Reduced Toxicity Conditioning for Thalassemia
Recruiting in Palo Alto (17 mi)
+1 other location
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: The Hospital for Sick Children
Disqualifiers: Cardiac dysfunction, Renal impairment, Hepatic dysfunction, Active infections, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?
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.
Is the treatment for thalassemia using drugs like Sirolimus and Abatacept safe?
How is the drug combination of Abatacept and Sirolimus unique for treating thalassemia?
This treatment is unique because it combines Abatacept, which helps prevent severe immune reactions after stem cell transplants, with Sirolimus, which boosts the production of beneficial fetal hemoglobin and enhances immune cell function, offering a potentially safer and more effective approach for thalassemia patients.23456
Eligibility Criteria
This trial is for kids and teens (1-18 years old) with high-risk thalassemia, which requires regular blood transfusions. They should have a sibling or family donor for bone marrow transplant, not be eligible for gene therapy, and able to take oral meds. Excluded are those with severe organ dysfunction, active infections like HIV/hepatitis B/C, previous transplants or gene therapy, pregnant women or significant allergies to the treatment drugs.Inclusion Criteria
I can take pills and will follow the study plan.
I've had a full iron status check and recent MRI scans of my heart and liver.
I am between 1-18 years old and need regular blood transfusions for thalassemia.
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Exclusion Criteria
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. Any condition that would preclude serial follow up. 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). 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
My eligibility is not affected by my sex, race, or ethnicity.
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Pre-transplant Immunosuppression
Administration of pre-transplant immunosuppression as part of the reduced-toxicity conditioning regimen
2 weeks
Transplant and GVHD Prophylaxis
Allogeneic transplant with abatacept and sirolimus as GVHD prophylaxis
100 days
Follow-up
Participants are monitored for safety and effectiveness after transplant, including immune reconstitution and GVHD assessment
365 days
Treatment Details
Interventions
- Abatacept (Immunomodulator)
- Sirolimus (Immunosuppressant)
Trial OverviewThe study tests a new transplant method using two drugs: Abatacept and Sirolimus in children with thalassemia who need frequent blood transfusions. The goal is to see if this approach can improve long-term outcomes after bone marrow transplantation from family donors.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: PTIS followed by abatacept and sirolimusExperimental Treatment2 Interventions
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
Abatacept is already approved in European Union, United States, Canada, Japan for the following indications:
πͺπΊ Approved in European Union as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
- Psoriatic arthritis
πΊπΈ Approved in United States as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
- Psoriatic arthritis
π¨π¦ Approved in Canada as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
π―π΅ Approved in Japan as Orencia for:
- Rheumatoid arthritis
- Polyarticular juvenile idiopathic arthritis
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
The Hospital for Sick ChildrenToronto, Canada
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Who Is Running the Clinical Trial?
The Hospital for Sick ChildrenLead Sponsor
Thalassemia Foundation of CanadaCollaborator
References
A Rational Approach to Drug Repositioning in Ξ²-thalassemia: Induction of Fetal Hemoglobin by Established Drugs. [2022]Drug repositioning and the relevance of orphan drug designation for Ξ²-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', 'drug rescue', 'drug re-tasking' and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the "off-label" use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for Ξ²-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial.
Expression of Ξ³-globin genes in Ξ²-thalassemia patients treated with sirolimus: results from a pilot clinical trial (Sirthalaclin). [2022]Label="Introduction" NlmCategory="UNASSIGNED">β-thalassemia is caused by autosomal mutations in the β-globin gene, which induce the absence or low-level synthesis of β-globin in erythroid cells. It is widely accepted that a high production of fetal hemoglobin (HbF) is beneficial for patients with β-thalassemia. Sirolimus, also known as rapamycin, is a lipophilic macrolide isolated from a strain of Streptomyces hygroscopicus that serves as a strong HbF inducer in vitro and in vivo. In this study, we report biochemical, molecular, and clinical results of a sirolimus-based NCT03877809 clinical trial (a personalized medicine approach for β-thalassemia transfusion-dependent patients: testing sirolimus in a first pilot clinical trial, Sirthalaclin).
Effects of Sirolimus treatment on patients with β-Thalassemia: Lymphocyte immunophenotype and biological activity of memory CD4+ and CD8+ T cells. [2023]Inhibitors of the mammalian target of rapamycin (mTOR) have been proposed to improve vaccine responses, especially in the elderly. Accordingly, testing mTOR inhibitors (such as Sirolimus) and other geroprotective drugs might be considered a key strategy to improve overall health resilience of aged populations. In this respect, Sirolimus (also known as rapamycin) is of great interest, in consideration of the fact that it is extensively used in routine therapy and in clinical studies for the treatment of several diseases. Recently, Sirolimus has been considered in laboratory and clinical studies aimed to find novel protocols for the therapy of hemoglobinopathies (e.g. β-Thalassemia). The objective of the present study was to analyse the activity of CD4+ and CD8+ T cells in β-Thalassemia patients treated with Sirolimus, taking advantages from the availability of cellular samples of the NCT03877809 clinical trial. The approach was to verify IFN-γ releases following stimulation of peripheral blood mononuclear cells (PBMCs) to stimulatory CEF and CEFTA peptide pools, stimulatory for CD4+ and CD8+ T cells, respectively. The main results of the present study are that treatment of β-Thalassemia patients with Sirolimus has a positive impact on the biological activity and number of memory CD4+ and CD8+ T cells releasing IFN-γ following stimulation with antigenic stimuli present in immunological memory. These data are to our knowledge novel and in our opinion of interest, in consideration of the fact that β-Thalassemia patients are considered prone to immune deficiency.
Graft-versus-host Disease Prophylaxis With Abatacept Reduces Severe Acute Graft-versus-host Disease in Allogeneic Hematopoietic Stem Cell Transplant for Beta-thalassemia Major With Busulfan, Fludarabine, and Thiotepa. [2021]We hypothesized that the addition of 4 doses of abatacept to our standard acute graft-versus-host disease (GVHD) prophylaxis would reduce the incidence of day +100 severe acute GVHD in children with transfusion-dependent beta-thalassemia major undergoing a myeloablative allogeneic hematopoietic stem cell transplant (HSCT), without impacting engraftment.
Hematopoietic Stem Cell Transplantation for Severe Thalassemia Patients from Haploidentical Donors Using a Novel Conditioning Regimen. [2021]Patients with severe thalassemia commonly have a survival that is significantly shorter than that of the general population. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pretransplant immune suppression phase (PTIS) and 2 courses of dexamethasone and fludarabine, followed by pretransplant conditioning with fludarabine-i.v. busulfan and post-transplant graft-versus-host disease (GVHD) prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia (median age, 12 years; range, 1 to 28 years) with a minimum follow-up of 6 months (median, 15 months; range, 7 to 53 months); the 3-year projected overall and event-free survival is over 96%, and there have been no secondary graft failures. Of the first 31 patients, we had 2 graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific HLA antibodies (anti-DSAs), but after adjusting the PTIS to include bortezomib and rituximab for patients with high titers of anti-DSAs and using pharmacologic dose guidance for busulfan, we had no graft failures in the last 52 patients. Six (7%) of 83 patients developed severe GVHD. We conclude that this is a safe and efficacious approach to allogeneic SCT in thalassemia, yielding results comparable to those available for patients with fully matched donors.
T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. [2018]We conducted a pilot study employing extended T cell costimulation blockade (COSBL) with Abatacept along with sirolimus and post-transplantation cyclophosphamide (PTCy) in 10 patients (median age 12) with severe aplastic anemia (SAA). Nine patients engrafted in the COSBL group, compared to all 10 patients (median 14 vs 13days) treated on PTCy protocols without abatacept (CONTROL group). The incidence of acute graft-versus-host disease (GVHD) was 10.5% in the COSBL group compared to 50% in the CONTROL group (p=0.04). Chronic GVHD (12.5% vs 56%, p=0.02) and CMV reactivation (30% vs 80%, p=0.03) were also reduced in the COSBL group. T and NK cell subset analysis revealed higher CD56brightCD16- NK cells in the CONTROL group (p=0.004), but similar CD56dimCD16+ NK cells in both groups at day+30. Tregs (CD4+CD25+CD127dim/- FoxP3+) were markedly higher in the COSBL group at day+30 (8.4% vs 1.1%) and the trend was maintained through day+90 (p<0.01). The GVHD and Disease-free survival at one year in the COSBL group was 80% vs. 30% in the CONTROL group (p=0.05). Our preliminary findings suggest that COSBL in combination with PTCy and sirolimus might augment transplantation tolerance in children with SAA, probably due to synergistic effect on early recovery of Tregs.