Thal-Fabs: Reduced Toxicity Conditioning for High Risk Thalassemia

NCT05426252 | Recruiting Phase 1 DMC

• 1 other identifier: 1000075672
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate a novel transplant strategy for the long-term benefit of patients with transfusion dependent high-risk thalassemia.

Conditions

Thalassemia in Children

Keywords

thalassemia; reduced toxicity; abatacept; sirolimus; pre transplant immunosuppression

Outcome Measures

Primary Outcomes (3)

• Number of patients who have WBC engraftment by day +100

  Rate of neutrophil engraftment defined by the first day of 3 consecutive days of absolute neutrophil counts above 500/uL after bone marrow transplant.

  Until Day +100

• Number of patients who develop Grade II to IV acute GVHD at Day +100

  Incidence of Grade II or greater acute graft-versus-host disease (GvHD) post-transplant using criteria by Przepiorka et al, 1994

  Until Day +100

• Immune reconstitution

  Rate of immune reconstitution defined by recovery of CD4 cells post bone marrow transplantation

  Until Day +365

Secondary Outcomes (1)

• Number of patients who develop Chronic GVHD

  Day +100 until Day +365

Other Outcomes (3)

• Number of patients who will wean Sirolimus at 1 year post transplant

  Until Day +365

• Length of stay

  Until Day +365

• Cost effectiveness

  Until Day +365

Study Arms (1)

PTIS followed by abatacept and sirolimus

EXPERIMENTAL

Administration of reduced-toxicity conditioning regimen combined with pre-transplant immunosuppression, followed by abatacept and sirolimus as graft-versus-host disease (GVHD) prophylaxis for allogeneic transplant with either Human Leukocyte Antigen (HLA)-matched sibling donors or haploidentical donors

Drug: Abatacept; Drug: Sirolimus

Interventions

Abatacept DRUG

Abatacept, co-stimulation blockade, to be given for GVHD prophylaxis in combination with sirolimus post allogeneic hematopoietic stem cell transplantation.

Also known as: Orencia

PTIS followed by abatacept and sirolimus

Sirolimus DRUG

Sirolimus, mTOR inhibitor, to be given for GVHD prophylaxis in combination with abatacept post allogeneic hematopoietic stem cell transplantation.

Also known as: Rapamicin

PTIS followed by abatacept and sirolimus

Eligibility Criteria

• Age: 1 Year - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients with a diagnosis of transfusion dependent beta or alpha thalassemia (3 or 4 gene deletion) between the age of 1-18 years.
• Thalassemia genotype must be confirmed by molecular genetic testing.
• Patients with thalassemia must have at least one of the high-risk features:
• Age \>7 years
• Hepatomegaly (2 cm below costal margin)
• Inadequate iron chelation (liver iron content \>7mg/g dry weight)
• Severe alloimmunization
• Unable to tolerate iron chelation
• \. Patients must have had a complete evaluation of their iron status including measurement of serum ferritin, MRI of the heart and liver (within the previous 6 months prior to referral). Liver elastography (within the preceding 3 months) will be also obtained but not required.
• \. Ability to take oral medication and be willing to adhere to the study regimen.
• \. Patients who have a performance status of at least 70% Karnofsky or Lansky status prior to transplantation.
• \. Patients who are acceptable candidates for marrow transplantation based on their pre-BMT evaluation.
• \. Patients who have histocompatibility sibling or HLA haplo identical family member and have been medically approved as hematopoietic progenitor cell donors.
• \. Patients who are not candidates for gene therapy.
• \. Patients/legal guardians who sign informed consent for the protocol approved by the Research Ethical Board of the Hospital for Sick Children/University of Toronto.

You may not qualify if:

• Patients will not be excluded based on sex, race, or ethnic background.
• Patients will be excluded if they demonstrate significant functional deficits in major organs, which could interfere with the outcome following bone marrow transplant, including:
• Cardiac: Evidence of significant cardiac dysfunction (resting left ventricular ejection fraction of \< 50% with absence of improvement with exercise), marked cardiomegaly or uncontrollable hypertension.
• Renal: Evidence of \> 50% reduction in expected creatinine clearance or GFR \< 60mL/min/1.73m2
• Hepatic: Evidence of hepatic dysfunction evidenced by a serum direct (conjugate) bilirubin of \> 2.5 mg/dl, or ALT \> 5 times the upper limit of normal for age.
• Pulmonary: Evidence of focal or diffuse active infection or pneumonitis and the patient demonstrates a FEV1 \< 50% or carbon monoxide diffusing capacity (DLCO) of \< 50% predicted value (adjusted for hemoglobin). The patient should not require ventilation support.
• Presence of donor specific antibody (DSA) with mean fluorescence intensity (MFI) greater than 3,000.
• Previous stem cell transplant or gene therapy.
• Presence of cardiomyopathy with a T2\* \< 10ms per Cardiac MRI.
• Presence of significant liver iron deposition defined as liver iron content \>15mg/g liver dry weight. If iron chelation were optimized and reassessment within 6 months shows a decrease of LIC to \<15 with no evidence of cardiomyopathy, patient may still be considered for enrollment.
• Active HIV, hepatitis B or hepatitis C disease.
• Severe liver cirrhosis or bridging fibrosis on liver biopsy if previously done.
• Prior or current malignancy or myeloproliferative or immunodeficiency disorder.
• Evidence of active, deep seated, life-threatening infections despite therapy (e.g., certain fungal species, HIV, etc.).
• Patients will be excluded if they are women of childbearing potential who are currently pregnant (b-HCG+) or who are not practicing adequate contraception.

Sponsors & Collaborators

• The Hospital for Sick Children: lead
• Thalassemia Foundation of Canada: collaborator

Study Sites (1)

Yogi Chopra

Toronto, Ontario, Canada

RECRUITING

Related Publications (1)

• Raffa EH, Harris TM, Choed-Amphai C, Kirby-Allen M, Odame I, Ali M, Krueger J, Hermans KG, Tole S, Seelisch J, Klaassen RJ, Abbott L, Chopra YR, Wall DA, Chiang KY. Early Engraftment and Immune Kinetics Following Allogeneic Transplant Using a Novel Reduced-Toxicity Transplant Strategy in Children/Adolescents with High-Risk Transfusion-Dependent Thalassemia: Early Results of the ThalFAbS Trial. Transplant Cell Ther. 2025 Mar;31(3):180.e1-180.e12. doi: 10.1016/j.jtct.2024.12.016. Epub 2024 Dec 24.

  PMID: 39722321 DERIVED

MeSH Terms

Conditions

Thalassemia

Interventions

Abatacept; Sirolimus

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Macrolides; Lactones; Organic Chemicals

Study Officials

• Yogi Chopra, MD

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yogi Chopra, MD

CONTACT

+1 (416) 813-7654; yogi.chopra@sickkids.ca

Erilda Kapllani

CONTACT

+1 (416) 813-7654; bmt.cra@sickkids.ca

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Physician

Model Details: Single arm, non-randomized phase I/II trial

Study Record Dates

• First Submitted: June 11, 2022
• First Posted: June 21, 2022
• Study Start: March 22, 2022
• Primary Completion: December 31, 2025
• Study Completion (Estimated): December 31, 2026
• Last Updated: December 19, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)