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

Graft Versus Host Disease Clinical Trial

— CYRIC  

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.

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03263767
• Other study ID #: RC16_0435
• Status: Terminated
• Phase: Phase 2
• Start date: January 15, 2018
• Est. completion date: June 21, 2022

Study information

• Verified date: July 2022
• Source: Nantes University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 47
• Est. completion date: June 21, 2022
• Est. primary completion date: October 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Graft Versus Host Disease
• Graft vs Host Disease

Intervention

Drug:
• Fludarabine
30 mg/m² Intravenous 5 days from Day-6 to Day-2
• 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
• Cyclophosphamide
50 mg/kg intravenous 2 days at day +3 and day +4

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)
• nuclear cells
CD3+ cells if needed after transplantation

Drug:
• Thymoglobulin Injectable Product
At day -2 2.5 mg/kg for patients inclued after 14 dec 2020

Locations

Country	Name	City	State
France	Nantes Uh	Nantes

Sponsors (1)

Lead Sponsor	Collaborator
Nantes University Hospital

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of grade 3 and 4 acute GVHD cortico-resistant	acute GVHD will be evaluated from International Mount Sinai criteria	100 days after transplantation
Secondary	Engraftment	number of days in aplasia (neutrophils< 0.5 Giga/L and platelets<20 G/l, number of transfusions (red blood and platelets)	one year
Secondary	Engraftment	chimerism	one year
Secondary	disease free survival (DFS)	blood and bone marrow analysis	one year, the last follow-up visit
Secondary	Overall survival (OS)	clinical follow-up	one year, the last follow-up visit
Secondary	graft and relapse free survival	time between Day O and relapse	one year
Secondary	chronic GVHD	chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD	one year
Secondary	non relapse mortality (NRM)	number of death unrelated to relapse or disease progression	last follow-up visit
Secondary	Chimerism	proportion of full and mixed donor chimerism	1, 2, 3, 6 and 12 months after transplantation
Secondary	Immune reconstitution	lymphocytes, monocytes, T4, T8, Natural Killer (NK), B cells rates	3, 6 and 12 months after transplantation
Secondary	Identification of ghost factors associated with GVHD	Statistical Models to Identify Subjects with Ghost Prognosis Factors Nguyen JM. 2015	one year
Secondary	Adverse events of grade 3 and 4 after transplantation	time of occurring and frequency of grade 3 and grade 4 adverse events (CTCAE criteria)	one year
Secondary	Infections frequency	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	one year
Secondary	compare OS between patients with ATG and patients without ATG	OS	one year, last follow-up visit
Secondary	compare grade 2-4 and 3-4 acute GVHD between patients with ATG and patients without ATG	acute GVHD will be evaluated from International Mount Sinai criteria	one year
Secondary	compare chronic GVHD between patients with ATG and patients without ATG	chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD	one year
Secondary	compare DFS between patients with ATG and patients without ATG	DFS	one year, last follow-up visit
Secondary	compare Relapse between patients with ATG and patients without ATG	Relapse	one year, last follow-up visit
Secondary	compare NRM between patients with ATG and patients without ATG	NRM	one year, last follow-up visit
Secondary	compare Infections frequency between patients with ATG and patients without ATG	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	one year