Pembrolizumab, Olaparib, Recurrent/Advanced Gastric and Gastro-esophageal Junction(GEJ) Cancer With HRR Mutation and MSS

Study Overview
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Brief Summary
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Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Olaparib is a potent PARP inhibitor (PARP1, 2, and 3) that is being developed as a monotherapy as well as for combination with chemotherapy, ionizing radiation, and other anti-cancer agents including novel agents and immunotherapy. Paclitaxel is widely used in breast, lung and gastric cancer with every 3-week or weekly cycle. Various targeted anticancer agents have been investigated with paclitaxel and combination with ramucirumab, a monoclonal anti-VEGFR2 antibody, was approved as a 2nd line treatment.

Official Title
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An Open Label, Single-Arm, Multi-center Phase Ib/II Study to Evaluate the Efficacy of Paclitaxel in Combination With Pembrolizumab and Olaparib as a Second Line Treatment in Recurrent/Advanced Gastric and Gastro-esophageal Junction(GEJ) Cancer With Homologous Recombination Repair (HRR) Mutation and Microsatellite Stable (MSS).

Conditions
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Gastric Cancer Stage IV

Intervention / Treatment
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* Drug: olaparib+pembrolizumab+paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provided written informed consent for treatment. Age ≥ 19 years old measurable or evaluable disease based on RECIST 1.1. Lesions tumors with NGS evidence of somatic HRR mutations (harbor known or suspected deleterious mutations in BRCA1, BRCA2, ATM, or other HRR-genes: BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L) and MSS stauts (detected by IHC: MLH1, MSH2, MSH6, PMS2 or Promega PCR kit) Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 on time of patient's allocation. Adequate organ function as defined by the following criteria: A life expectancy of at least 3 months Is able to swallow and retain orally administered medications Failed first-line trastuzumab treatment for HER2 positive patients Highly effective contraception for both male and female subjects if the risk of conception exists. Left ventricular ejection fraction (LVEF) ≥50% Exclusion Criteria: A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation Has received 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 (eg, CTLA-4, OX 40, CD137) Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks prior to allocation. Has 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 drug. Is currently participating in or has participated in a study of an investigational agent including trastuzumab or has used an investigational device within 4 weeks prior to the first dose of study treatment. Has a 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 to the first dose of study drug. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Has known active CNS metastases and/or carcinomatous meningitis. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, PARP inhibitor and paclitaxel. Has active autoimmune disease that has required systemic treatment in the past 2 years Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Has an active infection requiring systemic therapy. Has a known history of Human Immunodeficiency Virus (HIV). Has an active of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive and HBV titer >2000 IU/ml) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. Has an active TB (Bacillus Tuberculosis) with treatment. Participant has received previous allogenic bone-marrow, tissue/solid organ transplant or double umbilical cord transplantation (dUCBT).

Ages Eligible for Study
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Minimum Age: 19 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: olaparib+pembrolizumab+paclitaxel<br> | Drug: olaparib+pembrolizumab+paclitaxel<br>* olaparib, 100 200mg, PO, bid, continuous pembrolizumab 200mg, IV, q 3 weeks paclitaxel 175g/m2 IV, q 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression free survival |  | 6 weeks | 
| dose limiting toxicity |  | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate |  | 6 weeks |