Aldoxorubicin monotherapy prolonged PFS and improved tumor response compared with doxorubicin among patients with metastatic or locally advanced unresectable soft tissue sarcoma, according to the results of a phase 2b randomized clinical trial.
Patients who received aldoxorubicin (CytRX Corporation) experienced manageable adverse events without unexpected events or evidence of acute cardiotoxicity, the researchers reported.
Standard therapy for advanced soft tissue sarcoma has not changed in decades and patient prognosis remains poor. Aldoxorubicin — a novel albumin-binding prodrug of doxorubicin — exhibited clinical activity in phase 1 trials, according to study background.
Sant P. Chawla, MD, founder and director of Sarcoma Oncology Center in Santa Monica, California, and colleagues sought to evaluate the efficacy of aldoxorubicin compared with doxorubicin in patients with advanced soft-tissue sarcoma. They conducted an international, open label phase 2b randomized clinical trial between August 2012 and December 2013.
The study included data from 123 patients (median age, 5 years; 54% women). The researchers randomly assigned patients (2:1) to 350 mg/m2 aldoxorubicin (equivalent to doxorubicin at 260 mg/m2; n = 83) or 75 mg/m2 doxorubicin (n = 40) once every 3 weeks for up to six cycles.
PFS served as the primary endpoint. Secondary endpoints included 6-month PFS, OS, tumor response rate and safety.
Patients who received aldoxorubicin experienced a longer median PFS — extended by 2.9 months (5.6 months vs. 2.7 months; P = .02) — and a greater proportion of patients achieved 6-month PFS (46% vs. 23%; P = .02).
The difference in median OS between the cohorts was 1.5 months, which did not meet statistical significance. Patients assigned to aldoxorubicin achieved a median OS of 15.8 months (95% CI, 13-not available), whereas patients assigned to doxorubicin achieved a median OS of 14.3 months (95% CI, 8.6-20.6).
Twenty patients assigned the treatment experienced a partial response compared with no patients assigned doxorubicin (25% vs. 0%).
A greater proportion of patients assigned aldoxorubicin experienced grade 3 or grade 4 neutropenia (29% vs. 12%), but grade 3 and grade 4 febrile neutropenia occurred more frequently in the doxorubicin arm (14% vs. 18%). Further, neither treatment produced acute cardiotoxic effects, although three patients assigned doxorubicin experienced left ventricular ejection fraction less than 50%.
The researchers acknowledged limitations of their research, including the small sample size and the potential for bias inherent in the open label study design.
“To our knowledge, aldoxorubicin is the first single agent to show significant superior activity over doxorubicin without substantially worsening toxicity,” Chawla and colleagues wrote. “Aldoxorubicin may be an important therapeutic option for patients with advanced soft tissue sarcoma, as well as other solid tumor types. In addition to the phase 3 study for soft tissue sarcoma, aldoxorubicin is currently under investigation in a phase 2b study in small cell lung cancer, a phase 2 study of glioblastoma and a pilot study of Kaposi’s sarcoma.”
The reduction in the rate of cardiotoxicities appears to be an advantage of aldoxorubicin compared with doxorubicin, Rashmi Chugh, MD, and Scott M. Schuetze, MD, PhD, both professors of medical oncology at University of Michigan, wrote in an accompanying editorial.
“Doxorubicin has been the mainstay of sarcoma chemotherapy for the last 40 years, and although its use is limited, predominantly by development of cardiomyopathy, it remains so,” Chugh and Schuetze wrote. “Taken together, the prior phase 1b/2 and the currently reported phase 2b trials by Chawla and colleagues provide encouraging preliminary results that aldoxorubicin can retain significant antisarcoma activity without the cardiac toxicity of doxorubicin. If the results are confirmed in the ongoing phase 3 study of aldoxorubicin in patients with advanced soft tissue sarcoma, medical oncologists may find an ‘old friend’ with a few new tricks.” – by Cameron Kelsall
Disclosure: CytRX Corporation provided funding for this study. Chawla reports research funding from CytRX, as well as consultant roles with Amgen, Berg Pharma, CytRx, GlaxoSmithKline, Roche and Threshold. Chugh and Schuetze report investigator roles for an ongoing phase 3 study of aldoxorubicin in patients with soft-tissue sarcoma sponsored by CytRx.