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

Background: Poly (ADP-ribose) polymerase (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 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. Methods: Patients with advanced solid tumors were treated with 100 mg/m 2 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 γ -H2AX and pNBS1). Results: Thirty-five patients were treated. DLTs included fatigue, diarrhea, febrile neutropenia, and neutropenia. The MTD was 100 mg/m 2 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 γ -H2AX and pNBS1 after veliparib/irinotecan compared to 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. data suggest no PK interactions between veliparib and irinotecan. In study, we assayed levels of nuclear γ -H2AX and pNBS1 in tumor after veliparib/irinotecan compared to irinotecan alone. γ -H2AX scores the presence of DNA double-strand breaks (28); phosphorylation of NBS1 (part of the MRN complex) indicates that DNA damage has been detected and suggests that the DNA repair process has been initiated. DNA in of veliparib; or persistence DNA and in veliparib, resulting DNA The latter is supported by in vitro which of double-strand breaks after combination slowed repair process in samples demonstrating increased γ H2AX or pNBS1 after veliparib/irinotecan compared to irinotecan alone, it is possible that DNA was nearly resolved at the 28- hour time point after irinotecan alone, but still at that time point after veliparib/irinotecan, consistent with veliparib-mediated retardation of repair. In this study, PRs were seen in BRCA carriers and WT patients. HR is required to faithfully process double-strand breaks arising during S phase following combined topoisomerase I and PARP inhibition, so that HR-deficient tumors may be overall more vulnerable. For this reason, the irinotecan/veliparib combination is being studied in two triple-negative breast cancer populations, including those with and without BRCA germline mutations. In summary, we have demonstrated the ability to safely inhibit PARP1/2 catalytic activity in combination with topoisomerase I inhibition. Further studies are necessary to reproducibly demonstrate modulation of the DDR in the context of loss of PARP1/2 function. Ultimately, randomized trials will be required to definitively demonstrate increased efficacy afforded by PARP inhibition in concert with DNA damage.