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Sirolimus (Rapamune ) for Relapse Prevention in People With Severe Aplastic Anemia Responsive to Immunosuppressive Therapy

Primary Purpose

Severe Aplastic Anemia

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sirolimus
Sponsored by
National Heart, Lung, and Blood Institute (NHLBI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Severe Aplastic Anemia focused on measuring Rapamycin, Relapse Prevention, Immune Tolerance

Eligibility Criteria

2 Years - 99 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • 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 cytogenetics, 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.

Sites / Locations

  • National Institutes of Health Clinical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Sirolimus

Standard of Care

Arm Description

sirolimus

no intervention

Outcomes

Primary Outcome Measures

To determine if the rate of relapse at 24 months after CSA discontinuation can be improved by conversion to sirolimus in severe aplastic anemia patients who have responded to IST.
Rate of relapse in both arms

Secondary Outcome Measures

Safety and tolerability of sirolimus.

Full Information

First Posted
December 1, 2016
Last Updated
October 24, 2023
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT02979873
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 23, 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 19, 2016 (Actual)
Primary Completion Date
August 31, 2024 (Anticipated)
Study Completion Date
August 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Aplastic Anemia
Keywords
Rapamycin, Relapse Prevention, Immune Tolerance

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
118 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Sirolimus
Arm Type
Experimental
Arm Description
sirolimus
Arm Title
Standard of Care
Arm Type
No Intervention
Arm Description
no intervention
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Intervention Description
Sirolimus will be started on day 1 for subjects in the Sirolimus arm. A baseline CBC will be obtained within one week of randomization, or on Day 0. Thereafter, CBC will be monitored on a weekly basis for subjects in both arms. In the event of relapse (see definition of outcomes Section 6.7), the patient shall return to the NIH CRC for evaluation to include bone marrow biopsy and aspirate to exclude clonal evolution to MDS. Assessment will include (i) flow cytometry phenotyping of peripheral blood mononuclear cells for regulatory T-cells (Tregs, e.g. CD4+ CD25high FOXP3+) and regulatory dendritic cells (DCregs) and (ii) proteomics assay (research labs).
Primary Outcome Measure Information:
Title
To determine if the rate of relapse at 24 months after CSA discontinuation can be improved by conversion to sirolimus in severe aplastic anemia patients who have responded to IST.
Description
Rate of relapse in both arms
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Safety and tolerability of sirolimus.
Time Frame
3 mo

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: Age greater than or equal to 2 years old Weight greater than 12 kg Previous diagnosis of SAA by bone marrow biopsy and cytogenetics, treated with lymphodepleting therapy ATG, cyclophosphamide or alemtuzumab that included cyclosporine. The lymphodepleting therapy must have been administered at least 12 months prior. Continuous treatment with cyclosporine for the previous 6 months (excluding minor dose delays not exceeding more than 30 days). 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: Evidence of relapse of aplastic anemia due to cyclosporine withdrawal during the previous 6 months Prior use of sirolimus or other mTOR inhibitor within 12 weeks of study entry 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) 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. Anaphylactic or hypersensitivity reaction to sirolimus 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. 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ivana Darden, R.N.
Phone
(301) 827-2988
Email
ivana.darden@nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Bhavisha A Patel, M.D.
Phone
(301) 402-3477
Email
bhavisha.patel@nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bhavisha A Patel, M.D.
Organizational Affiliation
National Heart, Lung, and Blood Institute (NHLBI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY8664111010
Email
prpl@cc.nih.gov

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
.This is a new requirement and the sharing of IPD is not discussed in the protocol.
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2017-H-0019.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

Sirolimus (Rapamune ) for Relapse Prevention in People With Severe Aplastic Anemia Responsive to Immunosuppressive Therapy

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