GVHD Prophylaxis With Post-transplantation Bendamustine in Refractory Leukemia

NCT02799147 | Completed Phase 1

• 1 other identifier: 05/16-n
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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.

  60 days

Secondary Outcomes (8)

• Relapse rate analysis

  365 days

• Non-relapse mortality analysis

  365 days

• Incidence of acute GVHD, grades II-IV

  180 days

• Incidence of chronic GVHD, moderate and severe (NIH criteria)

  365 days

• Overall survival analysis

  365 days

Study Arms (3)

280 mg/m2 bendamustine

EXPERIMENTAL

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; Drug: Fludarabine monophosphate; Drug: Busulfan; Drug: Bendamustine

200 mg/m2 bendamustine

EXPERIMENTAL

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; Drug: Fludarabine monophosphate; Drug: Busulfan; Drug: Bendamustine

140 mg/m2 bendamustine

EXPERIMENTAL

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; Drug: Fludarabine monophosphate; Drug: Busulfan; Drug: Bendamustine

Interventions

Allogeneic stem cell transplantation PROCEDURE

Also known as: HSCT

140 mg/m2 bendamustine; 200 mg/m2 bendamustine; 280 mg/m2 bendamustine

Fludarabine monophosphate DRUG

140 mg/m2 bendamustine; 200 mg/m2 bendamustine; 280 mg/m2 bendamustine

Busulfan DRUG

140 mg/m2 bendamustine; 200 mg/m2 bendamustine; 280 mg/m2 bendamustine

Bendamustine DRUG

140 mg/m2 bendamustine; 200 mg/m2 bendamustine; 280 mg/m2 bendamustine

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• \- Diagnosis: Acute Myeloblastic Leukemia Acute Lymphoblastic Leukemia Mixed-Lineage Acute Leukemias
• Disease, refractory to at list one course of induction chemotherapy or immunotherapy
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• St. Petersburg State Pavlov Medical University: lead

Study Sites (1)

First Pavlov State Medical University of St. Petersburg

Saint Petersburg, 197089, Russia

Location

Related Publications (1)

• 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.

  PMID: 27030315 BACKGROUND

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Leukemia, Biphenotypic, Acute; Immune System Diseases

Interventions

fludarabine phosphate; Busulfan; Bendamustine Hydrochloride

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Butyrates; Acids, Acyclic; Carboxylic Acids; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Boris V. Afanasyev, Professor

  St. Petersburg State Pavlov Medical University

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Vice-director for science of R.M. Gorbacheva Memorial Institute of Hematology, Oncology and Transplantation

Study Record Dates

• First Submitted: June 9, 2016
• First Posted: June 14, 2016
• Study Start: June 1, 2016
• Primary Completion: November 1, 2020
• Study Completion: November 1, 2020
• Last Updated: November 23, 2020

Record last verified: 2020-11

Locations

RU (1)