Phase II Study Shows Activity of Hypoxia-Activated Alkylating Prodrug in Combination With Doxorubicin in Advanced Soft-Tissue Sarcoma


Key Points

  • Six-month progression-free survival was 58%, median progression-free survival was 6.5 months, and median overall survival was 21.5 months.
  • A phase III trial of TH-302 is ongoing.

In a phase II study reported in the Journal of Clinical Oncology, Chawla et al found that the combination of a hypoxia-activated alkylating prodrug (TH-302) and doxorubicin was active in first-line treatment of advanced soft-tissue sarcoma. TH-302 is a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard.

Study Details

In the study, 91 patients received TH-302 300 at mg/m2 intravenously on days 1 and 8 and doxorubicin at 75 mg/m2 on day 1 of each 21-day cycle. After six cycles, patients with stable or responding disease could receive maintenance TH-302 at the same schedule. The primary endpoint was 6-month progression-free survival.

Survival Outcomes

Median follow-up was 19.4 months. The 6-month progression-free survival rate was 58% (95% confidence interval [CI] = 46%–68%), and median progression-free survival was 6.5 months (95% CI = 5.8–7.7 months). A total of 48 patients received TH-302 maintenance for a median of 10 cycles. Median progression-free survival after initiating maintenance was 3.7 months. Median overall survival was 21.5 months (95% CI = 16.0–26.2 months) and 1- and 2-year overall survival rates were 73% and 44%.

A total of 78% of patients received chemotherapy after discontinuing from the study, including regimens containing gemcitabine (38%), dacarbazine (21%), pazopanib (Votrient) (20%), ifosfamide (18%), and doxorubicin (14%), and 24% received subsequent radiotherapy.

Partial response was observed in 34% of patients and complete response in 2%. During maintenance, improvement from stable disease to partial response was observed in five patients and improvement from partial to compete response was observed in one.


The most common nonhematologic adverse events of any grade were nausea (75%), fatigue (70%), alopecia (54%), and stomatitis (52%). The most common grade 3 or 4 events were fatigue (12.1%) and hypoalbuminemia, hypokalemia, and hyponatremia (5.5% each). Grade 3 or hematologic toxicities included anemia in 36%, thrombocytopenia in 32%, and neutropenia in 31%, including 6%, 2%, and 2% during maintenance treatment. Overall, adverse events were less severe and less frequent during maintenance, and there was no evidence of TH-302-related hepatic, renal, or cardiac toxicity.

According to the authors, other data indicate 6-month progression-free survival rates of 30% to 56% with first-line chemotherapy for advanced soft tissue sarcoma and median overall survival of 8 to 12 months with first-line single-agent doxorubicin.

The authors concluded: “[Progression-free survival], overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced [soft-tissue sarcoma]. A phase III study of TH-302 is ongoing (NCT01440088).”

Sant P. Chawla, MD, of Sarcoma Oncology Center, Santa Monica, California, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by Threshold Pharmaceuticals and Merck KGaA. For full disclosures of the study authors, visit

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