Abstract PD09-06: Two phase I trials exploring different dosing schedules of carboplatin (C), paclitaxel (P), and the poly-ADP-ribose polymerase (PARP) inhibitor, veliparib (ABT-888) (V) with activity in triple negative breast cancer (TNBC)
Authors: Puhalla SL , Appleman LJ , Beumer JH , Tawbi H , Stoller RG , Owonikoko TK , Ramalingam SS , Belani CP , Brufsky AM , Abraham J , Shepherd SP , Giranda V , Chen AP , Chu E 
Published: August 2014

Abstract
Background: The histopathologic and molecular similarities between TNBC and BRCA-1 mutation related breast cancer provide rationale for the use of PARP inhibitors in treating sporadic TNBC. C and P are established drugs in the treatment of advanced breast cancer. In order to determine the recommend phase II dose (RP2D) of V in combination with C and P, two separate phase I trials evaluated the combination of V with C and P dosed weekly (q1wk) and every 3 weeks (q3wk).
Methods: Both phase I trials were a standard 3+3 dose escalation design of C, P, and V open to patients (pts) with advanced solid tumors and enriched for pts with TNBC. In the q1wk trial, C was given weekly on day 3 at an AUC of 2, P was given weekly on day 3 at a dose of 80 mg/m2, and V was escalated from 50 mg twice daily (BID) to a maximum of 200 mg BID on days 1–5 every week over 4 dose levels. In the q3wk trial, C was given on day 3 every 21 days at an AUC of 6, P was given on day 3 every 21 days with the dose escalated from 150 mg/m2 to a dose of 200 mg/m2, and V was given on days 1–7 every 21 days and escalated from 10 mg BID to a dose of 120 mg BID over 9 dose levels. Toxicity was assessed by CTCAE v. 4 and response was determined using RECIST criteria.
Results: The q1wk trial enrolled a total of 18 pts, 12 of whom had BC, and 10 had TNBC. One TNBC pt was BRCA-1+ and the remainder were sporadic. The trial will be completed with the enrollment of one additional patient on dose level 4. Ten breast cancer pts are evaluable for response. DLT's included thrombocytopenia on dose levels 3 (V at 150 mg BID) and 4 (V at 200mg BID), and both occurred in TNBC pts. The range of cycles administered to TNBC pts was 1–11. The q3wk trial enrolled a total of 75 pts, 14 had BC (12 evaluable for response), and 9 had TNBC. One of these pts had a BRCA mutation; 2 pts had a variant of undetermined significance. Three DLT's were observed on this schedule: febrile neutropenia (C at AUC 6, P at 200 mg/m2, V at 40 mg BID, 100 mg BID, and 120 mg BID) and grade 3 hyponatremia. No DLT's occurred in TNBC pts. The established RP2D for the q3wk schedule is C (AUC6), P (200mg/m2) and V (100mg bid) and additional pts are being accrued to an expansion cohort. The range of cycles administered to TNBC pts was 1–14. The clinical activity in TNBC is summarized in Table 1. Responses occurred in pts who had been previously treated both in the adjuvant and metastatic settings, as well as in those who received prior taxanes.

Conclusion: There is evidence of promising clinical activity and acceptable tolerability with carboplatin, paclitaxel, and veliparib on both dosing schedules. An additional 12 pts with TNBC will be accrued to the q1wk trial with pre- and post-treatment biopsies to further evaluate underlying mechanisms of sensitivity and response with regards to DNA repair pathways. Based on our phase I experience, further randomized trials are warranted in breast cancer, particularly TNBC.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-06.