TH-302 shows antitumor activity in combination with doxorubicin in advanced soft-tissue sarcoma.

  • Major finding: TH-302 shows antitumor activity in combination with doxorubicin in advanced soft-tissue sarcoma.

  • Concept: Targeting hypoxic tumor cells may improve clinical outcomes and limit metastatic spread.

  • Impact: The hypoxia-activated prodrug TH-302 may improve the efficacy of standard chemotherapy.

The standard of care for patients with advanced soft-tissue sarcoma is treatment with first-line chemotherapeutic agents such as doxorubicin. However, clinical response to these drugs is limited and is often accompanied by toxic side effects. Soft-tissue sarcomas are characterized by significant tumor hypoxia, which has been associated with chemotherapy resistance, metastasis, and poor prognosis, suggesting that targeting the hypoxic tumor microenvironment may be beneficial. Chawla and colleagues assessed the safety and efficacy of first-line treatment with doxorubicin in combination with TH-302, a prodrug that is preferentially activated under hypoxia to generate a cytotoxic alkylating active metabolite, in an open-label, single-arm phase II trial of 91 patients with advanced soft-tissue sarcoma. Compared with historical outcomes of response to doxorubicin treatment, patients receiving combination therapy exhibited a higher six-month progression-free survival (PFS) rate of 58%, a median PFS of 6.5 months, and a median overall survival of 21.5 months, suggesting that the addition of TH-302 may prolong survival compared with chemotherapy alone. Combined treatment with TH-302 and doxorubicin resulted in an overall response rate of 36%, with complete responses in 2 (2%) patients, partial responses in 30 (34%) patients, and a median response duration of 5.3 months. In addition, among 48 patients who received continuing TH-302 maintenance treatment following response to combination therapy, 5 patients with stable disease converted to a partial response and 1 patient with a partial response improved to a complete response. Treatment with TH-302 did not add to the toxicity of doxorubicin and was well tolerated as a maintenance therapy; the most common adverse events included hematologic toxicities, nausea, fatigue, and skin rash. These findings suggest that targeting hypoxic tumor cells improves the efficacy of doxorubicin and support further clinical testing of this therapeutic combination.

Chawla SP, Cranmer LD, Van Tine BA, Reed DR, Okuno SH, Butrynski JE, et al. Phase II study of the safety and antitumor activity of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma. J Clin Oncol 2014 Sep 2 [Epub ahead of print].