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Phase Ib study of the mitochondrial inhibitor ME-344 plus topotecan in patients with previously treated, locally advanced or metastatic small cell lung, ovarian and cervical cancers.

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Title: Phase Ib study of the mitochondrial inhibitor ME-344 plus topotecan in patients with previously treated, locally advanced or metastatic small cell lung, ovarian and cervical cancers.
Authors: Diamond, JR
Goff, B
Forster, MD
Bendell, JC
Britten, CD
Gordon, MS
Gabra, H
Waterhouse, DM
Poole, M
Ross Camidge, D
Hamilton, E
Moore, KM
Item Type: Journal Article
Abstract: Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m(2) on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m(2) was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.
Issue Date: 10-Mar-2017
Date of Acceptance: 20-Feb-2017
URI: http://hdl.handle.net/10044/1/45906
DOI: https://dx.doi.org/10.1007/s10637-017-0444-1
ISSN: 1573-0646
Publisher: Springer Verlag (Germany)
Start Page: 627
End Page: 633
Journal / Book Title: Investigational New Drugs
Volume: 35
Issue: 5
Copyright Statement: © 2017 Springer Science+Business Media New York. The final publication is available at Springer via https://dx.doi.org/10.1007/s10637-017-0444-1
Keywords: ME-344
Mitochondrial inhibitor
Ovarian cancer
Small cell lung cancer
Topotecan
1115 Pharmacology And Pharmaceutical Sciences
Oncology & Carcinogenesis
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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