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

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ClinicalTrials.gov Identifier: NCT04000698
Recruitment Status : Not yet recruiting
First Posted : June 27, 2019
Last Update Posted : September 6, 2019
Sponsor:
Information provided by (Responsible Party):
Federal Research Institute of Pediatric Hematology, Oncology and Immunology

Tracking Information
First Submitted Date  ICMJE June 25, 2019
First Posted Date  ICMJE June 27, 2019
Last Update Posted Date September 6, 2019
Estimated Study Start Date  ICMJE October 2019
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 26, 2019)
  • cumulative incidence of neutrophil and platelets engraftment at day +30 after HSCT [ Time Frame: 30 days after HSCT ]
  • Overall response rate [ Time Frame: 30 days after HSCT ]
    Proportion of patients with hematologic remission at time points
  • Partial response rate [ Time Frame: 30 days after HSCT ]
    Proportion of patients with MRD negativity at time points
  • Rate of toxicity stage > 3 according to CTCAE 5.0 [ Time Frame: 40 days after first drug administration ]
    Proportion of patients with allergic/ anaphylaxis reaction toxicity stage > 3 according to CTCAE 5.0
  • cumulative incidence of transplant-related mortality [ Time Frame: 100 days after HSCT ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2019)
  • Rate of expression of target molecule on blast cells [ Time Frame: 1 week before first drug administration ]
    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 [ Time Frame: 120 days after HSCT ]
  • cumulative incidence of chronic GvHD [ Time Frame: 1 year after HSCT ]
  • Rate of immune recovery at day 30 [ Time Frame: 30 ]
    Proportion of patients with early immune recovery: T-cell, NK- cell, B-cell >determined numbers
  • overall survival [ Time Frame: 1 year after HSCT ]
  • event-free survival [ Time Frame: 1 year after HSCT ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Personalized Targeted Preparative Regimen Before T-depleted Allogeneic HSCT in Children With Chemoresistent Acute Leukemias
Official Title  ICMJE 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Refractory Acute Myeloid Leukemia
  • Refractory Acute Lymphoblastic Leukemia
Intervention  ICMJE 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
Study Arms  ICMJE 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
Intervention: Drug: Preparative regimen
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 26, 2019)
25
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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%
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 25 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Larisa Shelikhova 84956647078 larisa.shelikhova@fccho-moscow.ru
Contact: Zhanna Shekhovtsova 84956647078 ext 7538 zhanna.shekhovtsova@fccho-moscow.ru
Listed Location Countries  ICMJE Russian Federation
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04000698
Other Study ID Numbers  ICMJE NCPHOI-2018-08
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Federal Research Institute of Pediatric Hematology, Oncology and Immunology
Study Sponsor  ICMJE Federal Research Institute of Pediatric Hematology, Oncology and Immunology
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Federal Research Institute of Pediatric Hematology, Oncology and Immunology
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP