- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02512679
Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells
Protocol for Related Donor Hematopoietic Stem Cell Transplantation (HSCT) for Treatment of Symptomatic Genetic Lymphohematological Diseases
Study Overview
Status
Conditions
- Metabolic Diseases
- Stem Cell Transplantation
- Chronic Granulomatous Disease
- Bone Marrow Transplantation
- Thalassemia
- Wiskott-Aldrich Syndrome
- Genetic Diseases
- Peripheral Blood Stem Cell Transplantation
- Pediatrics
- Diamond-Blackfan Anemia
- Allogeneic Transplantation
- Combined Immune Deficiency
- X-linked Lymphoproliferative Disease
Detailed Description
The present study is to evaluate de-escalation of the cyclophosphamide (CY) dose in an innovative conditioning regimen with fludarabine and alemtuzumab as additional agents to achieve immunoablation, in combination with Busulfan (BU) to achieve myeloablation. Replacement of at least part of the cyclophosphamide dose by fludarabine in the conditioning regimen would be expected to maintain immunosuppression (and, therefore, engraftment) while reducing transplant-related complications (mucositis, hepatotoxicity, cardiotoxicity, pulmonary toxicity, hemorrhagic cystitis, mucositis, and possibly GVHD), thereby improving disease-free survival rates. Similarly, the potential benefits of alemtuzumab in the proposed conditioning regimen are increased rates of hematopoietic engraftment with less toxicity than that observed with cyclophosphamide, ultimately resulting in improved immune function and enhanced quality of life (12,13). A fludarabine/alemtuzumab-based, less intensive conditioning regimen with adequate immunosuppressive activity could conceivably allow more successful engraftment of stem cells from related donors in patients with genetic lymphohematological diseases, as well as lower rates of transplant-related mortality.
Regimen-related toxicity is also believed to be a major contributing factor to GVHD (14). Therefore, conditioning regimens that cause less tissue injury may also lead to reduced GVHD. In the present study, the use of alemtuzumab in the conditioning regimen may be an added benefit, as this antibody causes T-cell depletion, thus, the risk of GVHD may also be reduced (15). The overall goal of the study is to improve the therapeutic index of HSCT by decreasing and, if possible, eliminating cyclophosphamide as a component of the pre-transplant conditioning for patients with genetic diseases of lymphohematopoiesis. The investigation will explore the risks and benefits of the proposed novel-conditioning regimen using a decreased dose of cyclophosphamide and additional immunosuppression with fludarabine and alemtuzumab to prevent graft rejection and recurrence of disease. The investigators will evaluate this regimen's impact on conditioning-related morbidity and mortality, and measure the success of the transplant procedure by engraftment and disease-free survival. If this regimen is able to successfully permit engraftment and reduce regimen-related toxicity, the next phase of treatment will test a further dose de-escalation for cyclophosphamide. It is anticipated that there will be four dose levels of cyclophosphamide in the overall study: 1) 105 mg/kg; 2) 70 mg/kg; 3) 35 mg/kg; and then finally, 4) 0 mg/kg. This study design was chosen to minimize study risks possibly associated with substitution of fludarabine and alemtuzumab for CY as immunoablation. The present protocol represents Level 1 in the study design; an amended protocol will be prepared prior to further de-escalation of the cyclophosphamide dose.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- All patients with lethal or sublethal genetic lymphohematological disease (such as Hemaphagocytic lymphohistiocytosis (HLH) / Familial Erythrophagocytic Lymphohistiocytosis (FEL), Hurler's Syndrome, Hunter's Syndrome, Kostmann's Syndrome, Blackfan-Diamond Anemia, Chronic granulomatous Disease (CGD), Red Cell Aplasia, CID, Sickle Cell Anemia, Thalassemia, Adreno-leukodystrophy, metachromatic leukodystrophy, Wiskott-Aldrich Syndrome, X-Linked Lymphoproliferative Disease (XLD), Metabolic diseases affecting hematopoiesis, but not limited to), who are candidates for allogeneic transplantation for their disease and have a histocompatible sibling or related donor, ages 0 to 21 years, will be candidates for this study protocol. The suitable related donor is a 10/10 or 9/10 allele Human Leukocyte Antigen (HLA) match with the patient. All patients who have previously had serious life- threatening events due to disease process may be included in the study. Patients must have adequate physical function and vital organ function to tolerate transplant procedure, as measured by:
- Cardiac: Shortening fraction >26% or left ventricular ejection fraction at rest must be > 40%.
- Hepatic: Bilirubin, Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) < 3x upper limit of normal (as per local laboratory) for age (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome).
- Renal: Serum creatinine < 2x upper limit of normal for age or if serum creatinine elevated beyond normal range patient must have creatinine Clearance or Glomerular filtration rate (GFR) >50% lower limit of normal for age.
- Pulmonary: Forced expiratory volume (FEV)1, Forced Vital Capacity (FVC), and Diffusing Lung Capacity for Carbon Monoxide (DLCO) (corrected for Hgb) > 50% predicted. For patients where pulse oximetry is performed, O2 saturation > 92%
- Evaluation of iron status in patients who have received more than 12 red cell transfusions. Measurements of serum ferritin levels and MRI of the liver and heart tissue will evaluate the iron stores. If high iron load is identified in these organs further evaluation will be done to determine the suitability as transplant recipient. Should these studies indicate that chelation is necessary the following should apply: That the treating hematologist will provide the specific chelation type and timing. Evaluation of organ iron load will be part of the HSCT work-up and if high iron load is identified then the BMT team will work with the hematologist attending in developing a plan for the patient.
Exclusion Criteria:
- Karnofsky performance status < 70%, or Lansky < 40% for patients < 16 years old.
- Uncontrolled bacterial, viral, or fungal infections (currently taking medication yet clinical symptoms progress).
- Seropositivity for the human immunodeficiency virus (HIV).
- Acute active hepatitis.
- Diagnosis of end-organ dysfunction that precludes the ability to tolerate the transplant procedure.
- Patients with a diagnosis of Fanconi Anemia are excluded.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: Cyclophosphamide Dose Level 1
Cyclophosphamide given by Intravenous (IV) at a total dose of 105 mg/kg, to be divided into three doses of one 35 mg/kg dose per day, for 3 days on the first level. Drug to be given in combination of Busulfan, Campath and Fludarabine |
given by IV at a total dose of 105 mg/kg, to be divided into three doses of one 35 mg/kg dose per day, for 3 days on the first level.
After ten patients the de-escalation will begin if the stopping rule is not met.
Other Names:
|
Other: Cyclophosphamide Dose Level 2
Cyclophosphamide given by intravenous (IV) at a total dose of 70 mg/kg (divided in two doses) given once a day for two days in combination with Busulfan, Campath and Fludarabine.
|
Level 2 will be 70mg/kg in 2 divided given once a day for 2 days;
Other Names:
|
Other: Cyclophosphamide Dose Level 3
Cyclophosphamide given by intravenous (IV) at total does of 35 mg/kg as a one time dose in combination with Busulfan, Fludarabine and Campath
|
Level 3 will be 35mg/kg as a one-time dose.
Other Names:
|
Other: Cyclophosphamide Dose Level 4
No cyclophosphamide given with Busulfan, Fludarabine and Campath
|
Level 4 will be no cytoxan.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants With Neutrophil Engraftment (=/>500 Cells/uL) and Platelet Engraftment (>20K Cell/uL) at 30 Days
Time Frame: 30 days
|
Absolute Neutrophil Count (ANC) =/>500;(recovery of white cell count - self sustain platelet above 20,000 per cubic milimeter (20K) - evaluation by Chimerism Study (STR or FISH) at day +30
|
30 days
|
Number of Participants With Disease Recurrence at 1 Year Post-transplant
Time Frame: 1 year
|
assess rate of disease recurrence ("late relapse") due to autologous recovery of recipient hematopoiesis at one year post-HSCT.
|
1 year
|
Number of Participants Who Developed Severe Mucositis, Veno-occlusive Disease (VOD), Toxicity of the Kidney, Liver, or Gastrointestinal (GI) Tract up to 1 Year Post-transplant
Time Frame: 1 year
|
Assessment of conditioning regimen related toxicity was evaluated and documented with daily assessment during hospitalization and post-transplant follow-up up to one year.
None of the subjects developed VOD necessitating any therapeutic intervention, severe mucositis, or toxicity of the Kidney, Liver or Gastrointestinal.
|
1 year
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Participants Who Developed Graft-Versus-Host-Disease (GVHD) as Determined by the Glucksberg Scale
Time Frame: 1 yr
|
Clinical evaluation on a daily basis during hospitalization and at each post transplant clinical visit, up to one year, to determine incidence of acute and chronic graft-versus-host disease using Glucksberg grading scale.
Acute graft-versus-host disease (aGVHD) develops within the first three months after transplantation and appears as a skin rash, often accompanied by hyperbilirubenemia, abnormal liver enzymes and gastrointestinal symptoms, as diarrhea, nausea and vomiting.
Level of aGVHD is graded from 1-4.
Chronic GVHD, typically a late complication of Blood and Marrow Transplantation (BMT) characterized by skin changes, sometimes sclerotic changes, with joint contractures, liver function abnormality, gastrointestinal symptoms and sometime other organ involvement such as eyes, lungs, and obliterative bronchiolitis (OB).
Chronic GVHD is graded as absent, limited, or extensive.
|
1 yr
|
Number of Participants Who Were Disease Progression-Free and Death-Free at 1 Year Post-transplant
Time Frame: 1 yr
|
Evaluation for engraftment, correction of the disease, transplant related complications and event-free survival and overall survival of the subjects post-transplant was undertaken by standard measures and evaluation of disease with disease-specific testing.
|
1 yr
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Neena Kapoor, M.D., Children's Hospital Los Angeles
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Immune System Diseases
- Lymphatic Diseases
- Immunoproliferative Disorders
- Bone Marrow Diseases
- Hematologic Diseases
- Blood Coagulation Disorders, Inherited
- Hemorrhagic Disorders
- Genetic Diseases, X-Linked
- Anemia
- Blood Coagulation Disorders
- Leukopenia
- Leukocyte Disorders
- Anemia, Hemolytic, Congenital
- Anemia, Hemolytic
- Hemoglobinopathies
- Anemia, Hypoplastic, Congenital
- Anemia, Aplastic
- Congenital Bone Marrow Failure Syndromes
- Bone Marrow Failure Disorders
- Phagocyte Bactericidal Dysfunction
- Primary Immunodeficiency Diseases
- Lymphopenia
- Red-Cell Aplasia, Pure
- Immunologic Deficiency Syndromes
- Granulomatous Disease, Chronic
- Thalassemia
- Metabolic Diseases
- Lymphoproliferative Disorders
- Genetic Diseases, Inborn
- Wiskott-Aldrich Syndrome
- Anemia, Diamond-Blackfan
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Cyclophosphamide
Other Study ID Numbers
- CCI-06-00177
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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