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Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide for Rescuing Patients With Graft Failure (HaploRescue)

Primary Purpose

Hematologic Diseases, Graft Failure, Allogeneic Hematopoietic Stem Cell Transplantation

Status

Not yet recruiting

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

haplo-SCT with PTCy

About this trial

This is an interventional other trial for Hematologic Diseases

Eligibility Criteria

3 Years - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Aged from 3 to 70 years
All hematological diseases
Suffering from primary or secondary (within the 60 days post-transplantation) graft failure after a 1st allo-SCT
With usual criteria for allo-SCT:
- ECOG ≤ 2
- No severe and uncontrolled infection
- Cardiac function compatible with high dose of cyclophosphamide
- Adequate organ function: ASAT and ALAT ≤ 2.5N, total bilirubin ≤ 2N, creatinine clearance ≥30ml / min
With identification of a haploidentical donor (brother, sister, parents, adult children or cousin)
Absence of donor specific antibody (DSA) detected in the patient with a MFI ≥ 1500 (antibodies directed towards the distinct haplotype between donor and recipient)
With health insurance coverage (bénéficiaire ou ayant droit).
Understand informed consent or optimal treatment and follow-up.
Contraception methods must be prescribed during all the duration of the research. Women and men of childbearing age must use contraceptive methods within 12 months and 6 months after the last dose of cyclophosphamide, respectively.
Having signed a written informed consent (2 parents for patients aged less than 18)

Exclusion Criteria:

Aged< 3 years old and >70 years old
With uncontrolled infection
With Seropositivity for HIV or HTLV-1 or active hepatitis B or C defined by a positive PCR HBV or HCV and associated hepatic cytolysis
Yellow fever vaccine within 2 months before transplantation
Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix)
Uncontrolled coronary insufficiency, recent myocardial infarction <6 month, current manifestations of heart failure, uncontrolled cardiac rhythm disorders, ventricular ejection fraction <50%
Heart failure according to NYHA (II or more)
Preexisting acute hemorrhagic cystitis
Renal failure with creatinine clearance < 30ml / min
Urinary tract obstruction
Pregnant (β-HCG positive) or breast-feeding
Who have any debilitating medical or psychiatric illness, which preclude understanding the inform consent as well as optimal treatment and follow-up
COVID vaccination or recent COVID disease <3 months
Tutorship or curatorship
Contraindications to treatments used during the research

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

haplo-SCT with PTCy

Arm Description

haploidentical (haplo) related donor Stem Cell Transplantation (haplo-SCT) with administration of post-transplantation cyclophosphamide (PTCy, which targets alloreactive T cells generated early after an HLA-mismatched transplant, sparing regulatory T cells and leaving unaffected the non-dividing hematopoietic stem cells)

Outcomes

Primary Outcome Measures

Overall Survival

Secondary Outcome Measures

Graft failure incidence

Neutrophils engraftment

3 consecutive days with neutrophiles >0.5 G/L

Platelets engraftment

7 consecutive days with platelets >20 G/L

Absolute numbers of neutrophils

Absolute number of platelets

Incidence of use of growth factors for poor hematopoietic reconstitution

Acute GvHD incidence

Chronic GvHD incidence

Relapse incidence

Progression free survival

Incidence of CMV infection

Incidence of EBV infection

Incidence of severe infections

Severe infections are defined as CTAE grade of 3 or 4

Incidence of severe infections

Severe infections are defined as CTAE grade of 3 or 4

Incidence of severe infections

Severe infections are defined as CTAE grade of 3 or 4

Incidence of severe infections

Severe infections are defined as CTAE grade of 3 or 4

Incidence of veino-occlusive disease (VOD)

Severity of veino-occlusive disease (VOD)

Non-relapse mortality

Incidence of cardiac toxicities

Overall survival

Interval between first allo-SCT and rescue haplo-SCT

Quality of life for adults

Quality of life will be assessed for adults using "European Organization for Research and Treatment of Cancer Quality of Life Questionnaire" EORTC QLQ-C30-V3 questionnaire.The QLQ-C30 is composed of both multi-item scales and single-item measures. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.

Quality of life for adults

Quality of life for minors

Quality of life will be assessed for minor using The Pediatric Quality of Life Inventory™ (PedsQL™) The 36-item PedsQL™ Family Impact Module is a parent-report instrument designed to assess the impact of pediatric chronic health conditions on parents and the family. It includes 6 subscales measuring parents' self-reported functioning. The scale has five Likert response options, 'never', 'almost never', 'sometimes', 'often' and 'almost always' (corresponding to scores of 100, 75, 50, 25 and 0). Higher scores indicate better functioning

Quality of life for minors

Proportion of patients with a donor chimerism of 90% or more

Immune reconstitution

Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

Immune reconstitution

Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

Immune reconstitution

Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

Immune reconstitution

Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

Iron overload estimation

Full Information

NCT ID

NCT05126186

First Posted

November 8, 2021

Last Updated

November 8, 2021

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT05126186

Brief Title

Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide for Rescuing Patients With Graft Failure

Acronym

HaploRescue

Official Title

Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide for Rescuing Patients With Graft Failure: a Phase II Study

Study Type

Interventional

2. Study Status

Record Verification Date

November 2021

Overall Recruitment Status

Not yet recruiting

Study Start Date

December 1, 2021 (Anticipated)

Primary Completion Date

December 1, 2025 (Anticipated)

Study Completion Date

December 1, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Prognosis of patients with graft failure is dismal, and re-transplantation is the sole option for long-term survival. Currently, there is no consensus concerning therapeutic options in patients with primary or secondary (within the 60 days post-transplantation) graft failure and finding a new donor within an acceptable delay is challenging. Literature is poor on the subject while the overall survival of such patients is about 30% at 1 year. This situation thus represents today a very challenging unmet medical need. Recently, haploidentical (haplo) related donor Stem Cell Transplantation (haplo-SCT) have improved dramatically outcomes using T-cell replete grafts with administration of post-transplantation cyclophosphamide (PTCy, which targets alloreactive T cells generated early after an HLA-mismatched transplant, sparing regulatory T cells and leaving unaffected the non-dividing hematopoietic stem cells) and standard post-transplant immune suppression with a calcineurin inhibitor (CNI) and mycophenolate mofetil. Our group re-transplanted a patient who experienced two consecutive graft failures and was successfully managed through a third haplo-SCT from her son using PTCy. We then retrospectively collected and analyzed data from 26 primary graft failure patients transplanted between 2011 and 2017 in 15 centers on behalf of French Society for Stem Cell Transplantation and Cell Therapy (SFGM-TC). The study population consisted mainly of patients with primary or secondary (within the 60 days post-transplantation) graft failure who underwent haplo-SCT and received PTCy as graft-versus-host-disease prophylaxis. The 1-year overall survival was about 60% suggesting that this approach might be a valid option in this particular poor clinical situation but now need validation through a phase II multicenter, national, prospective cohort study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hematologic Diseases, Graft Failure, Allogeneic Hematopoietic Stem Cell Transplantation

7. Study Design

Primary Purpose

Other

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

35 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

haplo-SCT with PTCy

Arm Type

Experimental

Arm Description

Intervention Type

Other

Intervention Name(s)

haplo-SCT with PTCy

Intervention Description

Conditioning regimen Fludarabine (30mg/m2/day from day -6 to day -4), Cyclophosphamide (14.5 mg/kg/day at day -6 and day -5) except for patients who received a total dose of Cyclophosphamide >100mg/Kg during the first Bone Marrow Transplantation Total Body Irradiation (2 Gray on day -1). Source of stem cell source Peripheral blood stem cell Minimal target dose of 4.106 CD34+ cells/kg of recipient GvHD prophylaxis Cyclophosphamide 50 mg/Kg/day at D+3 and D+4 Ciclosporine from day+5 (residual 200 à 300ng/l) Mycophenolate mofetyl at 15mg/Kg x2/day from day+5 Prevention of EBV reactivation Rituximab : 150mg/m2 intravenously at Day+5 post Haplo-SCT Each infusion of Rituximab will be preceded by administration of anti-pyretic and an antihistaminic.

Primary Outcome Measure Information:

Title

Overall Survival

Time Frame

at one year

Secondary Outcome Measure Information:

Title

Graft failure incidence

Time Frame

at 3 months

Title

Neutrophils engraftment

Description

3 consecutive days with neutrophiles >0.5 G/L

Time Frame

at day 100

Title

Platelets engraftment

Description

7 consecutive days with platelets >20 G/L

Time Frame

at day 100

Title

Absolute numbers of neutrophils

Time Frame

at 1 month

Title

Absolute numbers of neutrophils

Time Frame

at 2 months

Title

Absolute numbers of neutrophils

Time Frame

at 3 months

Title

Absolute numbers of neutrophils

Time Frame

at 6 months

Title

Absolute numbers of neutrophils

Time Frame

at 12 months

Title

Absolute numbers of neutrophils

Time Frame

through study completion, an average of 6 months

Title

Absolute number of platelets

Time Frame

at one month

Title

Absolute number of platelets

Time Frame

at 2 months

Title

Absolute number of platelets

Time Frame

at 3 months

Title

Absolute number of platelets

Time Frame

at 6 months

Title

Absolute number of platelets

Time Frame

at 12 months

Title

Absolute number of platelets

Time Frame

through study completion, an average of 6 months

Title

Incidence of use of growth factors for poor hematopoietic reconstitution

Time Frame

at 3 months

Title

Acute GvHD incidence

Time Frame

at 3 months

Title

Chronic GvHD incidence

Time Frame

at 24 months

Title

Relapse incidence

Time Frame

at 12 months

Title

Relapse incidence

Time Frame

at 24 months

Title

Progression free survival

Time Frame

at 12 months

Title

Progression free survival

Time Frame

at 24 months

Title

Incidence of CMV infection

Time Frame

at 12 months

Title

Incidence of EBV infection

Time Frame

at 12 months

Title

Incidence of severe infections

Description

Severe infections are defined as CTAE grade of 3 or 4

Time Frame

at 3 months

Title

Incidence of severe infections

Description

Severe infections are defined as CTAE grade of 3 or 4

Time Frame

at 6 months

Title

Incidence of severe infections

Description

Severe infections are defined as CTAE grade of 3 or 4

Time Frame

at 12 months

Title

Incidence of severe infections

Description

Severe infections are defined as CTAE grade of 3 or 4

Time Frame

at 24 months

Title

Incidence of veino-occlusive disease (VOD)

Time Frame

at 3 months

Title

Severity of veino-occlusive disease (VOD)

Time Frame

at 3 months

Title

Non-relapse mortality

Time Frame

at 24 months

Title

Incidence of cardiac toxicities

Time Frame

at 12 months

Title

Overall survival

Time Frame

at 24 months

Title

Interval between first allo-SCT and rescue haplo-SCT

Time Frame

at 60 days

Title

Quality of life for adults

Description

Time Frame

at 3 months

Title

Quality of life for adults

Description

Time Frame

at 6 months

Title

Quality of life for adults

Description

Time Frame

at 12 months

Title

Quality of life for adults

Description

Time Frame

at 24 months

Title

Quality of life for minors

Description

Time Frame

at 3 months

Title

Quality of life for minors

Description

Time Frame

at 6 months

Title

Quality of life for minors

Description

Time Frame

at 12 months

Title

Quality of life for minors

Description

Time Frame

at 24 months

Title

Proportion of patients with a donor chimerism of 90% or more

Time Frame

at 1 month

Title

Proportion of patients with a donor chimerism of 90% or more

Time Frame

at 3 months

Title

Proportion of patients with a donor chimerism of 90% or more

Time Frame

at 6 months

Title

Proportion of patients with a donor chimerism of 90% or more

Time Frame

at 12 months

Title

Immune reconstitution

Description

Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

Time Frame

at 3 months post-transplantation

Title

Immune reconstitution

Description

Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

Time Frame

at 6 months post-transplantation

Title

Immune reconstitution

Description

Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

Time Frame

at 12 months post-transplantation

Title

Immune reconstitution

Description

Immune reconstitution will be defined by analyzing T, B, NK, regulatory T cell levels in the peripheral blood

Time Frame

at 24 months post-transplantation

Title

Iron overload estimation

Time Frame

at 3 months

Title

Iron overload estimation

Time Frame

at 6 months

Title

Iron overload estimation

Time Frame

at 12 months

Title

Iron overload estimation

Time Frame

at 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Aged from 3 to 70 years All hematological diseases Suffering from primary or secondary (within the 60 days post-transplantation) graft failure after a 1st allo-SCT With usual criteria for allo-SCT: ECOG ≤ 2 No severe and uncontrolled infection Cardiac function compatible with high dose of cyclophosphamide Adequate organ function: ASAT and ALAT ≤ 2.5N, total bilirubin ≤ 2N, creatinine clearance ≥30ml / min With identification of a haploidentical donor (brother, sister, parents, adult children or cousin) Absence of donor specific antibody (DSA) detected in the patient with a MFI ≥ 1500 (antibodies directed towards the distinct haplotype between donor and recipient) With health insurance coverage (bénéficiaire ou ayant droit). Understand informed consent or optimal treatment and follow-up. Contraception methods must be prescribed during all the duration of the research. Women and men of childbearing age must use contraceptive methods within 12 months and 6 months after the last dose of cyclophosphamide, respectively. Having signed a written informed consent (2 parents for patients aged less than 18) Exclusion Criteria: Aged< 3 years old and >70 years old With uncontrolled infection With Seropositivity for HIV or HTLV-1 or active hepatitis B or C defined by a positive PCR HBV or HCV and associated hepatic cytolysis Yellow fever vaccine within 2 months before transplantation Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix) Uncontrolled coronary insufficiency, recent myocardial infarction <6 month, current manifestations of heart failure, uncontrolled cardiac rhythm disorders, ventricular ejection fraction <50% Heart failure according to NYHA (II or more) Preexisting acute hemorrhagic cystitis Renal failure with creatinine clearance < 30ml / min Urinary tract obstruction Pregnant (β-HCG positive) or breast-feeding Who have any debilitating medical or psychiatric illness, which preclude understanding the inform consent as well as optimal treatment and follow-up COVID vaccination or recent COVID disease <3 months Tutorship or curatorship Contraindications to treatments used during the research

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Régis Peffault de Latour

Phone

+33142385073

regis.peffaultdelatour@aphp.fr

First Name & Middle Initial & Last Name or Official Title & Degree

Matthieu Resche-Rigon

Phone

+33142499742

matthieu.resche-rigon@u-paris.fr

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Learn more about this trial

Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation With Post-transplant Cyclophosphamide for Rescuing Patients With Graft Failure

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