Back to resultsA Blood Stem Cell Transplant for Sickle Cell Disease
Primary Purpose
Sickle Cell Disease, Sickle Cell Disorder, Hemoglobinopathies
Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cyclophosphamide
Pentostatin
Rabbit anti-thymocyte globulin
Tacrolimus
Mycophenolate mofetil
CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant
Sponsored by
About this trial
This is an interventional treatment trial for Sickle Cell Disease focused on measuring Sickle Cell Disease, Sickle Cell Disorders, Hemoglobinopathies, Thalassemia, Anemia, Sickle Cell, Haploidentical Transplant, Nonmyeloablative Conditioning, CD4+ T cell, CD4+ T cell-depleted Hematopoietic Cell Transplant, Mixed Chimerism
Eligibility Criteria
Inclusion:
- 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.
Exclusion Criteria
- 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
Sites / Locations
- City of Hope Medical Center
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
COH-MC-17 and immunosuppressants
Arm Description
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.
Outcomes
Primary Outcome Measures
Toxicity per NCI-Common Terminology Criteria for Adverse Events version 4.0
Unacceptable Toxicity at least possibly related to COH-MC-17
Mixed Chimerism defined as 30-90% donor cells
Feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product
Secondary Outcome Measures
Adverse events of Grade 3 or higher
Neutrophil count ≥ 500/mm3, time to recovery
Platelet count ≥ 20,000/mm3, time to recovery
Marrow failure
Sickle cell disease related complications
Non-relapse mortality
Acute Graft versus Host Disease per 1994 Keystone Consensus Criteria
Chronic Graft versus Host Disease per 2014 National Institutes of Health Consensus Criteria
Overall Survival
Disease-Free Survival
Event-Free Survival
Disease Relapse
Persistent post-immunosuppressant mixed chimerism
Between 5% and 95% donor chimerism at two years post- transplant, at least 6 months post- immunosuppressant
Persistent immunosuppressant -dependent mixed chimerism
Between 5% and 95% donor chimerism at two years post- transplant and on immunosuppressant
Complete chimerism: >95% donor chimerism
Primary donor graft failure: Defined as < 5% donor chimerism by 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
Donor chimerism in blood
Donor chimerism in bone marrow
Percent HbS levels
Full Information
NCT ID
NCT03249831
First Posted
August 10, 2017
Last Updated
March 2, 2023
Sponsor
City of Hope Medical Center
Collaborators
California Institute for Regenerative Medicine (CIRM)
1. Study Identification
Unique Protocol Identification Number
NCT03249831
Brief Title
A Blood Stem Cell Transplant for Sickle Cell Disease
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
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 4, 2019 (Actual)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
Collaborators
California Institute for Regenerative Medicine (CIRM)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
Detailed Description
This is a pilot study to determine the safety and feasibility of the COH-MC-17 regimen and ability of the regimen to induce a mixed chimeric status in severe sickle cell disease patients (hemoglobin SS or S-βº Thalassemia). The COH-MC-17 regimen consists of a non-myeloablative regimen (cyclophosphamide, pentostatin and rabbit-anti-thymocyte globulin (ATG)) followed by a CD4+ T-cell-depleted haploidentical hematopoietic cell transplant (HaploHCT).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease, Sickle Cell Disorder, Hemoglobinopathies, Thalassemia, Anemia, Sickle Cell
Keywords
Sickle Cell Disease, Sickle Cell Disorders, Hemoglobinopathies, Thalassemia, Anemia, Sickle Cell, Haploidentical Transplant, Nonmyeloablative Conditioning, CD4+ T cell, CD4+ T cell-depleted Hematopoietic Cell Transplant, Mixed Chimerism
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)
8. Arms, Groups, and Interventions
Arm Title
COH-MC-17 and immunosuppressants
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Orally daily
Intervention Type
Drug
Intervention Name(s)
Pentostatin
Other Intervention Name(s)
NIPENT
Intervention Description
Intravenous
Intervention Type
Drug
Intervention Name(s)
Rabbit anti-thymocyte globulin
Other Intervention Name(s)
Rabbit ATG, Thymoglobulin
Intervention Description
Intravenous
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
PROGRAF®
Intervention Description
Initially IV. If patient tolerates, convert to oral.
Intervention Type
Drug
Intervention Name(s)
Mycophenolate mofetil
Other Intervention Name(s)
MMF, CellCept®, Myfortic
Intervention Description
IV or oral
Intervention Type
Biological
Intervention Name(s)
CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant
Other Intervention Name(s)
CD4+ T-cell depleted HaploHCT, CD4+ T-cell depleted hematopoietic progenitor cell (HPC) product
Intervention Description
Infusion
Primary Outcome Measure Information:
Title
Toxicity per NCI-Common Terminology Criteria for Adverse Events version 4.0
Time Frame
Day -22 to 2 years post-transplant
Title
Unacceptable Toxicity at least possibly related to COH-MC-17
Time Frame
Day -22 to Day +60 post-transplant
Title
Mixed Chimerism defined as 30-90% donor cells
Time Frame
Day +60 post-transplant
Title
Feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product
Time Frame
From apheresis to Day 0
Secondary Outcome Measure Information:
Title
Adverse events of Grade 3 or higher
Time Frame
Up to 2 years post-transplant
Title
Neutrophil count ≥ 500/mm3, time to recovery
Time Frame
Up to 2 years post-transplant
Title
Platelet count ≥ 20,000/mm3, time to recovery
Time Frame
Up to 2 years post-transplant
Title
Marrow failure
Time Frame
Up to 2 years post-transplant
Title
Sickle cell disease related complications
Time Frame
Up to 2 years post-transplant
Title
Non-relapse mortality
Time Frame
Up to 2 years post-transplant
Title
Acute Graft versus Host Disease per 1994 Keystone Consensus Criteria
Time Frame
Day + 100 post-transplant
Title
Chronic Graft versus Host Disease per 2014 National Institutes of Health Consensus Criteria
Time Frame
Day+ 180, + 1 year and +2 years post-transplant
Title
Overall Survival
Time Frame
Up to 2 years post-transplant
Title
Disease-Free Survival
Time Frame
Up to 2 years post-transplant
Title
Event-Free Survival
Time Frame
Up to 2 years post-transplant
Title
Disease Relapse
Time Frame
Up to 2 years post-transplant
Title
Persistent post-immunosuppressant mixed chimerism
Description
Between 5% and 95% donor chimerism at two years post- transplant, at least 6 months post- immunosuppressant
Time Frame
Up to 2 years post-transplant
Title
Persistent immunosuppressant -dependent mixed chimerism
Description
Between 5% and 95% donor chimerism at two years post- transplant and on immunosuppressant
Time Frame
+2 years post-transplant
Title
Complete chimerism: >95% donor chimerism
Time Frame
+2 years post-transplant
Title
Primary donor graft failure: Defined as < 5% donor chimerism by Day + 30 post- transplant
Time Frame
Day +30 post-transplant
Title
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
Title
Donor chimerism in blood
Time Frame
Day +30, Day +60, Day +100, Day+180, and +1 yr, +1.5 yr, +2yr post-transplant
Title
Donor chimerism in bone marrow
Time Frame
Day + 100, Day + 180 and + 1 yr post-transplant
Title
Percent HbS levels
Time Frame
Baseline, and then Day + 30, Day + 100, Day + 180, +1 yr, +1.5, +2yr post-transplant
Other Pre-specified Outcome Measures:
Title
Ratio donor: recipient de novo thymic T cells
Time Frame
Up to 2 years post-transplant
Title
Ratio donor: recipient FoxP3+ regulatory T cells
Time Frame
Up to 2 years post-transplant
Title
Tolerance status of donor: recipient type T cells
Time Frame
Up to 2 years post-transplant
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion:
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.
Exclusion Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joseph Rosenthal, MD
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
12. IPD Sharing Statement
Learn more about this trial
A Blood Stem Cell Transplant for Sickle Cell Disease
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