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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

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

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, +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

NCT ID

NCT02799147

First Posted

June 9, 2016

Last Updated

November 19, 2020

Sponsor

St. Petersburg State Pavlov Medical University

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

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

Arm Title

200 mg/m2 bendamustine

Arm Type

Experimental

Arm Description

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

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

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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