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

Autor: Edward Chu, Ronald G. Stoller, Hussein Tawbi, Shannon Puhalla, Chandra P. Belani, Alice P. Chen, Leonard Joseph Appleman, Taofeek K. Owonikoko, R. Donald Harvey, Vincent L. Giranda, Stacie Peacock Shepherd, Yan Lin, Yixing Jiang, Brian F. Kiesel, Jan H. Beumer, Suresh S. Ramalingam, Athanassios Argiris, Sandra Strychor, Daniel P. Petro
Rok vydání: 2012
Předmět:
Zdroj: Journal of Clinical Oncology. 30:3049-3049
ISSN: 1527-7755
0732-183X
Popis: 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.
Databáze: OpenAIRE
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