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

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> 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).<b>Results:</b> 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.<b>Conclusions:</b> The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. <i>Clin Cancer Res; 23(4); 899-907. ©2016 AACR</i>.