Phase I safety, pharmacokinetic and pharmacodynamic study of the poly (ADP-ribose) polymerase inhibitor veliparib with irinotecan in patients with advanced tumors
P. M. LoRusso, J. Li, A. Burger, L. K. Heilbrun, E. Sausville, S. Boerner, D. Smith, M. J. Pilat, J. Zhang, S. Tolaney, J. M. Cleary, A. Chen, L. Rubinstein, J. L. Boerner, A. Bowditch, D. Cai, T. Bell, A. Wolanski, A. Marrero, Y. Zhang, J. Ji, K. Ferry-Galow, R. Kinders, R. E. Parchment, G. I. Shapiro , Clinical Cancer Research , DOI: 10.1158/1078-0432.CCR-15-0652
Poly (ADP-ribose) polymerase (PARP) is essential for recognition and repair of DNA damage. In preclinical models, PARP inhibitors modulate topoisomerase I inhibitormediated DNA damage. This Phase I study determined the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) and pharmacodynamics (PD) of veliparib, an orally-bioavailable PARP 1/2 inhibitor, in combination with irinotecan.
Patients with advanced solid tumors were treated with 100 mg/m2 irinotecan on days 1 and 8 of a 21-day cycle. Twice-daily (BID) oral dosing of veliparib (10-50 mg) occurred days 3- 14 (Cycle 1) and days -1-14 (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 gamma-H2AX and pNBS1).
Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m2 irinotecan (days 1, 8) combined with veliparib 40 mg BID (days-1-14) on a 21-day cycle. Of 31 response-evaluable patients there were 6 (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 gamma-H2AX and pNBS1 after veliparib/irinotecan compared to irinotecan alone.
Veliparib can be safely combined with irinotecan at doses that inhibit PARP catalytic activity. Preliminary antitumor activity justifies further evaluation of the combination.