A Blood Stem Cell Transplant for Sickle Cell Disease
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|ClinicalTrials.gov Identifier: NCT03249831|
Recruitment Status : Active, not recruiting
First Posted : August 15, 2017
Last Update Posted : March 3, 2023
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Blood stem cells can produce red blood cells (which carry oxygen), white blood cells of the immune system (which fight infections) and platelets (which help the blood clot).
Patients with sickle cell disease produce abnormal red blood cells. A blood stem cell transplant from a donor is a treatment option for patients with severe sickle cell disease. The donor can be healthy or have the sickle cell trait. The blood stem cell transplant will be given to the patient as an intravenous infusion (IV). The donor blood stem cells will then make normal red blood cells - as well as other types of blood cells - in the patient. When blood cells from two people co-exist in the patient, this is called mixed chimerism.
Most children are successfully treated with blood stem cells from a sibling (brother/sister) who completely shares their tissue type (full-matched donor). However, transplant is not an option for patients who (1) have serious medical problems, and/or (2) do not have a full-matched donor. Most patients will have a relative who shares half of their tissue type (e.g. parent, child, and brother/sister) and can be a donor (half-matched or haploidentical donor).
Adult patients with severe sickle cell disease were successfully treated with a half-matched transplant in a clinical study. Researchers would like to make half-matched transplant an option for more patients by (1) improving transplant success and (2) reducing transplanted-related complications.
This research transplant is being tested in this Pilot study for the first time. It is different from a standard transplant because:
- Half-matched related donors will be used, and
- A new combination of drugs (chemotherapy) that does not completely wipe out the bone marrow cells (non-myeloablative treatment) will be used to prepare the patient for transplant, and
- Most of the donor CD4+ T cells (a type of immune cells) will be removed (depleted) before giving the blood stem cell transplant to the patient to improve transplant outcomes.
It is hoped that the research transplant:
- Will reverse sickle cell disease and improve patient quality of life,
- Will reduce side effects and help the patient recover faster from the transplant,
- Help the patient keep the transplant longer and
- Reduce serious transplant-related complications.
|Condition or disease||Intervention/treatment||Phase|
|Sickle Cell Disease Sickle Cell Disorder Hemoglobinopathies Thalassemia Anemia, Sickle Cell||Drug: Cyclophosphamide Drug: Pentostatin Drug: Rabbit anti-thymocyte globulin Drug: Tacrolimus Drug: Mycophenolate mofetil Biological: CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||3 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Pilot Study to Evaluate the Safety and Feasibility of Induction of Mixed Chimerism in Sickle Cell Disease Patients With COH-MC-17: a Non-Myeloablative, Conditioning Regimen and CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant|
|Actual Study Start Date :||January 4, 2019|
|Estimated Primary Completion Date :||December 31, 2024|
|Estimated Study Completion Date :||December 31, 2024|
Experimental: COH-MC-17 and immunosuppressants
Participants receive COH-MC-17: a 21-day nonmyeloablative conditioning regimen (cyclophosphamide, pentostatin and rabbit anti-thymocyte globulin), followed by CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant on Day 0.
Immunosuppressants (tacrolimus and mycophenolate mofetil) given on Day -1 onwards until discontinuation post-transplant.
The minimally manipulated transplant product is manufactured using the CliniMACS device.
Other Name: Cytoxan
Other Name: NIPENT
Drug: Rabbit anti-thymocyte globulin
Initially IV. If patient tolerates, convert to oral.
Other Name: PROGRAF®
Drug: Mycophenolate mofetil
IV or oral
Biological: CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant
- Toxicity per NCI-Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Day -22 to 2 years post-transplant ]
- Unacceptable Toxicity at least possibly related to COH-MC-17 [ Time Frame: Day -22 to Day +60 post-transplant ]
- Mixed Chimerism defined as 30-90% donor cells [ Time Frame: Day +60 post-transplant ]
- Feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product [ Time Frame: From apheresis to Day 0 ]
- Adverse events of Grade 3 or higher [ Time Frame: Up to 2 years post-transplant ]
- Neutrophil count ≥ 500/mm3, time to recovery [ Time Frame: Up to 2 years post-transplant ]
- Platelet count ≥ 20,000/mm3, time to recovery [ Time Frame: Up to 2 years post-transplant ]
- Marrow failure [ Time Frame: Up to 2 years post-transplant ]
- Sickle cell disease related complications [ Time Frame: Up to 2 years post-transplant ]
- Non-relapse mortality [ Time Frame: Up to 2 years post-transplant ]
- Acute Graft versus Host Disease per 1994 Keystone Consensus Criteria [ Time Frame: Day + 100 post-transplant ]
- Chronic Graft versus Host Disease per 2014 National Institutes of Health Consensus Criteria [ Time Frame: Day+ 180, + 1 year and +2 years post-transplant ]
- Overall Survival [ Time Frame: Up to 2 years post-transplant ]
- Disease-Free Survival [ Time Frame: Up to 2 years post-transplant ]
- Event-Free Survival [ Time Frame: Up to 2 years post-transplant ]
- Disease Relapse [ Time Frame: Up to 2 years post-transplant ]
- Persistent post-immunosuppressant mixed chimerism [ Time Frame: Up to 2 years post-transplant ]Between 5% and 95% donor chimerism at two years post- transplant, at least 6 months post- immunosuppressant
- Persistent immunosuppressant -dependent mixed chimerism [ Time Frame: +2 years post-transplant ]Between 5% and 95% donor chimerism at two years post- transplant and on immunosuppressant
- Complete chimerism: >95% donor chimerism [ Time Frame: +2 years post-transplant ]
- Primary donor graft failure: Defined as < 5% donor chimerism by Day + 30 post- transplant [ Time Frame: Day +30 post-transplant ]
- Secondary donor graft failure: Defined as < 5% donor chimerism beyond Day +30 in patients with prior documentation of ≥ 5% donor cells by Day +30 [ Time Frame: > Day + 30 up to 2 years post-transplant ]
- Donor chimerism in blood [ Time Frame: Day +30, Day +60, Day +100, Day+180, and +1 yr, +1.5 yr, +2yr post-transplant ]
- Donor chimerism in bone marrow [ Time Frame: Day + 100, Day + 180 and + 1 yr post-transplant ]
- Percent HbS levels [ Time Frame: Baseline, and then Day + 30, Day + 100, Day + 180, +1 yr, +1.5, +2yr post-transplant ]
- Ratio donor: recipient de novo thymic T cells [ Time Frame: Up to 2 years post-transplant ]
- Ratio donor: recipient FoxP3+ regulatory T cells [ Time Frame: Up to 2 years post-transplant ]
- Tolerance status of donor: recipient type T cells [ Time Frame: Up to 2 years post-transplant ]
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|Ages Eligible for Study:||18 Years to 45 Years (Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Confirmed diagnosis of hemoglobin SS or S-βº Thalassemia sickle cell disease
Severe disease status as defined by presence of one or more of the following:
- Clinically significant neurologic event (stroke) or any neurological deficit lasting > 24 hours; or increased transcranial Doppler velocity (>200 m/s). A stroke is defined as a sudden neurologic change lasting more than 24 hours that is accompanied by cerebral magnetic resonance imaging (MRI) changes.
- History of ≥ 1 episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea).
- History of ≥ 2 severe vaso-occlusive pain crises (VOC) per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea). A severe VOC is defined as an episode of pain lasting more than 2 hours severe enough to require care at a medical facility. Note that priapism that lasts more than 2 hours and requires care at a medical facility is also considered a VOC.
- Osteonecrosis of ≥ 2 joints despite the institution of supportive care measures.
- Prior treatment with regular RBC transfusion therapy, defined as receiving ≥ 8 transfusions per year for > 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome)
- No HLA matched sibling or 10/10 matched unrelated donor
Related donor who:
- Is genotypically haploidentical on HLA-A, B, C and DRB1 loci AND
- Meets institutional criteria
- Failed prior hydroxyurea therapy or have intolerance to hydroxyurea
- Meets protocol specified organ function criteria
- Women of childbearing potential or sexually active male: Agreement to use adequate contraception prior to study entry and 6 months post-transplant.
- Prior stem cell transplant
- Prior bone marrow transplant
- Concurrent other investigational agents, chemotherapy, biological therapy or radiation therapy
- Planned use of moderate and strong CYP3A4 inhibitors
- Active infection
- Major surgery within the last 30 days
- Clinically significant liver fibrosis or cirrhosis if on chronic transfusion therapy > 6 months
- Active malignancy (other than non-melanoma skin cancers)
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the pre- or post-transplant regimen.
- Women of childbearing potential: pregnant or breastfeeding
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03249831
|United States, California|
|City of Hope Medical Center|
|Duarte, California, United States, 91010|
|Principal Investigator:||Joseph Rosenthal, MD||City of Hope Medical Center|
|Responsible Party:||City of Hope Medical Center|
|Other Study ID Numbers:||
|First Posted:||August 15, 2017 Key Record Dates|
|Last Update Posted:||March 3, 2023|
|Last Verified:||March 2023|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Sickle Cell Disease
Sickle Cell Disorders
Anemia, Sickle Cell
CD4+ T cell
CD4+ T cell-depleted Hematopoietic Cell Transplant
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action