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Phase I study of PM00104 (Zalypsis (R)) administered as a 1-hour weekly infusion resting every fourth week in patients with advanced solid tumors

Lookup NU author(s): Dr Jane Margetts, Dr Yvette DrewORCiD, Professor Ruth Plummer

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Abstract

PM00104 (ZalypsisA (R)) is a new synthetic alkaloid with potent cytotoxic activity against tumor cell lines. This phase I clinical trial determined the maximal tolerated dose (MTD) and recommended dose (RD) for phase II trials of PM00104 administered as a 1-hour intravenous (i.v.) infusion weekly for three consecutive weeks resting every fourth week (d1,8,15 q4wk). Forty-nine patients with advanced solid malignancies received PM00104 following a toxicity-guided, accelerated, dose-escalation design. Doses evaluated ranged from 0.07 to 3.0 mg/m(2). Dose-limiting toxicities (DLTs) appeared at the highest doses tested and comprised grade 3 diarrhea and grade 4 lipase increase at 2.0 mg/m(2); grade 1 thrombocytopenia and grade 2 neutropenia with two infusion omissions, grade 3 fatigue and grade 4 febrile neutropenia at 2.5 mg/m(2); and grade 3/4 fatigue, grade 4 neutropenia lasting > 5 days and grade 4 thrombocytopenia at 3.0 mg/m(2). RD was established at 2.0 mg/m(2). PM00104-related adverse events at the RD were mostly grade 1/2, with fatigue, nausea and vomiting as the most common. Transient and manageable myelosuppression and transaminase increases were also reported. Main pharmacokinetic parameters increased linearly with dose. Disease stabilization lasting a parts per thousand yen3 months was found in 4 patients with cervical carcinoma, colorectal adenocarcinoma, lachrymal adenoid carcinoma, and bladder carcinoma (n = 1 each). In conclusion, PM00104 2.0 mg/m(2) 1-hour, d1,8,15 q4wk showed a positive risk-benefit ratio, which has supported its further evaluation in three ongoing phase II clinical trials.

Publication metadata

Author(s): Massard C, Margetts J, Amellal N, Drew Y, Bahleda R, Stevens P, Armand JP, Calvert H, Soria JC, Coronado C, Kahatt C, Alfaro V, Siguero M, Fernandez-Teruel C, Plummer R

Publication type: Article

Publication status: Published

Journal: Investigational New Drugs

Year: 2013

Volume: 31

Issue: 3

Pages: 623-630

Print publication date: 01/06/2013

Online publication date: 12/06/2012

Acceptance date: 28/05/2012

ISSN (print): 0167-6997

ISSN (electronic): 1573-0646

Publisher: Springer New York

URL: http://dx.doi.org/10.1007/s10637-012-9843-5

DOI: 10.1007/s10637-012-9843-5

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