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

Official title

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)

Overview

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.

Interventions

• Drug Thymoglobulin
  ATG: 2.5 mg /kg/day on day -2 and -1 (day 0 is allogenic transplantation)
• Drug Melphalan
  100mg/m² on day -2
• Drug Fludarabine
  30mg/m² on days -6, -5, -4, -3, and -2
• Drug Cyclophosphamid
  50 mg/kg on days +3 and +4.

Primary outcome measures

• Current GVHD-free, relapse-free survival (cGRFS) [Time frame: 15 years (the primary endpoint will be first assessed after 191 events have been reached)]

Secondary outcome measures (8)

• cGRFS according donor [Time frame: 15 years]
• Relapse/progression rate [Time frame: 15 years]
• Rate aGVHD [Time frame: 6 months]
• Rate cGVHD [Time frame: 24 months]
• Rate of Nonrelapse Mortality (NRM) [Time frame: 15 years]
• Rate of Leukemia Free Survival (LFS) [Time frame: 15 years]
• Rate of Overall Survival (OS) [Time frame: 15 years]
• Proportion of patients alive [Time frame: 15 years]

Eligibility criteria

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)

• Cardiac: Symptomatic coronary artery disease; ejection fraction <40%; uncontrolled arrhythmia, uncontrolled hypertension;
• 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%;
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Belgium · 10 centers

• ZNA Stuivenberg — Antwerp
• AZ Sint Jan Brugge — Bruges
• IJ Bordet — Brussels
• UZ Brussel — Brussels
• UCL St Luc — Brussels
• UZ Gent — Ghent
• UZ Leuven — Leuven
• CHU de Liège — Liège
• … and 2 more centers

Identifiers

NCT: NCT03852407 · BHS-TC14 · 2017-000824-91

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗