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

Abstract

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.

• Authors: Sant P Chawla, Zsuzsanna Papai, Guzel Mukhametshina, Kamalesh Sankhala, Leonid Vasylyev, Alexander Fedenko, Kenneth Khamly, Kristen Ganjoo, Rajnish Nagarkar, Scott Wieland, Daniel J Levitt
• Journal: JAMA oncology (JAMA Oncol) Vol. 1 Issue 9 Pg. 1272-80 (Dec 2015) ISSN: 2374-2445 [Electronic] United States
• PMID: 26378637 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Hydrazones
• Prodrugs
• Doxorubicin
• DOXO-EMCH

Topics

• Adult
• Aged
• Antibiotics, Antineoplastic (administration & dosage, adverse effects)
• Doxorubicin (administration & dosage, adverse effects, analogs & derivatives)
• Drug Administration Schedule
• Epidemiologic Methods
• Female
• Humans
• Hydrazones (administration & dosage, adverse effects)
• Infusions, Intravenous
• Male
• Middle Aged
• Neoplasm Metastasis
• Prodrugs (administration & dosage, adverse effects)
• Sarcoma (drug therapy)
• Treatment Outcome
• Young Adult