A Pilot Study of Fludarabine Plus Cyclophosphamide in Refractory Severe Aplastic Anemia
A Pilot Study of Fludarabine Plus Cyclophosphamide in Refractory Severe Aplastic Anemia
Sponsors
Source
National Institutes of Health Clinical Center (CC)
Oversight Info
Has Dmc
Yes
Brief Summary
Background:
- Severe aplastic anemia (SAA) can lead to problems with bone marrow health and result in
low blood cell counts, which require frequent transfusions. Standard initial treatment
for SAA involves injections of antithymocyte globulin (ATG) plus cyclosporine (CsA).
Patients with SAA who do not respond to initial treatment with ATG (refractory) have a
high risk of dying without additional treatment. In these cases, for those who do not
have a matched bone marrow transplant donor there is no well-defined standard therapy.
In our experience with patients who do not respond to horse ATG + CsA, only about
one-third of patients who are re-treated with rabbit ATG + CsA improve. Experience with
cyclophosphamide in the treatment of refractory severe aplastic anemia suggests that
this drug is able to improve blood counts in about 50% of cases. However, the
cyclophosphamide regimen has been associated with a significant infection risk (mostly
caused by fungus) in studies conducted over 10 years ago due to the lowering of the
white blood cell levels.
- Better antibiotic drugs against fungus have been developed and are widely used to treat
patients who have low white blood cell counts and are at risk of developing infections.
In SAA patients in particular, these newer antibiotics have had a large impact in
preventing and treating fungus infections. Researchers are revisiting the use of
cyclophosphamide at lower doses to minimize its side effects given in combination with
another immune suppressant, fludarabine.
Objectives:
- To determine the safety and effectiveness of the combination of fludarabine plus
cyclophosphamide in treating severe aplastic anemia that has not responded to initial
treatments.
Detailed Description
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized
by pancytopenia and a hypocellular bone marrow. Allogeneic hematopoietic stem cell
transplantation (HSCT) offers the opportunity for cure in 70 percent of patients, but most
patients are not suitable candidates for this treatment modality due to advanced age,
comorbidities or lack of a histocompatible donor. For these patients, comparable long-term
survival is attainable with immunosuppressive treatment (IST) with anti-thymocyte globulin
(ATG) and cyclosporine (CsA). However, approximately 1/3 of patients do not show blood count
improvement after ATG/CsA and are considered to have refractory disease. Furthermore,
analysis of our own extensive clinical data suggests that poor blood count responses to a
single course of ATG (nonrobust responders), even when transfusion-independence is achieved,
predicts a markedly worse prognosis compared to those who achieve a robust hematologic
improvement (protocol 90-H-0146) .
In patients who are refractory to horse ATG (h-ATG) and do not have a histocompatible
sibling, alternative donor (AD) HSCT or a repeat course of IST are options. Registry data
suggests that outcome for AD HSCT in SAA is not as favorable compared to a matched sibling
HSCT with long-term survival at about 40-50 percent and a higher risk of graft-versus-host
disease. However, in recent smaller retrospective studies survival after AD HSCT in children
rivals that of a sibling transplant when an unrelated donor who matches in 10 human leukocyte
antigen (HLA) loci (matched unrelated donor) is available. With repeat IST, response rates
with rabbit anti-thymocyte has varied from 22 percent up to 77 percent. Our experience in
refractory SAA (protocol 03-H-0249) is that rabbit ATG + CsA and alemtuzumab are equally
efficacious as salvage therapies, with a response rate of about 30 percent for each
treatment. For the 20-30 percent of patients who remain refractory after 2 courses of
treatment, further courses of IST have been of limited value with responses observed only
occasionally. In addition, efforts to improve initial IST in treatment-na ve patients
(addition of mycophenolate mofetil and sirolimus) have not yielded promising regimens with
activity in SAA (protocols 00-H-0032, 03-H-0193, and 06-H-0034). Therefore, novel regimens
are needed to improve outcomes in SAA for those without a histocompatible sibling, which
encompass the majority of patients with this disease.
The current limitations of IST in SAA are: 1) the majority of the responses observed
following initial h-ATG/CsA are partial with only a few patients achieving normal blood
counts; 2) 1/3 of patients are refractory to initial h-ATG/CsA; 3) response rate in these
refractory patients who are retreated is only 30 percent; 4) hematologic relapses occur in 35
percent of responders following initial response to h-ATG/CsA; 5) among relapsed patients
chronic use of CsA is not infrequent which often leads to toxicities from the long term
exposure to this drug (especially in older patients); and 6) clonal evolution is still
observed in 10-15% of patients. Towards the goal of addressing these limitations we are
proposing a novel regimen of fludarabine (Flu) plus cyclophosphamide (Cy) in SAA patients
refractory to horse ATG/CsA. The Hematology Branch has considerable experience with Flu/Cy as
part of the condition regimen in allotransplantation protocols (protocols 99-H-0050,
97-H-0196, 99-H-0064, 99-H-0050, 97-H-0196, 02-H-0111, 01-H0162, 03-H-0192, 04-H-0112,
06-H-0248, 07-H-0136). In addition, this regimen has been incorporated into the NCI's Surgery
Branch preparative regimen for autologous HSCT prior to infusion of tumor infiltrating
lymphocytes. Flu/Cy is well tolerated and a potent immunosuppressive regimen that is not
myeloablative. Therefore, we propose to investigate Flu/Cy to address the current limitations
of IST in SAA.
The main objective of this study is to assess the safety and efficacy of Flu/Cy in refractory
SAA. The primary endpoint will be hematologic response, defined as no longer meeting criteria
for SAA, at 6 months. Secondary endpoints are relapse, robustness of hematologic recovery at
6 months, response at 3 months and 12 months, survival, clonal evolution to paroxysmal
nocturnal hemoglobinuria (PNH), myelodysplasia and acute leukemia. The primary endpoint will
be changes absolute neutrophil count, platelet count, and reticulocyte count at 6 months.
Secondary endpoints will include time to relapse, changes in cytogenetics, and time to death.
Eligibility:
- Individuals at least 2 years of age who have severe aplastic anemia that has not improved
after treatment with horse ATG or both horse and rabbit ATG.
Design:
- After initial screening, medical history, and blood tests, participants will be admitted
to the inpatient unit at the National Institutes of Health Clinical Center.
- Participants will receive 2 days of cyclophosphamide, followed by 5 days of fludarabine.
- Participants will also receive antibiotics and other drugs to protect against bacterial,
fungal, and viral infections. Participants will take these drugs regularly until their
white blood cell counts improve.
- After discharge from the clinical center, participants will have follow-up evaluations
at 3 months, 6 months, and annually for 5 years. Evaluations will include blood samples
and periodic bone marrow biopsies.
Overall Status
Completed
Start Date
2010-08-01
Completion Date
2012-07-01
Primary Completion Date
2012-07-01
Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Measure |
Time Frame |
|
Response Rate at 6 Months |
6 months |
Secondary Outcome
Measure |
Time Frame |
|
Secondary Endpoints Will Evaluated for the Study to Include: (a) Hematologic Response at 3 and 12 Months and Yearly Thereafter; (b) Relapse (c) Clonal Evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH), Myelodysplasia or Acute Leukemia; (e) Survival. |
12 months |
Enrollment
1
Conditions
Intervention
Intervention Type
Drug
Intervention Name
Description
60 mg/kg
Arm Group Label
Flu/Cy Response at 6 months
Other Name
Cy
Intervention Type
Drug
Intervention Name
Description
125 mg/m squared
Arm Group Label
Flu/Cy Response at 6 months
Other Name
Flu
Eligibility
Criteria
-INCLUSION CRITERIA:
1. Severe aplastic anemia characterized by:
Bone marrow cellularity < 30 percent (excluding lymphocytes)
AND
At least two of the following:
- Absolute neutrophil count < 500/ microL
- Platelet count < 20,000/ microL
- Absolute reticulocyte count < 60,000/ microL
2. Failure to respond to an initial course of h-ATG/CsA at least 3 months post-treatment
or a suboptimal response to initial h-ATG/CsA defined by both platelet and
reticulocyte count < 50,000 /microL at 3 months post-treatment
OR
3. Refractory SAA unresponsive to both horse and rabbit ATG-based regimens
4. Age greater than or equal to 2 years old
5. Weight greater than or equal to 12 kg
EXCLUSION CRITERIA:
1. Diagnosis of Fanconi anemia
2. Cardiac ejection fraction < 30 percent (evaluated by ECHO)
3. Evidence of a clonal hematologic bone marrow disorder on cytogenetics. Patients with
the presence of trisomy 8, loss of Y or del(20q) will not be excluded in the absence
of dysplastic changes in the marrow. Patients with very severe neutropenia (ANC < 200
/microL) will not be excluded initially if cytogenetics are not available or pending.
If evidence of a clonal disorder is later identified, the patient will go off study)
4. Prior immunosuppressive therapy with high dose Cy
5. Infection not adequately controlled with appropriate therapy
6. Serologic evidence of HIV infection
7. 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 30 days is likely
8. Subjects with cancer who are on active chemotherapeutic treatment or who take drugs
with hematological effects
9. Current pregnancy or unwillingness to take oral contraceptives or refrain from
pregnancy if of childbearing potential
10. Not able to understand the investigational nature of the study or to give informed
consent
Gender
All
Minimum Age
2 Years
Maximum Age
N/A
Healthy Volunteers
No
Overall Official
Last Name |
Role |
Affiliation |
|
Danielle M Townsley, 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
2016-02-01
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Principal Investigator
Investigator Affiliation
National Institutes of Health Clinical Center (CC)
Investigator Full Name
Danielle Townsley, M.D.
Investigator Title
Hematology Clinician
Keywords
Has Expanded Access
No
Condition Browse
Secondary Id
10-H-0177
Number Of Arms
1
Intervention Browse
Mesh Term
Vidarabine
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Arm Group
Arm Group Label
Flu/Cy Response at 6 months
Arm Group Type
Experimental
Description
The primary objective is to assess Fludarabine/ Cyclophosphamide (Flu/Cy) hematological response in SAA.The primary endpoint will be response at six months.
Firstreceived Results Date
N/A
Reference
Citation
Rosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. 2003 Mar 5;289(9):1130-5.
PMID
12622583
Citation
Passweg JR, Pérez WS, Eapen M, Camitta BM, Gluckman E, Hinterberger W, Hows JM, Marsh JC, Pasquini R, Schrezenmeier H, Socié G, Zhang MJ, Bredeson C. Bone marrow transplants from mismatched related and unrelated donors for severe aplastic anemia. Bone Marrow Transplant. 2006 Apr;37(7):641-9.
PMID
16489361
Citation
Marsh JC, Hows JM, Bryett KA, Al-Hashimi S, Fairhead SM, Gordon-Smith EC. Survival after antilymphocyte globulin therapy for aplastic anemia depends on disease severity. Blood. 1987 Oct;70(4):1046-52.
PMID
3651599
Firstreceived Results Disposition Date
N/A
Study Design Info
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)
Study First Submitted
August 20, 2010
Study First Submitted Qc
August 20, 2010
Study First Posted
August 23, 2010
Last Update Submitted
February 3, 2016
Last Update Submitted Qc
February 3, 2016
Last Update Posted
March 2, 2016
Results First Submitted
June 5, 2014
Results First Submitted Qc
February 3, 2016
Results First Posted
March 2, 2016
ClinicalTrials.gov processed this data on December 13, 2019
Conditions
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conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
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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.