A Blood Stem Cell Transplant for Sickle Cell Disease

Sickle Cell Disease Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03249831
• Other study ID #: 16453
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: January 4, 2019
• Est. completion date: November 17, 2024

Study information

• Verified date: March 2024
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 3
• Est. completion date: November 17, 2024
• Est. primary completion date: November 17, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

Inclusion:

1. Confirmed diagnosis of hemoglobin SS or S-ߺ 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

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Hemoglobinopathies
• Sickle Cell Disease
• Sickle Cell Disorder
• Thalassemia

Intervention

Drug:
• Cyclophosphamide
Orally daily
• Pentostatin
Intravenous
• Rabbit anti-thymocyte globulin
Intravenous
• Tacrolimus
Initially IV. If patient tolerates, convert to oral.
• Mycophenolate mofetil
IV or oral

Biological:
• CD4+ T-cell-depleted Haploidentical Hematopoietic Transplant
Infusion

Locations

Country	Name	City	State
United States	City of Hope Medical Center	Duarte	California

Sponsors (2)

Lead Sponsor	Collaborator
City of Hope Medical Center	California Institute for Regenerative Medicine (CIRM)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ratio donor: recipient de novo thymic T cells		Up to 2 years post-transplant
Other	Ratio donor: recipient FoxP3+ regulatory T cells		Up to 2 years post-transplant
Other	Tolerance status of donor: recipient type T cells		Up to 2 years post-transplant
Primary	Toxicity per NCI-Common Terminology Criteria for Adverse Events version 4.0		Day -22 to 2 years post-transplant
Primary	Unacceptable Toxicity at least possibly related to COH-MC-17		Day -22 to Day +60 post-transplant
Primary	Mixed Chimerism defined as 30-90% donor cells		Day +60 post-transplant
Primary	Feasibility of producing an infusion ready CD4+ T-cell-depleted hematopoietic product		From apheresis to Day 0
Secondary	Adverse events of Grade 3 or higher		Up to 2 years post-transplant
Secondary	Neutrophil count = 500/mm3, time to recovery		Up to 2 years post-transplant
Secondary	Platelet count = 20,000/mm3, time to recovery		Up to 2 years post-transplant
Secondary	Marrow failure		Up to 2 years post-transplant
Secondary	Sickle cell disease related complications		Up to 2 years post-transplant
Secondary	Non-relapse mortality		Up to 2 years post-transplant
Secondary	Acute Graft versus Host Disease per 1994 Keystone Consensus Criteria		Day + 100 post-transplant
Secondary	Chronic Graft versus Host Disease per 2014 National Institutes of Health Consensus Criteria		Day+ 180, + 1 year and +2 years post-transplant
Secondary	Overall Survival		Up to 2 years post-transplant
Secondary	Disease-Free Survival		Up to 2 years post-transplant
Secondary	Event-Free Survival		Up to 2 years post-transplant
Secondary	Disease Relapse		Up to 2 years post-transplant
Secondary	Persistent post-immunosuppressant mixed chimerism	Between 5% and 95% donor chimerism at two years post- transplant, at least 6 months post- immunosuppressant	Up to 2 years post-transplant
Secondary	Persistent immunosuppressant -dependent mixed chimerism	Between 5% and 95% donor chimerism at two years post- transplant and on immunosuppressant	+2 years post-transplant
Secondary	Complete chimerism: >95% donor chimerism		+2 years post-transplant
Secondary	Primary donor graft failure: Defined as < 5% donor chimerism by Day + 30 post- transplant		Day +30 post-transplant
Secondary	Secondary donor graft failure: Defined as < 5% donor chimerism beyond Day +30 in patients with prior documentation of = 5% donor cells by Day +30		> Day + 30 up to 2 years post-transplant
Secondary	Donor chimerism in blood		Day +30, Day +60, Day +100, Day+180, and +1 yr, +1.5 yr, +2yr post-transplant
Secondary	Donor chimerism in bone marrow		Day + 100, Day + 180 and + 1 yr post-transplant
Secondary	Percent HbS levels		Baseline, and then Day + 30, Day + 100, Day + 180, +1 yr, +1.5, +2yr post-transplant