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J Neurooncol. 2016 Jan;126(2):309-16. doi: 10.1007/s11060-015-1966-z. Epub 2015 Oct 27.

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

Author information

1
Paul Carbone Comprehensive Cancer Center, University of Wisconsin, 600 Highland Avenue, Madison, WI, 53792, USA. hirobins@wisc.edu.
2
NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA.
3
National Cancer Institute at the National Institutes of Health, Bethesda, MD, USA.
4
Ohio State University Medical Center, Columbus, OH, USA.
5
University of Texas-MD Anderson Cancer Center, Houston, TX, USA.
6
Candence Cancer Center, Warrenville, USA.
7
University of Kansas, Kansas City, KS, USA.
8
UPMC-Shadyside Hospital, Pittsburgh, PA, USA.
9
National Cancer Institute Radiation Oncology Branch, Bethesda, MD, USA.
10
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
11
University of Rochester, Rochester, NY, USA.
12
Legacy Health, Portland, OR, USA.
13
University of Utah Health Science Center, Salt Lake City, UT, USA.
14
Departments of Neurosciences and Radiation Medicine & Applied Sciences, UC San Diego Health Sciences, La Jolla, CA, USA.
15
University of Chicago, Chicago, IL, USA.
16
University of Maryland Medical Systems, Baltimore, MD, USA.

Abstract

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).

KEYWORDS:

ABT-888; Glioblastoma; Temozolomide; Velparib

PMID:
26508094
PMCID:
PMC4720526
DOI:
10.1007/s11060-015-1966-z
[Indexed for MEDLINE]
Free PMC Article

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