RT Journal Article
SR Electronic
T1 Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of the Poly(ADP-ribose) Polymerase (PARP) Inhibitor Veliparib (ABT-888) in Combination with Irinotecan in Patients with Advanced Solid Tumors
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 3227
OP 3237
DO 10.1158/1078-0432.CCR-15-0652
VO 22
IS 13
A1 LoRusso, Patricia M.
A1 Li, Jing
A1 Burger, Angelika
A1 Heilbrun, Lance K.
A1 Sausville, Edward A.
A1 Boerner, Scott A.
A1 Smith, Daryn
A1 Pilat, Mary Jo
A1 Zhang, Jie
A1 Tolaney, Sara M.
A1 Cleary, James M.
A1 Chen, Alice P.
A1 Rubinstein, Lawrence
A1 Boerner, Julie L.
A1 Bowditch, Adam
A1 Cai, Dongpo
A1 Bell, Tracy
A1 Wolanski, Andrew
A1 Marrero, Allison M.
A1 Zhang, Yiping
A1 Ji, Jiuping
A1 Ferry-Galow, Katherine
A1 Kinders, Robert J.
A1 Parchment, Ralph E.
A1 Shapiro, Geoffrey I.
YR 2016
UL http://clincancerres.aacrjournals.org/content/22/13/3227.abstract
AB Purpose: PARP is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitor–mediated DNA damage. This phase I study determined the MTD, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics (PD) of veliparib, an orally bioavailable PARP1/2 inhibitor, in combination with irinotecan.Experimental Design: Patients with advanced solid tumors were treated with 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily oral dosing of veliparib (10–50 mg) occurred on days 3 to 14 (cycle 1) and days −1 to 14 (subsequent cycles) followed by a 6-day rest. PK studies were conducted with both agents alone and in combination. Paired tumor biopsies were obtained after irinotecan alone and veliparib/irinotecan to evaluate PARP1/2 inhibition and explore DNA damage signals (nuclear γ-H2AX and pNBS1).Results: Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m2 irinotecan (days 1 and 8) combined with veliparib 40 mg twice daily (days −1–14) on a 21-day cycle. Of 31 response-evaluable patients, there were six (19%) partial responses. Veliparib exhibited linear PK, and there were no apparent PK interactions between veliparib and irinotecan. At all dose levels, veliparib reduced tumor poly(ADP-ribose) (PAR) content in the presence of irinotecan. Several samples showed increases in γ-H2AX and pNBS1 after veliparib/irinotecan compared with irinotecan alone.Conclusions: Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination. Clin Cancer Res; 22(13); 3227–37. ©2016 AACR.