A Phase II Study of Oral Cyclophosphamide and Sirolimus (OCR) in Advanced Sarcoma

Inclusion Criteria: * Progressive or recurrent, advanced (unresectable or metastatic) high-grade osteosarcoma, Ewing's or soft tissue sarcoma previously treated with chemotherapy. * Bi-dimensionally measurable lesion(s) on cross-sectional radiography, such as computed tomography or magnetic resonance imaging, within 2 weeks of enrollment. * ECOG/Zubrod performance score 0, 1 or 2. * Total WBC \>3,000, neutrophil count \>1,000, platelet count \>100,000 within 2 weeks of enrollment. * Serum creatinine \<2.0 times the institutional upper limit of normal (IULN) within 2 weeks of enrollment. * AST and ALT \<2.5 times IULN (or if liver involvement by sarcoma \<5 times IULN) within 2 weeks of enrollment. * Able to ingest oral medications. * Sexually active women and men of childbearing potential must agree to use an effective method of birth control during the course of the study and for up to 1 month following the last dose of the study drug, in a manner such that risk of pregnancy is minimized. Surgical sterilization, oral contraceptive pills, intrauterine device, double barrier (e.g. condom and diaphragm or spermicidal agents) or abstinence are acceptable forms of birth control. * Women of childbearing potential must have a negative pregnancy test within 2 weeks prior to treatment. * Patient must be \>16 years of age at the time the consent document is signed by the patient. * A paraffin block containing sarcoma, either from a previous surgery or recent biopsy, must be available for correlative studies. If a paraffin block containing sarcoma is not available, patients are required to undergo biopsy to obtain tissue for the correlative studies. Exclusion Criteria: * Active infection requiring antibiotic treatment. * Diabetes mellitus not under good control (e.g. hemoglobin A1c \> 8% or fasting glucose \> 180 mg/dl) with oral agents or insulin. * Prior treatment with mTOR inhibitor for sarcoma. * Less than 3 weeks from prior treatment with chemotherapy to start of treatment with cyclophosphamide and sirolimus. Toxicities from prior chemotherapy (except alopecia) should be grade 1 or less before starting treatment with cyclophosphamide and sirolimus. * Prior radiation less than two weeks since the administration of the last fraction of radiation therapy to the start of treatment. Patients must have recovered from grade 2 or higher radiation-associated toxicities to be eligible. All measurable lesions, which are being targeted, must be outside previously radiated fields or have documented progression at least 6 weeks after completion of radiation. * Untreated or active CNS involvement by sarcoma. * Active second malignancy other than carcinoma in situ. Patients with malignancy other than sarcoma in remission are eligible. * Women who are pregnant or breastfeeding.