Clinical trial NCT03658772: Grapiprant and Pembrolizumab in Patients With Advanced or Progressive MSS Colorectal Cancer
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Microsatellite Stable Colorectal Cancer
Keywords: Keynote-878
ARY-007
Immuno-Oncology
checkpoint inhibitor
EP4
IK-007
Lead sponsor: Arrys Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2018-09-05
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Cohort 1 to be enrolled before Cohort 2
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Safety and tolerability of grapiprant alone and in combination with pembrolizumab
timeFrame: Up to 90 days after the end of treatment (average of 7 months)
measure: Define the recommended phase 2 dose (RP2D) of grapiprant combined with pembrolizumab
timeFrame: Through Cycle 1 (21 days)
Secondary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 7 months
measure: Duration of Response (DOR)
timeFrame: 7 months
measure: Progression -free survival (PFS)
timeFrame: Up to 12 months
measure: Disease control rate (DCR)
timeFrame: 7 months
measure: Overall survival (OS)
timeFrame: Up to 2 years from start of study drug.
measure: Duration of treatment (DOT)
timeFrame: 7 months
measure: Serum tumor marker changes
timeFrame: 7 months
measure: Pharmacodynamic immune effects in paired tumor biopsies
timeFrame: predose through cycle 3 (each cycle is 21 days)
measure: PGEM as a pharmacodynamic and predictive biomarker
timeFrame: PreScreening through 7 months
measure: PK of grapiprant: Tmax
timeFrame: 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: PK of grapiprant: AUC0 last
timeFrame: 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: Plasma decay half-life (t1/2)
timeFrame: 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: Apparent oral clearance (CL/F)
timeFrame: 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: Peak to trough ratio
timeFrame: 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: Observed accumulation ratio
timeFrame: 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)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Cancer Center - Scottsdale
state: Arizona
city: Aurora
country: United States
facility: University of Colorado Denver-Anschutz Medical Campus
state: Colorado
city: Nashville
country: United States
facility: Sarah Cannon Research Institute, LLC (SCRI)
state: Tennessee
city: San Antonio
country: United States
facility: New Experimental Therapeutics of San Antonio-NEXT Oncology
state: Texas
Study officials:
affiliation: Ikena Oncology
name: Sergio Santillana, MD
role: STUDY_DIRECTOR
affiliation: Ikena Oncology
name: Sergio Santillana, MD
role: STUDY_CHAIR
References:
citation: 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.