Background: Talazoparib is the most potent PARP inhibitor in clinical development (IC50 = 0.57 nMol/L). When talazoparib is combined with DNA damaging agents a synergistic effect mediated through enhanced PARP inhibition and PARP trapping is seen. Here we report first in human combination studies of talazoparib with temozolomide (TEM) or irinotecan (IRI) with biomarker correlates of response. Methods: A phase I dose escalation study evaluated escalating doses of talazoparib (? 0.5 mg PO QD) with either TEM (? 25 mg/m2 PO days 1-5) (Arm A) or IRI (? 25 mg/m2 IV q2 weeks) (Arm B) every 28 days in patients with advanced malignancies. In both arms the dose of talazoparib was escalated first up to the single agent maximum tolerated dose (MTD) of 1.0 mg before the dose of chemotherapy was increased. The primary endpoint was the determination of the maximum tolerated dose (MTD), and secondary endpoints included pharmacokinetics, tumor response, and biomarkers. DLTs were assessed during the 1st cycle of each dose level. RECIST version 1.1 assessment was done every 8 weeks. Prior TEM or IRI was permitted. A subset of patients had tumor assessment using next generation sequencing (NGS) to identify genomic aberrations distinct from BRCA mutations. Results: 41 patients received escalating doses (0.5-1.0 mg) of talazoparib and either TEM or IRI: 19 patients in Arm A and 22 in Arm B. Median age was 57 (21-77), all PS were 0 or 1 and the median number of prior chemotherapy regimens was 6 (1-15). The MTD for each arm was talazoparib 1.0 mg and 37.5 mg/m2 for either TEM or IRI. Confirmed partial responses (PR) were seen in 4/7 (57%) germline BRCA wild-type platinum-resistant ovarian cancer patients, and PRs were seen in one patient each with Ewing's Sarcoma, cervical adenocarcinoma, small cell lung cancer and triple negative breast cancer. There was a correlation between response and the presence of deleterious somatic mutations in non-BRCA DNA repair genes (e.g. PALB2, RAD51D, MSH2). In the ovarian patients, Homologous Recombination Deficiency (HRD) scores ?42 was correlated with response. The most common grade 3/4 AE's (?5%) related to the treatment combination talazoparib + TEM were neutropenia (28%), anemia (33%) and thrombocytopenia (33%), and for the combination talazoparib + IRI were thrombocytopenia (13%), anemia (27%) and neutropenia (31%). No significant PK interactions were seen between talazoparib and either TEM or IRI. Conclusions: The combination of talazoparib with either TEM or IRI is generally well tolerated in patients with heavily pre-treated advanced malignancies. Regardless of histology, there was a correlation with the presence of specific genomic alterations (not confined to DNA repair) and a PR by RECIST. These data support further evaluation of talazoparib in combination with TEM or IRI in tumors to evaluate efficacy and safety with a focus on relevant somatic mutations, pathway predictors and/or response/resistance biomarkers.

Citation Format: Zev A. Wainberg, J. Randolph Hecht, Gottfried E. Konecny, Jonathan W. Goldman, Saeed Sadeghi, Bartosz Chmielowski, Arun Singh, Richard S. Finn, Diego Martinez, Lisa Yonemoto, John Glaspy, Dennis J. Slamon. Safety and efficacy results from a phase I dose-escalation trial of the PARP inhibitor talazoparib in combination with either temozolomide or irinotecan in patients with advanced malignancies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT011.