ATCT-27NRG ONCOLOGY/RTOG 0929: A RANDOMIZED PHASE I/II STUDY OF ABT-888IN COMBINATION WITH TEMOZOLOMIDE IN RECURRENT TEMOZOLOMIDE RESISTANT GLIOBLASTOMA

INTRODUCTION: This study tested the hypothesis that ABT-888 (veliparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent, TMZ-refractory glioblastoma (GBM) patients. METHODS: The combination regimen (TMZ/ABT-888) was tested using 2 randomized schedules (5 or 21 days of a 28 day cycle). Two cohorts were studied: bevacizumab naive (BEV-N), and BEV refractory (BEV-R). Six-month progression free survival (PFS6) was the primary endpoint, with hypothesized rates of 30% for BEV-N and 15% for BEV-R; using one-sample binomial tests; alpha = 0.10 and 90% power. Arm 1 combined 40 mg BID ABT-888 with TMZ using the 21/ 28 day schedule at 75 mg/m2. Arm 2 combined ABT-888 (40 mg BID) with TMZ using the 5/ 28 day TMZ at 150-200 mg/m2. RESULTS: Of 151 BEV-N and 74 BEV-R patients, 10 were ineligible. The incidence rate of grade 3/4 myelosuppression was 20.0%. For both arms, PFS6 for BEV-N was 17.0%; 4.4% for BEV-R. Median overall survival (OS) was 10.3 months (95% CI, 8.4-12.0) for BEV-N and 4.7months (95%CI, 3.5-5.6) for BEV-R. The median PFS was essentially the same for both arms and both cohorts at ∼2.0M (95% CI, 1.9-2.1). CONCLUSIONS: The combination of TMZ and ABT-888 did not significantly improve PFS6 for either BEV-N or BEV-R patients with recurrent GBM who had been previously treated with TMZ. For both groups of patients, the objective response rate was low, and did not differ by treatment arm, and the OS and PFS were similar for both treatment arms. Although MGMT status was not included for eligibility and therefore not analyzed, the low response rates, low PFS and low OS suggest that the likelihood of a clinically meaningful benefit for an MGMT-defined subset is remote. Support: Supported by grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, and UG1CA189867 from the National Cancer Institute (NCI) and AbbVie.