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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Microsatellite Stable Colorectal Cancer

Intervention / Treatment
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* Drug: grapiprant
* Drug: grapiprant and pembrolizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Cohort 1 to be enrolled before Cohort 2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Single Agent run-in with grapiprant and then combination treatment of grapiprant and pembrolizumab. | Drug: grapiprant<br>* 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.<br>* Other names: IK-007;Drug: grapiprant and pembrolizumab<br>* Cohort 2 will be administered 21-day combination treatment cycles of oral grapiprant in combination with IV pembrolizumab.<br>* Other names: IK-007;|
| Experimental: Cohort 2<br>Participants will be treated with grapiprant in combination with pembrolizumab. | Drug: grapiprant and pembrolizumab<br>* Cohort 2 will be administered 21-day combination treatment cycles of oral grapiprant in combination with IV pembrolizumab.<br>* Other names: IK-007;|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Keynote-878, ARY-007, Immuno-Oncology, checkpoint inhibitor, EP4, IK-007