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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 5, 2019
Sponsor:
Information provided by (Responsible Party):
Federal Research Institute of Pediatric Hematology, Oncology and Immunology

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
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.
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : December 2022


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




Primary Outcome Measures :
  1. cumulative incidence of neutrophil and platelets engraftment at day +30 after HSCT [ Time Frame: 30 days after HSCT ]
  2. Overall response rate [ Time Frame: 30 days after HSCT ]
    Proportion of patients with hematologic remission at time points

  3. Partial response rate [ Time Frame: 30 days after HSCT ]
    Proportion of patients with MRD negativity at time points

  4. 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

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

Secondary Outcome Measures :
  1. 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

  2. cumulative incidence of acute GVHD grade II-IV [ Time Frame: 120 days after HSCT ]
  3. cumulative incidence of chronic GvHD [ Time Frame: 1 year after HSCT ]
  4. 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

  5. overall survival [ Time Frame: 1 year after HSCT ]
  6. event-free survival [ Time Frame: 1 year after HSCT ]


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Ages Eligible for Study:   up to 25 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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%

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04000698


Contacts
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Contact: Larisa Shelikhova 84956647078 larisa.shelikhova@fccho-moscow.ru
Contact: Zhanna Shekhovtsova 84956647078 ext 7538 zhanna.shekhovtsova@fccho-moscow.ru

Locations
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Russian Federation
Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology Not yet recruiting
Moscow, Russian Federation, 117997
Contact: Zhanna Shekhovtsova, MD    4956647078 ext 7538    zhanna.shekhovtsova@fccho-moscow.ru   
Contact: Eugene Pashanov, PhD    +79262205578    e.pashanov@gmail.com   
Principal Investigator: Michael Maschan, PhD         
Sponsors and Collaborators
Federal Research Institute of Pediatric Hematology, Oncology and Immunology

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Responsible Party: Federal Research Institute of Pediatric Hematology, Oncology and Immunology
ClinicalTrials.gov Identifier: NCT04000698     History of Changes
Other Study ID Numbers: NCPHOI-2018-08
First Posted: June 27, 2019    Key Record Dates
Last Update Posted: September 5, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Venetoclax
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Antineoplastic Agents