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

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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

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.

Condition or disease Intervention/treatment Phase
Microsatellite Stable Colorectal Cancer Drug: grapiprant Drug: grapiprant and pembrolizumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 53 participants
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
Official Title: 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)
Actual Study Start Date : September 20, 2018
Estimated Primary Completion Date : August 2020
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.

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

Experimental: Cohort 2
Participants will be treated with grapiprant in combination with pembrolizumab.
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




Primary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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)

  5. 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

  6. 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

  7. 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

  8. 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.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: 7 months ]
    Proportion of participants who achieved PR or better during the study per RECIST 1.1

  2. Duration of Response (DR) [ Time Frame: 7 months ]
    Time when criteria for response are met, to the first documentation of relapse or progression

  3. Progression -free survival (PFS) [ Time Frame: Up to 12 months ]
    Participants who discontinue treatment without disease progression

  4. Disease control rate (DCR) [ Time Frame: 7 months ]
    Percentage of partipcants who achieved a CR, PR and stable disease

  5. 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.

  6. Duration of treatment (DOT) [ Time Frame: 7 months ]
    Disease response for time of duration on treatment

  7. 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



Information from the National Library of Medicine

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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

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.

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): NCT03658772


Contacts
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Contact: Janine McDermott 781-392-5556 Janine.mcdermott@arrystherapeutics.com

Locations
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United States, Arizona
Mayo Clinic Cancer Center - Scottsdale Recruiting
Phoenix, Arizona, United States, 85054
Contact: Mayo Clinical Trials Office    855-776-0015      
United States, Colorado
University of Colorado Denver-Anschutz Medical Campus Recruiting
Aurora, Colorado, United States, 80045
Contact: Elizabeth Freas       elizabeth.freas@ucdenver.edu   
United States, Tennessee
Sarah Cannon Research Institute, LLC (SCRI) Recruiting
Nashville, Tennessee, United States, 37203
Contact: Lisa Morris       Lisa.MorrisLaperriere@SarahCannon.com   
United States, Texas
New Experimental Therapeutics of San Antonio-NEXT Oncology Recruiting
San Antonio, Texas, United States, 78240
Contact: Sarah Gomez       sgomez@nextsat.com   
Sponsors and Collaborators
Arrys Therapeutics
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Jeffrey Ecsedy Arrys Therapeutics
Study Director: Jason Sager, MD Arrys Therapeutics

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Responsible Party: Arrys Therapeutics
ClinicalTrials.gov Identifier: NCT03658772     History of Changes
Other Study ID Numbers: ARYS-001
Keynote-878 ( Other Identifier: Merck Sharp & Dohme Corp. )
First Posted: September 5, 2018    Key Record Dates
Last Update Posted: November 1, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Arrys Therapeutics:
Keynote-878
ARY-007
Immuno-Oncology
checkpoint inhibitor
EP4
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Colonic Diseases
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents