Phase I dose-escalation and pharmacokinetic (PK) study of a(6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) in patients with advanced cancers

Abstract

Listen

Translate article

2125 Background: The anthracyclines are among the most useful agents in the treatment of solid malignancies and exhibit a wide range of antitumor activity. Adriamycin is most commonly used, but therapy is associated with significant bone marrow and organ toxicities. Therefore, an albumin-binding prodrug of adriamycin with acid-sensitive properties, i.e. (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH), was developed that binds to circulating albumin with high affinity after intravenous application in a first step thus preventing rapid diffusion of adriamycin into healthy tissue. Due to a passive accumulation of albumin in solid tumors, DOXO-EMCH is targeted to the tumor and releases adriamycin in the acidic environment of tumor tissue. DOXO-EMCH has shown superior antitumor efficacy and an improved toxicity profile in various animal models compared to adriamycin. The objectives of this phase I trial is to evaluate the safety profile and pharmacokinetics of DOXO-EMCH in order to assess the maximum tolerated dose (MTD), evaluate dose-limiting toxicity (DLT), and to preliminarily assess the antitumor activity of intravenous single dosing in 3 week intervals in patients with advanced cancer. Methods: Cohorts of 3 patients with advanced cancer disease were treated with an intravenous infusion of DOXO-EMCH over 30 minutes once every 3 weeks at dose levels 27 mg/m2 (20 mg/m2 adriamycin equivalent), 54 mg/m2 (40 mg/m2 adriamycin equivalent) and 108 m2 (80 mg/m2 adriamycin equivalent) so far. Blood sampling for of PK analysis was performed. Results: 10 patients (6 female, 4 male) were treated with DOXO-EMCH so far, median age was 55.8 years. Treatment with DOXO-EMCH was well tolerated up to 40 mg/m2 adriamycin equivalent, whereas treatment with 54mg/m2 adriamycin equivalent was still ongoing. The MTD was not established. One out of 3 patients evaluable for response had a minor response after 2 cycles of DOXO-EMCH dosed with 27 mg/m2. Conclusions: Intravenous infusion once every 3 weeks of DOXO-EMCH was well tolerated and showed potential antitumor activity. The study is ongoing. No significant financial relationships to disclose.