Grapiprant (ARY-007) and Pembrolizumab in Patients With Advanced or Metastatic Post-PD-1/L1 NSCLC Adenocarcinoma

Study Overview
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Brief Summary
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This study will be conducted in adult participants diagnosed with NSCLC who have been previously treated for a minimum of 12 weeks with any PD-1 or PD-L1 checkpoint inhibitor. This is a phase 1b/2, 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 disease response with grapiprant based on investigator assessments. Pharmacokinetics, pharmacodynamics and response biomarkers will also be assessed.

Official Title
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Open Label, Single Arm, Phase 1b/2 Study to Evaluate the Safety and Efficacy of Grapiprant (ARY-007) in Combination With Pembrolizumab in Patients With Advanced or Metastatic Post-PD-1/L1 Non-Small Cell Lung Cancer (NSCLC) Adenocarcinoma

Conditions
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Non-small Cell Lung Cancer Adenocarcinoma

Intervention / Treatment
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* Drug: grapiprant and pembrolizumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male and female adult patients at least 18 years of age on day of signing informed consent Histologically confirmed non-small cell lung cancer (NSCLC) adenocarcinoma Advanced (stage IIIb) disease that is not amenable to curative intent treatment with concurrent chemoradiation and metastatic (stage IV) patients Progressed clinically and/or radiographically per RECIST v1.1 after receiving a PD-1 or PD-L1 antagonist for a minimum of 12 weeks Measurable disease per RECIST v1.1 Disease that can be safely accessed via bronchoscopic, thoracoscopic or percutaneous biopsy for multiple core biopsies and participant is willing to provide tissue from newly obtain biopsies on study in a subgroup of patients Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Adequate organ function Highly effective birth control Able to swallow and absorb oral tablets Key Exclusion Criteria: Current use of NSAIDs, COX-2 inhibitors Known epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS gene alteration No history of smoking (≤100 cigarettes lifetime) History of severe hypersensitivity reactions to a PD-1/L1 antibody Received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to treatment or 5 half-lives, whichever is shorter Received prior radiotherapy within 2 weeks of start of study treatment Has received a live vaccine within 30 days prior to the first dose of study treatment Taking strong CYP3A4 or P-glycoprotein inhibitors or inducers Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment Known additional malignancy that is progressing or has required active treatment within the past 3 years (with some permitted exceptions) Known active CNS metastases and/or carcinomatous meningitis Active autoimmune disease that has required systemic treatment in past 2 years History of pneumonitis that required steroids or has current pneumonitis Has an active infection requiring systemic therapy Recent or current GI ulcer, colitis or non-immune colitis Known history of human immunodeficiency virus (HIV) infection, or known active Hepatitis B, or Hepatitis C virus infection Has had an allogeneic tissue/solid organ transplant Clinically significant (i.e.active) cardiovascular disease

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: grapiprant and pembrolizumab combination<br>Participants will be treated with grapiprant in combination with pembrolizumab. | Drug: grapiprant and pembrolizumab<br>* Participants will be administered 21-day 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 in combination with pembrolizumab | Number of incidence, severity, relationship, concomitant medications administered, 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) | 
| Objective response rate (ORR) | Proportion of participants who achieved PR or better during the study per RECIST 1.1 and iRECIST | 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Participants who discontinue treatment without disease progression | Up to 12 months | 
| Overall survival (OS) | Date of study drug to date of death due to any cause | Up to 2 years from start of study drug | 
| Duration of treatment (DoT) | Disease response for time of duration on treatment | 7 months | 
| Disease control rate (DCR) | Percentage of patients who have achieved CR, PR and stable disease | 7 months | 
| Duration of response (DoR) | Time from documentation of tumor response to disease progression per RECIST and iRECIST 1.1 | Up to 12 months | 
| PK of grapiprant: AUC | Area under the plasma concentration-time curve | 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: Cmax | Peak serum concentration of grapiprant | 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 | 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 | 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 | 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 | 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). | 
| Pharmacodynamic immune effects in paired tumor biopsies | Asses changes in tumor infiltrating helper T cells, cytoxic T cells and regulatory monocyte/macrophages with study treatment | Predose through cycle 3 (each cycle is 21 days) |