Abstract P4-22-21: NCI9782: A phase 1 study of talazoparib in combination with carboplatin and paclitaxel in patients with advanced solid tumors

Abstract

Abstract Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and activated by DNA strand breaks. DNA damage from carboplatin is associated with activation of PARP. Preclinical data indicate that PARP inhibition potentiates the anti-tumor effect of platinum chemotherapy. Talazoparib (T) is an oral, selective PARP inhibitor with a single agent maximum tolerated dose (MTD) of 1mg orally qd. Primary dose-limiting toxicity (DLT) was thrombocytopenia. This phase I study combines T with the commonly used chemotherapy regimen of carboplatin (C) and paclitaxel (P). Methods: Two dosing schedules are being investigated. In both schedules, C is administered on day 1 and P on days 1, 8, and 15 of a 21-day cycle. T (100-1000mcg) is dosed once daily for days 1-7 (schedule A) or days 1-3 (schedule B) starting on day 1. A 3+3 design is used for dose escalation. Key eligibility criteria include age 318 with a measurable or evaluable solid incurable malignancy. Patients (pts) must have tumor type that is expected to respond to C + P or have BRCA germline or somatic mutation. Stable, treated brain metastases are allowed. No prior C for metastatic disease is allowed. Pts must have platelets>150 and no need for anticoagulation. After 4-6 cycles of combination therapy, pts may continue the combination, change to C and intermittent T without P or change to T alone with continuous daily dosing. Each schedule will have a 6 subject dose expansion at the MTD. The starting dose level for schedule B will be the MTD from schedule A. Results: Schedule A cohort results are reported: 11 pts (median age 59 [range 39-68]; 8 female; 3 male) have been enrolled. Pts had breast (6), ovarian (2), pancreatic (1), and SCC of oropharynx (1) and concurrent ovarian and pancreatic (1). Five pts are BRCA2+ and 3 pts are BRCA1+. Dose level 3 on schedule A (T 350mcg with C AUC 6 and P 80mg/m2) exceeded the MTD with 2 of 3 pts experiencing hematologic dose limiting toxicities (DLTs) including 1 pt with grade (gr) 3 neutropenic fever and gr 4 thrombocytopenia and another pt with grade 3/4 neutropenia lasting > 7 days. Most common AEs include neutropenia (grade 3-4: 7), anemia (grade 3-4: 3), and thrombocytopenia (grade 3-4: 4). Results from expansion of dose level 2 (T 250mcg with C AUC 6 and T 80mg/m2) will be presented. The 11 pts were on study a median of 9 weeks (range 9-36+). Four pts have discontinued study therapy: 1 due to need for anticoagulation for PE, 1 for prolonged cytopenias, and 2 for disease progression. Of the 8 pts with measurable disease evaluated for response to date, 4 had SD, 1 had a cPR, 1 had radiographic CR, and 2 with PD. A pt with BRCA 1+ triple negative breast cancer has maintained a prolonged PR (36+ weeks) even after dose reductions to T 100mcg with C AUC 3. One pt with ovarian cancer (BRCA WT) has radiographic CR (CA 125 remains mildly elevated) after 15+ weeks of therapy. Conclusion: PARP inhibition with talazoparib days 1-7 in combination with carboplatin and paclitaxel leads to DLT of myelosuppression. However, clinical responses are seen even with lower dose combinations. Citation Format: Turk A, Chan N, Leal T, O'Regan R, Tevaarwerk A, Rice L, Campbell T, Barroilhet L, Mehnert J, Eickhoff J, Kolesar J, Liu G, Wisinski K. NCI9782: A phase 1 study of talazoparib in combination with carboplatin and paclitaxel in patients with advanced solid tumors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-21.