Phase Ib Trial Of Cisplatin (C), Gemcitabine (G), And Veliparib (V) In Patients With Known Or Potential Brca Or Palb2-Mutated Pancreas Adenocarcinoma (Pc).

4023 Background: 5% to 8% PC have BRCA 1,2 mutations; higher in Ashkenazi Jewish with PC (10-15%). Pre-clinical data demonstrates that DNA-damaging drugs (C) and poly-ADP ribose polymerase inhibitors (PARPi) have significant activity in BRCA mut PC models. This trial evaluates the optimal dose of V with fixed doses of C and G in PC. Methods: Primary endpoints: Determination of dose-limiting toxicity (DLT) and Recommended Phase II Dose (RP2D), safety (NCI CTCAE 4.0). Secondary endpoints: RECIST 1.1 response rate (RR), duration of response, progression-free survival, overall survival and correlatives involving tumor biopsies to evaluate mechanisms of sensitivity, resistance to platinum and PARPi. Eligibility: Untreated BRCA, PALB2 mut PC or strong personal/family history of pancreas or BRCA-related malignancy; measurable stage III/IV PC; ECOG 0-1. Treatment Plan: C 25mg/m2 IV, G 600mg/m2 IV, both d3, 10, q 3 weeks and V PO BID day 1- X. Results: Between 02/12– 10/13, N= 33 screened, 17 enrolled. Male = 10, Female = 7. Median age = 60 years (range 42- 72). BRCA = 9. Non-BRCA = 8. Four dose levels of V evaluated; 2 DLT’s at V 80 mg PO BID continuous dosing (Table). Grade 3-4 toxicities: Anemia, neutropenia, thrombocytopenia, fatigue. 1 fatal bowel perforation tumor/diverticulitis*. For N= 9 BRCA patients: 5 (56%) partial responses (PR), 4 (44%) stable disease. For N= 8 non-BRCA: 5 stable, 2 progression. N= 5 BRCA patients continue on study and 7 of 9 BRCA patients are alive. Tissue analyses on BRCA subset will be presented. Conclusions: The RP2D of veliparib is 80 mg PO BID day 1-12 q 3 weeks with fixed dose C + G. Main grade 3-4 toxicities are hematologic, fatigue. The combination of C, G + V shows high activity in BRCA mut PC. A randomized phase II trial evaluating C, G +/- V is underway in BRCA/PALB2 mut PC (NCT01585805). Funding and acknowledgements: National Cancer Institute CTEP, Lustgarten Foundation, AbbVie. Clinical trial information: NCT01585805. Veliparib PO BID N DLT BRCA subgroup 20 mg, day 1-12 3 - N= 2, 1 PR, 1 SD* 40 mg, day 1-12 3 - N= 1, 1 PR 80 mg, day 1-12 6 - N= 5, 2 PR, 3 SD 80 mg, day 1-21 5 2 (grade 4 platelets, ANC) N= 1, 1 PR