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

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.

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

Study Overview

• Status: Unknown
• Conditions: Refractory Acute Myeloid Leukemia; Refractory Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Preparative regimen

Detailed 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.

• Study Type: Interventional
• Enrollment (Anticipated): 25
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Larisa Shelikhova; Phone Number: 84956647078; Email: larisa.shelikhova@fccho-moscow.ru

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 117997
    • Recruiting
    • Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 25 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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%

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: intervention/treatment; 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; 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

What is the study measuring?

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
cumulative incidence of chronic GvHD		1 year after HSCT
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
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

Collaborators and Investigators

• Sponsor: Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 15, 2019
• Primary Completion (ANTICIPATED): July 1, 2022
• Study Completion (ANTICIPATED): December 1, 2022

Study Registration Dates

• First Submitted: June 25, 2019
• First Submitted That Met QC Criteria: June 26, 2019
• First Posted (ACTUAL): June 27, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 20, 2020
• Last Update Submitted That Met QC Criteria: November 19, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, Lymphoid; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Other Study ID Numbers: NCPHOI-2018-08

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No