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

The purpose of this Phase II study 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.

Study Overview

• Status: Completed
• Conditions: Osteosarcoma
• Intervention / Treatment: Drug: Cyclophosphamide and Sirolimus

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral Cyclophosphamide and Sirolimus (OCR); Sarcoma patients were given oral Cyclophosphamide and Sirolimus (OCR) in 28 day cycles.	Drug: Cyclophosphamide and Sirolimus; The dose of cyclophosphamide will start at 200 mg (4 tablets) per day on day 1 and will be taken for 7 days every other week of a 28 day cycle. Subjects will take 12 mg (12 tablets) of sirolimus on day 1 of treatment as a loading dose followed by 4 mg (4 tablets) daily continuously; Other Names: Sirolimus (rapamycin, Rapamune)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Alive Without Disease Progression	Patients who were evaluable for response to therapy, alive and without evidence of sarcoma disease progression. Target lesions followed were lesions that had progressed by World Health Organization (WHO) criteria. Disease progression is defined as a greater than or equal to 25% increase in the sum of the product of target lesions, or unequivocal progression of non-target lesions or the appearance of new tumor lesions >10mm.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Overall Survival Time	Median overall duration of survival.	48 weeks

Collaborators and Investigators

• Sponsor: University of Michigan Rogel Cancer Center
• Investigators: Principal Investigator: Scott Schuetze, MD, PhD, University of Michigan Rogel Cancer Center

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: August 27, 2008
• First Submitted That Met QC Criteria: August 28, 2008
• First Posted (Estimate): August 29, 2008

Study Record Updates

• Last Update Posted (Estimate): September 28, 2015
• Last Update Submitted That Met QC Criteria: August 31, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: Cyclophosphamide; Sirolimus; sarcoma; Progressive or recurrent, advanced (unresectable or metastatic) high-grade osteosarcoma, Ewing's or soft tissue sarcoma previously treated with chemotherapy.
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Sarcoma; Osteosarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Cyclophosphamide; Sirolimus
• Other Study ID Numbers: UMCC 2008.049