849 Preliminary report of a randomized phase II study comparing two different ifosfamide (IF) regimens in advanced soft tissue sarcoma patients (PTS) failing first-line anthracyclines

9563 Objectives: The current first line standard chemotherapy for advanced soft-tissue sarcomas is the combination of doxorubicine and ifosfamide. Liposomal encapsulation is a strategy pursued to reduce toxicity and improve tumor uptake. There are so far only limited systematic data regarding the efficacy of liposomal anthracyclines in advanced soft-tissue sarcomas. We have previously reported on a phase II study with liposomal daunorubicine (L-Dauno) with ifosfamide, named IDx1. Here we report on an additional cohort of the phase II study using liposomal doxorubicine (L-Doxo). Methods: In a single-arm two cohort phase II study 55 patients with advanced soft-tissue sarcoma had received first line a maximum of 6 cycles (median 2 cycles) of ifosphamide (5 g/m2) and in cohort 1 L-Dauno (100 mg/m2, 40 patients) or in cohort 2 the approximate equivalent of L-Doxo (75 mg/m2, 15 patients). Cycles were repeated every 4 weeks in absence of disease progression. Primary study endpoint was response rate. Results: The overall response rate was 25% (n = 14). In the L-Dauno group the results were as follows: CR 3% (n = 1), PR 29% (n = 10), SD 17% (n = 6), PD 37% (n = 13), NED or intermittent death 14% (n = 5), and in the L-Doxo group: PR 20% (n =3), SD 26% (n =4) and PD 53% (n = 8). Interestingly, all three liposarcoma patients (two in the L-Dauno group, one in the L-Doxo group) responded, whereas liposarcoma usually carries a poor response rate. For both combinations toxicity was similarly tolerable with short episodes of hematotoxicity (leucocyte nadir on day 9, platelet nadir on day 11), 11 febrile episodes, no grade 3 or 4 mucositis, no cardiac toxicity and 5 episodes of grade 2 acute ifosfamide-related CNS-toxicity. Based on the hematotoxicity kinetics, three weekly regimens appear feasible. Conclusion: The combination of liposomal anthracyclines and ifosfamide is a safe and effective first line regimen in the treatment for advanced soft tissue sarcoma. Further evaluation in a randomized trial will be pursued. The unexpected high responsiveness of liposarcoma warrants further phase II investigation. 1Siehl JM et al. Cancer 2005. No significant financial relationships to disclose.

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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

Journal of Clinical Oncology ◽

10.1200/jco.2013.54.3660 ◽

2014 ◽

Vol 32 (29) ◽

pp. 3299-3306 ◽

Cited By ~ 87

Author(s):

Sant P. Chawla ◽

Lee D. Cranmer ◽

Brian A. Van Tine ◽

Damon R. Reed ◽

Scott H. Okuno ◽

...

Keyword(s):

Overall Survival ◽

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Partial Response ◽

Phase Ii ◽

Phase Ii Study ◽

Complete Response ◽

Phase Iii ◽

First Line ◽

Advanced Soft Tissue Sarcoma

Purpose TH-302, a prodrug of the cytotoxic alkylating agent bromo-isophosphoramide mustard, is preferentially activated in hypoxic conditions. This phase II study investigated TH-302 in combination with doxorubicin, followed by single-agent TH-302 maintenance therapy in patients with first-line advanced soft tissue sarcoma (STS) to assess progression-free survival (PFS), response rate, overall survival, safety, and tolerability. Patients and Methods In this open-label phase II study, TH-302 300 mg/m2 was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m2 on day 1 of each 21-day cycle. After six cycles, patients with stable and/or responding disease could receive maintenance monotherapy with TH-302. Results Ninety-one patients initiated TH-302 plus doxorubicin induction treatment. The PFS rate at 6 months (primary efficacy measure) was 58% (95% CI, 46% to 68%). Median PFS was 6.5 months (95% CI, 5.8 to 7.7 months); median overall survival was 21.5 months (95% CI, 16.0 to 26.2 months). Best tumor responses were complete response (n = 2 [2%]) and partial response (n = 30 [34%]). During TH-302 maintenance (n = 48), five patients improved from stable disease to partial response, and one patient improved from partial to complete response. The most common adverse events during induction were fatigue, nausea, and skin and/or mucosal toxicities as well as anemia, thrombocytopenia, and neutropenia. These were less severe and less frequent during maintenance. There was no evidence of TH-302–related hepatic, renal, or cardiac toxicity. Conclusion PFS, overall survival, and tumor response compared favorably with historical outcomes achieved with other first-line chemotherapies for advanced STS. A phase III study of TH-302 is ongoing (NCT01440088).

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