Sirolimus reduced tumor-related morbidity and resulted in biochemical and radiographic response in patients with progressive sarcoma

Abstract

9503 Background: Chemotherapy options for palliative treatment of advanced sarcomas are limited and studies are underway to identify new classes of active agents. Second generation inhibitors of the mammalian target of rapamycin (mTOR) are being tested in phase II trials. Objective responses of sarcomas to the mTOR inhibitor AP23573 have been reported. Sirolimus (rapamycin) is a macrocyclic triene antibiotic that inhibits activation of S6 kinase, the cdk2/cyclinE complex and phosphorylation of retinoblastoma protein and causes cell cycle arrest in G1-S phase. Methods: We report the cases of four (out of 20) patients (pts) with progressive, metastatic sarcoma failing 2–6 chemotherapies treated with sirolimus and followed for clinical benefit. Sirolimus was self-administered daily with (n=2) or without (n=2) daily oral cyclophosphamide 200 mg every other week. Patients were followed in clinic for disease and toxicity assessments every 2 weeks. Molecular analysis of mTOR targets will be performed. Results: Patients with MFH, leiomyosarcoma, angiosarcoma and osteosarcoma were treated using 4–8 mg sirolimus daily for a median of 16 weeks (range 8–28 wks). Three pts were symptomatic from disease and had reduced performance status prior to treatment. All 3 pts had subjective improvement in tumor-related symptoms and 2 had improvement in performance status. LDH and bilirubin fell from 1,712 u/L and 5.6 mg/dl to 388 u/L and 1.1 mg/dl, respectively, in the pt with angiosarcoma during 3 months of sirolimus and cyclophosphamide. Alkaline phosphatase fell from 791 u/L to 120 u/L in the pt with osteosarcoma over 6 weeks of simolimus and cyclophosphamide. Three pts had minor radiographic improvement in tumor and remain on treatment. One pt has died of disease progression. Treatment was well tolerated. Conclusions: Sirolimus treatment was associated with improvement in tumor-related symptoms, performance status and biochemical markers of disease activity and inhibited tumor growth in pts with advanced sarcoma failing multiple prior therapies. Phase I studies of sirolimus in advanced cancer are underway at the University of Chicago. Formal study of sirolimus in advanced sarcoma is contemplated. No significant financial relationships to disclose.