Brief Title
Sirolimus and Cyclosporine for Treatment-Resistant Aplastic Anemia
Official Title
A Phase I/II Trial of Sirolimus (Rapamune) and Cyclosporine in Patients With Refractory Aplastic Anemia
Brief 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.
Detailed 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.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Safety and tolerability of sirolimus and cyclosporine in each stratum of participants
Secondary Outcome
Response rate
Condition
Anemia, Aplastic
Intervention
Sirolimus
Study Arms / Comparison Groups
1
Description: Participants will be treated with sirolimus and cyclosporine. In phase I, each dose cohort will initially enroll three patients. If no dose-limiting toxicity (DLT) is observed by Day 28 in any patient of a cohort, then 3 patients will be treated with the next highest sirolimus dose. If 1 out of 3 patients in any cohort experiences a DLT, then 3 more patients will be enrolled in that cohort. If no more patients have a DLT by Day 28, then sirolimus dose escalation will proceed. If one or more patients experience a DLT then that dose level will be considered to be the maximum tolerated sirolimus dose, and Phase II patients will be treated at the next lowest level. Cyclosporine will be given as a twice daily oral dose.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
52
Start Date
May 2006
Completion Date
December 2009
Primary Completion Date
July 2009
Eligibility Criteria
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
Gender
All
Ages
21 Years - N/A
Accepts Healthy Volunteers
No
Contacts
, 310-794-0738,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00319878
Organization ID
RDCRN 5403
Secondary IDs
U54RR019397-01
Study Sponsor
Office of Rare Diseases (ORD)
Collaborators
Rare Diseases Clinical Research Network
Study Sponsor
, ,
Verification Date
October 2008