Personalized Targeted Preparative Regimen Before T-depleted Allogeneic HSCT in Children With Chemoresistent Acute Leukemias

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficiency of personalized targeted therapy in combination with high-dose chemotherapy as part of a preparative regimen before T-depleted allogeneic hematopoietic stem cell transplantation in children with chemoresistant acute leukemias

Detailed Description
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The outcome of hematopoietic stem cell transplantation (HSCT) in a cohort of children with chemorefractory leukemia is poor. The incidence of relapse exceeds 50% and survival varies from 10 to 40%. Additional attempts at remission induction with various combinations of chemotherapy are unlikely to improve the outcome and will contribute to toxicity. The hypothesis of the study is that personalized targeted therapy combined with high-dose chemotherapy may improve the outcome of allogeneic HSCT in a cohort of pediatric patients with refractory leukemia. Bcl-2, CD38, CD184 were chosen as potential targets due to frequent expression in pediatric acute leukemias, availability of marketed targeted therapies venetoclax, daratumumab and prelixafor, and expected non-overlapping toxicity profile of these agents and the conditioning regimen.

Official Title
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A Phase I-II Pilot Clinical Trial of Safety and Efficacy of Personalized Targeted Preparative Regimen With Allogeneic TcRαβ/CD19-depleted Hematopoietic Stem Cell Transplantation and Posttransplant Donor T- Cells Infusion in Children With Chemoresistаnt Acute Leukemia.

Conditions
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Refractory Acute Myeloid Leukemia, Refractory Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Preparative regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to give informed consent (for patients > 14 years old). For subjects < 18 years old their legal guardian must give informed consent Disease stage Acute myeloid leukemia (AML), relapsed or refractory, failure to achieve hematologic remission after at least to courses of intensive chemotherapy, including at least one course with high-dose AraC and fludarabine Acute lymphoblastic leukemia (ALL), relapsed or refractory, failure to achieve hematologic remission after at least two high-dose therapy blocks Patient eligible for current hematopoietic stem cell transplantation protocol The BCL-2 expression must be detected on greater than 30% of tumor cells (AML and ALL) by flow cytometry CD38 expression must be detected on greater than 30% of tumor cells (AML and ALL) by flow cytometry CD184 Patients must have measurable or evaluable disease at the time of enrollment, which may include any evidence of disease including minimal residual disease detected by flow cytometry, cytogenetics, or polymerase chain reaction (PCR) analysis. Patient Clinical Performance Status: Karnofsky >50% or Lansky >50% Patient Life Expectancy >12 weeks Patients who agree to long-term follow up for up to 5 years Exclusion Criteria: Age >25 years Patients with uncontrolled infections Clearance of creatinine < 70 ml/min Cardiac ejection fraction < 40% Patients who can perform pulmonary function tests will be excluded if they have a diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) of < 50% predicted; patients who are unable to perform pulmonary function tests will be excluded if the oxygen (O2) saturation is < 92% on room air Patients who have liver function test (LFTs) (including total bilirubin, aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) >= twice the upper limit of normal Karnofsky/Lansky Scale <70%

Ages Eligible for Study
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Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intervention/treatment<br>Preparative chemotherapy before allogeneic HSCT Fludarabin Cytarabine Venetoclax Daratumomab Vecanoid treosulfan fludarabine thiophosphomide Venetoclax Plerixafor abatacept tocilizumab rituximab HSCT from the haploidentical donor, ex vivo depleted of alpha/beta T lymphocytes | Drug: Preparative regimen<br>* Preparative chemotherapy before allogeneic HSCT Fludarabin Cytarabine Venetoclax Daratumomab Vecanoid Condition treosulfan fludarabine thiophosphomide Venetoclax Plerixafor GVHD prophylaxis abatacept tocilizumab rituximab HSCT from the haploidentical donor, ex vivo depleted of alpha/beta T lymphocytes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| cumulative incidence of neutrophil and platelets engraftment at day +30 after HSCT |  | 30 days after HSCT | 
| Overall response rate | Proportion of patients with hematologic remission at time points | 30 days after HSCT | 
| Partial response rate | Proportion of patients with MRD negativity at time points | 30 days after HSCT | 
| Rate of toxicity stage > 3 according to CTCAE 5.0 | Proportion of patients with allergic/ anaphylaxis reaction toxicity stage > 3 according to CTCAE 5.0 | 40 days after first drug administration | 
| cumulative incidence of transplant-related mortality |  | 100 days after HSCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of expression of target molecule on blast cells | Proportion of patients with target molecule on blast cells: CD38 and/or CD 184 and/or Bcl2 | 1 week before first drug administration | 
| cumulative incidence of acute GVHD grade II-IV |  | 120 days after HSCT | 
| cumulative incidence of chronic GvHD |  | 1 year after HSCT | 
| Rate of immune recovery at day 30 | Proportion of patients with early immune recovery: T-cell, NK- cell, B-cell >determined numbers | 30 | 
| overall survival |  | 1 year after HSCT | 
| event-free survival |  | 1 year after HSCT |