A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study.
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).
Paul Carbone Comprehensive Cancer Center, University of Wisconsin, 600 Highland Avenue, Madison, WI, 53792, USA. hirobins@wisc.edu.
H Ian
HI
Robins
NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA.
Peixin
P
Zhang
National Cancer Institute at the National Institutes of Health, Bethesda, MD, USA.
Mark R
MR
Gilbert
Ohio State University Medical Center, Columbus, OH, USA.
Arnab
A
Chakravarti
University of Texas-MD Anderson Cancer Center, Houston, TX, USA.
John F
JF
de Groot
Candence Cancer Center, Warrenville, USA.
Sean A
SA
Grimm
University of Kansas, Kansas City, KS, USA.
Fen
F
Wang
UPMC-Shadyside Hospital, Pittsburgh, PA, USA.
Frank S
FS
Lieberman
National Cancer Institute Radiation Oncology Branch, Bethesda, MD, USA.
Andra
A
Krauze
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
Andy M
AM
Trotti
University of Rochester, Rochester, NY, USA.
Nimish
N
Mohile
Legacy Health, Portland, OR, USA.
Andrew Y J
AY
Kee
University of Utah Health Science Center, Salt Lake City, UT, USA.
Howard
H
Colman
Ohio State University Medical Center, Columbus, OH, USA.
Robert
R
Cavaliere
Departments of Neurosciences and Radiation Medicine & Applied Sciences, UC San Diego Health Sciences, La Jolla, CA, USA.
Santosh
S
Kesari
University of Chicago, Chicago, IL, USA.
Steven J
SJ
Chmura
University of Maryland Medical Systems, Baltimore, MD, USA.
Minesh
M
Mehta
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy*; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004359:Drug Therapy, Combination; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D016019:Survival Analysis; D000077204:Temozolomide; D016896:Treatment Outcome; D055815:Young Adult
D018906:Antineoplastic Agents, Alkylating; D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D000068258:Bevacizumab; D003606:Dacarbazine; D000077204:Temozolomide
ABT-888; Glioblastoma; Temozolomide; Velparib