title: First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma: A Phase 2b Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01514188.
authors.affiliation: Sarcoma Oncology Center, Santa Monica, California.
authors.forename: Sant P
authors.initials: SP
authors.lastname: Chawla
authors.affiliation: State Health Center, Oncology Department, Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Papai
authors.affiliation: State Healthcare Institute Republican Clinical Oncological Center of the Ministry of Health of the Republic of Tatarstan, Kazan, Republic of Tatarstan, Russia.
authors.forename: Guzel
authors.initials: G
authors.lastname: Mukhametshina
authors.affiliation: Cancer Therapy and Research Center, San Antonio, Texas5now with Sarcoma Oncology Center, Santa Monica, California.
authors.forename: Kamalesh
authors.initials: K
authors.lastname: Sankhala
authors.affiliation: Institute of Medical Radiology, Kharkiv, Ukraine.
authors.forename: Leonid
authors.initials: L
authors.lastname: Vasylyev
authors.affiliation: Blokhin Cancer Research Center, Moscow, Russian Federation.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fedenko
authors.affiliation: Epworth Healthcare and Clinical Trials Research Centre, Richmond, Victoria, Australia.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Khamly
authors.affiliation: Division of Oncology, Department of Medicine, Stanford School of Medicine, Stanford, California.
authors.forename: Kristen
authors.initials: K
authors.lastname: Ganjoo
authors.affiliation: Curie Manavata Cancer Centre, Nashik, Maharashtra, India.
authors.forename: Rajnish
authors.initials: R
authors.lastname: Nagarkar
authors.affiliation: CytRx Corporation, Los Angeles, California.
authors.forename: Scott
authors.initials: S
authors.lastname: Wieland
authors.affiliation: CytRx Corporation, Los Angeles, California.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Levitt
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects; D012509:Sarcoma / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D006835:Hydrazones; D011355:Prodrugs; D004317:Doxorubicin; C575867:DOXO-EMCH