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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 2020

Interventions

  • Drug: grapiprant and pembrolizumab
    • Participants will be administered 21-day cycles of oral grapiprant in combination with IV pembrolizumab

Arms, Groups and Cohorts

  • Experimental: grapiprant and pembrolizumab combination
    • Participants will be treated with grapiprant in combination with pembrolizumab.

Clinical Trial Outcome Measures

Primary Measures

  • Safety and tolerability of grapiprant in combination with pembrolizumab
    • Time Frame: Up to 90 days after the end of treatment (average of 7 months)
    • Number of incidence, severity, relationship, concomitant medications administered, and duration of treatment emergent adverse events using CTCAE v5.0
  • 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
  • Objective response rate (ORR)
    • Time Frame: 7 months
    • Proportion of participants who achieved PR or better during the study per RECIST 1.1 and iRECIST

Secondary Measures

  • Progression-free survival (PFS)
    • Time Frame: Up to 12 months
    • Participants who discontinue treatment without disease progression
  • 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
  • Duration of treatment (DoT)
    • Time Frame: 7 months
    • Disease response for time of duration on treatment
  • Disease control rate (DCR)
    • Time Frame: 7 months
    • Percentage of patients who have achieved CR, PR and stable disease
  • Duration of response (DoR)
    • Time Frame: Up to 12 months
    • Time from documentation of tumor response to disease progression per RECIST and iRECIST 1.1
  • PK of grapiprant: AUC
    • Time Frame: 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
  • PK of grapiprant: Cmax
    • Time Frame: 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 serum concentration of grapiprant
  • Plasma decay half-life (t1/2)
    • Time Frame: 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
  • Apparent oral clearance (CL/F)
    • Time Frame: 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
  • Peak to trough ratio
    • Time Frame: 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
  • Observed accumulation ratio
    • Time Frame: 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
  • Pharmacodynamic immune effects in paired tumor biopsies
    • Time Frame: Predose through cycle 3 (each cycle is 21 days)
    • Asses changes in tumor infiltrating helper T cells, cytoxic T cells and regulatory monocyte/macrophages with study treatment

Participating in This Clinical Trial

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

Key Exclusion Criteria:

  • Current use of NSAIDs, COX-2 inhibitors
  • Known epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS gene alteration, BRAF gene mutation
  • 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
  • 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, Hepatitis B, or active Hepatitis C virus infection
  • Clinically significant (i.e.active) cardiovascular disease

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Arrys Therapeutics
  • Collaborator
    • Merck Sharp & Dohme Corp.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Jeffrey Ecsedy, Study Director, Arrys Therapeutics
    • Jason Sager, MD, Study Director, Arrys Therapeutics
  • Overall Contact(s)
    • Janine McDermott, MS, 781-392-5556, janine.mcdermott@arrystherapeutics.com

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