A Study of Immune Suppression Treatment for People With Sickle Cell Disease or β-Thalassemia Who Are Going to Receive an Allogeneic Hematopoietic Cell Transplantation (HCT)

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT05736419

Collaborator

(none)

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Hematopoietic Cell Transplantation/HCT involves receiving healthy blood-forming cells (stem cells) from a donor to replace the diseased or damaged cells in participants' bone marrow. The researchers think giving participants treatment with fludarabine and dexamethasone, drugs that lower the activity of the body's immune system (immune suppression), before standard conditioning therapy and HCT may help prevent serious side effects, including graft failure and GvHD. In this study, depending on how participants' body responds to the fludarabine and dexamethasone, the study doctor may decide participants should receive another drug, called cyclophosphamide, instead of fludarabine. In addition, depending on the results of participants' routine blood tests, participants may receive the drugs bortezomib and rituximab, which also help with immune suppression.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Disease Thalassemia, Beta Thalassemia	Drug: Fludarabine Drug: Cyclophosphamide Drug: Tacrolimus Drug: Mycophenolate Mofetil Biological: Rabbit ATG Drug: Dexamethasone Drug: Bortezomib Drug: Rituximab	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

24 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Pre-Transplant Immune Suppression With Hematopoietic Cell Transplantation From Haploidentical Donors for Adults and Children With Sickle Cell Disease or ß-Thalassemia (Haplo PTCy)

Actual Study Start Date :

Feb 9, 2023

Anticipated Primary Completion Date :

Feb 9, 2026

Anticipated Study Completion Date :

Feb 9, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Participants with Sickle Cell Disease or β-Thalassemia Participants will have severe sickle cell disease or transfusion-dependent β-thalassemia.	Drug: Fludarabine PK-guided fludarabine dosing will be used for each of the 2 cycles, using the InsightRx DoseMeRx platform. Drug: Cyclophosphamide Cyclophosphamide will be administered Post-Transplant Drug: Tacrolimus Tacrolimus will be administered beginning on day +5 Drug: Mycophenolate Mofetil Mycophenolate mofetil (MMF) will be administered three times daily starting on day +5. Biological: Rabbit ATG The dose and schedule of ATG will be determined according to the nomogram in Appendix A Drug: Dexamethasone Standard Regimen: Dexamethasone on days -68 to -64 and days -40 to -36. Drug: Bortezomib Bortezomib on days -71, -68, -65, -61, -43, -40, -37, and -33 Drug: Rituximab Rituximab on days -71, -58, -43, and -30.

Arm

Intervention/Treatment

Experimental: Participants with Sickle Cell Disease or β-Thalassemia

Participants will have severe sickle cell disease or transfusion-dependent β-thalassemia.

Drug: Fludarabine

PK-guided fludarabine dosing will be used for each of the 2 cycles, using the InsightRx DoseMeRx platform.

Drug: Cyclophosphamide

Cyclophosphamide will be administered Post-Transplant

Drug: Tacrolimus

Tacrolimus will be administered beginning on day +5

Drug: Mycophenolate Mofetil

Mycophenolate mofetil (MMF) will be administered three times daily starting on day +5.

Biological: Rabbit ATG

The dose and schedule of ATG will be determined according to the nomogram in Appendix A

Drug: Dexamethasone

Standard Regimen: Dexamethasone on days -68 to -64 and days -40 to -36.

Drug: Bortezomib

Bortezomib on days -71, -68, -65, -61, -43, -40, -37, and -33

Drug: Rituximab

Rituximab on days -71, -58, -43, and -30.

Outcome Measures

Primary Outcome Measures

Number of participants with treatment related mortality/TRM or primary graft failure [1 year]
The primary outcome is to estimate treatment-related mortality (TRM) or primary graft failure at 1 year post-HCT.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age > 12 and < 35 years. Patients of age 2-12 and 35-50 years will be included after 8 patients reach day 100 without TRM and if ≥ 4 of the first 8 patients reach day 100 without graft failure or grade III-IV acute GvHD.
Suitable haploidentical donor.
Performance score ≥ 70% by Karnofsky Performance Scale or 0 to 1 by ECOG (age > 16 years), or Lansky Play-Performance Scale ≥ 70% (age ≤ 16 years).
Adequate major organ system function as demonstrated by:
For patients ≥ 18 years of age:
eGFR ≥ 50 mL/min by Cockcroft-Gault formula
For patients < 18 years of age:
Serum creatinine clearance: glomerular filtration rate [GFR]) must be >50 mL/min/1.73 m2 as calculated by the Schwartz formula
Conjugated (direct) bilirubin less than 2x upper limit of normal.
ALT or AST ≤ 3 times institutional upper limit of normal.
Left ventricular ejection fraction ≥ 50%.
Diffusing capacity for carbon monoxide (DLCO) ≥ 50% predicted, corrected for hemoglobin. For children < 7 years of age who are unable to perform PFT, oxygen saturation > 92% on room air by pulse oximetry.
For SCD patients: HbSS, HbSC, HbS/β° with one or more of the following complications:
Acute chest syndrome: 2 or more episodes in the 2 years preceding enrollment
Vaso-occlusive episodes: 3 or more episodes in the 2 years preceding enrollment
Recurrent priapism: 2 or more episodes in the 2 years preceding enrollment
History of osteomyelitis or osteonecrosis
Cerebrovascular disease:
Imaging evidence of prior overt or silent stroke
History of a neurologic event resulting in focal neurologic deficits lasting > 24 hours
Abnormal transcranial Doppler: Timed average maximum mean velocity ≥ 200 cm/sec in terminal portion of the carotid or proximal portion of the middle cerebral artery or > 185 cm/sec plus evidence of intracranial vasculopathy if imaging TCD is used
Pulmonary hypertension: Confirmed by right heart catheterization with mean pulmonary arterial pressure ≥ 25 mmHg or mean pulmonary vascular resistance > 2 Wood units
Red blood cell alloimmunization (> 3 alloantibodies)
For thalassemia patients: Any genotype, with all of the following:
Onset of red blood cell transfusion dependence during the first 3 years of life
RBC transfusion history > 225 mL/kg/year or > 15 lifetime RBC transfusions
Pre-transfusion hemoglobin ≤ 7 g/dL
Hepatosplenomegaly
Patient or the patient's legal representative, parent(s) or guardian should be able to provide written informed consent. Assent of a minor if participant's age is at least seven and less than eighteen years.
For sexually active men and women of childbearing potential, must agree to use a form of contraception considered effective and medically acceptable by the Investigator.

Exclusion Criteria:

Prior myeloablative allogeneic HCT.
Overt stroke or CNS instrumentation (e.g. for Moyamoya disease) within 6 months of enrollment.
Liver cirrhosis. Mild fibrosis will be permitted, i.e. fine reticulin or grade 1 of 4, with bridging fibrosis.
Hepatic iron content ≥ 3 mg Fe/g liver dry weight
HIV positive
Active hepatitis B or C.
Other uncontrolled infections.
BMI > 40.
Other malignancy/cancer diagnosis unless in remission after definitive therapy for a minimum of 2 years. Exceptions: Ductal carcinoma in situ, basal cell carcinoma, cervical intraepithelial neoplasia.
Positive pregnancy test in a woman with child-bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization.
Inability to comply with medical therapy or follow-up.
Known history of allergic reactions to any constituents of the cell product, including a known history of allergic reactions to DMSO.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan Kettering at Basking Ridge (Consent only)	Basking Ridge	New Jersey	United States	07920
2	Memorial Sloan Kettering Monmouth (Consent only)	Middletown	New Jersey	United States	07748
3	Memorial Sloan Kettering Bergen (Consent only)	Montvale	New Jersey	United States	07645
4	Memorial Sloan Kettering Suffolk - Commack (Consent only)	Commack	New York	United States	11725
5	Memorial Sloan Kettering Westchester (Consent only)	Harrison	New York	United States	10604
6	Memorial Sloan Kettering Nassau (All protocol activities)	Rockville Centre	New York	United States	11553