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

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.

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.

Study Overview

• Status: Terminated
• Conditions: Graft Versus Host Disease
• Intervention / Treatment: Drug: Fludarabine; Radiation: Full body irradiation; Drug: Cyclophosphamide; Drug: Cyclophosphamide; Other: stem cell transplantation; Other: nuclear cells; Drug: Clofarabine; Drug: Thymoglobulin Injectable Product

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 Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Nantes, France
    • Nantes UH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / 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	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: Clofarabine; 30 mg/m² Intravenous 5 days from Day-6 to Day-2
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	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: Clofarabine; 30 mg/m² Intravenous 5 days from Day-6 to Day-2; Drug: Thymoglobulin Injectable Product; At day -2 2.5 mg/kg for patients inclued after 14 dec 2020; Other Names: ATG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Engraftment	chimerism	one year
disease free survival (DFS)	blood and bone marrow analysis	one year, the last follow-up visit
Overall survival (OS)	clinical follow-up	one year, the last follow-up visit
graft and relapse free survival	time between Day O and relapse	one year
chronic GVHD	chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD	one year
non relapse mortality (NRM)	number of death unrelated to relapse or disease progression	last follow-up visit
Chimerism	proportion of full and mixed donor chimerism	1, 2, 3, 6 and 12 months after transplantation
Immune reconstitution	lymphocytes, monocytes, T4, T8, Natural Killer (NK), B cells rates	3, 6 and 12 months after transplantation
Identification of ghost factors associated with GVHD	Statistical Models to Identify Subjects with Ghost Prognosis Factors Nguyen JM. 2015	one year
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
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
compare OS between patients with ATG and patients without ATG	OS	one year, last follow-up visit
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
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
compare DFS between patients with ATG and patients without ATG	DFS	one year, last follow-up visit
compare Relapse between patients with ATG and patients without ATG	Relapse	one year, last follow-up visit
compare NRM between patients with ATG and patients without ATG	NRM	one year, last follow-up visit
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

Collaborators and Investigators

• Sponsor: Nantes University Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 15, 2018
• Primary Completion (ACTUAL): October 21, 2021
• Study Completion (ACTUAL): June 21, 2022

Study Registration Dates

• First Submitted: August 21, 2017
• First Submitted That Met QC Criteria: August 23, 2017
• First Posted (ACTUAL): August 28, 2017

Study Record Updates

• Last Update Posted (ACTUAL): July 15, 2022
• Last Update Submitted That Met QC Criteria: July 13, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: acute GVHD; High dose cyclophosphamide; Peripheral haemopoietic stem cell transplant; allogenic transplantation; RIC (reduced-intensity conditioning)
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Clofarabine; Fludarabine; Thymoglobulin
• Other Study ID Numbers: RC16_0435

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No