A phase I study of topotecan, carboplatin and the PARP inhibitor veliparib in acute leukemias, aggressive myeloproliferative neoplasms, and chronic myelomonocytic leukemia

Keith W. Pratz, Michelle A. Rudek, Ivana Gojo, Mark R. Litzow, Michael A. McDevitt, Jiuping Ji, Larry M. Karnitz, James G. Herman, Robert J. Kinders, B. Douglas Smith, Steven D. Gore, Hetty E. Carraway, Margaret M. Showel, Douglas E. Gladstone, Mark J. Levis, Hua Ling Tsai, Gary Rosner, Alice Chen, Scott H. Kaufmann, Judith E. Karp

Research output: Contribution to journalArticle

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)899-907
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number4
DOIs
StatePublished - Feb 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'A phase I study of topotecan, carboplatin and the PARP inhibitor veliparib in acute leukemias, aggressive myeloproliferative neoplasms, and chronic myelomonocytic leukemia'. Together they form a unique fingerprint.

Cite this