Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin.
OBJECTIVE
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.


METHODS
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.
Unger
Clemens
C
Department Medical Oncology, Tumor Biology Center, Freiburg, Germany. unger@tumorbio.uni-freiburg.de
Häring
Brigitte
B
Medinger
Michael
M
Drevs
Joachim
J
Steinbild
Simone
S
Kratz
Felix
F
Mross
Klaus
K
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D006835:Hydrazones / Q000009:adverse effects* / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000009:adverse effects* / Q000493:pharmacokinetics; D012867:Skin / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D006835:Hydrazones; D011355:Prodrugs; C085780:doxorubicin(6-maleimidocaproyl)hydrazone; D004317:Doxorubicin