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

被引:20
作者
Diamond, Jennifer R. [1 ]
Goff, Barbara [2 ]
Forster, Martin D. [3 ]
Bendell, Johanna C. [4 ]
Britten, Carolyn D. [5 ]
Gordon, Michael S. [6 ]
Gabra, Hani [7 ]
Waterhouse, David M. [8 ]
Poole, Mark [9 ]
Camidge, D. Ross [1 ]
Hamilton, Erika [4 ]
Moore, Kathleen M. [10 ]
机构
[1] Univ Colorado, Ctr Canc, 12801 E 17th Ave,Mailstop 8117, Aurora, CO 80045 USA
[2] Univ Washington, Seattle Canc Care Alliance, Seattle, WA USA
[3] Sarah Cannon Res Inst UK, London, England
[4] Sara Cannon Res Inst, Tennessee Oncol, Nashville, TN USA
[5] Med Univ South Carolina, Charleston, SC 29425 USA
[6] Pinnacle Oncol Hematol, Scottsdale, AZ USA
[7] Imperial Coll London, London, England
[8] Oncol Hematol Care, Cincinnati, OH USA
[9] MEI Pharma, San Diego, CA USA
[10] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA
关键词
ME-344; Topotecan; Mitochondrial inhibitor; Ovarian cancer; Small cell lung cancer; SOLID TUMORS; DEATH; RESISTANCE; RECURRENT; COMPLEX;
D O I
10.1007/s10637-017-0444-1
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:627 / 633
页数:7
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