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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02293980
Recruitment Status : Active, not recruiting
First Posted : November 19, 2014
Last Update Posted : July 21, 2022
Sponsor:
Information provided by (Responsible Party):
Peloton Therapeutics, Inc.

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
ccRCC RCC Kidney Cancer Clear Cell Renal Cell Carcinoma Renal Cell Carcinoma Drug: MK-3795 Drug: Nivolumab Drug: Cabozantinib 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.

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Study Type : Interventional  (Clinical Trial)
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 : November 25, 2014
Actual Primary Completion Date : January 31, 2017
Estimated Study Completion Date : November 30, 2023


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 Name: 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 Name: PT2385, PT-2385, HIF-2a, MK-3795

Drug: Nivolumab
IV infusion
Other Name: 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 Name: PT2385, PT-2385, HIF-2a, MK-3795

Drug: Cabozantinib
Oral administration
Other Name: Cabometyx




Primary Outcome Measures :
  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 Outcome Measures :
  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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02293980


Locations
Show Show 25 study locations
Sponsors and Collaborators
Peloton Therapeutics, Inc.
Investigators
Layout table for investigator information
Study Director: Medical Director Merck Sharp & Dohme LLC
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Peloton Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT02293980    
Other Study ID Numbers: 3795-001
PT2385-101 ( Other Identifier: Peloton Study ID )
MK-3795-001 ( Other Identifier: Merck )
First Posted: November 19, 2014    Key Record Dates
Last Update Posted: July 21, 2022
Last Verified: July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Additional relevant MeSH terms:
Layout table for MeSH terms
Carcinoma
Carcinoma, Renal Cell
Kidney Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action