title: A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia.
abstract: OBJECTIVE
  In preclinical studies, the PARP inhibitor veliparib enhanced the antileukemic action of temozolomide through potentiation of DNA damage. Accordingly, we conducted a phase 1 study of temozolomide with escalating doses of veliparib in patients with relapsed, refractory acute myeloid leukemia (AML) or AML arising from aggressive myeloid malignancies.
  
  
  METHODS
  Patients received veliparib [20-200 mg once a day on day 1 and twice daily on days 4-12 in cycle 1 (days 1-8 in cycle ≥2)] and temozolomide [150-200 mg/m2daily on days 3-9 in cycle 1 (days 1-5 in cycle ≥2)] every 28 to 56 days. Veliparib pharmacokinetics and pharmacodynamics [ability to inhibit poly(ADP-ribose) polymer (PAR) formation and induce H2AX phosphorylation] were assessed. Pretreatment levels of MGMT and PARP1 protein, methylation of the MGMT promoter, and integrity of the Fanconi anemia pathway were also examined.
  
  
  RESULTS
  Forty-eight patients were treated at seven dose levels. Dose-limiting toxicities were oral mucositis and esophagitis lasting >7 days. The MTD was veliparib 150 mg twice daily with temozolomide 200 mg/m2daily. The complete response (CR) rate was 17% (8/48 patients). Veliparib exposure as well as inhibition of PAR polymer formation increased dose proportionately. A veliparib-induced increase in H2AX phosphorylation in CD34+cells was observed in responders. Three of 4 patients with MGMT promoter methylation achieved CR.
  
  
  CONCLUSIONS
  Veliparib plus temozolomide is well tolerated, with activity in advanced AML. Further evaluation of this regimen and of treatment-induced phosphorylation of H2AX and MGMT methylation as potential response predictors appears warranted. Clin Cancer Res; 23(3); 697-706. ©2016 AACR.
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland. igojo1@jhmi.edu.
authors: Ivana
authors: I
authors: Gojo
authors: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.|Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Jan H
authors: JH
authors: Beumer
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Keith W
authors: KW
authors: Pratz
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Michael A
authors: MA
authors: McDevitt
authors: Department of Medicine, University of Maryland Greenebaum Cancer Center, Baltimore, Maryland.
authors: Maria R
authors: MR
authors: Baer
authors: Department of Statistics, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Amanda L
authors: AL
authors: Blackford
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: B Douglas
authors: BD
authors: Smith
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Steven D
authors: SD
authors: Gore
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Hetty E
authors: HE
authors: Carraway
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Margaret M
authors: MM
authors: Showel
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Mark J
authors: MJ
authors: Levis
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Amy E
authors: AE
authors: Dezern
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Douglas E
authors: DE
authors: Gladstone
authors: Laboratory of Human Toxicology and Pharmacology, Applied/Developmental Research Support Directorate, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland.
authors: Jiuping Jay
authors: JJ
authors: Ji
authors: Laboratory of Human Toxicology and Pharmacology, Applied/Developmental Research Support Directorate, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland.
authors: Lihua
authors: L
authors: Wang
authors: Laboratory of Human Toxicology and Pharmacology, Applied/Developmental Research Support Directorate, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland.
authors: Robert J
authors: RJ
authors: Kinders
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Marie
authors: M
authors: Pouquet
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Ismail
authors: I
authors: Ali-Walbi
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Michelle A
authors: MA
authors: Rudek
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Weijie
authors: W
authors: Poh
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: James G
authors: JG
authors: Herman
authors: Division of Oncology Research and Department of Molecular Pharmacology, Mayo Clinic, Rochester, Minnesota.
authors: Larry M
authors: LM
authors: Karnitz
authors: Division of Oncology Research and Department of Molecular Pharmacology, Mayo Clinic, Rochester, Minnesota.
authors: Scott H
authors: SH
authors: Kaufmann
authors: Cancer Therapy Evaluation Program, NCI, Rockville, Maryland.
authors: Alice
authors: A
authors: Chen
authors: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.
authors: Judith E
authors: JE
authors: Karp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D004941:Esophagitis / Q000139:chemically induced; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000032:analysis; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012074:Remission Induction; D016879:Salvage Therapy; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
chemical_list: D001562:Benzimidazoles; C468783:H2AX protein, human; D006657:Histones; D009363:Neoplasm Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D025521:Tumor Suppressor Proteins; C521013:veliparib; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D045643:DNA Repair Enzymes; D000077204:Temozolomide