A Phase II Study of Oral Cyclophosphamide and Sirolimus (OCR) in Advanced Sarcoma
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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 Design
Arms and Interventions
| 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:
|
Outcome Measures
Primary Outcome Measures
- Number of Patients Alive Without Disease Progression [6 months]
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.
Secondary Outcome Measures
- Median Overall Survival Time [48 weeks]
Median overall duration of survival.
Eligibility Criteria
Criteria
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.
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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.
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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.
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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.
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Active second malignancy other than carcinoma in situ. Patients with malignancy other than sarcoma in remission are eligible.
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Women who are pregnant or breastfeeding.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Michigan | Ann Arbor | Michigan | United States | 48109 |
Sponsors and Collaborators
- University of Michigan Rogel Cancer Center
Investigators
- Principal Investigator: Scott Schuetze, MD, PhD, University of Michigan Rogel Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- UMCC 2008.049
Study Results
Participant Flow
| Recruitment Details | Participants came in to the University of Michigan Health System outpatient Hematology/Oncology clinic and were consented to participate in this research project after a description of the research was presented by their physician. Forty-nine eligible patients were enrolled from September 2008 to December 2009. |
|---|---|
| Pre-assignment Detail | Eligible participants previously treated with chemotherapy underwent screening. Fifty-one patients were consented, 49 enrolled. |
| Arm/Group Title | Oral Cyclophosphamide and Sirolimus (OCR) |
|---|---|
| Arm/Group Description | Sarcoma patients were given oral Cyclophosphamide and Sirolimus (OCR) in 28 day cycles. 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 |
| Period Title: Overall Study | |
| STARTED | 49 |
| COMPLETED | 47 |
| NOT COMPLETED | 2 |
Baseline Characteristics
| Arm/Group Title | Oral Cyclophosphamide and Sirolimus (OCR) |
|---|---|
| Arm/Group Description | Sarcoma patients were given oral Cyclophosphamide and Sirolimus (OCR) in 28 day cycles. 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 |
| Overall Participants | 49 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
40
81.6%
|
| >=65 years |
9
18.4%
|
| Age (years) [Median (Full Range) ] | |
| Median (Full Range) [years] |
57
|
| Sex: Female, Male (Count of Participants) | |
| Female |
21
42.9%
|
| Male |
28
57.1%
|
| Region of Enrollment (participants) [Number] | |
| United States |
49
100%
|
Outcome Measures
| Title | Number of Patients Alive Without Disease Progression |
|---|---|
| Description | 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. |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients that tolerated and completed at least one 28 day cycle of therapy were considered evaluable |
| Arm/Group Title | Oral Cyclophosphamide and Sirolimus (OCR) |
|---|---|
| Arm/Group Description | Sarcoma patients were given oral Cyclophosphamide and Sirolimus (OCR) in 28 day cycles. 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 |
| Measure Participants | 47 |
| Number [participants] |
10
20.4%
|
| Title | Median Overall Survival Time |
|---|---|
| Description | Median overall duration of survival. |
| Time Frame | 48 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| All patients who completed at least one 28 day cycle |
| Arm/Group Title | Oral Cyclophosphamide and Sirolimus (OCR) |
|---|---|
| Arm/Group Description | Sarcoma patients were given oral Cyclophosphamide and Sirolimus (OCR) in 28 day cycles. 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 |
| Measure Participants | 47 |
| Median (95% Confidence Interval) [days] |
298
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Oral Cyclophosphamide and Sirolimus (OCR) | |
| Arm/Group Description | Sarcoma patients were given oral Cyclophosphamide and Sirolimus (OCR) in 28 day cycles. 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 | |
All Cause Mortality |
||
| Oral Cyclophosphamide and Sirolimus (OCR) | ||
| Affected / at Risk (%) | # Events | |
| Total | / (NaN) | |
Serious Adverse Events |
||
| Oral Cyclophosphamide and Sirolimus (OCR) | ||
| Affected / at Risk (%) | # Events | |
| Total | 17/49 (34.7%) | |
| Cardiac disorders | ||
| Hypotension | 1/49 (2%) | 1 |
| Gastrointestinal disorders | ||
| Dehydration | 1/49 (2%) | 1 |
| Distension/bloating, abdominal | 1/49 (2%) | 1 |
| Enteritis (inflammation of the small bowel) | 1/49 (2%) | 1 |
| Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation) | 1/49 (2%) | 1 |
| Pain | 1/49 (2%) | 1 |
| General disorders | ||
| Fatigue | 1/49 (2%) | 1 |
| Fever | 4/49 (8.2%) | 4 |
| Death | 2/49 (4.1%) | 2 |
| Pain - Other | 1/49 (2%) | 1 |
| Hepatobiliary disorders | ||
| Cholecystitis | 1/49 (2%) | 1 |
| Infections and infestations | ||
| Infection with Grade 3 or 4 neutrophils | 2/49 (4.1%) | 2 |
| Infection with normal ANC or Grade 1 or 2 neutrophils | 1/49 (2%) | 1 |
| Metabolism and nutrition disorders | ||
| Potassium, serum-high (hyperkalemia) | 1/49 (2%) | 1 |
| Potassium, serum-low (hypokalemia) | 1/49 (2%) | 1 |
| Musculoskeletal and connective tissue disorders | ||
| Pain | 1/49 (2%) | 1 |
| Nervous system disorders | ||
| Confusion | 1/49 (2%) | 1 |
| Renal and urinary disorders | ||
| Urinary retention (including neurogenic bladder) | 1/49 (2%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea (shortness of breath) | 2/49 (4.1%) | 2 |
| Hypoxia | 1/49 (2%) | 1 |
| Vascular disorders | ||
| Hemorrhage, CNS | 1/49 (2%) | 1 |
| Hemorrhage, pulmonary/upper respiratory | 1/49 (2%) | 1 |
| Thrombosis/thrombus/embolism | 2/49 (4.1%) | 2 |
Other (Not Including Serious) Adverse Events |
||
| Oral Cyclophosphamide and Sirolimus (OCR) | ||
| Affected / at Risk (%) | # Events | |
| Total | 36/49 (73.5%) | |
| Blood and lymphatic system disorders | ||
| Hemoglobin | 19/49 (38.8%) | 31 |
| Leukocytes (total WBC) | 10/49 (20.4%) | 17 |
| Lymphopenia | 25/49 (51%) | 42 |
| Neutrophils/granulocytes (ANC/AGC) | 8/49 (16.3%) | 9 |
| Platelets | 6/49 (12.2%) | 10 |
| Gastrointestinal disorders | ||
| Diarrhea | 4/49 (8.2%) | 4 |
| Nausea | 8/49 (16.3%) | 8 |
| Vomiting | 4/49 (8.2%) | 4 |
| General disorders | ||
| Fatigue | 11/49 (22.4%) | 12 |
| Fever | 5/49 (10.2%) | 5 |
| Pain | 3/49 (6.1%) | 3 |
| Investigations | ||
| Mucositis/stomatitis (clinical exam) | 3/49 (6.1%) | 3 |
| Creatinine | 4/49 (8.2%) | 6 |
| Triglyceride, serum-high (hypertriglyceridemia) | 3/49 (6.1%) | 4 |
| Metabolism and nutrition disorders | ||
| Weight loss | 3/49 (6.1%) | 3 |
| Glucose, serum-high (hyperglycemia) | 6/49 (12.2%) | 9 |
| Renal and urinary disorders | ||
| Cystitis | 3/49 (6.1%) | 3 |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea (shortness of breath) | 5/49 (10.2%) | 5 |
| Vascular disorders | ||
| Thrombosis/thrombus/embolism | 3/49 (6.1%) | 3 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Scott Schuetze |
|---|---|
| Organization | University of Michigan |
| Phone | 734-647-8925 |
| scotschu@umich.edu |
- UMCC 2008.049