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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT00319878
Other study ID # RDCRN 5403
Secondary ID U54RR019397-01BM
Status Recruiting
Phase Phase 1/Phase 2
First received April 28, 2006
Last updated October 6, 2008
Start date May 2006
Est. completion date December 2009

Study information

Verified date October 2008
Source Office of Rare Diseases (ORD)
Contact Lynn Tihopu
Phone 310-794-0738
Is FDA regulated No
Health authority United States: Federal Government
Study type Interventional

Clinical Trial Summary

Aplastic anemia is a rare autoimmune disorder in which the bone marrow production of blood cells is greatly decreased or absent. Symptoms include fatigue, weakness, tiny reddish-purple marks on the skin, abnormal bruising, and bleeding from the gums, nose, or intestine. While some cases of aplastic anemia are caused by medications, toxic exposures, or inherited genes, most often the cause remains unknown. The purpose of this study is to determine the safety and efficacy of combining two drugs, sirolimus and cyclosporine, for treating individuals with aplastic anemia that has not responded to other treatments.


Description:

The most successful treatment for aplastic anemia is bone marrow transplantation. However, few patients are eligible for this procedure. For others, treatment usually consists of immunosuppressive agents, such as antithymocyte globulin (ATG) and cyclosporine. Unfortunately, even with immunosuppressive therapy, relapse is common. New combinations of medications may offer alternative and more effective treatment options. Sirolimus and cyclosporine are two drugs routinely used to suppress the immune system and prevent rejection in patients who have received organ transplants. While cyclosporine has been proven effective for treating aplastic anemia, sirolimus has not been tested for this disease. This study will evaluate the safety and efficacy of sirolimus in combination with cyclosporine for treating individuals with aplastic anemia that has not responded to other treatments.

This study will last at least 6 months. Participants will first be screened to verify diagnosis of aplastic anemia. The screening will include a physical examination, blood test, bone marrow biopsy from the pelvic bone, and review of medications and medical history. Individuals who are eligible will then start the first treatment period. Participants will receive two medications: cyclosporine will be taken twice a day and sirolimus will be taken once a day. Depending on side effects, the doses of either drug may be temporarily stopped or lowered. On Day 1, blood will be drawn and females will undergo a pregnancy test. Subsequent study visits will occur weekly for the first month, every 2 weeks for 2 months, and then once a month for the remainder of the study. Each visit will include a physical examination, vital sign assessment, and review of side effects and medications. Blood tests will be performed weekly for the first 3 weeks, and then every 2 weeks.

After 6 months of treatment, if a participant has shown improvements in disease status without major side effects, the treatment will continue. Over time the doses may be lowered. If a participant has not improved while on the study medication, treatment will stop at 6 months. Whenever treatment is discontinued, the participant will again undergo a physical examination, blood tests, and bone marrow biopsy.


Recruitment information / eligibility

Status Recruiting
Enrollment 52
Est. completion date December 2009
Est. primary completion date July 2009
Accepts healthy volunteers No
Gender Both
Age group 21 Years and older
Eligibility Inclusion Criteria:

- Diagnosis of moderate or severe aplastic anemia with bone marrow cellularity of less than 25%

- Falls within one of the following descriptions at the time of the original diagnosis:

1. For severe aplastic anemia, fulfills any two of the following three criteria: absolute neutrophil count less than 500/uL; absolute reticulocyte count less than 60,000/uL; and platelet count less than 20,000/uL

2. For moderate aplastic anemia, fulfills any two of the following three criteria: absolute neutrophil count less than 1200/ul; hemoglobin less than 8 g/dL with corrected reticulocyte count less than 1%; and platelet count less than 60,000/uL (Note: Participants who have progressed from moderate to severe aplastic anemia prior to study entry will be classified as having severe aplastic anemia)

- Diagnosis of refractory aplastic anemia, as defined by a failure to achieve at least a partial response to ATG within 6 months of treatment. Individuals who had a prior response to ATG but who have relapsed and not responded to salvage ATG are eligible. Individuals with relapsed disease who are not candidates for salvage ATG because they experienced a serious or life-threatening complication prior to ATG are also eligible.

- A Karnofsky performance status of at least 60%

- Adequate organ function, as defined by creatine levels less than 1.5 times the upper limit normal (ULN), and liver function tests (AST, bilirubin) less than 2 times the ULN

- Women of childbearing age must be willing to use effective contraception throughout the study

Exclusion Criteria:

- Received ATG treatment less than 6 months prior to study entry

- Candidate for related allogeneic stem cell transplantation

- Active uncontrolled infection

- History of myelodysplastic syndrome or bone marrow cytogenetic abnormalities

- History of Fanconi's anemia or other congenital form of aplastic anemia

- Treatment with an investigational agent within 1 month of study entry

- HIV infection

- Pregnant or breastfeeding

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment


Related Conditions & MeSH terms


Intervention

Drug:
Sirolimus
Oral loading dose followed by a once daily dose: Cohort 1: Loading Dose - 1.2 mg; Daily Dose - 0.4 mg Cohort 2: % Dose Increase - 100%; Loading Dose - 2.4 mg; Daily Dose - 0.8 mg Cohort 3: % Dose Increase - 67%; Loading Dose - 3.9 mg; Daily Dose - 1.3 mg Cohort 4: % Dose Increase - 50%; Loading Dose - 6.0 mg; Daily Dose - 2.0 mg
Cyclosporine
Dose of 5 mg/kg divided as a twice daily oral dose

Locations

Country Name City State
United States Taussig Cancer Center, Cleveland Clinic Foundation Cleveland Ohio
United States Penn State University Cancer Center Hershey Pennsylvania
United States UCLA Center for Health Sciences Los Angeles California
United States Lee Moffitt Cancer Center Tampa Florida

Sponsors (2)

Lead Sponsor Collaborator
Office of Rare Diseases (ORD) Rare Diseases Clinical Research Network

Country where clinical trial is conducted

United States, 

References & Publications (4)

Brodsky RA, Chen AR, Brodsky I, Jones RJ. High-dose cyclophosphamide as salvage therapy for severe aplastic anemia. Exp Hematol. 2004 May;32(5):435-40. — View Citation

Maciejewski JP, Risitano AM. Aplastic anemia: management of adult patients. Hematology Am Soc Hematol Educ Program. 2005:110-7. — View Citation

Paquette RL. Diagnosis and management of aplastic anemia and myelodysplastic syndrome. Oncology (Williston Park). 2002 Sep;16(9 Suppl 10):153-61. Review. — View Citation

Young NS. Immunosuppressive treatment of acquired aplastic anemia and immune-mediated bone marrow failure syndromes. Int J Hematol. 2002 Feb;75(2):129-40. Review. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary Safety and tolerability of sirolimus and cyclosporine in each stratum of participants Measured at Month 6 Yes
Secondary Response rate Measured at Months 3 and 6 No
Secondary Duration of hematologic response Measured at Month 6 No
Secondary Rate of clonal disease evolution Measured at Month 6 No
Secondary Survival Measured at Month 6 No
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