First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma: A Phase 2b Randomized Clinical Trial

Importance: Standard therapy for advanced soft-tissue sarcoma has not changed substantially in decades, and patient prognosis remains poor. Aldoxorubicin, a novel albumin-binding prodrug of doxorubicin, showed clinical activity against advanced soft-tissue sarcoma in phase 1 studies.

Objective: To evaluate efficacy and safety of aldoxorubicin vs doxorubicin in patients with advanced soft-tissue sarcoma.

Design, setting, and participants: International, multicenter, phase 2b, open-label, randomized study at general community practices, private practices, or institutional practices. Between August 2012 and December 2013, 140 patients with previously untreated locally advanced, unresectable, or metastatic soft-tissue sarcoma were screened.

Interventions: Randomization (2:1) to aldoxorubicin 350 mg/m2 (dose equivalent to doxorubicin 260 mg/m2) or doxorubicin 75 mg/m2, administered once every 3 weeks for up to 6 cycles.

Main outcomes and measures: Primary end point was progression-free survival. Secondary end points were 6-month progression-free survival, overall survival, tumor response rate, and safety. All efficacy end points were evaluated by independent and local review.

Results: A total of 126 patients were randomized, and 123 received aldoxorubicin (n = 83) or doxorubicin (n = 40). Median (range) patient age was 54.0 (21-77 years); 42 (34%) had leiomyosarcoma. By independent review, median progression-free survival was significantly improved (5.6 [95% CI, 3.0-8.1] vs 2.7 [95% CI, 1.6-4.3] months; P =.02) with aldoxorubicin compared with doxorubicin, as was the rate of 6-month progression-free survival (46% and 23%; P =.02). Median overall survival was 15.8 (95% CI, 13.0 to not available) months with aldoxorubicin and 14.3 (95% CI, 8.6-20.6) months with doxorubicin (P =.21). Overall tumor response rate (by Response Evaluation Criteria in Solid Tumors, version 1.1) by independent review was higher with aldoxorubicin than with doxorubicin (25% [20 patients, all partial response] vs 0%). Grade 3 or 4 neutropenia was more frequent with aldoxorubicin than with doxorubicin (24 [29%] vs 5 [12%]), but not grade 3 or 4 febrile neutropenia (12 [14%] vs 7 [18%]). No acute cardiotoxic effects were observed with either treatment, although left ventricular ejection fraction less than 50% occurred in 3 of 40 patients receiving doxorubicin.

Conclusions and relevance: Single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response. Aldoxorubicin therapy exhibited manageable adverse effects, without unexpected events, and without evidence of acute cardiotoxicity. Further investigation of aldoxorubicin therapy in advanced soft-tissue sarcoma is warranted.

Trial registration: clinicaltrials.gov Identifier: NCT01514188.

Indexed on Europe PMC as PubMed record 26378637 (DOI 10.1001/jamaoncol.2015.3101). Matched by DOI alone: one trial page and one treatment page cite this DOI among their external links (the pages are listed under Related), and this page was written so that the citation resolves inside OnCo. No figure has been checked by an editor.