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

Refractory Acute Myeloid Leukemia Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04000698
• Other study ID #: NCPHOI-2018-08
• Status: Recruiting
• Phase: Phase 3
• Start date: October 15, 2019
• Est. completion date: December 2022

Study information

• Verified date: November 2020
• Source: Federal Research Institute of Pediatric Hematology, Oncology and Immunology
• Contact: Larisa Shelikhova
• Phone: 84956647078
• Email: larisa.shelikhova[@]fccho-moscow.ru
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: December 2022
• Est. primary completion date: July 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 25 Years

Eligibility

Inclusion Criteria:

1. Ability to give informed consent (for patients > 14 years old). For subjects < 18 years old their legal guardian must give informed consent

2. 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

3. Patient eligible for current hematopoietic stem cell transplantation protocol

4. The BCL-2 expression must be detected on greater than 30% of tumor cells (AML and ALL) by flow cytometry

5. CD38 expression must be detected on greater than 30% of tumor cells (AML and ALL) by flow cytometry

6. CD184

7. 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.

8. Patient Clinical Performance Status: Karnofsky >50% or Lansky >50%

9. Patient Life Expectancy >12 weeks

10. 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%

Related Conditions & MeSH terms

• Leukemia
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Refractory Acute Lymphoblastic Leukemia
• Refractory Acute Myeloid Leukemia

Intervention

Drug:
• Preparative regimen
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

Locations

Country	Name	City	State
Russian Federation	Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology	Moscow

Sponsors (1)

Lead Sponsor	Collaborator
Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	cumulative incidence of neutrophil and platelets engraftment at day +30 after HSCT		30 days after HSCT
Primary	Overall response rate	Proportion of patients with hematologic remission at time points	30 days after HSCT
Primary	Partial response rate	Proportion of patients with MRD negativity at time points	30 days after HSCT
Primary	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
Primary	cumulative incidence of transplant-related mortality		100 days after HSCT
Secondary	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
Secondary	cumulative incidence of acute GVHD grade II-IV		120 days after HSCT
Secondary	cumulative incidence of chronic GvHD		1 year after HSCT
Secondary	Rate of immune recovery at day 30	Proportion of patients with early immune recovery: T-cell, NK- cell, B-cell >determined numbers	30
Secondary	overall survival		1 year after HSCT
Secondary	event-free survival		1 year after HSCT