TY - JOUR
T1 - A phase I study of topotecan, carboplatin and the PARP inhibitor veliparib in acute leukemias, aggressive myeloproliferative neoplasms, and chronic myelomonocytic leukemia
AU - Pratz, Keith W.
AU - Rudek, Michelle A.
AU - Gojo, Ivana
AU - Litzow, Mark R.
AU - McDevitt, Michael A.
AU - Ji, Jiuping
AU - Karnitz, Larry M.
AU - Herman, James G.
AU - Kinders, Robert J.
AU - Smith, B. Douglas
AU - Gore, Steven D.
AU - Carraway, Hetty E.
AU - Showel, Margaret M.
AU - Gladstone, Douglas E.
AU - Levis, Mark J.
AU - Tsai, Hua Ling
AU - Rosner, Gary
AU - Chen, Alice
AU - Kaufmann, Scott H.
AU - Karp, Judith E.
N1 - Funding Information:
We thank the patients who participated in this study, the nurses and physicians who cared for them, and Rebecca Rickliss, Karen Flatten, Kevin Peterson, Yiping Zhang, Paula Schneider, and Cathy Huntoon for technical assistance with the correlative studies. This work is supported by NIH grants U01 CA070095, UM1 CA186691, U01 CA69912, and UM1 CA186686. The Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins was funded by NIH grants P30 CA006973 and UL1 TR 001079. The National Clinical Target validation lab was funded by NCI Contract no HHSN261200800001E. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2017/2/15
Y1 - 2017/2/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-16-1274
DO - 10.1158/1078-0432.CCR-16-1274
M3 - Article
C2 - 27551000
AN - SCOPUS:85012878602
SN - 1078-0432
VL - 23
SP - 899
EP - 907
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -