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.
abstract: 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.
authors: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. geoffrey_shapiro@dfci.harvard.edu.
authors: Patricia M
authors: PM
authors: LoRusso
authors: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors: Jing
authors: J
authors: Li
authors: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors: Angelika
authors: A
authors: Burger
authors: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors: Lance K
authors: LK
authors: Heilbrun
authors: University of Maryland Greenebaum Cancer Center, Baltimore, Maryland.
authors: Edward A
authors: EA
authors: Sausville
authors: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors: Scott A
authors: SA
authors: Boerner
authors: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors: Daryn
authors: D
authors: Smith
authors: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. Wayne State University, Detroit, Michigan.
authors: Mary Jo
authors: MJ
authors: Pilat
authors: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors: Jie
authors: J
authors: Zhang
authors: Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors: Sara M
authors: SM
authors: Tolaney
authors: Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors: James M
authors: JM
authors: Cleary
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
authors: Alice P
authors: AP
authors: Chen
authors: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
authors: Lawrence
authors: L
authors: Rubinstein
authors: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors: Julie L
authors: JL
authors: Boerner
authors: Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors: Adam
authors: A
authors: Bowditch
authors: Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors: Dongpo
authors: D
authors: Cai
authors: Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors: Tracy
authors: T
authors: Bell
authors: Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors: Andrew
authors: A
authors: Wolanski
authors: Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors: Allison M
authors: AM
authors: Marrero
authors: Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors: Yiping
authors: Y
authors: Zhang
authors: Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors: Jiuping
authors: J
authors: Ji
authors: Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors: Katherine
authors: K
authors: Ferry-Galow
authors: Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors: Robert J
authors: RJ
authors: Kinders
authors: Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors: Ralph E
authors: RE
authors: Parchment
authors: Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
authors: Geoffrey I
authors: GI
authors: Shapiro
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018797:Cell Cycle Proteins / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009687:Nuclear Proteins / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects
chemical_list: D001562:Benzimidazoles; D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; C112156:NBN protein, human; D009687:Nuclear Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D000077146:Irinotecan; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002166:Camptothecin