Abstract P6-15-01: A Phase 1b Study To Assess the Safety and Tolerability of the PARP Inhibitor Iniparib (BSI-201) in Combination with Irinotecan for the Treatment of Patients with Metastatic Breast Cancer (MBC)

Abstract

Abstract Background: Inhibition of poly (ADP-ribose) polymerase-1 (PARP1), a key regulator of DNA repair and cell proliferation, potentiates the anti-tumor activity of DNA-damaging chemotherapy agents, including irinotecan, a topoisomerase inhibitor (Ossovskaya et al. AACR 2009). Combination of gemcitabine and carboplatin with the PARP inhibitor iniparib has demonstrated promising efficacy and safety in patients with triple-negative MBC (O'Shaughnessy et al. SABCS 2009). Single agent irinotecan is active in heavily pre-treated metastatic breast cancer (MBC), with response rates (RR) up to 23% (Perez et al. JCO 2004;22:2849). A Phase 1 dose-escalation study of iniparib in advanced solid tumors showed no dose-limiting toxicities (DLTs) at iniparib doses of 0.5 to 8.0 mg/kg (Kopetz et al. ASCO 2008). That study was expanded here to determine the maximum-tolerated dose (MTD) of irinotecan that can be used in combination with fixed dose iniparib in patients with locally advanced or MBC. Methods: Patients were treated with a 3+3 study design to determine safety of iniparib (8 mg/kg IV twice-weekly on Days 1, 4, 8, and 11 every 21 days) in combination with escalating doses of irinotecan (80 — 125 mg/m2 IV on Days 1 and 8 every 21 days). RRs were measured per modified RECIST criteria. Serial pharmacokinetic (PK) assessments were performed during Cycle 1, and archived paraffin-embedded tumor samples were collected to correlate markers of hypoxia (CAIX) with PARP1 expression (as measured by immunohistochemistry [IHC]) and response. Results: The median age of 34 patients who received therapy was 50 years (range, 32-84), and the median number of prior therapies was 2 (range, 0-6). Preliminary analysis show that tumors from 22 (65%) patients were ER-/PR-/HER2- (triple-negative), 10 (29%) were ER+/HER2-, and 1 (3%) was HER2+. One DLT of Grade 3 diarrhea with lower GI bleed was observed, thus establishing the optimal regimen from this study at 8 mg/kg iniparib + 125 mg/m2 irinotecan. Other toxicities included neutropenia, anemia and diarrhea. Of 26 patients evaluable for response, 5 (19%) had partial response (PR), 10 (38%) had stable disease (SD) for >4 cycles of therapy, and 9 (35%) developed progressive disease (PD) as best response. Of 10 patients who had reached 6 cycles at time of analysis, 5 (50%) had SD. Median follow-up time was 11 weeks. PK and IHC evaluations are ongoing and will be presented, along with mature response data. Conclusions: An MTD of 8 mg/kg iniparib and 125 mg/m2 irinotecan was identified in patients with MBC. Iniparib in combination with irinotecan was well tolerated and showed promising efficacy, with evidence of clinical benefit (RR + SD ≥6 cycles) in 50% in patients with treatment-refractory MBC. (ClinicalTrials.gov number, NCT00298675) Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-01.