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

• ClinicalTrials.gov Identifier: NCT03658772
• Recruitment Status: Active, not recruiting
• First Posted: September 5, 2018
• Last Update Posted: April 22, 2022
• Sponsor: Arrys Therapeutics
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Arrys Therapeutics

Study Description

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 54 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: June 1, 2022
• Estimated Study Completion Date: September 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; Single Agent run-in with grapiprant and then combination treatment of grapiprant and pembrolizumab.	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 Names: ARYS-007; IK-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; IK-007
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; IK-007

Outcome Measures

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

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 (DOR) [ 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 participants 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 ]
   Time of duration on treatment
7. Serum tumor marker changes [ Time Frame: 7 months ]
   Assess changes in serum tumor markers including but not limited to carcinoembryonic antigen (CEA), when appropriate (eg. CA-19.9, CA125, and lactate dehyrogenase (LDH)) with disease response.
8. 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
9. PGEM as a pharmacodynamic and predictive biomarker [ Time Frame: PreScreening through 7 months ]
   Evaluate disease response in all evaluable participants and in those with a positive initial assessment of Urine prostaglandin E2 metabolite (PGEM)
10. PK 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
11. 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)
12. 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
13. 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
14. 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
15. 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.

Eligibility Criteria

• 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.
• Able to swallow and absorb oral tablets.

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 and aspirin products within 3 days (preferably 7 days) before treatment initiation or at anytime during the study unless used for management of AE.
• History of severe hypersensitivity reactions to chimeric or humanized antibodies
• Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to treatment, or 5 half-lives, whichever is shorter.
• 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 active 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.

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic Cancer Center - Scottsdale

Phoenix, Arizona, United States, 85054

United States, Colorado

University of Colorado Denver-Anschutz Medical Campus

Aurora, Colorado, United States, 80045

United States, Tennessee

Sarah Cannon Research Institute, LLC (SCRI)

Nashville, Tennessee, United States, 37203

United States, Texas

New Experimental Therapeutics of San Antonio-NEXT Oncology

San Antonio, Texas, United States, 78240

Sponsors and Collaborators

Arrys Therapeutics

Merck Sharp & Dohme LLC

Investigators

• Study Director: Sergio Santillana, MD; Ikena Oncology
• Study Chair: Sergio Santillana, MD; Ikena Oncology

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Wang D, Cabalag CS, Clemons NJ, DuBois RN. Cyclooxygenases and Prostaglandins in Tumor Immunology and Microenvironment of Gastrointestinal Cancer. Gastroenterology. 2021 Dec;161(6):1813-1829. doi: 10.1053/j.gastro.2021.09.059. Epub 2021 Oct 2.

• Responsible Party: Arrys Therapeutics
• ClinicalTrials.gov Identifier: NCT03658772
• Other Study ID Numbers: ARYS-001; Keynote-878 ( Other Identifier: Merck Sharp & Dohme Corp. )
• First Posted: September 5, 2018
• Last Update Posted: April 22, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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; IK-007

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action