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CHICAGO -- An investigational treatment for soft tissue sarcoma missed its goal in a phase III trial but still might be the "anthracycline of the future," a researcher said here.

The drug, aldodoxorubicin, binds to circulating albumin and accumulates in tumors, where the acidic environment causes it to release the standard anthracycline doxorubicin, according to Sant Chawla, MD, of the Sarcoma Oncology Center in Santa Monica, Calif.

In an earlier study, the drug significantly improved progression-free survival (PFS) compared with doxorubicin itself, Chawla said in an oral session at the American Society of Clinical Oncology (ASCO) annual meeting.

But in a larger phase III trial, measured against investigators' choice of other therapies including doxorubicin, the drug failed to show superior PFS, although it demonstrated a trend in that direction, Chawla said.

On the other hand, the drug was significantly better than control drugs in patients with leiomyosarcoma and liposarcoma, he said, and had less cardiotoxicity than doxorubicin.

Indeed, the safety data is "compelling" -- especially when combined with evidence of activity -- and should support further research on the drug, commented ASCO session discussant Vinod Ravi, MD, of the MD Anderson Cancer Center in Houston.

"Even if the efficacy is only equivalent between the two drugs," aldodoxorubicin "still has a role ... as a new generation anthracycline" because it appears to have less toxicity than doxorubicin, he said.

Ravi added that such things as the heterogeneity of sarcomas and previous line of therapy for trial participants might have combined to reduce the benefit of aldodoxorubicin in the phase III trial, compared with the phase II trial.

In particular, he noted that about two-thirds of patients taking aldodoxorubicin -- a prodrug of doxorubicin -- had previous experience with doxorubicin itself. "If you've used doxorubicin before, and the patient has been unable tolerate it or has relapsed, reusing the prodrug does have the potential to reduce PFS," he said.

The study randomly assigned 433 patients, with a range of relapsed and refractory sarcomas, to 350 mg/m² every 3 weeks or to standard treatment with the investigator's choice of pazopanib (Votrient), gemcitabine(Gemzar)/docetaxel, dacarbazine, doxorubicin, or ifosfamide.

At each participating site, investigators in advance chose three of the five regimens to treat patients randomized to the control arm and could use any of the three for an individual participant, Chawla said.

In both arms, about two-third of patients had previously been treated with doxorubicin, and about 55% had L-sarcomas, specifically leiomyosarcoma or liposarcoma.

About a quarter of the patients randomized to control were actually treated with doxorubicin, although among those only 5% had previously been given the drug, compared with 66% of those treated with aldodoxorubicin.

In the intent-to-treat population, the time to progression or death was 4.11 months for aldodoxorubicin and 2.96 months for control therapies, Chawla reported. The difference yielded a hazard ratio in favor of aldodoxorubicin of 0.81, but it did not reach statistical significance.

Overall survival was also slightly greater for the drug (15.11 vs 13.31 months) but also was not significant.

But in the subset of patients with L-sarcomas. PFS was 5.32 months for those getting the drug versus 2.6 months for those in the control arm. The difference yielded a hazard ratio of 0.62, which was significant.

Chawla said grades 3 and 4 adverse events were more severe in the aldodoxorubicin arm than in the control arm, especially anemia, neutropenia, and febrile neutropenia, but the profile was comparable to what was seen among control patients treated with doxorubicin.

However, cardiotoxicity was considerably lower with 3.8% of the aldodoxorubicin patients and 8.5% of those getting doxorubicin experiencing at least a 20% drop in left ventricular ejection fraction (LVEF) at any time after the start of the trial.

Also, only 4.2% of aldodoxorubicin patients had an LVEF below 50% at any point during the study, compared with 19.1% of those taking doxorubicin.

Surprisingly, the drug appeared to be less likely than doxorubicin to cause alopecia, Chawla noted. "Patients on aldodoxorubicin did not lose their hair," he said. "I still do not know what the mechanism is."

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