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

Primary Purpose

Refractory Acute Myeloid Leukemia, Refractory Acute Lymphoblastic Leukemia

Status

Unknown status

Phase

Phase 3

Locations

Russian Federation

Study Type

Interventional

Intervention

Preparative regimen

About this trial

This is an interventional treatment trial for Refractory Acute Myeloid Leukemia

Eligibility Criteria

undefined - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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%

Sites / Locations

Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and ImmunologyRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

intervention/treatment

Arm Description

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

Outcomes

Primary Outcome Measures

cumulative incidence of neutrophil and platelets engraftment at day +30 after HSCT

Overall response rate

Proportion of patients with hematologic remission at time points

Partial response rate

Proportion of patients with MRD negativity at time points

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

cumulative incidence of transplant-related mortality

Secondary Outcome Measures

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

cumulative incidence of acute GVHD grade II-IV

cumulative incidence of chronic GvHD

Rate of immune recovery at day 30

Proportion of patients with early immune recovery: T-cell, NK- cell, B-cell >determined numbers

overall survival

event-free survival

Full Information

NCT ID

NCT04000698

First Posted

June 25, 2019

Last Updated

November 19, 2020

Sponsor

Federal Research Institute of Pediatric Hematology, Oncology and Immunology

1. Study Identification

Unique Protocol Identification Number

NCT04000698

Brief Title

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

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.

Study Type

Interventional

2. Study Status

Record Verification Date

November 2020

Overall Recruitment Status

Unknown status

Study Start Date

October 15, 2019 (Actual)

Primary Completion Date

July 2022 (Anticipated)

Study Completion Date

December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Federal Research Institute of Pediatric Hematology, Oncology and Immunology

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief 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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Refractory Acute Myeloid Leukemia, Refractory Acute Lymphoblastic Leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

25 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

intervention/treatment

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Preparative regimen

Intervention Description

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

Primary Outcome Measure Information:

Title

cumulative incidence of neutrophil and platelets engraftment at day +30 after HSCT

Time Frame

30 days after HSCT

Title

Overall response rate

Description

Proportion of patients with hematologic remission at time points

Time Frame

30 days after HSCT

Title

Partial response rate

Description

Proportion of patients with MRD negativity at time points

Time Frame

30 days after HSCT

Title

Rate of toxicity stage > 3 according to CTCAE 5.0

Description

Proportion of patients with allergic/ anaphylaxis reaction toxicity stage > 3 according to CTCAE 5.0

Time Frame

40 days after first drug administration

Title

cumulative incidence of transplant-related mortality

Time Frame

100 days after HSCT

Secondary Outcome Measure Information:

Title

Rate of expression of target molecule on blast cells

Description

Proportion of patients with target molecule on blast cells: CD38 and/or CD 184 and/or Bcl2

Time Frame

1 week before first drug administration

Title

cumulative incidence of acute GVHD grade II-IV

Time Frame

120 days after HSCT

Title

cumulative incidence of chronic GvHD

Time Frame

1 year after HSCT

Title

Rate of immune recovery at day 30

Description

Proportion of patients with early immune recovery: T-cell, NK- cell, B-cell >determined numbers

Time Frame

Title

overall survival

Time Frame

1 year after HSCT

Title

event-free survival

Time Frame

1 year after HSCT

10. Eligibility

Sex

All

Maximum Age & Unit of Time

25 Years

Accepts Healthy Volunteers

Eligibility Criteria

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%

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Larisa Shelikhova

Phone

84956647078

larisa.shelikhova@fccho-moscow.ru

First Name & Middle Initial & Last Name or Official Title & Degree

Zhanna Shekhovtsova

Phone

84956647078

Ext

7538

zhanna.shekhovtsova@fccho-moscow.ru

Facility Information:

Facility Name

Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology

City

Moscow

ZIP/Postal Code

117997

Country

Russian Federation

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Zhanna Shekhovtsova, MD

Phone

4956647078

Ext

7538

zhanna.shekhovtsova@fccho-moscow.ru

First Name & Middle Initial & Last Name & Degree

Eugene Pashanov, PhD

Phone

+79262205578

e.pashanov@gmail.com

First Name & Middle Initial & Last Name & Degree

Michael Maschan, PhD

12. IPD Sharing Statement

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

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