GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia

Sponsor
St. Petersburg State Pavlov Medical University (Other)
Overall Status
Completed
CT.gov ID
NCT02799147
Collaborator
(none)
27
1
3
53
0.5

Study Details

Study Description

Brief Summary

Several groups have demonstrated very low incidence of acute and chronic graft-versus-host disease (GVHD) with post-transplantation cyclophosphamide (PTCy) in haploidentical, unrelated and related allogeneic stem cell transplantation (SCT). Nonetheless for majority of the grafts, except for 10/10 HLA-matched bone marrow, with this type of prophylaxis require concomitant administration of calcineurin inhibitors±MMF, which delays immune reconstitution and development of graft-versus-leukemia (GVL) effect. So, despite reduction of transplant-related mortality, use of PTCy doesn't lead to the reduction of relapse incidence. This is particularly important for relapsed or refractory acute leukemia patients, where, despite all efforts to intensify conditioning regimens, relapses after SCT occur in more than 50% of patients, and long-term survival rarely exceeds 10-20%. In preclinical model of haploidentical SCT the substitution of post-transplantation cyclophosphamide with bendamustine, led to comparable GVHD control, but significantly augmented GVL effect. To test this hypothesis and improve the outcome of allogeneic SCT in refractory acute leukemia patients we initiated a pilot trial with high-dose post-transplantation bendamustine for GVHD prophylaxis. The selection of doses is based on the previous dose-escalation studies. Additional immunosuppression could be added for mismatched grafts.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
27 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Dose-escalation Study of Graft-versus-host Disease Prophylaxis With High-dose Post-transplantation Bendamustine in Patients With Refractory Acute Leukemia
Actual Study Start Date :
Jun 1, 2016
Actual Primary Completion Date :
Nov 1, 2020
Actual Study Completion Date :
Nov 1, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: 280 mg/m2 bendamustine

10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3 and +4: Bendamustine 140 mg/m2/day iv.

Procedure: Allogeneic stem cell transplantation
Other Names:
  • HSCT
  • Drug: Fludarabine monophosphate

    Drug: Busulfan

    Drug: Bendamustine

    Experimental: 200 mg/m2 bendamustine

    10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3 and +4: Bendamustine 100 mg/m2/day iv

    Procedure: Allogeneic stem cell transplantation
    Other Names:
  • HSCT
  • Drug: Fludarabine monophosphate

    Drug: Busulfan

    Drug: Bendamustine

    Experimental: 140 mg/m2 bendamustine

    10 patients Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -3: Busulfan 1 mg/kg po qid №14 Day 0: Infusion of unmanipulated graft Day +3, +4: Bendamustine 70 mg/m2/day iv.

    Procedure: Allogeneic stem cell transplantation
    Other Names:
  • HSCT
  • Drug: Fludarabine monophosphate

    Drug: Busulfan

    Drug: Bendamustine

    Outcome Measures

    Primary Outcome Measures

    1. Engraftment rate [60 days]

      Engraftment is defined as the first of 3 consecutive days with an ANC>500 per μl and WBC>1000 per μl. Platelet engraftment is not mandatory for the endpoint.

    Secondary Outcome Measures

    1. Relapse rate analysis [365 days]

    2. Non-relapse mortality analysis [365 days]

    3. Incidence of acute GVHD, grades II-IV [180 days]

    4. Incidence of chronic GVHD, moderate and severe (NIH criteria) [365 days]

    5. Overall survival analysis [365 days]

    6. Event-free survival analysis [365 days]

    7. Toxicity (NCI CTCAE 4.03) [100 days]

      Toxicity parameters based on NCI CTCAE 4.03 grades: hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), mucositis (attending physician assessment), hemorrhagic cystitis (attending physician assessment), cardiotoxicity (ECG, echocardiography). Additional toxicity parameters: incidence and severity of veno-occlusive disease, incidence of transplant-associated microangiopathy

    8. Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence [100 days]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Diagnosis: Acute Myeloblastic Leukemia Acute Lymphoblastic Leukemia Mixed-Lineage Acute Leukemias

    • Disease, refractory to at list one course of induction chemotherapy or immunotherapy

    • More than 5% clonal blasts in the bone marrow or peripheral blood at the time of inclusion

    • Signed informed consent

    • Matched related, 8-10/10 HLA-matched unrelated or haploidentical donor available. The HLA typing is performed by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1.

    • No second tumors

    • No severe concurrent illness

    • No previous autologous or allogeneic stem cell transplantations

    Exclusion Criteria:
    • Karnofsky index <70%

    • Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50%

    • Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted

    • Respiratory distress >grade I

    • Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >1.5 upper normal limits

    • Creatinine clearance < 60 mL/min

    • Uncontrolled bacterial or fungal infection at the time of enrollment, defined by CRP level >70 mg/L or positive procalcitonin in patient with adequate empirical antibacterial and antifungal therapy.

    • Requirement for vasopressor support at the time of enrollment

    • Pregnancy

    • Somatic or psychiatric disorder making the patient unable to sign informed consent

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 First Pavlov State Medical University of St. Petersburg Saint-Petersburg Russian Federation 197089

    Sponsors and Collaborators

    • St. Petersburg State Pavlov Medical University

    Investigators

    • Study Director: Boris V. Afanasyev, Professor, St. Petersburg State Pavlov Medical University

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Ivan S Moiseev, Vice-director for science of R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, St. Petersburg State Pavlov Medical University
    ClinicalTrials.gov Identifier:
    NCT02799147
    Other Study ID Numbers:
    • 05/16-n
    First Posted:
    Jun 14, 2016
    Last Update Posted:
    Nov 23, 2020
    Last Verified:
    Nov 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Keywords provided by Ivan S Moiseev, Vice-director for science of R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation, St. Petersburg State Pavlov Medical University
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Nov 23, 2020