American Association for Cancer Research
10780432ccr150652-sup-146889_2_supp_3319644_919rfx.pdf (997.35 kB)

Supplementary Figure 1 from 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

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journal contribution
posted on 2023-03-31, 18:27 authored by 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, Geoffrey I. Shapiro

Supplementary Figure S1. Study schema.





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.