Non-small Cell Lung Cancer Adenocarcinoma
Conditions
Brief summary
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.
Interventions
Participants will be administered 21-day cycles of oral grapiprant in combination with IV pembrolizumab
Sponsors
Merck Sharp & Dohme LLC
Arrys Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability of grapiprant in combination with pembrolizumab | 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 | Through Cycle 1 (21 days) | Number, incidence and severity of treatment related adverse events as assessed by CTCAE 5.0 |
| Objective response rate (ORR) | 7 months | Proportion of participants who achieved PR or better during the study per RECIST 1.1 and iRECIST |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease control rate (DCR) | 7 months | Percentage of patients who have achieved CR, PR and stable disease |
| Duration of response (DoR) | Up to 12 months | Time from documentation of tumor response to disease progression per RECIST and iRECIST 1.1 |
| PK of grapiprant: AUC | 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 | 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 |
| Progression-free survival (PFS) | Up to 12 months | Participants who discontinue treatment without disease progression |
| Apparent oral clearance (CL/F) | 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 | 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 | 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 | 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 |
| Plasma decay half-life (t1/2) | 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 |
| Overall survival (OS) | 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) | 7 months | Disease response for time of duration on treatment |
Countries
United States
Outcome results
None listed