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GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia

Primary Purpose

Leukemia, Acute Lymphoblastic, Acute Myeloid Leukemia, Mixed-Lineage Acute Leukemias

Status
Completed
Phase
Phase 1
Locations
Russian Federation
Study Type
Interventional
Intervention
Allogeneic stem cell transplantation
Fludarabine monophosphate
Busulfan
Bendamustine
Sponsored by
St. Petersburg State Pavlov Medical University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Acute Lymphoblastic focused on measuring Allogeneic Transplantation, Hematopoietic Stem Cell Transplantation, Leukemia, Acute Lymphoblastic, Acute Myeloid Leukemia, Mixed-Lineage Acute Leukemias, Immune System Diseases, Immunosuppressive Agents, Myeloablative Agonists, Busulfan, Fludarabine, Antineoplastic Agents, Alkylating, Bendamustine Hydrochloride

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • First Pavlov State Medical University of St. Petersburg

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

280 mg/m2 bendamustine

200 mg/m2 bendamustine

140 mg/m2 bendamustine

Arm Description

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.

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

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.

Outcomes

Primary Outcome Measures

Engraftment rate
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

Relapse rate analysis
Non-relapse mortality analysis
Incidence of acute GVHD, grades II-IV
Incidence of chronic GVHD, moderate and severe (NIH criteria)
Overall survival analysis
Event-free survival analysis
Toxicity (NCI CTCAE 4.03)
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
Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence

Full Information

First Posted
June 9, 2016
Last Updated
November 19, 2020
Sponsor
St. Petersburg State Pavlov Medical University
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1. Study Identification

Unique Protocol Identification Number
NCT02799147
Brief Title
GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia
Official Title
Dose-escalation Study of Graft-versus-host Disease Prophylaxis With High-dose Post-transplantation Bendamustine in Patients With Refractory Acute Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Completed
Study Start Date
June 2016 (Actual)
Primary Completion Date
November 2020 (Actual)
Study Completion Date
November 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
St. Petersburg State Pavlov Medical University

4. Oversight

Data Monitoring Committee
No

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Acute Lymphoblastic, Acute Myeloid Leukemia, Mixed-Lineage Acute Leukemias
Keywords
Allogeneic Transplantation, Hematopoietic Stem Cell Transplantation, Leukemia, Acute Lymphoblastic, Acute Myeloid Leukemia, Mixed-Lineage Acute Leukemias, Immune System Diseases, Immunosuppressive Agents, Myeloablative Agonists, Busulfan, Fludarabine, Antineoplastic Agents, Alkylating, Bendamustine Hydrochloride

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
27 (Actual)

8. Arms, Groups, and Interventions

Arm Title
280 mg/m2 bendamustine
Arm Type
Experimental
Arm Description
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.
Arm Title
200 mg/m2 bendamustine
Arm Type
Experimental
Arm Description
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
Arm Title
140 mg/m2 bendamustine
Arm Type
Experimental
Arm Description
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.
Intervention Type
Procedure
Intervention Name(s)
Allogeneic stem cell transplantation
Other Intervention Name(s)
HSCT
Intervention Type
Drug
Intervention Name(s)
Fludarabine monophosphate
Intervention Type
Drug
Intervention Name(s)
Busulfan
Intervention Type
Drug
Intervention Name(s)
Bendamustine
Primary Outcome Measure Information:
Title
Engraftment rate
Description
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.
Time Frame
60 days
Secondary Outcome Measure Information:
Title
Relapse rate analysis
Time Frame
365 days
Title
Non-relapse mortality analysis
Time Frame
365 days
Title
Incidence of acute GVHD, grades II-IV
Time Frame
180 days
Title
Incidence of chronic GVHD, moderate and severe (NIH criteria)
Time Frame
365 days
Title
Overall survival analysis
Time Frame
365 days
Title
Event-free survival analysis
Time Frame
365 days
Title
Toxicity (NCI CTCAE 4.03)
Description
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
Time Frame
100 days
Title
Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence
Time Frame
100 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boris V. Afanasyev, Professor
Organizational Affiliation
St. Petersburg State Pavlov Medical University
Official's Role
Study Director
Facility Information:
Facility Name
First Pavlov State Medical University of St. Petersburg
City
Saint-Petersburg
ZIP/Postal Code
197089
Country
Russian Federation

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
Consultations are ongoing about how IPD initiative fits the local law "About personal data 152-fz".
Citations:
PubMed Identifier
27030315
Citation
Stokes J, Hoffman EA, Zeng Y, Larmonier N, Katsanis E. Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation. Br J Haematol. 2016 Jul;174(1):102-16. doi: 10.1111/bjh.14034. Epub 2016 Mar 31.
Results Reference
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GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia

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