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Ref Type Journal Article
PMID (27551000)
Authors Pratz KW, Rudek MA, Gojo I, Litzow MR, McDevitt MA, Ji J, Karnitz LM, Herman JG, Kinders RJ, Smith BD, Gore SD, Carraway HE, Showel MM, Gladstone DE, Levis MJ, Tsai HL, Rosner G, Chen A, Kaufmann SH, Karp JE
Title A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 4
Date 2017 Feb 15
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown leukemia not applicable Carboplatin + Topotecan + Veliparib Phase I Actionable In a Phase I trial, the combination of Hycamtin (topotecan), Paraplatin (carboplatin), and Veliparib (ABT-888) resulted in an overall response rate of 33% (33/99) in leukemia patients and a response rate of 64% (14/22) in patients with aggressive myeloproliferative neoplasms or chronic myelomonocytic leukemia (PMID: 27551000). 27551000
Unknown unknown acute myeloid leukemia not applicable Carboplatin + Topotecan + Veliparib Phase I Actionable In a Phase I trial, the combination of Hycamtin (topotecan), Paraplatin (carboplatin), and Veliparib (ABT-888) resulted in a response rate of 25% (19/77) in patients with acute myeloid leukemia (PMID: 27551000). 27551000