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

Phase 2

Recruiting

• Conditions: Acute Myeloid Leukemia in Remission; Myelodysplastic Syndromes; Chronic Myeloid Leukemia in Remission; Myeloproliferative Syndrome; Myeloproliferative Disorder; Acute Lymphoid Leukemia in Remission; Multiple Myeloma; Chronic Lymphoid Leukemia; Non Hodgkin Lymphoma; Hodgkin Lymphoma
• Interventions: Drug: Melphalan; Drug: Thymoglobulin; Drug: Fludarabine; Drug: Cyclophosphamid

• Registration Number: NCT03852407
• Lead Sponsor: University of Liege

Brief Summary

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).

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 Timeline

• Study First Submitted: 2019-01-21
• Study Start: 2019-02-04
• Study First Submitted QC: 2019-02-20
• Study First Posted: 2019-02-25
• Status Verified: 2022-10
• Last Update Submitted: 2022-10-11
• Last Update Posted: 2022-10-12
• Primary Completion: 2033-11-01
• Study Completion: 2038-11-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 114

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fludarabine-Melphalan-Cyclophosphamide	Melphalan	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.
Fludarabine-Melphalan-Cyclophosphamide	Fludarabine	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.
Fludarabine-Melphalan-Cyclophosphamide	Cyclophosphamid	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.
Fludarabine-Melphalan-thymoglobulin	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.
Fludarabine-Melphalan-thymoglobulin	Fludarabine	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.
Fludarabine-Melphalan-thymoglobulin	Melphalan	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.

Primary Outcome Measures

Name	Time	Method
Current GVHD-free, relapse-free survival (cGRFS)	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

Secondary Outcome Measures

Name	Time	Method
cGRFS according donor	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
Relapse/progression rate	15 years	To assess the relapse/progression rate for patients conditioned with FM-PTCy or FM-ATG
Rate aGVHD	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.
Rate cGVHD	24 months	To assess rate of grade of moderate-severe chronic GVHD in patients conditioned with FM or FM-ATG.
Rate of Nonrelapse Mortality (NRM)	15 years	To assess rate of Nonrelapse Mortality in patients conditioned with FM-PTCy or FM-ATG.
Rate of Leukemia Free Survival (LFS)	15 years	To assess rate of Leukemia Free Survival in patients conditioned with FM-PTCy or FM-ATG.
Rate of Overall Survival (OS)	15 years	To assess rate of Overall Survival in patients conditioned with FM-PTCy or FM-ATG.
Proportion of patients alive	15 years	To assess the proportion of patients alive without active disease and without systemic immunosuppression

Trial Locations

Locations (10)

CHU UCL Namur Godinne; 🇧🇪 Yvoir, Belgium

UZ Gent; 🇧🇪 Gent, Belgium

UCL St Luc; 🇧🇪 Brussels, Belgium

AZ Delta Roeselare; 🇧🇪 Roeselare, Belgium

AZ Sint Jan Brugge; 🇧🇪 Brugge, Belgium

ZNA Stuivenberg; 🇧🇪 Antwerp, Belgium

IJ Bordet; 🇧🇪 Brussels, Belgium

UZ Leuven; 🇧🇪 Leuven, Belgium

CHU de Liège; 🇧🇪 Liège, Belgium

UZ Brussel; 🇧🇪 Brussels, Belgium