Brief Title
Sirolimus (Rapamune ) for Relapse Prevention in People With Severe Aplastic Anemia Responsive to Immunosuppressive Therapy
Official Title
A Randomized Trial of Sirolimus (Rapamune(R)) for Relapse Prevention in Patients With Severe Aplastic Anemia Responsive to Immunosuppressive Therapy
Brief Summary
Background:
People with severe aplastic anemia (SAA) do not make enough red and white blood cells, and/or
platelets. Their body's immune system stops the bone marrow from making these cells. The
treatment cyclosporine leads to better blood counts. But when this treatment is stopped, the
disease may return in 1 in 3 people. The drug sirolimus may help by suppressing the immune
system.
Objective:
To evaluate and compare the usefulness of sirolimus in preventing aplastic anemia from
returning after cyclosporine is stopped, compared with stopping cyclosporine alone.
Eligibility:
People ages 2 and older with SAA who:
Have responded to immunosuppressive therapy that includes cyclosporine, and continue to take
cyclosporine
Are not taking drugs with hematologic effects
Design:
Participants will be screened with:
Medical history
Physical exam
Blood and urine tests
Bone marrow biopsy: The area above the hipbone will be numbed. A thin needle will remove
some bone marrow.
Participants will be randomly assigned to a group. All will stop cyclosporine. Group 1 will
take sirolimus by mouth at the same time each day for 3 months with close monitoring. Group 2
will not receive the study drug but will be monitored closely.
Participants will have clinical tests for the first 3 months:
Weekly blood test
Monthly fasting blood test
For group 1, measurements of sirolimus in the blood every 1 2 weeks
Participants will have clinic visits at 3 months, 12 months, and annually for 5 years after
the study starts. They may have another visit if their SAA returns. These will include:
Blood and urine tests
Bone marrow biopsy
Detailed Description
- Most acquired aplastic anemia ensues from immune-mediated destruction of hematopoietic
stem and progenitor cells
- Immunosuppression is the definitive treatment of patients with acquired aplastic anemia
who are not candidates for immediate hematopoietic stem cell transplantation.
- Horse ATG combined with the calcineurin inhibitor, cyclosporine (CsA), remains standard
as first-line immunosuppressive therapy (IST).
- Hematologic responses to transfusion independence occur in about two thirds of patients
with standard IST and in 80-90% of patients treated with IST in combination with the
growth factor eltrombopag.
- About 30% to 40% of patients relapse after discontinuation of cyclosporine. Many achieve
disease control after the reinitiation of CSA, but remain CSA dependent indefinitely.
- Evidence from mouse models of bone marrow failure indicates that conversion from
cyclosporine to the mTOR inhibitor, sirolimus (SRL), results in immune tolerance which
can endure the eventual withdrawal of SRL.
- We hypothesize that CSA to SRL conversion will significantly decrease the relapse rate
after immunosuppressive therapy for acquired aplastic anemia.
- This study will investigate the safety and efficacy of SRL for preventing relapse in
patients previously treated with IST who remain on CSA. The primary endpoint is rate of
relapse at 2 years following conversion from CSA to SRL, versus stopping CSA.
- Biological sampling of peripheral blood and bone marrow aspirates during treatment will
be used to investigate changes to lymphocyte phenotypes and cytokine profiles.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
To determine if the rate of relapse at 24 months after CSA discontinuation can be improved by conversion to sirolimus in severeaplastic anemia patients who have responded to IST.
Secondary Outcome
Safety and tolerability of sirolimus.
Condition
Severe Aplastic Anemia
Intervention
Sirolimus
Study Arms / Comparison Groups
Sirolimus
Description: sirolimus
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
118
Start Date
December 19, 2016
Completion Date
August 31, 2023
Primary Completion Date
August 31, 2023
Eligibility Criteria
- INCLUSION CRITERIA:
1. Age greater than or equal to 2 years old
2. Weight greater than 12 kg
3. Previous diagnosis of SAA by bone marrow biopsy and cytogenics, treated with
lymphodepleting therapy ATG, cyclophosphamide or alemtuzumab that included
cyclosporine. The lymphodepleting therapy must have been administered at least 12
months prior.
4. Continuous treatment with cyclosporine for the previous 6 months (excluding minor
dose delays not exceeding more than 30 days).
5. Evidence of a hematologic response to an lymphodepletion-based regimen as
evidence of at least two of the following:
- Absolute neutrophil count greater than or equal to 500/uL
- Platelet count greater than or equal to 20,000/uL (without transfusion support)
- Absolute reticulocyte count greater than or equal to 60,000/uL (or hemoglobin 10 gm/dL
without transfusion support)
EXCLUSION CRITERIA:
1. Evidence of relapse of aplastic anemia due to cyclosporine withdrawal during the
previous 6 months
2. Prior use of sirolimus or other mTOR inhibitor within 12 weeks of study entry
3. Myelodysplastic syndrome or acute myeloid leukemia, according to WHO diagnostic
criteria (if baseline BM consistent with MDS after enrollment, patients will be
considered ineligible and immediately exit the study, and the subject can be replaced
with another subject)
4. Patients that are on CYP3A4 inhibitors and cannot replace these medications with other
equivalent medications for the period of study: protease inhibitors (ritonavir,
indinavir, nelfinavir, saquinavir), some macrolide antibiotics (clarithromycin,
telithromycin, erythromycin), azole anti-fungals (fluconazole, itraconazole,
ketoconazole), metroclopramide, felodipine, nifedipine, carbamazepine, phenobarbital,
grapefruit juice and St. John s Wort.
5. Anaphylactic or hypersensitivity reaction to sirolimus
6. Patients with infections not adequately responding to appropriate therapy as evidenced
by persistence of a clear source of infection that, in the view of the investigator,
would preclude safe treatment with sirolimus.
7. Current pregnancy, or unwillingness to take oral contraceptives or use the barrier
methods of birth control or practice abstinence to refrain from pregnancy if of
childbearing potential during the course of the study 8. Lactating women, due to the
potentially harmful effects on the nursing child.
9. Patients who have received live vaccines within the past 30 days
10. Patients with cancer who are actively receiving chemotherapeutic treatment or who take
drugs with hematological effects such as thrombopoietin receptor agonists (such as
eltrombopag), granulocyte-colony stimulating factor or erythroid stimulating agents.
11. Moribund status such that death within 7 to 10 days is likely. Comorbidities of such
severity that in the view of the Investigator it would likely preclude the patient's
ability to tolerate sirolimus.
12. Inability to understand the investigational nature of the study or to give informed
consent or without a legally authorized representative or surrogate that can provide
informed consent.
Gender
All
Ages
2 Years - 99 Years
Accepts Healthy Volunteers
No
Contacts
Neal S Young, M.D., (301) 827-2988, [email protected]
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT02979873
Organization ID
170019
Secondary IDs
17-H-0019
Responsible Party
Sponsor
Study Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
Study Sponsor
Neal S Young, M.D., Principal Investigator, National Heart, Lung, and Blood Institute (NHLBI)
Verification Date
March 23, 2021