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|Ref Type||Journal Article|
|Authors||LoRusso PM, Li J, Burger A, Heilbrun LK, Sausville EA, Boerner SA, Smith D, Pilat MJ, Zhang J, Tolaney SM, Cleary JM, Chen AP, Rubinstein L, Boerner JL, Bowditch A, Cai D, Bell T, Wolanski A, Marrero AM, Zhang Y, Ji J, Ferry-Galow K, Kinders RJ, Parchment RE, Shapiro GI|
|Title||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.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2016 Jul 01|
|Abstract Text||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.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 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).Thirty-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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||breast cancer||not applicable||Irinotecan + Veliparib||Phase I||Actionable||In a Phase I trial, Veliparib (ABT-888) and Camptosar (irinotecan) combination therapy resulted in partial response in 33% (3/9) of patients with advanced breast cancer (PMID: 26842236).||26842236|
|Unknown unknown||Advanced Solid Tumor||not applicable||Irinotecan + Veliparib||Phase I||Actionable||In a Phase I trial, Veliparib (ABT-888) and Camptosar (irinotecan) combination therapy resulted in partial response in 19% (6/31) and stable disease in 42% (13/31) of patients with advanced solid tumors (PMID: 26842236).||26842236|
|Unknown unknown||colon cancer||not applicable||Irinotecan + Veliparib||Phase I||Actionable||In a Phase I trial, Veliparib (ABT-888) and Camptosar (irinotecan) combination therapy resulted in partial response in 50% (2/4) of patients with colon cancer (PMID: 26842236).||26842236|