Clinical trial NCT05426252: Thal-Fabs: Reduced Toxicity Conditioning for High Risk Thalassemia
Official title: Thal-FabS: Novel Transplant Strategy for High-risk Thalassemia Patients - a Phase I/II Trial of Early Fludarabine Followed by Abatacept and Sirolimus Immunosuppression
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Thalassemia in Children
Keywords: thalassemia
reduced toxicity
abatacept
sirolimus
pre transplant immunosuppression
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
Collaborators: name: Thalassemia Foundation of Canada
First posted: 2022-06-21
Enrollment: 20
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single arm, non-randomized phase I/II trial
Primary purpose: TREATMENT

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.

Detailed description: Patients with high-risk thalassemia meeting the eligibility criteria for this study will be entered sequentially until completion or closure of the study.

The hypothesis is that a 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 is feasible and safe and can be delivered with less toxicity, durable donor engraftment, and minimal GVHD.

Eligibility criteria: Inclusion Criteria: In order to be eligible to participate in this study, the recipient must meet all of the following criteria:

1. Patients with a diagnosis of transfusion dependent beta or alpha thalassemia (3 or 4 gene deletion) between the age of 1-18 years.
2. Thalassemia genotype must be confirmed by molecular genetic testing.
3. 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

3. 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.

4. Ability to take oral medication and be willing to adhere to the study regimen.

5. Patients who have a performance status of at least 70% Karnofsky or Lansky status prior to transplantation.

6. Patients who are acceptable candidates for marrow transplantation based on their pre-BMT evaluation.

7. Patients who have histocompatibility sibling or HLA haplo identical family member and have been medically approved as hematopoietic progenitor cell donors.

8. Patients who are not candidates for gene therapy.

9. 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.

Exclusion Criteria: The recipient who meets any of the following criteria will be excluded from participation in this study:

1. Patients will not be excluded based on sex, race, or ethnic background.
2. 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.
3. Presence of donor specific antibody (DSA) with mean fluorescence intensity (MFI) greater than 3,000.
4. Previous stem cell transplant or gene therapy.
5. Presence of cardiomyopathy with a T2\* \< 10ms per Cardiac MRI.
6. 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.
7. Active HIV, hepatitis B or hepatitis C disease.
8. Severe liver cirrhosis or bridging fibrosis on liver biopsy if previously done.
9. Prior or current malignancy or myeloproliferative or immunodeficiency disorder.
10. Evidence of active, deep seated, life-threatening infections despite therapy (e.g., certain fungal species, HIV, etc.).
11. Patients will be excluded if they are women of childbearing potential who are currently pregnant (b-HCG+) or who are not practicing adequate contraception.
12. Any condition that would preclude serial follow up.
13. Patients with a known life-threatening allergy to components of the pre transplant immunosuppression (fludarabine), conditioning (treosulfan, cyclophosphamide or anti-thymocyte globulin) or graft versus host prophylactic regimen (abatacept, sirolimus).
14. Any condition or diagnosis, that could in the opinion of the Principal Investigator or delegate interfere with the participant's ability to comply with study instructions, might confound the interpretation of the study results, or put the participant at risk

Donor Eligibility:

Donors will not be considered research subjects as the stem cell collection procedure is standard of care and will not be considered part of the research.

In order to be eligible to participate in this study, the donor must meet all of the following criteria:

1. May have thalassemia or sickle trait.
2. Will also consider ABO match and lack of donor specific anti-HLA antibodies.
3. Donors must be minimal of 15 kg weight and have completed routine donor evaluations as per our standard of care.
4. Donors must have signed (by patient or legal guardian) informed consent for the protocol approved by the Research Ethical Board of the Hospital for Sick Children/University of Toronto.
5. No evidence of transmissible diseases in compliance with the Health Canada CTO regulations
6. Not pregnant or lactating
7. Must not be allergic to granulocyte colony stimulating factor (G-CSF)

Primary outcomes:
measure: Number of patients who have WBC engraftment by day +100
timeFrame: Until Day +100
measure: Number of patients who develop Grade II to IV acute GVHD at Day +100
timeFrame: Until Day +100
measure: Immune reconstitution
timeFrame: Until Day +365
Secondary outcomes:
measure: Number of patients who develop Chronic GVHD
timeFrame: Day +100 until Day +365
Other outcomes:
measure: Number of patients who will wean Sirolimus at 1 year post transplant
timeFrame: Until Day +365
measure: Length of stay
timeFrame: Until Day +365
measure: Cost effectiveness
timeFrame: Until Day +365
Locations:
city: Toronto
country: Canada
facility: Yogi Chopra
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Yogi Chopra, MD
role: PRINCIPAL_INVESTIGATOR
References: