GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia

November 19, 2020 updated by: Ivan S Moiseev, St. Petersburg State Pavlov Medical University

Dose-escalation Study of Graft-versus-host Disease Prophylaxis With High-dose Post-transplantation Bendamustine in Patients With Refractory Acute Leukemia

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

27

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Russian Federation
      • Saint-Petersburg, Russian Federation, 197089
        • First Pavlov State Medical University of St. Petersburg

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / 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.
Drug: Bendamustine
Drug: Busulfan
Drug: Fludarabine monophosphate
Procedure: Allogeneic stem cell transplantation
Other Names:
  • HSCT
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
Drug: Bendamustine
Drug: Busulfan
Drug: Fludarabine monophosphate
Procedure: Allogeneic stem cell transplantation
Other Names:
  • HSCT
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.
Drug: Bendamustine
Drug: Busulfan
Drug: Fludarabine monophosphate
Procedure: Allogeneic stem cell transplantation
Other Names:
  • HSCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Engraftment rate
Time Frame: 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.
60 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Non-relapse mortality analysis
Time Frame: 365 days
365 days
Overall survival analysis
Time Frame: 365 days
365 days
Event-free survival analysis
Time Frame: 365 days
365 days
Relapse rate analysis
Time Frame: 365 days
365 days
Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence
Time Frame: 100 days
100 days
Incidence of acute GVHD, grades II-IV
Time Frame: 180 days
180 days
Incidence of chronic GVHD, moderate and severe (NIH criteria)
Time Frame: 365 days
365 days
Toxicity (NCI CTCAE 4.03)
Time Frame: 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
100 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

St. Petersburg State Pavlov Medical University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 1, 2016

Primary Completion (ACTUAL)

November 1, 2020

Study Completion (ACTUAL)

November 1, 2020

Study Registration Dates

First Submitted

June 9, 2016

First Submitted That Met QC Criteria

June 9, 2016

First Posted (ESTIMATE)

June 14, 2016

Study Record Updates

Last Update Posted (ACTUAL)

November 23, 2020

Last Update Submitted That Met QC Criteria

November 19, 2020

Last Verified

November 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 05/16-n

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Consultations are ongoing about how IPD initiative fits the local law "About personal data 152-fz".

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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