Sickle Cell Anemia Clinical Trial
Official title:
Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Sickle Cell Anemia From HLA Matched or Partially-Matched Related Donors
This is a clinical research trial in which a novel preparatory regimen was developed for
bone marrow transplant (BMT) which eliminates the primary obstacle to transplant, the lack
of a matched sibling donor. It is believed this regimen is sufficiently efficacious and
sufficiently gentle to apply to patients with sickle cell anemia and related disorders. It
is proposed to characterize the efficacy and toxicity of this regimen in high risk patients
with sickle cell anemia using criteria for patient selection that have been accepted in
prior BMT trials in patients with sickle cell disease, specifically only the subset of
patients whose prior clinical behavior indicates that they are at high risk for serious
morbidity and early mortality. In addition, it is proposed to characterize the
pathophysiology of a consistent febrile response seen in the haploidentical BMT regimen the
investigators have developed at Thomas Jefferson University (TJU).
The primary goal of this study is to determine the response rate to a reduced intensity
conditioning regimen which consists of fludarabine, cytarabine, low dose total body
irradiation and cyclophosphamide in patients with severe sickle cell anemia.
Status | Terminated |
Enrollment | 2 |
Est. completion date | August 2011 |
Est. primary completion date | August 2011 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years to 45 Years |
Eligibility |
Inclusion Criteria: Patient Selection: i) Patients with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C disease, or sickle cell-ß0-thalassemia) confirmed by hemoglobin electrophoresis. ii) Patients should have one or more of the following: 1. History of acute chest syndrome requiring recurrent hospitalization or exchange transfusion (Acute chest syndrome is defined as pulmonary infiltrate involving at least one complete lung segment, consistent with alveolar consolidation but not atelectasis, accompanied by chest pain, fever, cough, tachypnea or wheezing) 2. History of nonhemorrhagic stroke or central nervous system event lasting longer than 24 hours 3. Recurrent vaso-occlusive pain (=5 episodes during the past two years) or recurrent priapism requiring hospitalization or visits to the emergency room or sickle cell day unit 4. Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50% of normal predicted value) with progression on ACE inhibitor therapy iii) Patient must have failed therapy with hydroxyurea, as HU as evidenced by at least 6 months of maximum HU dosage for sickle cell disease, i.e. dose escalation to a level which caused some minimal hematologic toxicity in terms of CBC values. Failure to respond must also be documented by no significant increase in subjects HbF levels at this maximally tolerated dosage.AND development/ persistence of items listed in (ii) Patients who are deemed not eligible for hydroxyurea by the primary hematologist will be considered eligible without having failed hydroxyurea. Non-eligibility for hydroxyurea therapy is based on: (1) the diagnoses of SC disease and sickle cell-ß0-thalassemia in which no clear evidence supports the use of hydroxyurea therapy and thus treatment with hydroxyurea is not considered the standard of care in these entities (2) the presence of high hemoglobin F levels in patients with sickle cell anemia and documented Hereditary Persistence of Fetal Hemoglobin (HPFH) in which hydroxyurea is not considered the standard of care (3) severe adverse reactions to hydroxyurea in patients with sickle cell anemia based on, but not limited to, count suppression, GI intolerance, and dermatomyositis Patient unwillingness to be compliant with hydroxyurea therapy is not an acceptable reason for non-eligibility iv) Patients must have an acceptable related donor 1. who is matched at the HLA-A;B; C; DR loci (8 of 8 match) or mismatched for at most one locus (7 of 8 match) (well matched related donor 2. who is mismatched at 2-4 alleles (haplo-identical) v) Patient age greater than 18 - 45 years vi) ECOG performance status 0-2/ Karnofsky 70-100% vii) Written informed consent obtained from the patient. viii) Transaminases <3X ULN; patients with transaminases greater than the ULN but less than 3XULN will be evaluated by the hepatology service and will undergo further imaging and biopsy as deemed necessary by hepatology. They will not be considered eligible unless cleared by hepatology. Exclusion Criteria: Patient Selection: i) Pregnancy/ unwillingness to use adequate contraception during study period ii) Liver disease including 1. Acute hepatitis (transaminases >3x normal value) 2. Chronic hepatitis C 3. Chronic hepatitis B or history of exposure to hepatitis B iii) Cardiac ejection fraction < 50% iv) Pulmonary hypertension - as evidenced by findings on resting echocardiogram of pulmonary artery systolic pressure = 40 mmHg or any evidence of right ventricular dysfunction (hypokinesis or RV dilation) v) Severe renal impairment (GFR <30% of predicted normal value) vi) Severe residual functional neurologic impairment (other than hemiplegia alone) vii) DLCO =50 viii) Any evidence of infection by the human immunodeficiency virus ix) Psychiatric disorder that would preclude patients from signing an informed consent x) Severe neuro-cognitive or executive function making informed consent possible |
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
United States | Thomas Jefferson University | Philadelphia | Pennsylvania |
Lead Sponsor | Collaborator |
---|---|
Thomas Jefferson University | National Heart, Lung, and Blood Institute (NHLBI) |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Stable Engraftment | To determine if the reduced intensity preparative regimen of fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation will generate stable engraftment with donor hematopoietic stem cells in at least 80% of patients with severe sickle cell anemia. | 180 days post-infusion | No |
Secondary | Organ Toxicity | To assess organ toxicity related to fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation in a population with severe sickle cell anemia. | 30 days post infusion | Yes |
Secondary | Overall Survival | To determine the overall survival at 6 months post-transplant in patients receiving a matched or partially-matched related donor transplant after reduced-intensity conditioning. | 6 months post infusion | Yes |
Secondary | Acute Graft Versus Host Disease | To describe the incidence and severity of acute and chronic GVHD following this reduced intensity transplant from partially matched related donors using a combination of cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis. | 100 days post infusion | Yes |
Secondary | Correction of Hemoglobinopathy | To evaluate the extent of correction of hemoglobinopathy following this reduced intensity transplant. | 100 days post infusion through 5 years post infusion | No |
Secondary | Immune Recovery | To assess the pace of lymphoid recovery and associated risk for opportunistic infections and relapse (return to recipient erythropoiesis) in this patient population. | 100 days post infusion through 5 years post infusion | Yes |
Secondary | Quality of Life | To describe the quality of life and functional status following transplantation. | Through 5 years post infusion | No |
Secondary | Cytokine Profile | To characterize the profiles of cytokines released following administration of the lymphoid portion of the transplant (donor lymphocyte infusion [DLI]). | Through 5 years after infusion | No |
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT04134299 -
To Assess Safety, Tolerability and Physiological Effects on Structure and Function of AXA4010 in Subjects With Sickle Cell Disease
|
N/A | |
Completed |
NCT04581356 -
Voxelotor Sickle Cell Exercise Study
|
Phase 4 | |
Completed |
NCT02712346 -
The Role of Endothelin-1 in Sickle Cell Disease
|
Phase 1 | |
Withdrawn |
NCT02162225 -
Study of Beet Juice for Patients With Sickle Cell Anemia
|
Phase 2 | |
Completed |
NCT01976416 -
Novel Use Of Hydroxyurea in an African Region With Malaria
|
Phase 3 | |
Completed |
NCT01137721 -
State Of The Art Functional Imaging In Sickle Cell Disease
|
||
Withdrawn |
NCT00937144 -
Endothelial Function in Patients With Sickle Cell Anemia Before and After Sildenafil
|
Phase 4 | |
Completed |
NCT00512564 -
Clinical and Laboratory Assessment of Iron Overload in Sickle Cell Anemia and Sickle Cell Thalassemia
|
N/A | |
Completed |
NCT00512226 -
Iron Overload Assesment in Sickle Cell Anemia and Sickle Cell Thalassemia
|
N/A | |
Completed |
NCT00004143 -
Allogeneic Mixed Chimerism Stem Cell Transplant Using Campath for Hemoglobinopathies & Bone Marrow Failure Syndromes
|
Phase 2 | |
Completed |
NCT00004412 -
Phase II Randomized Trial:Arginine Butyrate Plus Standard Local Therapy in Patients With Refractory Sickle Cell Ulcers
|
Phase 2 | |
Withdrawn |
NCT01925001 -
Phase 2 Study of MP4CO to Treat Vaso-occlusive Sickle Crisis
|
Phase 2 | |
Completed |
NCT01848691 -
Carbon Monoxide Monitor for the Measurement of End-Tidal Carbon Monoxide Levels in Children With or Without Hemolysis
|
N/A | |
Completed |
NCT01783990 -
Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Follow-up Observational Study II Protocol
|
||
Completed |
NCT00874172 -
Effectiveness of New Analgesic Strategy Compared to the Usal Antalgic Strategy
|
N/A | |
Completed |
NCT01000155 -
Efficacy of Vorinostat to Induce Fetal Hemoglobin in Sickle Cell Disease
|
Phase 2 | |
Completed |
NCT00399074 -
Sulfadoxine- Pyrimethamine Versus Weekly Chloroquine for Malaria Prevention in Children With Sickle Cell Anemia
|
Phase 3 | |
Completed |
NCT00236093 -
Extension Study of ACTIQ Treatment for Children and Adolescents With Breakthrough Pain
|
Phase 2 | |
Completed |
NCT00004492 -
Phase I/II Randomized Study of Hydroxyurea With or Without Clotrimazole in Patients With Sickle Cell Anemia
|
Phase 1/Phase 2 | |
Completed |
NCT02065596 -
Hematopoietic Stem Cell Transplant for Sickle Cell Disease
|
Phase 1 |