A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study

• Published in: Journal of neuro-oncology 2016-01, Vol.126 (2), p.309-316
• Main Authors: Robins, H. Ian, Zhang, Peixin, Gilbert, Mark R., Chakravarti, Arnab, de Groot, John F., Grimm, Sean A., Wang, Fen, Lieberman, Frank S., Krauze, Andra, Trotti, Andy M., Mohile, Nimish, Kee, Andrew Y. J., Colman, Howard, Cavaliere, Robert, Kesari, Santosh, Chmura, Steven J., Mehta, Minesh
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating - adverse effects; Antineoplastic Agents, Alkylating - therapeutic use; Benzimidazoles - adverse effects; Benzimidazoles - therapeutic use; Bevacizumab - therapeutic use; Brain Neoplasms - drug therapy; Clinical Study; Dacarbazine - adverse effects; Dacarbazine - analogs & derivatives; Dacarbazine - therapeutic use; Disease-Free Survival; Drug Resistance, Neoplasm - drug effects; Drug Therapy, Combination; Female; Glioblastoma - drug therapy; Humans; Male; Medicine; Medicine & Public Health; Middle Aged; Neurology; Oncology; Poly(ADP-ribose) Polymerase Inhibitors - adverse effects; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Survival Analysis; Temozolomide; Treatment Outcome; Young Adult
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-015-1966-z

This study tested the hypothesis that ABT-888 (velparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent TMZ refractory glioblastoma patients. The combination regimen (TMZ/ABT-888) was tested using two randomized schedules (5 vs. 21 days), with 6-month progression free survival (PFS6) as the primary endpoint. The maximum tolerated dose (MTD) for TMZ using the 21 day of 28 TMZ schedule, in concert with 40 mg BID ABT-888 was determined in a phase I portion of this study, and previously reported to be 75 mg/m 2 (arm1). The MTD for ABT-888 (40 mg BID) and the 5 of 28 day TMZ (150–200 mg/m 2 ) schedule was known from prior trials (arm2). Two cohorts were studied: bevacizumab (BEV) naïve (n = 151), and BEV refractory (n = 74). Overall ten patients were ineligible. The incidence rate of grade 3/4 myelosuppression over all was 20.0 %. For the BEV refractory cohort, the PFS 6 was 4.4 %; for the BEV naïve cohort, PFS6 was 17 %. Overall survival was similar for both arms in both the BEV naïve [median survival time (MST) 10.3 M; 95 % CI 8.4–12] and BEV refractory cohort (MST 4.7 M; 95 %CI 3.5–5.6). The median PFS was essentially the same for both arms and both cohorts at ~2.0 M (95 % CI 1.9–2.1).