Paclitaxel, Pembrolizumab, and Olaparib for the Treatment of Previously Treated Advanced Stomach Cancer

Inclusion Criteria

• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Advanced histologically-confirmed gastric or gastro-esophageal junction adenocarcinoma
• Patients must have received and progressed on only one prior line of systemic therapy for advanced disease * Prior therapy must include a fluoropyrimidine and platinum-based regimen * Adjuvant/neoadjuvant chemotherapy may be considered as a prior regimen, if recurrence or metastatic disease developed within 6 months of completion
• Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
• Patient agreeable to a biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator)
• Life expectancy of greater than 3 months
• Leukocytes >= 3,000/mm^3
• Absolute neutrophil count >= 1,500/mm^3
• Platelets >= 100,000/mm^3
• Hemoglobin >= 8 g/dL
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< upper limit of normal (ULN) if total bilirubin > 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN
• Creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 30 mL/min (if using the Cockcroft-Gault formula)
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment
• A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
• Patient understands the study regimen, its requirements, risks and discomforts and is able and willing to sign the informed consent form in accordance with regulatory and institutional guidelines must be obtained before the performance of any protocol related procedures that are not part of normal patient care. Subjects must be competent to report adverse events (AEs), understand the drug dosing schedule and use of medications to control AEs.

Exclusion Criteria

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically and clinically stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and without requirement of steroids for at least 14 days prior to first dose of study treatment
• Is expected to require any other form of systemic or localized antineoplastic therapy while on study
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• Has received prior therapy with paclitaxel or PARP inhibitor. Previous paclitaxel may be allowed if no progression on or within 6 months of receiving this drug
• History of severe hypersensitivity reaction to paclitaxel, pembrolizumab or related compounds and/or to any of their components
• Allergy to dexamethasone, diphenhydramine and famotidine
• Is taking a moderate or strong CYP3A inhibitor
• Has uncontrolled intercurrent acute or chronic medical illness
• Has a known additional malignancy that is progressing and has required active treatment within the past 1 year. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or other cancers that have undergone potentially curative therapy are not excluded
• Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks prior to study treatment * Note: Participants must have recovered from all AEs due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible * Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist) are live attenuated vaccines and are not allowed
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
• Has active autoimmune disease. Subjects with Graves or Hashimoto’s disease, vitiligo, type I diabetes mellitus, psoriasis or other conditions not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects requiring systemic treatment for autoimmune disease in the past may be approved by the principal investigator
• 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
• Prior tissue or organ allograft regardless of need for immunosuppression, including corneal allograft. Exceptions can be approved by the principal investigator if loss of the graft is not a clinical concern. Patients with history of allogeneic bone marrow transplantation will be excluded
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Requirement for daily supplemental oxygen
• Patients with a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has a confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
• Has a known history of human immunodeficiency virus (HIV)
• Has active hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or hepatitis C virus (defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection. Patients who are hepatitis C antibody positive and viral load negative will be permitted to enroll
• Has uncontrolled infection requiring systemic therapy
• Subjects unable to undergo venipuncture and/or tolerate venous access
• Has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to study drug initiation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In the case of a positive human chorionic gonadotropin (HCG) test, a transvaginal ultrasound must be used to confirm lack of pregnancy