Butrynski, James E.

Purpose. Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles. Results. Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p=0.47). Median OS was not reached in either arm. Conclusions. Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.

TPS10591 Background: Osteosarcoma is a rare cancer and 33% of patients who have completed primary treatment will recur. The Src pathway has been implicated in the metastatic behavior of several tumors including osteosarcoma where 95% of samples express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor. The recommended phase II dose in adults was found to be 175mg daily. The primary goal of this study is to determine if treatment with Saracatinib can increase progression free survival (PFS) for patients who have undergone complete resection of metastatic osteosarcoma nodules in the lung. Secondary goals are evaluation of overall survival, time to treatment failure, and evaluation of several biological correlatives. Methods: This is a multi-institutional, phase II.5, placebo-controlled study with an accrual goals of 88 randomized patients. Patients between 15 and 75 years, with histological confirmation of recurrent osteosarcoma, localized to the lung, who have potential for complete surgical resection, are eligible for enrollment. After complete resection, patients are randomized to treatment with saracatinib or placebo, of a daily oral dose of 175 mg, continuously for up to 1 year or until progression. Patients who recur in the lung while on-study and who are amenable to complete surgical resection will be un-blinded. Those patients who received placebo may have the option to undergo surgical resection. If fully resected, they will be offered therapy with saracatinib under the same treatment guidelines as above. As of January 2013, 38 patients have enrolled and 32 patients met the criteria to be randomized and began oral therapy with either saracatinib or placebo. An interim analysis is planned after 40 patients have been randomized. Clinical trial information: NCT00752206.

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/m 2 was administered intravenously on days 1 and 8 with doxorubicin 75 mg/m 2 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).