A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia.

Autor:	Pratz KW; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. Kpratz1@jhmi.edu., Rudek MA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Gojo I; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Litzow MR; Mayo Clinic, Rochester, Minnesota., McDevitt MA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Ji J; National Clinical Target Validation Laboratory, Frederick National Laboratory for Cancer Research, Bethesda, Maryland., Karnitz LM; Mayo Clinic, Rochester, Minnesota., Herman JG; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Kinders RJ; Frederick National Laboratory for Cancer Research, Frederick, Maryland., Smith BD; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Gore SD; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Carraway HE; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Showel MM; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Gladstone DE; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Levis MJ; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Tsai HL; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Rosner G; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland., Chen A; IDB/CTEP/NCI, National Cancer Institute, Rockville, Maryland., Kaufmann SH; Mayo Clinic, Rochester, Minnesota., Karp JE; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2017 Feb 15; Vol. 23 (4), pp. 899-907. Date of Electronic Publication: 2016 Aug 22.
DOI:	10.1158/1078-0432.CCR-16-1274
Abstrakt:	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/m 2 /d + carboplatin 120-150 mg/m 2 /d on days 3-7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m 2 /d + carboplatin 150 mg/m 2 /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 . (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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