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Grapiprant and Pembrolizumab in Patients With Advanced or Progressive MSS Colorectal Cancer

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03658772
Recruitment Status : Recruiting
First Posted : September 5, 2018
Last Update Posted : November 1, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Arrys Therapeutics

Tracking Information
First Submitted Date  ICMJE August 24, 2018
First Posted Date  ICMJE September 5, 2018
Last Update Posted Date November 1, 2019
Actual Study Start Date  ICMJE September 20, 2018
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 3, 2018)
  • Safety and tolerability of grapiprant alone and in combination with pembrolizumab [ Time Frame: Up to 90 days after the end of treatment (average of 7 months) ]
    Number of incidence, severity, and duration of treatment emergent adverse events using CTCAE v5.0
  • Define the recommended phase 2 dose (RP2D) of grapiprant combined with pembrolizumab [ Time Frame: Through Cycle 1 (21 days) ]
    Number, incidence and severity of treatment related adverse events as assessed by CTCAE 5.0
  • Pharmacokinetics of grapiprant: Tmax [ Time Frame: Safety Run-in (7 days); Days 1 and 2 of first 2 cycles (every 21 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 42 days) through end of treatment (average of 4 months) ]
    First time to reach maximum [peak] observed plasma concentration
  • PK of grapiprant: AUC0-Last [ Time Frame: Safety Run-in (7 days); Days 1 and 2 of first 2 cycles (every 21 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 42 days) through end of treatment (average of 4 months) ]
    Area under the plasma concentration- time curve from time 0 to the end of the dosing interval (AUC0-last)
  • Plasma decay half-life (t1/2) [ Time Frame: Safety Run-in (7 days); Days 1 and 2 of first 2 cycles (every 21 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 42 days) through end of treatment (average of 4 months) ]
    Measurement of half-life of grapiprant after dosing
  • Apparent oral clearance (CL/F) [ Time Frame: Safety Run-in (7 days); Days 1 and 2 of first 2 cycles (every 21 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 42 days) through end of treatment (average of 4 months) ]
    Rate of elimination of the drug from plasma after oral administration inistration
  • Peak to trough ratio [ Time Frame: Safety Run-in (7 days); Days 1 and 2 of first 2 cycles (every 21 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 42 days) through end of treatment (average of 4 months) ]
    Measure how drug effect is sustained over dose interval
  • Observed accumulation ratio [ Time Frame: Safety Run-in (7 days); Days 1 and 2 of first 2 cycles (every 21 days), followed by Day 1 of every even cycle beginning with cycle 4 (every 42 days) through end of treatment (average of 4 months) ]
    Relationship between the dosing interval and the rate of elimination for the drug.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 20, 2018)
  • Overall Response Rate (ORR) [ Time Frame: 7 months ]
    Proportion of participants who achieved PR or better during the study per RECIST 1.1
  • Duration of Response (DR) [ Time Frame: 7 months ]
    Time when criteria for response are met, to the first documentation of relapse or progression
  • Progression -free survival (PFS) [ Time Frame: Up to 12 months ]
    Participants who discontinue treatment without disease progression
  • Disease control rate (DCR) [ Time Frame: 7 months ]
    Percentage of partipcants who achieved a CR, PR and stable disease
  • Overall survival (OS) [ Time Frame: Up to 2 years from start of study drug. ]
    Date of study drug to date of death due to any cause. If no documentation of death at time of the analysis will be censored as of the date last known to be alive, or the data cutoff date, whichever is earlier.
  • Duration of treatment (DOT) [ Time Frame: 7 months ]
    Disease response for time of duration on treatment
  • Pharmacodynamic immune effects in paired tumor biopsies [ Time Frame: predose through cycle 3 (each cycle is 21 days) ]
    Assess changes in tumor infiltrating helper T cells, cytotoxic T cells and regulatory monocyte/macrophages with study drug treatment
Original Secondary Outcome Measures  ICMJE
 (submitted: September 3, 2018)
  • Overall Response Rate (ORR) [ Time Frame: 7 months ]
    Proportion of participants who achieved PR or better during the study per RECIST 1.1
  • Duration of Response (DR) [ Time Frame: 7 months ]
    Time when criteria for response are met, to the first documentation of relapse or progression
  • Progression -free survival (PFS) [ Time Frame: Up to 12 months ]
    Participants who discontinue treatment without disease progression
  • Disease control rate [ Time Frame: 7 months ]
    Percentage of partipcants who achieved a CR, PR and stable disease
  • Overall survival (OS) [ Time Frame: Up to 2 years from start of study drug. ]
    Date of study drug to date of death due to any cause. If no documentation of death at time of the analysis will be censored as of the date last know to be alive, or the data cutoff date, whichever is earlier.
  • Duration of treatment (DOT) [ Time Frame: 7 months ]
    Disease response for time of duration on treatment
  • Pharmacodynamic immune effects in paired tumor biopsies [ Time Frame: predose through cycle 3 (each cycle is 21 days) ]
    Assess changes in tumor infiltrating helper T cells, cytotoxic T cells and regulatory monocyte/macrophages with study drug treatment
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Grapiprant and Pembrolizumab in Patients With Advanced or Progressive MSS Colorectal Cancer
Official Title  ICMJE An Open-label, Single-arm, Phase 1b Study to Evaluate the Safety and Efficacy of Grapiprant (ARY-007) in Combination With Pembolizumab in Patients With Advanced or Progressive Microsatellite Stable (MSS) Colorectal Cancer (CRC)
Brief Summary This study will be conducted in adult participants diagnosed with any form of an advanced or progressive MSS CRC for which 1st and 2nd line standard therapy (at least one of which contained fluorouracil) is no longer effective or is intolerable. This is a phase 1b, multi-center, open label study designed to assess safety and tolerability of grapiprant in combination with pembrolizumab, to determine the recommended phase 2 dose (RP2D) with pembrolizumab, and to evaluate and characterize the PK of grapiprant alone and in combination with pembrolizumab. Disease response, pharmacodynamics, and response biomarkers will also be assessed.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:
Cohort 1 to be enrolled before Cohort 2
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Microsatellite Stable Colorectal Cancer
Intervention  ICMJE
  • Drug: grapiprant
    Cohort 1 will be treated for 1 week with oral grapiprant as a single agent, followed by 21-day combination treatment cycles of oral grapiprant in combination with IV pembrolizumab.
    Other Name: ARYS-007
  • Drug: grapiprant and pembrolizumab
    Cohort 2 will be administered 21-day combination treatment cycles of oral grapiprant in combination with IV pembrolizumab.
    Other Names:
    • ARYS-007, MK3475
    • KEYNOTE-878
Study Arms  ICMJE
  • Experimental: Cohort 1

    Single Agent run-in with grapiprant and Combination treatment of grapiprant and pembrolizumab.

    Dose Escalation with oral grapiprant at 300mg BID, 450mg q12h, 600mg q12h.

    Interventions:
    • Drug: grapiprant
    • Drug: grapiprant and pembrolizumab
  • Experimental: Cohort 2
    Participants will be treated with grapiprant in combination with pembrolizumab.
    Intervention: Drug: grapiprant and pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 3, 2019)
53
Original Estimated Enrollment  ICMJE
 (submitted: September 3, 2018)
25
Estimated Study Completion Date  ICMJE August 2020
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • Male and female adult patients 18 years of age or older on day of signing informed consent.
  • Patients must have a histologically confirmed advanced, metastatic, or progressive Microsatellite Stable (MSS) Colorectal Cancer (CRC) per institutional standards.
  • Patient has received at least two prior lines of therapy for advanced or metastatic CRC, at least one of which included fluorouracil.
  • Highly effective birth control.
  • Measurable disease.
  • Accessible tumor that can be safely accessed for multiple core biopsies and patient is willing to provide tissue from newly obtain biopsies before and during treatment.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  • Adequate organ function.

Key Exclusion Criteria:

  • Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
  • Current use of NSAIDs, COX-2 inhibitors.
  • History of severe hypersensitivity reactions to chimeric or humanized antibodies.
  • Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
  • Known additional malignancy that is progressing or has required active treatment within the past 3 years.
  • Known active CNS metastases and/or carcinomatous meningitis.
  • Active autoimmune disease that has required systemic treatment in past 2 years.
  • History of non-infectious pneumonitis that required steroids or has current pneumonitis.
  • Active infection requiring systemic therapy.
  • Recent (within the last 12 months) or current GI ulcer, colitis or non-immune colitis.
  • Known history of human immunodeficiency virus (HIV) infection, Hepatitis B, or Hepatitis C virus infection.
  • Clinically significant (i.e. active) cardiovascular disease
  • Allogeneic tissue/solid organ transplant
  • Medical conditions requiring concomitant administration of strong CYP3A4 or P glycoprotein inhibitors or inducers.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Janine McDermott 781-392-5556 Janine.mcdermott@arrystherapeutics.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03658772
Other Study ID Numbers  ICMJE ARYS-001
Keynote-878 ( Other Identifier: Merck Sharp & Dohme Corp. )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Arrys Therapeutics
Study Sponsor  ICMJE Arrys Therapeutics
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Study Director: Jeffrey Ecsedy Arrys Therapeutics
Study Director: Jason Sager, MD Arrys Therapeutics
PRS Account Arrys Therapeutics
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP