Post Transplant Cyclophosphamide (PTCY) as Sole Graft Versus Host Disease (GVHD) Prophylaxis for Matched Allotransplant: CYRIC

Sponsor

Nantes University Hospital (Other)

Overall Status

Terminated

CT.gov ID

NCT03263767

Collaborator

(none)

Enrollment

Location

Arms

53.2

Actual Duration (Months)

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Acute or chronic graft versus host disease is still the major complication of stem cells transplantation regarding morbidity and mortality.

Recently, high dose cyclophosphamide utilization early after post-transplantation (day+ 3 and +4) not only for patients with HLA- haploidentical donor but also for patients with Human Leukocyte Antigen (HLA)-compatible donor, showed a great control of graft versus host disease after transplantation, allowing to consider stopping immunosuppressive treatment after the transplantation (Neoral=cyclosporine, cell-cept=mycophenolate mofetil). Indeed, this step has already been completed in myeloablative transplantation in adult patients.

This approach could enable to avoid in the end several complications related to long term immunosuppressive drugs administration, while promoting quicker immunity recovery.

Condition or Disease	Intervention/Treatment	Phase
Graft Versus Host Disease	Drug: Fludarabine Drug: Clofarabine Radiation: Full body irradiation Drug: Cyclophosphamide Drug: Cyclophosphamide Other: stem cell transplantation Other: nuclear cells Drug: Thymoglobulin Injectable Product	Phase 2

Detailed Description

The BALTIMORE conditioning regiment will be used in this study with peripheral stem cell transplantation and fludarabine will be replaced by clofarabine for myeloid diseases (Acute Myeloide Leukemia, Myelodysplasia , myelofibrosis, Chronic Myeoloid Leukemia..) because of better antitumoral activity in this setting.

Study Design

Study Type:

Interventional

Actual Enrollment :

47 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase II Study Testing Prophylaxis Feasibility of Graft Versus Host Disease With Only High Dose Cyclophosphamide Post-transplantation for Patients Eligible to a Reduced-intensity Conditioning Regiment Prior to Allogenic Transplantation With a Compatible Familial or Non-familial Donor.

Actual Study Start Date :

Jan 15, 2018

Actual Primary Completion Date :

Oct 21, 2021

Actual Study Completion Date :

Jun 21, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LYMPHOID HEMOPATHY without ATG patients with lymphoid hemopathy	Drug: Fludarabine 30 mg/m² Intravenous 5 days from Day-6 to Day-2 Radiation: Full body irradiation 2 grays at Day-1 Drug: Cyclophosphamide 14 mg/kg intravenous 2 days at Day - 6 and day -5 Drug: Cyclophosphamide 50 mg/kg intravenous 2 days at day +3 and day +4 Other Names: hight dose Other: stem cell transplantation at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells) Other Names: graft Other: nuclear cells CD3+ cells if needed after transplantation Other Names: Donor Lymphocytes Injection (DLI)
Experimental: MYELOID HEMOPATHY without ATG patients with myeloid hemopathy	Drug: Clofarabine 30 mg/m² Intravenous 5 days from Day-6 to Day-2 Radiation: Full body irradiation 2 grays at Day-1 Drug: Cyclophosphamide 14 mg/kg intravenous 2 days at Day - 6 and day -5 Drug: Cyclophosphamide 50 mg/kg intravenous 2 days at day +3 and day +4 Other Names: hight dose Other: stem cell transplantation at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells) Other Names: graft Other: nuclear cells CD3+ cells if needed after transplantation Other Names: Donor Lymphocytes Injection (DLI)
Experimental: LYMPHOID HEMOPATHY witH ATG patients inclued after 14 dec 2020, received a conditionnement regimen with ATG on Day -2 to reduce GVHD GRADE 1-2 incidence	Drug: Fludarabine 30 mg/m² Intravenous 5 days from Day-6 to Day-2 Radiation: Full body irradiation 2 grays at Day-1 Drug: Cyclophosphamide 14 mg/kg intravenous 2 days at Day - 6 and day -5 Drug: Cyclophosphamide 50 mg/kg intravenous 2 days at day +3 and day +4 Other Names: hight dose Other: stem cell transplantation at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells) Other Names: graft Other: nuclear cells CD3+ cells if needed after transplantation Other Names: Donor Lymphocytes Injection (DLI) Drug: Thymoglobulin Injectable Product At day -2 2.5 mg/kg for patients inclued after 14 dec 2020 Other Names: ATG
Experimental: MYELOID HEMOPATHY with ATG patients inclued after 14 dec 2020, received a conditionnement regimen with ATG on Day -2 to reduce GVHD GRADE 1-2 incidence	Drug: Clofarabine 30 mg/m² Intravenous 5 days from Day-6 to Day-2 Radiation: Full body irradiation 2 grays at Day-1 Drug: Cyclophosphamide 14 mg/kg intravenous 2 days at Day - 6 and day -5 Drug: Cyclophosphamide 50 mg/kg intravenous 2 days at day +3 and day +4 Other Names: hight dose Other: stem cell transplantation at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells) Other Names: graft Other: nuclear cells CD3+ cells if needed after transplantation Other Names: Donor Lymphocytes Injection (DLI) Drug: Thymoglobulin Injectable Product At day -2 2.5 mg/kg for patients inclued after 14 dec 2020 Other Names: ATG

Outcome Measures

Primary Outcome Measures

Incidence of grade 3 and 4 acute GVHD cortico-resistant [100 days after transplantation]
acute GVHD will be evaluated from International Mount Sinai criteria

Secondary Outcome Measures

Engraftment [one year]
number of days in aplasia (neutrophils< 0.5 Giga/L and platelets<20 G/l, number of transfusions (red blood and platelets)
Engraftment [one year]
chimerism
disease free survival (DFS) [one year, the last follow-up visit]
blood and bone marrow analysis
Overall survival (OS) [one year, the last follow-up visit]
clinical follow-up
graft and relapse free survival [one year]
time between Day O and relapse
chronic GVHD [one year]
chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD
non relapse mortality (NRM) [last follow-up visit]
number of death unrelated to relapse or disease progression
Chimerism [1, 2, 3, 6 and 12 months after transplantation]
proportion of full and mixed donor chimerism
Immune reconstitution [3, 6 and 12 months after transplantation]
lymphocytes, monocytes, T4, T8, Natural Killer (NK), B cells rates
Identification of ghost factors associated with GVHD [one year]
Statistical Models to Identify Subjects with Ghost Prognosis Factors Nguyen JM. 2015
Adverse events of grade 3 and 4 after transplantation [one year]
time of occurring and frequency of grade 3 and grade 4 adverse events (CTCAE criteria)
Infections frequency [one year]
time of occurring and frequency of viral (CytoMegalo Virus, Epstein Barr virus , BKV, adenovirus), bacterial, parasite and yeast infections, evaluated by Polymerase Chain Reaction (PCR), blood and urines cultures, biopsy if applicable
compare OS between patients with ATG and patients without ATG [one year, last follow-up visit]
OS
compare grade 2-4 and 3-4 acute GVHD between patients with ATG and patients without ATG [one year]
acute GVHD will be evaluated from International Mount Sinai criteria
compare chronic GVHD between patients with ATG and patients without ATG [one year]
chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD
compare DFS between patients with ATG and patients without ATG [one year, last follow-up visit]
DFS
compare Relapse between patients with ATG and patients without ATG [one year, last follow-up visit]
Relapse
compare NRM between patients with ATG and patients without ATG [one year, last follow-up visit]
NRM
compare Infections frequency between patients with ATG and patients without ATG [one year]
time of occurring and frequency of viral (CytoMegalo Virus, Epstein Barr virus , BKV, adenovirus), bacterial, parasite and yeast infections, evaluated by Polymerase Chain Reaction (PCR), blood and urines cultures, biopsy if applicable

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

adults ≤ 70 years old
indication to stem cells transplantation with reduced-intensity conditioning regimen
with a HLA-compatible familial 10/10 or non-familial donor
Written signed informed consent form
woman with childbearing potential under efficient control birth method during the trial and up to 12 months after cyclophosphamide stop
men under efficient control birth method during the trial and up to 6 months after cyclophosphamide stop
Negative serology to B and C hepatitis and to HIV
Affiliated to social security

Exclusion Criteria:

- Eligible to myeloablative contioning regimen
Other progressive malignancy disease or history of prior other malignancy in the last two years, with the exception of: curatively treated basal cell carcinoma or carcinoma in situ of the cervix
Progressive mental illness disease
Pregnant or Breastfeeding woman
woman with childbearing potential without any efficient control birth
Serious concomitant infection and not controlled
Contra-indications to allogenic transplantation, especially:
Cardiac: left ventricular ejection fraction <45% assessed by transthoracic echography or isotopic method (isotopic gamma-angiography)
Respiratory: DLCO limiting fludarabine and busulfan use (DLCO< 40% of theorical value)
Renal: creatinine clearance < 60ml/min (MDRD method)
Hepatic: transaminases >5 Uper Per Normal (UPN) or bilirubin> 2 UPN
Contra-indications to cyclophosphamide:
Urinary tract infections
Acute urothelial toxicity due to cytotoxic chemotherapy or to radiotherapy
Obstruction of urines flow
Pre-existing hemorrhagic cystitis
Yellow fever vaccination
Cardiac condition preventing high dose cyclophosphamide utilization :
New York Heart Association (NYHA) functional class II, III or IV
Rhythmic, valvular or ischemic cardiomyopathy
Minor
Patient under guardianship or curatorship
Patient under judicial protection
Known or suspected hypersensitivity to cyclophosphamide
Known or suspected hypersensitivity to rabbit proteins