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

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

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.

Study Overview

• Status: Terminated
• Conditions: Non-small Cell Lung Cancer Adenocarcinoma
• Intervention / Treatment: Drug: grapiprant and pembrolizumab

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
    • Grand Rapids, Michigan, United States, 49546
      • START Midwest
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Abramson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: grapiprant and pembrolizumab combination; Participants will be treated with grapiprant in combination with pembrolizumab.	Drug: grapiprant and pembrolizumab; Participants will be administered 21-day cycles of oral grapiprant in combination with IV pembrolizumab; Other Names: MK-3475; ARYS-007; IK-007; KEYNOTE-888

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)
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)

Collaborators and Investigators

• Sponsor: Arrys Therapeutics
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Study Director: Jason Sager, MD, Arrys Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2019
• Primary Completion (Actual): February 15, 2021
• Study Completion (Actual): February 15, 2021

Study Registration Dates

• First Submitted: October 3, 2018
• First Submitted That Met QC Criteria: October 3, 2018
• First Posted (Actual): October 4, 2018

Study Record Updates

• Last Update Posted (Actual): February 21, 2021
• Last Update Submitted That Met QC Criteria: February 19, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: ARYS-002; KEYNOTE-888 (Other Identifier: MERCK)

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