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

• Sponsor: Federal Research Institute of Pediatric Hematology, Oncology and Immunology (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04000698
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 37.6
• Patients Per Site Per Month: 0.7

Study Details

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

Condition or Disease	Intervention/Treatment	Phase
Refractory Acute Myeloid Leukemia; Refractory Acute Lymphoblastic Leukemia	Drug: Preparative regimen	Phase 3

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 Design

• Study Type: Interventional
• Anticipated Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: Oct 15, 2019
• Anticipated Primary Completion Date: Jul 1, 2022
• Anticipated Study Completion Date: Dec 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. cumulative incidence of neutrophil and platelets engraftment at day +30 after HSCT [30 days after HSCT]

2. Overall response rate [30 days after HSCT]

   Proportion of patients with hematologic remission at time points

3. Partial response rate [30 days after HSCT]

   Proportion of patients with MRD negativity at time points

4. Rate of toxicity stage > 3 according to CTCAE 5.0 [40 days after first drug administration]

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

5. cumulative incidence of transplant-related mortality [100 days after HSCT]

Secondary Outcome Measures

1. Rate of expression of target molecule on blast cells [1 week before first drug administration]

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

2. cumulative incidence of acute GVHD grade II-IV [120 days after HSCT]

3. cumulative incidence of chronic GvHD [1 year after HSCT]

4. Rate of immune recovery at day 30 [30]

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

5. overall survival [1 year after HSCT]

6. event-free survival [1 year after HSCT]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 25 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. Patient eligible for current hematopoietic stem cell transplantation protocol

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

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

4. CD184

5. 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.

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

7. Patient Life Expectancy >12 weeks

8. 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%

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology	Moscow		Russian Federation	117997

Sponsors and Collaborators

• Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Federal Research Institute of Pediatric Hematology, Oncology and Immunology
• ClinicalTrials.gov Identifier: NCT04000698
• Other Study ID Numbers: NCPHOI-2018-08
• First Posted: Jun 27, 2019
• Last Update Posted: Nov 20, 2020
• Last Verified: Nov 1, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Study Results

No Results Posted as of Nov 20, 2020