Operating completely in the dark, I was more interested in DOXO-EMCH than in 406. Phase II of course never opened for recruitment, but is that the only reason you didn't mention it?
Parking, and perhaps already parked by Tuck or ????.....
Cardiovasc Toxicol. 2007;7(2):108-13.
Role of mtDNA lesions in anthracycline cardiotoxicity.
Lebrecht D, Walker UA.
Department of Rheumatology and Clinical Immunology, Albert-Ludwigs University, Medizinische Universitätsklinik, Freiburg, Germany.
Doxorubicin (adriamycin) is an effective drug in the treatment of many malignancies. Its prolonged use is, however, limited by an irreversible, dose-dependent and progressive cardiomyopathy, which may become evident even years after completion of therapy. Data from rats and humans show that oxidative phosphorylation is impaired rapidly after acute doxorubicin-exposure. Such respiratory chain dysfunction is known to enhance the production of reactive oxygen species and may lead to quantitative and qualitative injury of mitochondrial DNA (mtDNA) and its encoded respiratory chain subunits. MtDNA depletion, mtDNA mutations and respiratory defects then accumulate with time also in the absence of continued anthracycline exposure. Chronic cardiotoxicity then manifests, when the bioenergetic capacity of the organelles is severely impaired. The mitochondrial damage in late-onset doxorubicin cardiomyopathy is heart specific and not found in skeletal muscle. DOXO-EMCH, a 6-maleimidocaproyl hydrazone derivative of doxorubicin has evolved from the search for less cardiotoxic anthracyclines. At equieffective antitumor doses, DOXO-EMCH has a substantially lower heart toxicity than free doxorubicin.
Clin Cancer Res. 2007 Aug 15;13(16):4858-66.
Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin.
Unger C, Häring B, Medinger M, Drevs J, Steinbild S, Kratz F, Mross K.
Department Medical Oncology, Tumor Biology Center, Freiburg, Germany. unger@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. |
