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

Primary Purpose

Graft Versus Host Disease

Status
Terminated
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Fludarabine
Clofarabine
Full body irradiation
Cyclophosphamide
Cyclophosphamide
stem cell transplantation
nuclear cells
Thymoglobulin Injectable Product
Sponsored by
Nantes University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft Versus Host Disease focused on measuring Peripheral haemopoietic stem cell transplant, High dose cyclophosphamide, acute GVHD, allogenic transplantation, RIC (reduced-intensity conditioning)

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Nantes Uh

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

LYMPHOID HEMOPATHY without ATG

MYELOID HEMOPATHY without ATG

LYMPHOID HEMOPATHY witH ATG

MYELOID HEMOPATHY with ATG

Arm Description

patients with lymphoid hemopathy

patients with myeloid hemopathy

patients inclued after 14 dec 2020, received a conditionnement regimen with ATG on Day -2 to reduce GVHD GRADE 1-2 incidence

patients inclued after 14 dec 2020, received a conditionnement regimen with ATG on Day -2 to reduce GVHD GRADE 1-2 incidence

Outcomes

Primary Outcome Measures

Incidence of grade 3 and 4 acute GVHD cortico-resistant
acute GVHD will be evaluated from International Mount Sinai criteria

Secondary Outcome Measures

Engraftment
number of days in aplasia (neutrophils< 0.5 Giga/L and platelets<20 G/l, number of transfusions (red blood and platelets)
Engraftment
chimerism
disease free survival (DFS)
blood and bone marrow analysis
Overall survival (OS)
clinical follow-up
graft and relapse free survival
time between Day O and relapse
chronic GVHD
chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD
non relapse mortality (NRM)
number of death unrelated to relapse or disease progression
Chimerism
proportion of full and mixed donor chimerism
Immune reconstitution
lymphocytes, monocytes, T4, T8, Natural Killer (NK), B cells rates
Identification of ghost factors associated with GVHD
Statistical Models to Identify Subjects with Ghost Prognosis Factors Nguyen JM. 2015
Adverse events of grade 3 and 4 after transplantation
time of occurring and frequency of grade 3 and grade 4 adverse events (CTCAE criteria)
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
compare OS between patients with ATG and patients without ATG
OS
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
compare chronic GVHD between patients with ATG and patients without ATG
chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD
compare DFS between patients with ATG and patients without ATG
DFS
compare Relapse between patients with ATG and patients without ATG
Relapse
compare NRM between patients with ATG and patients without ATG
NRM
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

Full Information

First Posted
August 21, 2017
Last Updated
July 13, 2022
Sponsor
Nantes University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03263767
Brief Title
Post Transplant Cyclophosphamide (PTCY) as Sole Graft Versus Host Disease (GVHD) Prophylaxis for Matched Allotransplant: CYRIC
Acronym
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.
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Terminated
Why Stopped
Security criteria (MTD)
Study Start Date
January 15, 2018 (Actual)
Primary Completion Date
October 21, 2021 (Actual)
Study Completion Date
June 21, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nantes University Hospital

4. Oversight

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
Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graft Versus Host Disease
Keywords
Peripheral haemopoietic stem cell transplant, High dose cyclophosphamide, acute GVHD, allogenic transplantation, RIC (reduced-intensity conditioning)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
47 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LYMPHOID HEMOPATHY without ATG
Arm Type
Experimental
Arm Description
patients with lymphoid hemopathy
Arm Title
MYELOID HEMOPATHY without ATG
Arm Type
Experimental
Arm Description
patients with myeloid hemopathy
Arm Title
LYMPHOID HEMOPATHY witH ATG
Arm Type
Experimental
Arm Description
patients inclued after 14 dec 2020, received a conditionnement regimen with ATG on Day -2 to reduce GVHD GRADE 1-2 incidence
Arm Title
MYELOID HEMOPATHY with ATG
Arm Type
Experimental
Arm Description
patients inclued after 14 dec 2020, received a conditionnement regimen with ATG on Day -2 to reduce GVHD GRADE 1-2 incidence
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Intervention Description
30 mg/m² Intravenous 5 days from Day-6 to Day-2
Intervention Type
Drug
Intervention Name(s)
Clofarabine
Intervention Description
30 mg/m² Intravenous 5 days from Day-6 to Day-2
Intervention Type
Radiation
Intervention Name(s)
Full body irradiation
Intervention Description
2 grays at Day-1
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Intervention Description
14 mg/kg intravenous 2 days at Day - 6 and day -5
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
hight dose
Intervention Description
50 mg/kg intravenous 2 days at day +3 and day +4
Intervention Type
Other
Intervention Name(s)
stem cell transplantation
Other Intervention Name(s)
graft
Intervention Description
at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells)
Intervention Type
Other
Intervention Name(s)
nuclear cells
Other Intervention Name(s)
Donor Lymphocytes Injection (DLI)
Intervention Description
CD3+ cells if needed after transplantation
Intervention Type
Drug
Intervention Name(s)
Thymoglobulin Injectable Product
Other Intervention Name(s)
ATG
Intervention Description
At day -2 2.5 mg/kg for patients inclued after 14 dec 2020
Primary Outcome Measure Information:
Title
Incidence of grade 3 and 4 acute GVHD cortico-resistant
Description
acute GVHD will be evaluated from International Mount Sinai criteria
Time Frame
100 days after transplantation
Secondary Outcome Measure Information:
Title
Engraftment
Description
number of days in aplasia (neutrophils< 0.5 Giga/L and platelets<20 G/l, number of transfusions (red blood and platelets)
Time Frame
one year
Title
Engraftment
Description
chimerism
Time Frame
one year
Title
disease free survival (DFS)
Description
blood and bone marrow analysis
Time Frame
one year, the last follow-up visit
Title
Overall survival (OS)
Description
clinical follow-up
Time Frame
one year, the last follow-up visit
Title
graft and relapse free survival
Description
time between Day O and relapse
Time Frame
one year
Title
chronic GVHD
Description
chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD
Time Frame
one year
Title
non relapse mortality (NRM)
Description
number of death unrelated to relapse or disease progression
Time Frame
last follow-up visit
Title
Chimerism
Description
proportion of full and mixed donor chimerism
Time Frame
1, 2, 3, 6 and 12 months after transplantation
Title
Immune reconstitution
Description
lymphocytes, monocytes, T4, T8, Natural Killer (NK), B cells rates
Time Frame
3, 6 and 12 months after transplantation
Title
Identification of ghost factors associated with GVHD
Description
Statistical Models to Identify Subjects with Ghost Prognosis Factors Nguyen JM. 2015
Time Frame
one year
Title
Adverse events of grade 3 and 4 after transplantation
Description
time of occurring and frequency of grade 3 and grade 4 adverse events (CTCAE criteria)
Time Frame
one year
Title
Infections frequency
Description
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
Time Frame
one year
Title
compare OS between patients with ATG and patients without ATG
Description
OS
Time Frame
one year, last follow-up visit
Title
compare grade 2-4 and 3-4 acute GVHD between patients with ATG and patients without ATG
Description
acute GVHD will be evaluated from International Mount Sinai criteria
Time Frame
one year
Title
compare chronic GVHD between patients with ATG and patients without ATG
Description
chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD
Time Frame
one year
Title
compare DFS between patients with ATG and patients without ATG
Description
DFS
Time Frame
one year, last follow-up visit
Title
compare Relapse between patients with ATG and patients without ATG
Description
Relapse
Time Frame
one year, last follow-up visit
Title
compare NRM between patients with ATG and patients without ATG
Description
NRM
Time Frame
one year, last follow-up visit
Title
compare Infections frequency between patients with ATG and patients without ATG
Description
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
Time Frame
one year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Nantes Uh
City
Nantes
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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