This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Unger, C. Articles by Mross, K. Search for Related Content PubMed PubMed Citation Articles by Unger, C. Articles by Mross, K.

Phase I and Pharmacokinetic Study of the (6-Maleimidocaproyl)Hydrazone Derivative of Doxorubicin

Authors' Affiliation: Department Medical Oncology, Tumor Biology Center, Freiburg, Germany

Requests for reprints: Clemens Unger, Department Medical Oncology, Tumor Biology Center, Breisacherstrasse 117, D-79117 Freiburg, Germany. E-mail: unger{at}tumorbio.uni-freiburg.de.

Purpose: The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that shows superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats, and dogs compared with doxorubicin. The purpose of the phase I study was to characterize the toxicity profile of DOXO-EMCH, establish a recommended dose for phase II studies, and assess potential anticancer activity.

Experimental Design: A starting dose of 20 mg/m² doxorubicin equivalents was chosen. Forty-one patients with advanced cancer disease were treated with an i.v. infusion of DOXO-EMCH once every 3 weeks at a dose level of 20 to 340 mg/m² doxorubicin equivalents.

Results: Treatment with DOXO-EMCH was well tolerated up to 200 mg/m² without manifestation of drug-related side effects. Myelosuppression (grade 1-2) and mucositis (grade 1-2) were the predominant adverse effects at dose levels of 260 mg/m² and myelosuppression (grade 1-3) as well as mucositis (grade 1-3) were dose limiting at 340 mg/m². No cardiac toxicity was observed. Of 30 of 41 evaluable patients, 12 patients (40%) had progressive disease, 15 patients (57%) had stable disease, and 3 patients (10%) had a partial remission.

Conclusions: DOXO-EMCH showed a good safety profile and was able to induce tumor regressions in tumor types known to be anthracycline-sensitive tumors, such as breast cancer, small cell lung cancer, and sarcoma. The recommended doxorubicin equivalent dose for phase II studies is 260 mg/m².