Results Of A Phase Ii Trial Of Sirolimus (S) And Cyclophosphamide (C) In Advanced Sarcoma.

10003 Background: Activation of the PI3-kinase/AKT/mTOR pathway has been demonstrated in sarcoma sub-types. Trials of single-agent mTOR inhibitors in sarcoma have shown low objective response rates but progression-free survival (PFS) rates suggest possible cytostatic effect. The combination of S and C demonstrated anti-sarcoma activity in Pediatric Preclinical Testing Program models. Methods: We conducted a phase II Simon Minimax trial of S (12 mg dose on day 1 followed by 4 mg daily) and C (200 mg orally daily for 7 days every other week) in patients (pts) with advanced bone or soft tissue sarcoma. Dose of S and C were reduced for grade ≥3 toxicity. C was held for neutrophil <1K or platelet <75K. Primary objective was to estimate 6-month PFS rate with a target of ≥25%. Pts were followed for tumor response (WHO criteria) by imaging every 2 months. Sirolimus serum levels were measured after 4 weeks; lipid and plasma VEGF levels were measured before and after 4 weeks of treatment. Archived tumor tissue was analyzed for total and phosphorylated mTOR and S6 by quantitative immunofluorescence. Log rank test and cox regression analyses were used to evaluate survival endpoints. Results: 49 eligible pts (21F/28M) were enrolled from 9/08-12/09. Median age was 57 years (range 19-82) and number of prior therapies was 2 (1-6). 16 pts had leiomyosarcoma, 9 liposarcoma, 6 undifferentiated, 6 bone and 12 other sarcoma subtype. Median/mean trough S level was 8.7/9.7 ng/ml (range 1.3-25.8). 2 pts each experienced grade ≥3 dyspnea, thrombosis, cystitis and 3 pts grade 3 infection; 3 deaths on treatment were attributed to disease progression. 10 of 47 evaluable pts were progression-free for ≥6 months and 2 completed >12 months of treatment. Median PFS was 103 days, and 6-month PFS rate was 21% (SD: 0.06%). Median survival was 328 days. Normal triglyceride level at baseline and lower level of mTOR pathway activation correlated with longer PFS (p=0.02 and p=0.05) and overall survival (p=0.06 and p=0.03). VEGF plasma levels did not correlate with outcome. Conclusions: Combination of S and C was tolerated by most patients and 1/5th had stable sarcoma for ≥6 months. Contrary to hypothesis, sarcomas with higher level of mTOR activation showed earlier progression on S.