Sirolimus and Cyclosporine for Treatment-Resistant Aplastic Anemia

Anemia, Aplastic Clinical Trial

Official title:

A Phase I/II Trial of Sirolimus (Rapamune) and Cyclosporine in Patients With Refractory Aplastic Anemia

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

• Anemia
• Anemia, Aplastic

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