Palifosfamide added to doxorubicin did not improve survival outcomes in patients with metastatic soft tissue sarcoma, compared with doxorubicin alone, a study showed.

The phase III randomized trial did not meet its amended primary endpoint, as there was no significant difference in progression-free survival (PFS) among patients in the two-drug regimen arm.

“This study represents one of the largest international efforts among sarcoma centers to date,” wrote Christopher W. Ryan, MD, of the Oregon Health & Science University, Knight Cancer Institute, Portland, Ore., and his coauthors (J Clin Oncol. 2016 Sept 12. doi: 10.1200/JCO.2016.67.668).

“Single-agent doxorubicin thus remains a reference standard for the treatment of metastatic soft tissue sarcoma,” they wrote.

Doxorubicin has remained the standard first-line treatment for most sarcoma patients for more than 4 decades. Palifosfamide, a tris salt of isophosphoramide mustard, has previously demonstrated broad activity against sarcoma in experimental models.

In addition, a randomized phase II trial showed improved PFS for combined doxorubicin and palifosfamide, compared with doxorubicin alone, with a hazard ratio (HR) of 0.43 (95% CI, 0.19-0.95).

Based on those promising results, Dr. Ryan and his colleagues conducted a phase III trial that evaluated the two-drug combination with doxorubicin alone as first-line treatment of metastatic soft tissue sarcoma.

The cohort included 447 patients who were randomly assigned 1:1 to receive either doxorubicin 75 mg/m2 IV on day 1 plus palifosfamide 150 mg/m2 per day IV on days 1-3, or doxorubicin plus placebo once every 21 days for up to six cycles.

The primary endpoint of the study was PFS by independent radiologic review.

There was no significant difference in PFS between the two cohorts. For the combination therapy group, the median PFS was 6.0 months, compared with 5.2 months for doxorubicin plus placebo (HR, 0.86; 95% CI, 0.68-1.08; P = .19).

Similar results were observed for median overall survival, which was also similar in the two treatment groups: 15.9 months for doxorubicin plus palifosfamide and 16.9 months for doxorubicin plus placebo (HR, 1.05; 95% CI, 0.79-1.39; P = .74).

As for toxicity, all patients had at least one treatment-emergent adverse event, with the most common of any grade being alopecia, nausea, and fatigue.

Grade 3-4 adverse events were more frequently observed in patients receiving doxorubicin plus palifosfamide (63.6%) than in the single-therapy group (50.9%; P = .0075).

“The median PFS of 5.2 months and OS [overall survival] of nearly 17 months with doxorubicin should serve as a reference in the design of future studies in the first-line treatment of metastatic soft tissue sarcoma,” Dr. Ryan and his associates said.

The study was supported by ZIOPHARM Oncology. Dr. Ryan and several of the coauthors reported multiple relationships with industry.