Randomized phase II study of 2nd-line FOLFIRI versus modified FOLFIRI with PARP inhibitor ABT-888 (veliparib) (NSC-737664) in metastatic pancreatic cancer (mPC): SWOG S1513.

Abstract

TPS4147 Background: PC is characterized by multiple DNA repair defects, including in BRCA1/ 2, and other homologous recombination (HR) genes such as FANC, ATM, ATR (Waddell N, Nature 2015). Folinic acid/5-fluorouracil/ irinotecan (FOLFIRI) is a 2nd line therapy option in mPC, but overall survival (OS) averages only 6 mos (Yoo C, Br J Cancer 2009). It is known that PARP facilitates repair from topoisomerase 1-associated DNA damage, and that preclinically PARP inhibitors (PARPi) increase DNA breaks from camptothecins, resulting in synergistic antitumor effects (Smith LM, Clin Cancer Res 2005, Davidson D, Invest New Drugs 2013). PARPi are active in mPC harboring BRCA1/2 mutations. Given the preclinical synergism between ABT-888 with irinotecan, and the safety and preliminary efficacy noted in a phase I trial (Berlin J, J Clin Oncol 2014; abstr 2574), we designed a randomized phase II study of mFOLFIRI /ABT-888 vs FOLFIRI alone for 2nd line mPC patients (pts). Blood and tumor samples are collected at baseline to retrospectively analyze biomarkers related to DNA repair capacity, including the HRD assay and BROCA-HR, a targeted multi-gene sequencing to detect alterations within the Fanconi Anemia-BRCA (HR), non-homologous end joining (NHEJ), and DNA mismatch repair pathways, and correlate with efficacy. Methods: Phase II study in 143 pts randomized (1:1) to mFOLFIRI/ABT-888 or FOLFIRI. For optimal PARP inhibition, ABT-888 is dosed Days (D) 1-7 and mFOLFIRI (no 5-FU bolus) D3-5 in 14D-cycles. In the control arm, FOLFIRI is dosed D1-3 in 14D-cycles. Primary endpoint: compare OS between treatment arms; secondary endpoints: safety, progression-free survival, response rates; translational: correlate germline/somatic BRCA1/2 mutations, and other DNA repair biomarkers with efficacy in each arm. Standard eligibility criteria apply. Assuming that the addition of ABT-888 will increase OS from 6 to 9 mos, 128 eligible pts (143 pts total) are required, based on a one-sided type 1 error of 10%, and 80% power. Kaplan-Meier methodology will be used to estimate median OS for each treatment arm. This study is open to accrual (NCT02890355). Clinical trial information: NCT02890355.