• Patricia M LoRusso, Jing Li, Angelika Burger, Lance K Heilbrun, Edward A Sausville, Scott A Boerner, Daryn Smith, Mary Jo Pilat, Jie Zhang, Sara M Tolaney, James M Cleary, Alice P Chen, Lawrence Rubinstein, Julie L Boerner, Adam Bowditch, Dongpo Cai, Tracy Bell, Andrew Wolanski, Allison M Marrero, Yiping Zhang, Jiuping Ji, Katherine Ferry-Galow, Robert J Kinders, Ralph E Parchment, and Geoffrey I Shapiro.
• Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. geoffrey_shapiro@dfci.harvard.edu.
• Clin Cancer Res. 2016 Jul 1; 22 (13): 3227-37.

PurposePARP 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 DesignPatients with advanced solid tumors were treated with 100 mg/m(2) 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).ResultsThirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m(2) 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.ConclusionsVeliparib 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.©2016 American Association for Cancer Research.

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