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

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)

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.

Study Overview

• Status: Completed
• Conditions: Microsatellite Stable Colorectal Cancer
• Intervention / Treatment: Drug: grapiprant; Drug: grapiprant and pembrolizumab

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Cancer Center - Scottsdale
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver-Anschutz Medical Campus
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute, LLC (SCRI)
  • Texas
    • San Antonio, Texas, United States, 78240
      • New Experimental Therapeutics of San Antonio-NEXT Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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: IK-007; 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: IK-007; ARYS-007, MK3475; KEYNOTE-878

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of grapiprant alone and in combination with pembrolizumab	Number of incidence, severity, and duration of treatment emergent adverse events using CTCAE v5.0	Up to 90 days after the end of treatment (average of 7 months)
Define the recommended phase 2 dose (RP2D) of grapiprant combined with pembrolizumab	Number, incidence and severity of treatment related adverse events as assessed by CTCAE 5.0	Through Cycle 1 (21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Proportion of participants who achieved PR or better during the study per RECIST 1.1	7 months
Duration of Response (DOR)	Time when criteria for response are met, to the first documentation of relapse or progression	7 months
Progression -free survival (PFS)	Participants who discontinue treatment without disease progression	Up to 12 months
Disease control rate (DCR)	Percentage of participants who achieved a CR, PR and stable disease	7 months
Overall survival (OS)	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.	Up to 2 years from start of study drug.
Duration of treatment (DOT)	Time of duration on treatment	7 months
Serum tumor marker changes	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.	7 months
Pharmacodynamic immune effects in paired tumor biopsies	Assess changes in tumor infiltrating helper T cells, cytotoxic T cells and regulatory monocyte/macrophages with study drug treatment	predose through cycle 3 (each cycle is 21 days)
PGEM as a pharmacodynamic and predictive biomarker	Evaluate disease response in all evaluable participants and in those with a positive initial assessment of Urine prostaglandin E2 metabolite (PGEM)	PreScreening through 7 months
PK of grapiprant: Tmax	First time to reach maximum [peak] observed plasma concentration	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)
PK of grapiprant: AUC0 last	Area under the plasma concentration time curve from time 0 to the end of the dosing interval (AUC0 last)	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).
Plasma decay half-life (t1/2)	Measurement of half-life of grapiprant after dosing	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)
Apparent oral clearance (CL/F)	Rate of elimination of the drug from plasma after oral administration	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)
Peak to trough ratio	Measure how drug effect is sustained over dose interval	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)
Observed accumulation ratio	Relationship between the dosing interval and the rate of elimination for the drug.	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)

Collaborators and Investigators

• Sponsor: Arrys Therapeutics
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Sergio Santillana, MD, Ikena Oncology; Study Chair: Sergio Santillana, MD, Ikena Oncology

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2018
• Primary Completion (Actual): March 7, 2023
• Study Completion (Actual): March 7, 2023

Study Registration Dates

• First Submitted: August 24, 2018
• First Submitted That Met QC Criteria: September 3, 2018
• First Posted (Actual): September 5, 2018

Study Record Updates

• Last Update Posted (Actual): October 24, 2023
• Last Update Submitted That Met QC Criteria: October 23, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: checkpoint inhibitor; Immuno-Oncology; Keynote-878; ARY-007; EP4; IK-007
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: ARYS-001; Keynote-878 (Other Identifier: Merck Sharp & Dohme Corp.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No