A Study of Pembrolizumab and Olaparib for People With Metastatic Pancreatic Ductal Adenocarcinoma and Homologous Recombination Deficiency or Exceptional Treatment Response to Platinum-Based Therapy

Inclusion Criteria

• •1. This is an on-platinum maintenance trial either in a first-line or second-line setting.
• •Participants must have either stable disease or responding disease on current first-line or second-line platinum treatment for metastatic disease.
• •2. Male or female patients with cytologically or histologically confirmed metastatic pancreas adenocarcinoma or acinar cell carcinoma with homologous recombination gene alterations or platinum sensitivity.
• •Patients will be assigned to cohorts based on their genetic alterations and clinical response.
• •Patient stratification to different Cohorts will be in the order of more canonical homologous recombination-gene (HR-gene) order. For example, patients who meet criteria for both A and B Cohorts, they will be assigned to Cohort A, not B. Cohorts will be defined as following by CLIA-approved NGS or MSK-IMPACT Part A or C:
• •* Cohort A: Patients with either pathogenic germline or somatic alterations of 3 core HR-genes (BRCA1/2, or PALB2) who have stable or responding disease on first-line or second-line platinum therapy in two consecutive imaging assessments over at least 4 months or 16 weeks are eligible for inclusion in Cohort A.
• •* Cohort B: Patients with either pathogenic somatic or germline non-core 15 HR-gene alterations (ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, MUTYH, NBN, RAD50, RAD51, RAD51C, RTEL1) who have stable or responding disease on first-line or second-line platinum therapy in two consecutive imaging assessments over at least 4 months are eligible for inclusion in Cohort B.
• •* Cohort C: Patients without any of the above HR-gene alterations included in Cohort A and B who have platinum-sensitivity, which is defined as a partial response (PR) or complete response (CR) for the best overall response (BOR) during at least 4 months on platinum-based therapy. Variants of unknown significance of candidate HR-genes from Cohort A or B will be eligible for Cohort C if they meet the partial response to platinum criterion.
• •* Variants of unknown significance (VUS) or benign polymorphisms of above 17 HR-genes from Cohort A and B are considered non-pathogenic and will be excluded from cohort A or B. However, if the participant demonstrates platinum sensitivity, patient can be considered eligible for Cohort C.
• •4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 .
• •5. Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined as below:
• •* Absolute neutrophil count (ANC) ≥1500/μL
• •* Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
• •* Platelets ≥100 000/μL
• •* Total bilirubin ≤ 2 × ULN
• •* AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for if liver metastases)
• •* Creatinine ≤2 × ULN
• •6. Patients with measurable disease and/or non-measurable or no evidence of disease assessed at baseline by CT (or MRI where CT is contraindicated) are eligible.
• •7. Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test. Postmenopausal is defined as:
• •* Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments
• •* Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the postmenopausal range for women under 50
• •* Radiation-induced oophorectomy with last menses \>1 year ago
• •* Chemotherapy-induced menopause with \>1-year interval since last menses
• •* Surgical sterilization (bilateral oophorectomy or hysterectomy)
• •4. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML.
• •5. Previous allogeneic bone marrow transplant.
• •6. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required for eligibility. The patient can receive a stable dose of corticosteroids before and during the study as long as the steroids were started at least 4 weeks prior to treatment and the steroid dose is \< 10 mg/day. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
• •7. Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• •8. 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.
• •9. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).
• •10. Patients with known active hepatitis (i.e. Hepatitis B or C).
• •1. Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.
• •2. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• •3. Has a known history of active TB (Bacillus tuberculosis).
• •11. Any prior treatment with any PARP inhibitor, including olaparib.
• •12. Any previous treatment with any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• •13. Has received systemic therapy 2 weeks prior to starting treatment