Aldoxorubicin Misses Primary Endpoint in Phase III Sarcoma Study

Daniel Levitt, MD, PhD

Treatment with aldoxorubicin failed to improve progression-free survival (PFS) compared with investigator's choice of therapy for patients with advanced soft tissue sarcoma, according to findings from a phase III study released by the developer of the cytotoxic agent, CytRx Corporation.

The analysis, which was conducted after 191 progression events, showed a median PFS of 4.17 months with aldoxorubicin compared with 4.04 months with investigator's choice of therapy, which included doxorubicin or pazopanib (HR, 0.91). Findings were not yet announced for secondary endpoints, with follow up still ongoing for overall survival. Full results are expected at an upcoming meeting, with findings from a second analysis anticipated in the fourth quarter of 2016.

"For the current evaluation, we did not show a significant difference between aldoxorubicin and investigator's choice of therapy for PFS, the study's primary endpoint," said Daniel Levitt, MD, PhD, executive vice president and chief medical officer of CytRx. "Importantly, however, we saw a clear indication of activity in preplanned secondary endpoints, including objective response rate and disease control rate."

The phase III study randomized 433 patients with metastatic, locally advanced, or unresectable soft tissue sarcomas to receive aldoxorubicin or investigator's choice of therapy. All enrolled patients had received at least 1 prior systemic therapy. The investigator's choice arm included doxorubicin, ifosfamide, dacarbazine, pazopanib, or gemcitabine plus docetaxel.

Prior to entering the study, approximately 67% of patients had received doxorubicin. These patients were evenly distributed between the two arms. The primary endpoint of the study, PFS, was designed under a special protocol assessment from the FDA. Secondary endpoints focused on overall survival, objective response rate (ORR), and safety.

Patients treated with aldoxorubicin experienced an improvement in ORR compared with investigator's choice that was described as a “doubling in response,” although the statistical significance of this improvement was not announced. The disease control rate (ORR plus stable disease) was also improved versus investigator's choice (P = .048). Aldoxorubicin-related adverse events were consistent with prior studies.

In regards to response rates, Levitt said the company was going to wait to release these data until the medical meeting later this year, although they did not say which. He did note that findings were similar regardless of frontline therapy, including those who received frontline doxorubicin.

"While results from this current analysis are immature, a near doubling of response rates with aldoxorubicin suggests a highly active therapy which may benefit certain patients with soft tissue sarcoma," lead investigator Sant Chawla, MD, director of the Sarcoma Oncology Center in Santa Monica, California, said in a statement.

The study was initiated in January 2014 and underwent a brief clinical hold in November 2014. According to the company, the hold, which was related to 1 patient on a compassionate use program, may have altered the first analysis of the study.

"Because enrollment was interrupted by a clinical hold, both PFS and response data need to be analyzed at a future date to account for patients enrolled later in the trial," said Chawla. "I look forward to this subsequent analysis providing a more complete understanding of aldoxorubicin's potential in this very challenging disease."

In a prior phase IIb study, 123 patients with advanced soft tissue sarcoma received aldoxorubicin (n = 83) or doxorubicin (n = 40). Median PFS was 5.6 months with aldoxorubicin versus 2.7 months with doxorubicin. The median overall survival was 15.8 months with aldoxorubicin versus 14.3 months with doxorubicin (P  =  .21).

The PFS rate at 6 months was 46% versus 23%, with aldoxorubicin and doxorubicin, respectively (P = .02). The ORR with aldoxorubicin was 25% compared with 0% for doxorubicin.

There were no acute cardiotoxic events with either treatment. Grade 3/4 neutropenia occurred in 29% of those treated with aldoxorubicin versus 12% with doxorubicin; however, the rates of grade 3/4 febrile neutropenia were similar between the two arms (14% vs 18%, aldoxorubicin and doxorubicin, respectively).

A number of studies continue to assess aldoxorubicin, including a phase I study looking at the drug with gemcitabine for solid tumors (NCT02235688). Additionally, a phase II study is comparing the agent with topotecan for patients with metastatic small cell lung cancer (NCT02200757).

Chawla SP, Papai Z, Mukhametshina G, et al. First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma. JAMA Oncol. 2015;1(9):1272-1280.