A Randomized Trial of a Novel Immunosuppressive Combination of ATG, CsA and Sirolimus (Rapamune) vs a Slow Taper Cyclosporine Regimen in Subjects With Severe Aplastic Anemia
Improving Immunosuppressive Treatment for Patients With Severe Aplastic Anemia
Sponsors
Source
National Institutes of Health Clinical Center (CC)
Oversight Info
Is Fda Regulated Drug
Yes
Is Fda Regulated Device
No
Brief Summary
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized
by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation and
immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA) have
dramatically changed the natural course of this illness, with 5 year survival of 75% in
patients undergoing either treatment. Since most patients are not suitable candidates for
hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a
histocompatible sibling, efforts at NHLBI have focused on improving immunosuppression
treatment in order to improve response rates, survival, and to decrease relapse.
In our experience of 122 patients treated at NHLBI with the combination of ATG and
cyclosporine, one quarter to one third did not respond; about 50% of responders relapsed; and
5 year survival was correlated with the robustness in blood cell count improvement at 3
months (reticulocyte or platelet count greater than or equal to 50,000 /uL). Why some
patients do not respond initially while others relapse is unclear. Autoreactive T cells may
be resistant to the effect of ATG/CsA (nonresponders), while in others residual autoreactive
T cells expand post-treatment leading to hematopoietic stem cell destruction and recurrent
pancytopenia (relapse). Therefore, novel immunosuppressive regimens to increase response
rates and hematologic recovery at 3 months and to decrease relapse rates are needed. An
ongoing NHLBI trial, which is close to completing accrual, has added mycophenolate mofetil
(MMF) for a total of 18 months to standard ATG + CsA in an attempt to reduce the relapse rate
after cyclosporine is discontinued. Preliminary results have been disappointing, with no
marked reduction in relapse among patients who received MMF.
Sirolimus (rapamycin, Rapamune , RAPA) is a novel immunosuppressive agent, which acts
synergistically with cyclosporine by blocking T cell activation through CsA-resistant
pathways. The potentiation of the combination of CsA-RAPA has been established in vitro and
in the clinical setting, mainly in islet cell and solid organ transplantation. The
significant increase in response rate seen with the addition of CsA to ATG indicated that an
inhibitory effect on T lymphocytes is important in blocking autoreactive T cells in aplastic
anemia. The combination of CsA-RAPA may further block activated autoreactive T cells and
therefore lead to improved response rates (and survival) and decreased relapse rates.
This prospective randomized phase II study will investigate two different immunosuppressive
regimens in patients with severe aplastic anemia who have not received prior
immunosuppressive therapy. One arm will receive ATG + CsA in addition to sirolimus for 6
months, and the second arm will receive standard ATG + CsA for 6 months followed by a slow
taper of CsA with a 25% dose reduction every 3 months for the subsequent 18 months. This
trial will determine the effectiveness of sirolimus in patients with aplastic anemia as well
as the role of a cyclosporine taper in preventing relapses. Primary endpoint will be no
longer meeting criteria for severe aplastic anemia while secondary endpoints are relapse,
robustness of hematologic recovery at 3 months, survival, clonal evolution to PNH,
myelodysplasia and acute leukemia.
10/11/2005. The Sirolimus (Rapamune) arm of the trial was stopped for lack of efficacy. The
study will continue as a single arm study to establish if slow taper of CsA prevents relapse
rates after initial standard treatment with ATG followed by CsA for six months.
Detailed Description
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized
by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation and
immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA) have
dramatically changed the natural course of this illness, with 5 year survival of 75% in
patients undergoing either treatment. Since most patients are not suitable candidates for
hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a
histocompatible sibling, efforts at NHLBI have focused on improving immunosuppression
treatment in order to improve response rates, survival, and to decrease relapse.
In our experience of 122 patients treated at NHLBI with the combination of ATG and
cyclosporine, one quarter to one third did not respond; about 50% of responders relapsed; and
5 year survival was correlated with the robustness in blood cell count improvement at 3
months (reticulocyte or platelet count greater than or equal to 50,000 /uL). Why some
patients do not respond initially while others relapse is unclear. Autoreactive T cells may
be resistant to the effect of ATG/CsA (nonresponders), while in others residual autoreactive
T cells expand post-treatment leading to hematopoietic stem cell destruction and recurrent
pancytopenia (relapse). Therefore, novel immunosuppressive regimens to increase response
rates and hematologic recovery at 3 months and to decrease relapse rates are needed. An
ongoing NHLBI trial, which is close to completing accrual, has added mycophenolate mofetil
(MMF) for a total of 18 months to standard ATG + CsA in an attempt to reduce the relapse rate
after cyclosporine is discontinued. Preliminary results have been disappointing, with no
marked reduction in relapse among patients who received MMF.
Sirolimus (rapamycin, Rapamune , RAPA) is a novel immunosuppressive agent, which acts
synergistically with cyclosporine by blocking T cell activation through CsA-resistant
pathways. The potentiation of the combination of CsA-RAPA has been established in vitro and
in the clinical setting, mainly in islet cell and solid organ transplantation. The
significant increase in response rate seen with the addition of CsA to ATG indicated that an
inhibitory effect on T lymphocytes is important in blocking autoreactive T cells in aplastic
anemia. The combination of CsA-RAPA may further block activated autoreactive T cells and
therefore lead to improved response rates (and survival) and decreased relapse rates.
This prospective randomized phase II study will investigate two different immunosuppressive
regimens in patients with severe aplastic anemia who have not received prior
immunosuppressive therapy. One arm will receive ATG + CsA in addition to sirolimus for 6
months, and the second arm will receive standard ATG + CsA for 6 months followed by a slow
taper of CsA with a 25% dose reduction every 3 months for the subsequent 18 months. This
trial will determine the effectiveness of sirolimus in patients with aplastic anemia as well
as the role of a cyclosporine taper in preventing relapses. Primary endpoint will be no
longer meeting criteria for severe aplastic anemia while secondary endpoints are relapse,
robustness of hematologic recovery at 3 months, survival, clonal evolution to PNH,
myelodysplasia and acute leukemia.
10/11/2005. The Sirolimus (Rapamune) arm of the trial was stopped for lack of efficacy. The
study will continue as a single arm study to establish if slow taper of CsA prevents relapse
rates after initial standard treatment with ATG followed by CsA for six months.
3/2/2006. The protocol was closed to new accrual.
Overall Status
Completed
Start Date
2003-05-23
Completion Date
2015-09-08
Primary Completion Date
2005-11-15
Phase
Phase 2
Study Type
Interventional
Primary Outcome
Measure |
Time Frame |
|
Hematologic recovery in patients with severe aplastic anemia treated with a novel immunosuppressive combination of ATG, CsA and sirolimus. |
2 yrs |
Enrollment
77
Condition
Intervention
Eligibility
Criteria
- INCLUSION CRITERIA:
Severe aplastic anemia confirmed at NIH by:
1. . Bone marrow cellularity less than 30% (excluding lymphocytes)
2. . At least two of the following: Absolute neutrophil count less than 500/ uL; Platelet
count less than 20,000/ uL; Absolute reticulocyte count less than 60,000/ uL
Age greater than or equal to 2 years old
Weight greater than 12 kg
EXCLUSION CRITERIA:
Serum creatinine greater than 2.5 mg/dL
Underlying carcinoma (except local cervical, basal cell, squamous cell)
Prior immunosuppressive therapy with ATG, ALG, or high dose cyclophospamide.
Current pregnancy or lactation or unwillingness to take oral contraceptives or use an
effective method of birth control.
Diagnosis of Fanconi anemia or other congenital bone marrow failure syndromes
Evidence of a clonal disorder on cytogenetics. Patients with super severe neutropenia (ANC
less than 200/uL) will not be excluded if results of cytogenetics are not available or
pending.
Underlying immunodeficiency state including seropositivity for HIV
Inability to understand the investigational nature of the study or give informed consent
Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious,
or metabolic disease of such severity that it would preclude the patient s ability to
tolerate protocol therapy, or that death within 7-10 days is likely.
Gender
All
Minimum Age
2 Years
Maximum Age
110 Years
Healthy Volunteers
No
Overall Official
Last Name |
Role |
Affiliation |
|
Neal S Young, M.D. |
Principal Investigator |
National Heart, Lung, and Blood Institute (NHLBI) |
Location
Facility |
|
National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland 20892 United States |
Location Countries
Country
United States
Verification Date
2018-07-25
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Sponsor
Keywords
Has Expanded Access
No
Condition Browse
Secondary Id
03-H-0193
Number Of Arms
2
Intervention Browse
Mesh Term
Cyclosporins
Cyclosporine
Immunosuppressive Agents
Sirolimus
Everolimus
Arm Group
Arm Group Label
ATG+CsA+RA
Arm Group Type
Experimental
Description
ATG+CsA+RAPA for 6 months
Arm Group Label
ATG+CsA
Arm Group Type
Experimental
Description
ATG+CsA for 6 months followed by a slow CsA taper in the subsequent 18 months
Firstreceived Results Date
N/A
Reference
Citation
Bacigalupo A, Brand R, Oneto R, Bruno B, Socié G, Passweg J, Locasciulli A, Van Lint MT, Tichelli A, McCann S, Marsh J, Ljungman P, Hows J, Marin P, Schrezenmeier H. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy--The European Group for Blood and Marrow Transplantation experience. Semin Hematol. 2000 Jan;37(1):69-80. Review.
PMID
10676912
Citation
Young NS. Acquired aplastic anemia. Ann Intern Med. 2002 Apr 2;136(7):534-46. Review.
PMID
11926789
Citation
Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997 May 8;336(19):1365-72. Review.
PMID
9134878
Firstreceived Results Disposition Date
N/A
Study Design Info
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)
Study First Submitted
May 23, 2003
Study First Submitted Qc
May 23, 2003
Study First Posted
May 26, 2003
Last Update Submitted
August 11, 2018
Last Update Submitted Qc
August 11, 2018
Last Update Posted
August 14, 2018
ClinicalTrials.gov processed this data on August 31, 2018
Conditions
Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov,
conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.