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A Blood Stem Cell Transplant for Sickle Cell Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03249831
Recruitment Status : Recruiting
First Posted : August 15, 2017
Last Update Posted : July 15, 2019
Sponsor:
Collaborator:
California Institute for Regenerative Medicine (CIRM)
Information provided by (Responsible Party):
City of Hope Medical Center

Tracking Information
First Submitted Date  ICMJE August 10, 2017
First Posted Date  ICMJE August 15, 2017
Last Update Posted Date July 15, 2019
Actual Study Start Date  ICMJE January 4, 2019
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 10, 2017)
  • 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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2017)
  • 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 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: August 10, 2017)
  • 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 ]
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE A Blood Stem Cell Transplant for Sickle Cell Disease
Official Title  ICMJE 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
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:

  1. Half-matched related donors will be used, and
  2. 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
  3. 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:

  1. Will reverse sickle cell disease and improve patient quality of life,
  2. Will reduce side effects and help the patient recover faster from the transplant,
  3. Help the patient keep the transplant longer and
  4. 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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Sickle Cell Disease
  • Sickle Cell Disorder
  • Hemoglobinopathies
  • Thalassemia
  • Anemia, Sickle Cell
Intervention  ICMJE
  • Drug: Cyclophosphamide
    Orally daily
    Other Name: Cytoxan
  • Drug: Pentostatin
    Intravenous
    Other Name: NIPENT
  • Drug: Rabbit anti-thymocyte globulin
    Intravenous
    Other Names:
    • Rabbit ATG
    • Thymoglobulin
  • Drug: Tacrolimus
    Initially IV. If patient tolerates, convert to oral.
    Other Name: PROGRAF®
  • Drug: Mycophenolate mofetil
    IV or oral
    Other Names:
    • MMF
    • CellCept®
    • Myfortic
  • Biological: CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant
    Infusion
    Other Names:
    • CD4+ T-cell depleted HaploHCT
    • CD4+ T-cell depleted hematopoietic progenitor cell (HPC) product
Study Arms  ICMJE 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.

Interventions:
  • Drug: Cyclophosphamide
  • Drug: Pentostatin
  • Drug: Rabbit anti-thymocyte globulin
  • Drug: Tacrolimus
  • Drug: Mycophenolate mofetil
  • Biological: CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 10, 2017)
6
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion:

  1. Confirmed diagnosis of hemoglobin SS or S-βº Thalassemia sickle cell disease
  2. Severe disease status as defined by presence of one or more of the following:

    1. 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.
    2. 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).
    3. 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.
    4. Osteonecrosis of ≥ 2 joints despite the institution of supportive care measures.
    5. 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)
  3. No HLA matched sibling or 10/10 matched unrelated donor
  4. Related donor who:

    1. Is genotypically haploidentical on HLA-A, B, C and DRB1 loci AND
    2. Meets institutional criteria
  5. Failed prior hydroxyurea therapy or have intolerance to hydroxyurea
  6. Meets protocol specified organ function criteria
  7. Women of childbearing potential or sexually active male: Agreement to use adequate contraception prior to study entry and 6 months post-transplant.

Exclusion Criteria

  1. Prior stem cell transplant
  2. Prior bone marrow transplant
  3. Concurrent other investigational agents, chemotherapy, biological therapy or radiation therapy
  4. Planned use of moderate and strong CYP3A4 inhibitors
  5. Active infection
  6. Major surgery within the last 30 days
  7. Clinically significant liver fibrosis or cirrhosis if on chronic transfusion therapy > 6 months
  8. Active malignancy (other than non-melanoma skin cancers)
  9. History of allergic reactions attributed to compounds of similar chemical or biologic composition to any in the pre- or post-transplant regimen.
  10. Women of childbearing potential: pregnant or breastfeeding
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Joseph Rosenthal, MD 626-218-8442 jrosenthal@coh.org
Contact: Teresa Kim, RN 626-218-0263 teresakim@coh.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03249831
Other Study ID Numbers  ICMJE 16453
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party City of Hope Medical Center
Study Sponsor  ICMJE City of Hope Medical Center
Collaborators  ICMJE California Institute for Regenerative Medicine (CIRM)
Investigators  ICMJE
Principal Investigator: Joseph Rosenthal, MD City of Hope Medical Center
PRS Account City of Hope Medical Center
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP