A phase I study of veliparib (ABT-888) in combination with carboplatin and paclitaxel in advanced solid malignancies.

Abstract

3049 Background: Veliparib (ABT-888, NSC 737664) is an orally available inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and -2: enzymes that recruit base excision repair machinery to single-stranded DNA breaks. Expression of PARP-1 may be increased in cancer cells and confer resistance to DNA-damaging agents. The objectives of this phase I study included determination of the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics (PK) of veliparib in combination with paclitaxel (P) and carboplatin (C). Methods: Eligibility criteria included advanced solid tumors, ≤ 3 prior chemotherapy regimens for advanced disease, ECOG performance status 0-2. Veliparib was given PO BID on days 1-7 of each 21 day cycle, and P and C were administered on day 3. In dose levels 1-7, veliparib was not given during cycle 1 to serve as intra-patient control for toxicity and PK assessment, and DLT was evaluated during cycle 2. A standard “3+3” dose escalation was utilized starting at veliparib 20 mg BID, P 150 mg/m2, C AUC 5. Plasma concentrations of veliparib, P and C were determined by LC-MS/MS and AAS during cycle 1 and 2. Results: To date, 68 patients have been enrolled. Tumor types included lung (15), breast (14), melanoma (10), squamous cell of head/neck (7), and urothelial (5). Toxicities observed were expected with C plus P chemotherapy, including neutropenia, thrombocytopenia, peripheral neuropathy. DLTs were seen in 2 out of 7 evaluable patients at the maximum administered dose: veliparib 120 mg BID, P 200 mg/m2, C AUC 6, (febrile neutropenia, hyponatremia). Veliparib 80 mg, P 200 mg/m2, C AUC 6 was well tolerated with 1 out of 9 DLT (febrile neutropenia). Median number of cycles was 5 (1-17). Partial response was seen in 11 (Lung-2, breast-2, melanoma-2, urothelial-2, head and neck, gastric, unknown primary) and complete response in 1 patient with breast cancer and 1 patient with urothelial cancer. Stable disease was observed in 35 patients. Veliparib did not affect the PK disposition of P or C. Conclusions: Veliparib in combination with P and C was well-tolerated with a safety profile similar to P and C alone. Promising anti-tumor activity was observed in several tumor types.