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

The purpose of this Phase II study you are being asked to participate in will assess the
effectiveness of the combination of oral cyclophosphamide and sirolimus in sarcoma patients
with relapsed or widespread disease who cannot be cured by surgery, radiation or
conventional chemotherapy. Malignant connective tissue tumors of soft tissue and bone
(sarcomas) are highly aggressive cancers. There are few available chemotherapy treatments
that are active in treating sarcomas. Sarcomas that have metastasized (spread throughout the
body) are usually fatal. There is a great need to identify new active drugs to treat
metastatic or relapsed sarcomas. Low dose oral daily cyclophosphamide is an established
chemotherapy regimen for treatment of malignant and autoimmune disease and is generally well
tolerated. Sirolimus is approved for prevention of kidney rejection after transplantation.
Temsirolimus, a form of sirolimus, is approved for the treatment of kidney cancer. Sirolimus
combined with cyclophosphamide in animal models of sarcoma resulted in significant
anti-tumor activity. Tumor and blood samples will be studied to look for known protein
targets of the medication to help learn why certain subjects have a favorable response to
the treatment.

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.