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Post-transplantation Benadamustine and Cyclophosphamide in Patients With Refractory Myeloid Malignancies (PTBCy)

Primary Purpose

Myeloid Leukemia, Acute, Chronic Myeloid Leukemia, Myelodysplastic Syndromes

Status

Recruiting

Phase

Phase 2

Locations

Russian Federation

Study Type

Interventional

Intervention

Bendamustine Hydrochloride

Cyclophosphamid

About this trial

This is an interventional treatment trial for Myeloid Leukemia, Acute focused on measuring Bendamustine, Cyclophosphamide, Graft-versus-host disease, Graft-versus-leukemia effect, Refractory, Acute Myeloid leukemia, Hematopoietic Stem Cell Transplantation, Allogeneic

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with indication for allogeneic hematopoietic stem cell transplantation
Patients with 5-10/10 HLA-matched related or unrelated donor available. The donor and recipient must be identical by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1.
Peripheral blood stem cells or bone marrow as a graft source
Diagnosis:

Acute myeloid leukemia Chronic myeloid leukemia, Ph+ Myelodysplastic Syndromes Myeloprolipherative neoplasms

Salvage hematopoietic stem cell transplantation defined as:
Acute myeloid leukemia: >5% of clonal blasts despite adequate previous induction therapy or allogeneic stem cell transplantation Myelodysplastic Syndrome: >10% of blasts despite previous therapy with -7 or complex karyotype, or p53 mutation Chronic myeloid leukemia: blast crisis or acceleration phase despite at least 3 previous lines of TKIs Myeloprolipherative neoplasms : high tumor burden despite previous therapy, including >20 000 WBC/ ul or splenomegaly >15 cm
No severe concurrent illness

Exclusion Criteria:

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 >2 upper normal limits
Creatinine clearance < 60 mL/min
Uncontrolled bacterial or fungal infection at the time of enrollment
Requirement for vasopressor support at the time of enrollment
Karnofsky index <30%
Pregnancy
Somatic or psychiatric disorder making the patient unable to sign informed consent

Sites / Locations

RM Gorbacheva Research InstituteRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

PTBCy graft-versus-host disease prophylaxis

Arm Description

Days +3 through +4: Bendamustine 50 mg/m2 iv x 2 days; Days +3 through +4: Cyclophosphamide 25 mg/kg iv x 2 days; Days +5 through +35: Mycophenolate mofetil 30 mg/kg/day, maximum 3 g/day, iv or po x 30 days; Days +5 through +100: Tacrolimus 0.03 mg/kg/day with further correction by concentration

Outcomes

Primary Outcome Measures

Event-free survival analysis [ Time Frame: 1 year ]

Measure: Kaplan-Meier estimate of death or relapse, or graft failure

Secondary Outcome Measures

- Incidence of Cytokine release syndrome

Proportion of patients with cytokine release syndrome according to ASBMT Consensus Grading for Cytokine Release Syndrome, 2018

Incidence of HSCT-associated adverse events (safety and toxicity)

Toxicity assessment is based on NCI CTC AE 5.0 grades. Veno-occlusive disease incidence and severity assessment is based on EBMT criteria 2016. Transplant-associated microangiopathy incidence assessment is based on Cho et al.

Incidence of acute GVHD grade II-IV

Cumulative incidence of patients with acute GVHD II-IV grade

Incidence of moderate and severe chronic GVHD

Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria

Relapse rate analysis

Cumulative incidence of patients with relapse

Non-relapse mortality analysis

Cumulative incidence of patients with mortality without hematological relapse of malignancy

Overall survival analysis

Kaplan-Meier estimate of death from all causes

Full Information

NCT ID

NCT04943757

First Posted

June 21, 2021

Last Updated

April 4, 2022

Sponsor

St. Petersburg State Pavlov Medical University

1. Study Identification

Unique Protocol Identification Number

NCT04943757

Brief Title

Post-transplantation Benadamustine and Cyclophosphamide in Patients With Refractory Myeloid Malignancies

Acronym

PTBCy

Official Title

Graft-versus-host Disease Prophylaxis With Combination of Post-transplantation Benadamustine and Cyclophosphamide in Patients With Refractory Myeloid Malignancies (PTBCy)

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Recruiting

Study Start Date

January 21, 2021 (Actual)

Primary Completion Date

December 31, 2023 (Anticipated)

Study Completion Date

December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

St. Petersburg State Pavlov Medical University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Prognosis of patients undergoing salvage allogeneic stem cell transplantation for refractory leukemia or other refractory myeloid malignanies is poor. One of the approaches to augment graft-versus-leukemia effect the use of post-transplantation bendamustine in graft-versus-host disease prophylaxis. Despite high frequency of responses and durable remissions after this approach majority of patients develop a serious complication - cytokine release syndrome, which can be life-threatening in some patients. On the other hand post-transplantation cyclophocphamide was reported to abort cytokine release syndrome that sometimes occurs after graft transfusion in patients after haploidentical graft transfusion. The aim of this study is to evaluate if the combination of post-transplantation bendamustine (PTB) and post-transplantation cyclophosphamide (PTCY) facilitates comparable graft-versus leukemia effect to PTB, but with better safety profile and reduced incidence of severe cytokine release syndrome.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myeloid Leukemia, Acute, Chronic Myeloid Leukemia, Myelodysplastic Syndromes, Myeloproliferative Neoplasm

Keywords

Bendamustine, Cyclophosphamide, Graft-versus-host disease, Graft-versus-leukemia effect, Refractory, Acute Myeloid leukemia, Hematopoietic Stem Cell Transplantation, Allogeneic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

PTBCy graft-versus-host disease prophylaxis

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Bendamustine Hydrochloride

Intervention Description

50 mg/m2 iv Days +3 through +4 after allogeneic hematopoietic stem cell transplantation

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamid

Intervention Description

25 mg/kg iv Days +3 through +4 after allogeneic hematopoietic stem cell transplantation

Primary Outcome Measure Information:

Title

Event-free survival analysis [ Time Frame: 1 year ]

Description

Measure: Kaplan-Meier estimate of death or relapse, or graft failure

Time Frame

1 year

Secondary Outcome Measure Information:

Title

- Incidence of Cytokine release syndrome

Description

Proportion of patients with cytokine release syndrome according to ASBMT Consensus Grading for Cytokine Release Syndrome, 2018

Time Frame

100 days

Title

Incidence of HSCT-associated adverse events (safety and toxicity)

Description

Time Frame

100 days

Title

Incidence of acute GVHD grade II-IV

Description

Cumulative incidence of patients with acute GVHD II-IV grade

Time Frame

125 days

Title

Incidence of moderate and severe chronic GVHD

Description

Cumulative incidence of patients with moderate and severe chronic GVHD according to NIH 2015 criteria

Time Frame

1 year

Title

Relapse rate analysis

Description

Cumulative incidence of patients with relapse

Time Frame

1 year

Title

Non-relapse mortality analysis

Description

Cumulative incidence of patients with mortality without hematological relapse of malignancy

Time Frame

1 year

Title

Overall survival analysis

Description

Kaplan-Meier estimate of death from all causes

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with indication for allogeneic hematopoietic stem cell transplantation Patients with 5-10/10 HLA-matched related or unrelated donor available. The donor and recipient must be identical by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. Peripheral blood stem cells or bone marrow as a graft source Diagnosis: Acute myeloid leukemia Chronic myeloid leukemia, Ph+ Myelodysplastic Syndromes Myeloprolipherative neoplasms Salvage hematopoietic stem cell transplantation defined as: Acute myeloid leukemia: >5% of clonal blasts despite adequate previous induction therapy or allogeneic stem cell transplantation Myelodysplastic Syndrome: >10% of blasts despite previous therapy with -7 or complex karyotype, or p53 mutation Chronic myeloid leukemia: blast crisis or acceleration phase despite at least 3 previous lines of TKIs Myeloprolipherative neoplasms : high tumor burden despite previous therapy, including >20 000 WBC/ ul or splenomegaly >15 cm No severe concurrent illness Exclusion Criteria: 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 >2 upper normal limits Creatinine clearance < 60 mL/min Uncontrolled bacterial or fungal infection at the time of enrollment Requirement for vasopressor support at the time of enrollment Karnofsky index <30% Pregnancy Somatic or psychiatric disorder making the patient unable to sign informed consent

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Ivan S Moiseev, MD, Prof.

Phone

+79217961951

moisiv@mail.ru

First Name & Middle Initial & Last Name or Official Title & Degree

Sergey Bondarenko, MD, PhD

Phone

+78123386265

dr.sergeybondarenko@gmail.com

Facility Information:

Facility Name

RM Gorbacheva Research Institute

City

Saint Petersburg

ZIP/Postal Code

197022

Country

Russian Federation

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ivan Moiseev

Phone

+79217961951

moisiv@mail.ru

First Name & Middle Initial & Last Name & Degree

Alexandr Kulagin

Phone

+78123386265

bmt-director@1spbgmu.ru

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Request for sharing data with the study plan for the data will be evaluated under common conditions by Pavlov University Ethical Committee.

Citations:

PubMed Identifier

33845259

Citation

Moiseev I, Bondarenko S, Morozova E, Vlasova Y, Dotsenko A, Epifanovskaya O, Babenko E, Botina A, Baykov V, Surkova E, Lapin S, Beynarovich A, Borzenkova E, Golosgchapov O, Kanunnikov M, Kudyasheva O, Ovechkina V, Pirogova O, Porunova V, Rudakova T, Smikova O, Smirnova A, Afansyev B. Graft-versus-Host Disease Prophylaxis with Post-Transplantation Bendamustine in Patients with Refractory Acute Leukemia: A Dose-Ranging Study. Transplant Cell Ther. 2021 Jul;27(7):601.e1-601.e7. doi: 10.1016/j.jtct.2021.03.032. Epub 2021 May 7.

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Post-transplantation Benadamustine and Cyclophosphamide in Patients With Refractory Myeloid Malignancies

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