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

Multiple Myeloma Clinical Trial

— HLA  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03852407
• Other study ID #: BHS-TC14
• Secondary ID: 2017-000824-91
• Status: Recruiting
• Phase: Phase 2
• Start date: February 4, 2019
• Est. completion date: November 1, 2038

Study information

• Verified date: October 2022
• Source: University of Liege
• Contact: Frédéric Baron, MD,Ph
• Phone: +32 4 366 72 01
• Email: F.Baron[@]uliege.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 114
• Est. completion date: November 1, 2038
• Est. primary completion date: November 1, 2033
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoid Leukemia in Remission
• Acute Myeloid Leukemia in Remission
• Chronic Lymphoid Leukemia
• Chronic Myeloid Leukemia in Remission
• Hodgkin Lymphoma
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Lymphoma
• Multiple Myeloma
• Myelodysplastic Syndromes
• Myeloproliferative Disorder
• Myeloproliferative Disorders
• Myeloproliferative Syndrome
• Non Hodgkin Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Syndrome

Intervention

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

Locations

Country	Name	City	State
Belgium	ZNA Stuivenberg	Antwerp
Belgium	AZ Sint Jan Brugge	Brugge
Belgium	IJ Bordet	Brussels
Belgium	UCL St Luc	Brussels
Belgium	UZ Brussel	Brussels
Belgium	UZ Gent	Gent
Belgium	UZ Leuven	Leuven
Belgium	CHU de Liège	Liège
Belgium	AZ Delta Roeselare	Roeselare
Belgium	CHU UCL Namur Godinne	Yvoir

Sponsors (2)

Lead Sponsor	Collaborator
University of Liege	Belgian Hematological Society

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Hematopoietic engraftment	To assess hematopoietic (whole blood and T cell chimerism) engraftment in the 2 arms.	2 years
Other	Quality of immunologic reconstitution	To assess the quality of immunologic reconstitution in the 2 arms	5 years
Other	Timing of immunologic reconstitution	To assess the timing (days) of immunologic reconstitution in the 2 arms	5 years
Other	Incidences of bacterial infections	To assess the incidences of bacterial infections (number of episode, site, grade) in the 2 arms, in the whole group of patients	1 year
Other	Incidences of fungal infections	To assess the incidences of fungal infections (number of episode, site, grade) in the 2 arms, in the whole group of patients	1 year
Other	Incidences of viral infections	To assess the incidences of viral infections (number of episode, site, grade) in the 2 arms, in the whole group of patients	1 year
Other	Assess Thymoglobulin (ATG) Pharmacokinetic	To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm	10 days
Other	Assess ATG Pharmacokinetic in association with cGRFS	To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with cGRFS	15 years
Other	Assess ATG Pharmacokinetic in association with NRM	To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with NRM	15 years
Other	Assess ATG Pharmacokinetic in association with OS	To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with OS	15 years
Other	Assess ATG Pharmacokinetic in association with Relapse/progression	To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with Relapse/progression	15 years
Other	Assess ATG Pharmacokinetic in association with Infections	To assess kinetics of functional ATG serum levels (mg/L) in the FM-ATG arm in association with Infections	1 years
Other	Assess ATG Pharmacokinetic in association with immunologic reconstitution	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
Primary	Current GVHD-free, relapse-free survival (cGRFS)	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	cGRFS according donor	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
Secondary	Relapse/progression rate	To assess the relapse/progression rate for patients conditioned with FM-PTCy or FM-ATG	15 years
Secondary	Rate aGVHD	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
Secondary	Rate cGVHD	To assess rate of grade of moderate-severe chronic GVHD in patients conditioned with FM or FM-ATG.	24 months
Secondary	Rate of Nonrelapse Mortality (NRM)	To assess rate of Nonrelapse Mortality in patients conditioned with FM-PTCy or FM-ATG.	15 years
Secondary	Rate of Leukemia Free Survival (LFS)	To assess rate of Leukemia Free Survival in patients conditioned with FM-PTCy or FM-ATG.	15 years
Secondary	Rate of Overall Survival (OS)	To assess rate of Overall Survival in patients conditioned with FM-PTCy or FM-ATG.	15 years
Secondary	Proportion of patients alive	To assess the proportion of patients alive without active disease and without systemic immunosuppression	15 years