic Cleveland Ohio United States 44195
    15 The Ohio State University Columbus Ohio United States 43210
    16 Fox Chase Cancer Center Philadelphia Pennsylvania United States 19111
    17 University of Pittsburg Medical Center Pittsburgh Pennsylvania United States 15232
    18 The West Clinic Germantown Tennessee United States 38138
    19 Tennessee Oncology Nashville Tennessee United States 37203
    20 Vanderbilt Medical Center Nashville Tennessee United States 37232
    21 UT Southwestern Medical Center Dallas Texas United States 75239
    22 Virginia Cancer Specialists Fairfax Virginia United States 22031
    23 Swedish Cancer Institute Seattle Washington United States 98104
    24 University of Washington Seattle Washington United States 98109
    25 Medical College of Wisconsin Milwaukee Wisconsin United States 53226

    Sponsors and Collaborators

    • Peloton Therapeutics, Inc.

    Investigators

    • Study Director: Medical Director, Merck Sharp & Dohme LLC

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Peloton Therapeutics, Inc.
    ClinicalTrials.gov Identifier:
    NCT02293980
    Other Study ID Numbers:
    • 3795-001
    • PT2385-101
    • MK-3795-001
    First Posted:
    Nov 19, 2014
    Last Update Posted:
    Jul 21, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Renal Cell
    Kidney Neoplasms
    Nivolumab

    Study Results

    No Results Posted as of Jul 21, 2022