title: A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia.
abstract: Purpose:The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone.Experimental Design:Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML).Results:A total of 99 patients received veliparib 10-100 mg orally twice daily on days 1-8, 1-14, or 1-21 along with continuous infusion topotecan 1.0-1.2 mg/m2/d + carboplatin 120-150 mg/m2/d on days 3-7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage-induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27-0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+leukemia cells, with greater phosphorylation in cells from responders.Conclusions:The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias.Clin Cancer Res; 23(4); 899-907. ©2016 AACR.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. Kpratz1@jhmi.edu.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Pratz
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ivana
authors.initials: I
authors.lastname: Gojo
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.affiliation: National Clinical Target Validation Laboratory, Frederick National Laboratory for Cancer Research, Bethesda, Maryland.
authors.forename: Jiuping
authors.initials: J
authors.lastname: Ji
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Larry M
authors.initials: LM
authors.lastname: Karnitz
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.affiliation: Frederick National Laboratory for Cancer Research, Frederick, Maryland.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kinders
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Hetty E
authors.initials: HE
authors.lastname: Carraway
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Showel
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Gladstone
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Levis
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Hua-Ling
authors.initials: HL
authors.lastname: Tsai
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Gary
authors.initials: G
authors.lastname: Rosner
authors.affiliation: IDB/CTEP/NCI, National Cancer Institute, Rockville, Maryland.
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
mesh_terms: D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D005260:Female; D006801:Humans; D015456:Leukemia, Biphenotypic, Acute / Q000188:drug therapy*; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009196:Myeloproliferative Disorders / Q000188:drug therapy*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D001562:Benzimidazoles; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; C521013:veliparib; D019772:Topotecan; D016190:Carboplatin; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1