Allogeneic Hematopoietic Cell Transplantation From HLA-matched Donor After Flu-Mel-PTCy Versus Flu-Mel-ATG Reduced-intensity Conditioning (HLA)

October 11, 2022 updated by: Frédéric Baron, University of Liege

Allogeneic Hematopoietic Cell Transplantation From HLA-matched Donor After Flu-Mel-PTCy Versus Flu-Mel-ATG Reduced-intensity Conditioning: a Phase II Randomized Study From the Belgian Hematology Society (BHS)

The present project aims at comparing two conditioning regimens (FM-PTCy vs FM-ATG). The hypothesis is that one or the two regimens will lead to a 2-year cGRFS rate improvement from 30% (the cGRFS rate with FM without ATG/PTCy) to 45% (Pick-a-winner phase 2 randomized study).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This study is a multicenter, randomized, open-label, phase II study pick-a-winner study, comparing 2 conditioning regimens. A total of 114 eligible patients with HLA-matched donors will be randomized 1:1 between the FM-PTCy arm and the FM-ATG arm, with stratification for donor type (related or unrelated). The recruitment period is 3 years with a 5-year follow-up plus a 10-year additional long-term follow-up (for GVHD status, disease status, second malignancy and QOL). The whole study will be completed within 18 years.

Study Type

Interventional

Enrollment (Anticipated)

114

Phase

  • Phase 2

Contacts and Locations

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

Study Contact

  • Name: Frédéric Baron, MD,Ph
  • Phone Number: 0032497121806 +32 4 366 72 01
  • Email: F.Baron@uliege.be

Study Locations

  • Belgium
      • Antwerp, Belgium, 2060
      • Brugge, Belgium, 8000
      • Brussels, Belgium, 1090
      • Brussels, Belgium, 1000
      • Brussels, Belgium, 1200
      • Gent, Belgium, 9000
      • Leuven, Belgium, 3000
        • Recruiting
        • UZ Leuven
        • Contact:
        • Sub-Investigator:
          • Hélène Schoemans, MD PhD
      • Liège, Belgium, 4000
        • Recruiting
        • CHU de Liège
        • Sub-Investigator:
          • Evelyne Willems, MD
        • Contact:
          • Frédéric Baron, MD, PhD
          • Phone Number: +3243667201 +3243667201
          • Email: F.Baron@uliege.be
        • Contact:
        • Sub-Investigator:
          • Sophie Servais, MD
      • Roeselare, Belgium, 8800
      • Yvoir, Belgium, 5530

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 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Patients V.1.1. Diseases

Hematological malignancies confirmed histologically:

  • AML in morphological CR or not in morphological CR but not rapidly progressing (i.e. no need to give treatments such as hydroxyurea to maintain WBC count < 10 000 x109/mL);
  • MDS;
  • CML in CP or AP;
  • MPD not in blast crisis,
  • MDS/MPD overlap,
  • ALL in CR;
  • Multiple myeloma;
  • CLL;
  • Non-Hodgkin's lymphoma (aggressive NHL should have chemosensitive disease);

  • Hodgkin's disease with chemosensitive disease or responding to checkpoint inhibitors.

    * Clinical situations

    • Theoretical indication for a standard allo-transplant, but not feasible because:

  • Age > 50 yrs;
  • Unacceptable end organ performance;
  • The physician's decision;

  • The patient's decision

    • Underlying 'lower risk' disease, for which Reduced Intensity Conditioning is preferred (eg CLL, MCL)

      * Other inclusion criteria

    • Male or female; fertile patients must use a reliable contraception method;
    • Age 18-75 yrs (children of any age are not allowed in the protocol);
    • Informed consent given by patient or his/her guardian if indicated.

Donors

  • Male or female;
  • Any age;
  • Human Leukocyte Antigen (HLA)-identical sibling donor or 10 of 10 (HLA-A, -B, -C, -DRB1, and -DQB1) HLA allele matched unrelated donor;
  • Weight > 15 Kg (because of leukapheresis);
  • Fulfills criteria for allogeneic Peripheral Blood Stem Cell (PBSC) donation according to standard procedures;
  • Informed consent given by donor or his/her guardian if indicated, as per donor center standard procedures.

Exclusion Criteria:

Patients

  • Any condition not fulfilling inclusion criteria;
  • Human Immunodeficiency Virus positive;
  • Non-hematological malignancy(ies) (except non-melanoma skin cancer) active < 3 years before Hematopoietic Cell Transplantation (HCT).
  • Life expectancy severely limited by disease other than malignancy;
  • Central Nervous System involvement with disease refractory to intrathecal chemotherapy.

  • Terminal organ failure, except for renal failure (dialysis acceptable)

    1. Cardiac: Symptomatic coronary artery disease; ejection fraction <40%; uncontrolled arrhythmia, uncontrolled hypertension;
    2. Pulmonary: Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)< 40% and/or receiving supplementary continuous oxygen, Forced Expiratory Volume in 1 Second (FEV1)< 40%;
    3. Hepatic: Fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin >3 mg/dL, and symptomatic biliary disease;
  • Uncontrolled infection;
  • Karnofsky Performance Score <70%;
  • Patient is a fertile man or woman who is unwilling to use contraceptive techniques during and for 12 months following treatment;
  • Patient is a female who is pregnant or breastfeeding;
  • Any condition precluding the use of melphalan or Thymoglobulin;

Donors

  • Any condition not fulfilling inclusion criteria;
  • Unable to undergo leukapheresis because of poor vein access or other reasons.

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: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Fludarabine-Melphalan-Cyclophosphamide
FM-PTCy conditioning will consist in IV fludarabine 30 mg/m2 on days -6, -5, -4, -3, and -2 (total dose 150 mg/m2), melphalan given at the dose of 100 mg/m2 on day -2, and cyclophosphamide 50 mg/kg on days +3 and +4.
Drug: Melphalan
100mg/m² on day -2
Other Names:
  • alkeran
Drug: Fludarabine
30mg/m² on days -6, -5, -4, -3, and -2
Drug: Cyclophosphamid
50 mg/kg on days +3 and +4.
Other Names:
  • PTCy
Experimental: Fludarabine-Melphalan-thymoglobulin
FM-ATG conditioning will consist in IV fludarabine 30 mg/m2 on days -6, -5, -4, -3, and -2 (total dose 150 mg/m2), melphalan given at the dose of 100 mg/m2 on day -2, and ATG (Thymoglobulin®, Genzyme), at a dose of 2.5 mg/kg/d on days -2 and -1.
Drug: Melphalan
100mg/m² on day -2
Other Names:
  • alkeran
Drug: Fludarabine
30mg/m² on days -6, -5, -4, -3, and -2
Drug: Thymoglobulin
ATG: 2.5 mg /kg/day on day -2 and -1 (day 0 is allogenic transplantation)
Other Names:
  • ATG

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Current GVHD-free, relapse-free survival (cGRFS)
Time Frame: 15 years (the primary endpoint will be first assessed after 191 events have been reached)
To assess the current GVHD-free, relapse-free survival (cGRFS) for patients in the 2 arms
15 years (the primary endpoint will be first assessed after 191 events have been reached)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
cGRFS according donor
Time Frame: 15 years
To assess cGRFS for patients conditioned with FM-PTCy or FM-ATG separately in those transplanted with a related or an unrelated donor
15 years
Relapse/progression rate
Time Frame: 15 years
To assess the relapse/progression rate for patients conditioned with FM-PTCy or FM-ATG
15 years
Rate aGVHD
Time Frame: 6 months
To assess rate of grade II-IV and III-IV acute GVHD (Graft-versus-host disease) in patients conditioned with FM or FM-ATG.
6 months
Rate cGVHD
Time Frame: 24 months
To assess rate of grade of moderate-severe chronic GVHD in patients conditioned with FM or FM-ATG.
24 months
Rate of Nonrelapse Mortality (NRM)
Time Frame: 15 years
To assess rate of Nonrelapse Mortality in patients conditioned with FM-PTCy or FM-ATG.
15 years
Rate of Leukemia Free Survival (LFS)
Time Frame: 15 years
To assess rate of Leukemia Free Survival in patients conditioned with FM-PTCy or FM-ATG.
15 years
Rate of Overall Survival (OS)
Time Frame: 15 years
To assess rate of Overall Survival in patients conditioned with FM-PTCy or FM-ATG.
15 years
Proportion of patients alive
Time Frame: 15 years
To assess the proportion of patients alive without active disease and without systemic immunosuppression
15 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hematopoietic engraftment
Time Frame: 2 years
To assess hematopoietic (whole blood and T cell chimerism) engraftment in the 2 arms.
2 years
Quality of immunologic reconstitution
Time Frame: 5 years
To assess the quality of immunologic reconstitution in the 2 arms
5 years
Timing of immunologic reconstitution
Time Frame: 5 years
To assess the timing (days) of immunologic reconstitution in the 2 arms
5 years
Incidences of bacterial infections
Time Frame: 1 year
To assess the incidences of bacterial infections (number of episode, site, grade) in the 2 arms, in the whole group of patients
1 year
Incidences of fungal infections
Time Frame: 1 year
To assess the incidences of fungal infections (number of episode, site, grade) in the 2 arms, in the whole group of patients
1 year
Incidences of viral infections
Time Frame: 1 year
To assess the incidences of viral infections (number of episode, site, grade) in the 2 arms, in the whole group of patients
1 year
Assess Thymoglobulin (ATG) Pharmacokinetic
Time Frame: 10 days
To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm
10 days
Assess ATG Pharmacokinetic in association with cGRFS
Time Frame: 15 years
To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with cGRFS
15 years
Assess ATG Pharmacokinetic in association with NRM
Time Frame: 15 years
To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with NRM
15 years
Assess ATG Pharmacokinetic in association with OS
Time Frame: 15 years
To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with OS
15 years
Assess ATG Pharmacokinetic in association with Relapse/progression
Time Frame: 15 years
To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with Relapse/progression
15 years
Assess ATG Pharmacokinetic in association with Infections
Time Frame: 1 years
To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with Infections
1 years
Assess ATG Pharmacokinetic in association with immunologic reconstitution
Time Frame: 5 years
To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with immunologic reconstitution (CD4 and NAIVE T cells counts)
5 years

Collaborators and Investigators

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

Sponsor

University of Liege

Collaborators

Belgian Hematological Society

Investigators

  • Principal Investigator: Frédéric Baron, MD,Ph, Centre Hospitalier Universitaire de Liège

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)

February 4, 2019

Primary Completion (Anticipated)

November 1, 2033

Study Completion (Anticipated)

November 1, 2038

Study Registration Dates

First Submitted

January 21, 2019

First Submitted That Met QC Criteria

February 20, 2019

First Posted (Actual)

February 25, 2019

Study Record Updates

Last Update Posted (Actual)

October 12, 2022

Last Update Submitted That Met QC Criteria

October 11, 2022

Last Verified

October 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BHS-TC14
  • 2017-000824-91 (EudraCT Number)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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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