A Phase 1/2 interventional study of Cyclophosphamide and Fludarabine in Aplastic Anemia, Neutropenia and Pancytopenia, sponsored by National Heart, Lung, and Blood Institute (NHLBI). Completed at 1 site in United States. Open to participants aged 2 Years and older. Per ClinicalTrials.gov, last updated 2021-07-02.
Sponsored by National Heart, Lung, and Blood Institute (NHLBI) · Phase 1/2, Interventional, and Treatment
Background:
Objectives:
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:
Design:
371 studies on the registry are indexed under Anemia, Aplastic; 98 are open to participants now.
This study's enrollment of 1 is below the median of 37 across 281 interventional studies indexed under Anemia, Aplastic.
Browse Anemia, Aplastic studies →National Heart, Lung, and Blood Institute (NHLBI) is the lead sponsor of 1,143 studies on the registry; 71 are open to participants now.
Of its 58 completed or terminated interventional studies of FDA-regulated products, 51 (88%) have results posted.
Counted across the registry records on this site, refreshed daily.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Severe aplastic anemia characterized by:
Bone marrow cellularity \< 30 percent (excluding lymphocytes)
AND
At least two of the following:
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
EXCLUSION CRITERIA:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Relapsed and refractory
Relapsed: the illness came back after treatment had worked. Refractory: it did not respond to treatment, or stopped responding while still on it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
LVEF (left ventricular ejection fraction)
The share of blood the heart’s main pumping chamber (the left ventricle) pushes out with each beat, measured by an echocardiogram (heart ultrasound) or a MUGA scan. About 50–70% is normal.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Participants with Severe Aplastic Anemia will receive Fludarabine at 125 mg/m squared plus Cyclophosphamide at 60 mg/kg (Flu/Cy).
Drug: Cyclophosphamide · Drug: Fludarabine
60 mg/kg
Also known as: Cy
125 mg/m squared
Also known as: Flu
Response Rate at 6 Months
The primary objective is to assess hematologic response of Refractory Severe aplastic anemia (SAA) subjects to who have received fludarabine and cyclophosphamide. Subjects blood counts will be evaluated at 6 months to assess a hematologic response. The hematologic response will be defined as complete, partial or no response.
Time frame: 6 months
Number of Participants With Hematologic Response
Number of participants with hematologic response at 3 and 12 months and yearly. The hematologic response will be defined as complete, partial or no response.
Time frame: 3 months
Number of Patients Who Experienced Disease Relapse
Number of patients who relapsed who experienced disease relapse following Fludarabine Plus Cyclophosphamide in Refractory Severe Aplastic Anemia
Time frame: 6 months
Number of Participants With Clonal Evolution
Number of participants with Severe Aplastic Anemia who received Fludarabine Plus Cyclophosphamide that experienced Clonal Evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH), Myelodysplasia or Acute Leukemia.
Time frame: 6 months
Participant Survival Following Fludarabine/ Cyclophosphamide in Participants With Severe Aplastic Anemia
Participant survival at 6 months following Fludarabine/ Cyclophosphamide in participants with Severe Aplastic Anemia
Time frame: 6 months
1 participant was enrolled in this study
| Milestone | Fludarabine/Cyclophosphamide in Participants With Severe Aplastic Anemia |
|---|---|
| Started | 1 |
| Completed | 1 |
| Not completed | 0 |
The primary objective is to assess hematologic response of Refractory Severe aplastic anemia (SAA) subjects to who have received fludarabine and cyclophosphamide. Subjects blood counts will be evaluated at 6 months to assess a hematologic response. The hematologic response will be defined as complete, partial or no response.
| participants | Fludarabine/Cyclophosphamide in Participants With Severe Aplastic Anemia |
|---|---|
| No Response | 1 |
| Partial Response | 0 |
| Complete Response | 0 |
Number of participants with hematologic response at 3 and 12 months and yearly. The hematologic response will be defined as complete, partial or no response.
| Participants | Fludarabine/Cyclophosphamide in Participants With Severe Aplastic Anemia at 3 Months |
|---|---|
| Complete Response | 0 |
| Partial Response | 0 |
| No Response | 1 |
Number of patients who relapsed who experienced disease relapse following Fludarabine Plus Cyclophosphamide in Refractory Severe Aplastic Anemia
| Participants | Fludarabine/ Cyclophosphamide in Participants With Severe Aplastic Anemia |
|---|---|
| Number of Patients Who Experienced Disease Relapse | 0 |
Number of participants with Severe Aplastic Anemia who received Fludarabine Plus Cyclophosphamide that experienced Clonal Evolution to Paroxysmal Nocturnal Hemoglobinuria (PNH), Myelodysplasia or Acute Leukemia.
| Participants | Fludarabine/ Cyclophosphamide in Participants With Severe Aplastic Anemia |
|---|---|
| Number of Participants With Clonal Evolution | 0 |
Participant survival at 6 months following Fludarabine/ Cyclophosphamide in participants with Severe Aplastic Anemia
| Participants | Fludarabine/ Cyclophosphamide in Participants With Severe Aplastic Anemia |
|---|---|
| Participant Survival Following Fludarabine/ Cyclophosphamide in Participants With Severe Aplastic Anemia | 1 |
Collected over 6 months. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Fludarabine/Cyclophosphamide in Participants With Severe Aplastic Anemia | 0/1 (0%) | 1/1 (100%) | 0/1 (0%) |
| Event | Fludarabine/Cyclophosphamide in Participants With Severe Aplastic Anemia |
|---|---|
| infectionInfections and infestations | 1/1 |
| neutropenic feverInfections and infestations | 1/1 |
| Age, Categorical(Participants) | Fludarabine/Cyclophosphamide in Participants With Severe Aplastic Anemia |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 0 |
| >=65 years | 1 |
| Sex: Female, Male(Participants) | Fludarabine/Cyclophosphamide in Participants With Severe Aplastic Anemia |
|---|---|
| Female | 1 |
| Male | 0 |
| Ethnicity (NIH/OMB)(Participants) | Fludarabine/Cyclophosphamide in Participants With Severe Aplastic Anemia |
|---|---|
| Hispanic or Latino | 0 |
| Not Hispanic or Latino | 1 |
| Unknown or Not Reported | 0 |
| Region of Enrollment(participants) | Fludarabine/Cyclophosphamide in Participants With Severe Aplastic Anemia |
|---|---|
| United States | 1 |
This study is completed, as verified in Feb 2016. You cannot join it, but the record below documents what was studied.
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Studies of the drugs tested here: Cyclophosphamide · Fludarabine
National Heart, Lung, and Blood Institute (NHLBI) →