Abstract OT3-02-06: A phase 1 study of BMN 673 in combination with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782)
Authors: Mullvain JA , Leal T , Eickhoff J , Kolesar JM , Liu G , DiPaola RS , Wisinski KB 
Published: May 2016

Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and are activated by DNA strand breaks. DNA damage from carboplatin has been associated with activation of PARP. Preclinical data indicate that PARP inhibition potentiates the anti-tumor effect of platinum chemotherapy. BMN 673 (Talazoparib) is an oral, selective PARP inhibitor. The phase I single agent maximum tolerated dose (MTD) of BMN 673 given once daily was 1mg po qd. Myelosuppresion was primary dose-limiting toxicity (DLT), including grade 3-4 thrombocytopenia. Carboplatin with paclitaxel is a current standard treatment for many solid tumors, including ovarian, bladder, upper gastrointestinal, breast and non-small cell lung cancer. Myelosuppression, including thrombocytopenia, is also seen with this combination. This phase 1 study is combining BMN 673 with carboplatin once every 3 weeks and weekly paclitaxel.

Trial Design: Two dosing schedules are being investigated. In both schedules intravenous carboplatin will be administered on day 1 and paclitaxel on days 1, 8, 15 of a 21-day cycle. BMN 673 will be dosed orally once daily for days 1-7 (schedule A) or days 1-3 (schedule B) starting on day 1 of each cycle. After 4-6 cycles of the combination therapy, subjects may continue the combination, change to carboplatin and intermittent BMN 673 without paclitaxel or change to BMN 673 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. The MTD for each schedule will be considered the recommended phase 2 dose (RP2D). Pharmacokinetic samples will be collected. Planned exploratory correlative studies include RAD51 and gamma-H2AX changes in peripheral blood mononuclear cells and examination of mechanism of secondary resistance by comparing mutation profiles in tumors from biopsy specimens.

Key eligibility criteria include age 18 or older with a measurable or evaluable solid tumor malignancy that is metastatic or unresectable. Subjects must have tumor type for which there is a reasonable expectation of response to carboplatin and paclitaxel or they must have BRCA germline or somatic mutation. Adequate performance status and organ function is required. Stable, treated brain metastases are allowed. No prior carboplatin for metastatic disease is allowed.

Objectives: The primary objectives are to determine the MTD and RP2D of BMN 673 given on the 7 and 3 day schedules in combination with carboplatin and paclitaxel. Secondary objectives include evaluation of the anti-tumor activity, pharmacokinetic parameters, and the safety and tolerability of the combination.

Statistical Plan: A standard 3+3 phase 1 dose escalation design is used. Assuming 3-6 subjects per dose level with two schedules including 6 subject dose expansion cohorts and assuming 6 inevaluable subjects, the maximum sample size is 66.

Study Status: The trial will be activating in summer 2015 at the Cancer Institute of New Jersey and University of Wisconsin. It is anticipated that 2-3 patients will be accrued per month with accrual completed within 28 months. For more information: www.clinicaltrials.gov (NCT02317874).

Citation Format: Mullvain JA, Leal T, Eickhoff J, Kolesar JM, Liu G, DiPaola RS, Wisinski KB. A phase 1 study of BMN 673 in combination with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-06.