Clinical trial NCT03852407: 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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
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
Keywords: hematological malignancies
Graft versus host disease
GVHD
Progression free survival
Allogeneic hematopoeitic cell transplantation
HLA-matched donor
reduced intensity conditioning
Overall survival
ATG PK
Immunosuppressive regimen
Prophylaxis
Lead sponsor: University of Liege
Sponsor class: OTHER
Collaborators: name: Belgian Hematological Society
First posted: 2019-02-25
Enrollment: 114
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

  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.

Primary outcomes:
measure: Current GVHD-free, relapse-free survival (cGRFS)
timeFrame: 15 years (the primary endpoint will be first assessed after 191 events have been reached)
Secondary outcomes:
measure: cGRFS according donor
timeFrame: 15 years
measure: Relapse/progression rate
timeFrame: 15 years
measure: Rate aGVHD
timeFrame: 6 months
measure: Rate cGVHD
timeFrame: 24 months
measure: Rate of Nonrelapse Mortality (NRM)
timeFrame: 15 years
measure: Rate of Leukemia Free Survival (LFS)
timeFrame: 15 years
measure: Rate of Overall Survival (OS)
timeFrame: 15 years
measure: Proportion of patients alive
timeFrame: 15 years
Other outcomes:
measure: Hematopoietic engraftment
timeFrame: 2 years
measure: Quality of immunologic reconstitution
timeFrame: 5 years
measure: Timing of immunologic reconstitution
timeFrame: 5 years
measure: Incidences of bacterial infections
timeFrame: 1 year
measure: Incidences of fungal infections
timeFrame: 1 year
measure: Incidences of viral infections
timeFrame: 1 year
measure: Assess Thymoglobulin (ATG) Pharmacokinetic
timeFrame: 10 days
measure: Assess ATG Pharmacokinetic in association with cGRFS
timeFrame: 15 years
measure: Assess ATG Pharmacokinetic in association with NRM
timeFrame: 15 years
measure: Assess ATG Pharmacokinetic in association with OS
timeFrame: 15 years
measure: Assess ATG Pharmacokinetic in association with Relapse/progression
timeFrame: 15 years
measure: Assess ATG Pharmacokinetic in association with Infections
timeFrame: 1 years
measure: Assess ATG Pharmacokinetic in association with immunologic reconstitution
timeFrame: 5 years
Locations:
city: Antwerp
country: Belgium
facility: ZNA Stuivenberg
city: Brugge
country: Belgium
facility: AZ Sint Jan Brugge
city: Brussels
country: Belgium
facility: IJ Bordet
city: Brussels
country: Belgium
facility: UZ Brussel
city: Brussels
country: Belgium
facility: UCL St Luc
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: CHU de Liège
city: Roeselare
country: Belgium
facility: AZ Delta Roeselare
city: Yvoir
country: Belgium
facility: CHU UCL Namur Godinne
Study officials:
affiliation: Centre Hospitalier Universitaire de Liege
name: Frédéric Baron, MD,Ph
role: PRINCIPAL_INVESTIGATOR
References: