A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma

Abstract

BACKGROUND: Aldoxorubicin, a prodrug of doxorubicin, covalently binds to serum albumin, allowing for the administration of much higher doses of doxorubicin in a previous clinical study. The current phase 1B/2 study evaluated the safety of aldoxorubicin, including preliminary efficacy and safety of its maximum tolerated dose (MTD RESULTS: A total of 25 patients were enrolled, including 17 patients (68%) with advanced soft tissue sarcoma (STS). The MTD of aldoxorubicin was 350 mg/m 2 ; dose-limiting toxicities included grade 4 neutropenia and grade 3 febrile neutropenia (NCI CTCAE v4.0). Drug-related adverse events included myelosuppression, nausea, fatigue, alopecia, stomatitis, vomiting, and oropharyngeal pain. No clinically significant cardiac toxicities were reported. Seven patients (28%) had elevated serum troponin levels while taking part in the study, but these elevations were not clinically significant or associated with cardiac findings. A partial response was achieved in 20% of patients, and stable disease was reported in 40% of patients. The median progression-free survival was 4.80 months, and the median overall survival was 11.25 months. Among patients with STS who were treated at the MTD (13 patients), a partial response was achieved in 38% and stable disease in 46%; the median progression-free survival was 11.25 months and the median overall survival was 21.71 months. CONCLUSIONS: Aldoxorubicin at a dose of 350 mg/m 2 administered once every 21 days for up to 8 cycles was found to be acceptably safe and demonstrated preliminary efficacy in patients with advanced solid tumors, including STS. Further investigation of aldoxorubicin is ongoing.

The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery

“…Exendin-4, a GLP-1 homologue (CJC-1131) for treatment of type 2 diabetes, is one example that has entered clinical trials [234][235][236], where the half-life has been shown to be increased from only a few hours for the GLP-1 analogue to 9-15 days for the C34-conjugated drug [237]. Another example of in vivo conjugation is coupling of an acidic sensitive prodrug of doxorubicin (Aldoxorubicin) to C34 post intravenous administration, which is currently in clinical trials for treatment of sarcoma [238]. This strategy aims for cleavage of the hydrazine linker connecting albumin and doxorubicin upon exposure to the acidic environment in tumor tissues [238].…”

“…Another example of in vivo conjugation is coupling of an acidic sensitive prodrug of doxorubicin (Aldoxorubicin) to C34 post intravenous administration, which is currently in clinical trials for treatment of sarcoma [238]. This strategy aims for cleavage of the hydrazine linker connecting albumin and doxorubicin upon exposure to the acidic environment in tumor tissues [238]. As FcRn-mediated transport is dependent on binding at acidified endosomal pH, it remains to be investigated whether the acidic-sensitive linker is protected or cleaved.…”

Current and advancing systemic treatment options for soft tissue sarcomas

“…The median PFS was 11.25 months and median OS 21.71 months. Of note, five out of the eight patients who demonstrated response had previously been treated with an anthracycline [51]. A subsequent Phase II study randomizing patients to aldoxorubicin or doxorubicin in first-line STS was presented at the American Society of Clinical Oncology annual meeting 2014.…”

Aldoxorubicin for the treatment of advanced soft tissue sarcoma

“…The recommended aldoxorubicin dose was determined to be 350 mg/m 2 (260 mg/m 2 doxorubicin dose equivalent). In the Phase Ib portion of the second study, 25 patients with advanced solid tumors, including 17 with STS, received aldoxorubicin at 230, 350 or 450 mg/m 2 once every 21 days for up to eight cycles [45]. The 350 mg/m 2 dose was confirmed as the maximum tolerated dose (MTD).…”

“…Additional patients were enrolled to bring the total to 13 patients with STS treated with aldoxorubicin 350 mg/m 2 [45]. This patient cohort completed a median of six cycles (range 1 --8).…”