GVHD - Graft-Versus-Host Disease, Haploidentical Stem Cell Transplantation, HSCT
Conditions
Keywords
Cyclophosphamide toxicities, Cyclophosphamide dose reduction, Graft-Versus-Host Disease: GVHD, Hematopoietic stem cell transplantation
Brief summary
Phase III comparative, open-label, randomized (1:1) trial designed to evaluate the efficacy of reducing the total dose of PTCy to 70 mg/kg on GREFS compared to the standard dose of 100 mg/kg, in patients undergoing haploidentical HSCT for the treatment of a hematological malignancy, two years after HSCT.
Detailed description
The primary endpoint is the assessment of the GREFS at 2 years after HSCT, a composite endpoint defined as the probability of survival without severe GVHD, relapse/progression of the hematological malignancy, or PTCy-associated adverse event, whichever comes first from transplantation.
Interventions
DRUGCyclophosphamide 35mg/kg/day
Cyclophosphamide will be administered intravenously (IV) post-HSCT at the experimental dose (70 mg/kg, divided into two doses of 35 mg/kg/day (Adjusted Body Weight) on days +3 and +4).
DRUGCyclophosphamide 50mg/kg/day
Cyclophosphamide will be administered intravenously (IV) post-HSCT at the standard dose (100 mg/kg, divided into two doses of 50 mg/kg/day (Adjusted Body Weight) on days +3 and +4).
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
The randomization will be stratified by age (\< 60 years versus ≥ 60 years), disease risk index (low and intermediate versus high and very-high), and antithymocyte globulin use (yes versus no).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * Confirmed hematological malignancy with an indication for allogeneic HSCT * Presence of a haploidentical donor willing to donate PBSC * Patient planned to receive a thiotepa-based conditioning regimen * Provision of written informed consent Affiliation to a social security system (excluding "Aide Médicale d'État")
Exclusion criteria
* Karnofsky performance status \< 70% * Life expectancy \< 1 month, as determined by the attending physician * Acute or chronic heart failure, defined as left ventricular ejection fraction \< 40% * Pulmonary dysfunction with diffusion capacity \< 50% of predicted values * Renal impairment with estimated glomerular filtration rate (eGFR) \< 45 mL/min (calculated using the CKD-EPI formula) * Decompensated hemolytic anemia * Fanconi anemia and other DNA breakage repair disorders * Acute urothelial toxicity due to cytotoxic chemotherapy or radiotherapy * Obstruction of urinary outflow * Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines * Combination with products containing Hypericum perforatum * Combination with medicines that are substrates for the multidrug efflux transporter P-glycoprotein (P-gp) or the organic anion transporter proteins (OATP) and for which elevated plasma concentrations are associated with serious and/or life-threatening events, e.g., bosentan, dabigatran etexilate and aliskiren * Active non-controlled infectious disease * Positive HIV status * Pregnancy, breast-feeding, or refusal to use effective contraception for the duration of the study and 6 months after the last treatment dose * Individuals under legal protection measures or unable to provide consent (e.g., severe neurological or psychiatric disorders, or deprivation of liberty by judicial or administrative decision) * Hypersensitivity to the active substance or any of the excipients * Concurrent participation in another investigational therapeutic study * Inability to comply with study procedures as assessed by the investigator based on objective criteria, including but not limited to: * Significant language barrier in the absence of adequate translation support * Social or geographic situation preventing follow-up and adherence to visit schedule * Ongoing substance abuse likely to interfere with protocol compliance * Documented cognitive or functional impairment not otherwise covered under legal protection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| GVHD-free, relapse-free, event-free survival (GREFS) | Day 0 to first occurrence of acute grade III-IV GVHD, severe chronic GVHD, relapse, death, grade 3-4 cardiac event, or grade 3-4 BK virus-associated HC (up to 24 months post-transplant); platelet recovery (>50 × 10^9/L) assessed until Day +60 | The primary endpoint is the assessment of the GREFS at 2 years after HSCT, a composite endpoint defined as the probability of survival without severe GVHD, relapse/progression of the hematological malignancy, or PTCy-associated adverse event, whichever comes first from transplantation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Non-relapse mortality | From transplantation until death without evidence of relapse or up to 24 months, whichever occurs first Description: NRM refers to death without evidence of disease relapse. | — |
| Cumulative incidence of relapse | From transplantation until the occurrence of relapse or up to 24 months, whichever occurs first | Cumulative incidence functions (CIFs) will estimate outcomes such as relapse |
| Disease-free survival (DFS) | At two years | DFS is defined as survival without relapse or progression, the endpoints will be censored at two years to address differences in follow-up between groups |
| GVHD-free, relapse-free survival (GRFS) | From transplantation until the occurrence of acute grade III-IV GVHD, severe chronic GVHD, relapse, death, or up to 24 months, whichever occurs first | GRFS encompasses survival free from acute grade III-IV GVHD, chronic GVHD requiring systemic immunosuppression, or relapse |
| Cost-effectiveness | From transplantation until 2 years | The endpoint of the medico-economic analysis is the incremental cost-utility ratio (ICUR) at 24 months of reducing the total dose of PTCy to 70 mg/kg on GREFS compared to the standard dose of 100 mg/kg. The incremental cost-utility ratio will be calculated in cost per QALY gained. The secondary endpoint is the incremental cost-effectiveness ratio (ICER) at 24 months. The incremental cost-effectiveness ratio will be calculated in cost per life-years gained. |
| Cytokine profiles | Inclusion, Day 0, Day 15-35, Day 90, Day 365 | This ancillary study will evaluate cytokine profiles in relation to PTCy doses using a multiplex test based on fluorescence-coded beads |
| Gut microbiota | Inclusion, Day 0, Day 15-35, Day 90 | This ancillary study will evaluate gut microbiota: richness based on α-diversity indexes |
| Overall survival (OS) | From transplantation until death from any cause or up to 24 months, whichever occurs first | Overall survival (OS) at 2 years is defined as survival irrespective of disease status |
| Quality of life FACT-BMT | At 1, 3, 6, 12, and 24 months after HSCT | Quality of life compared to baseline using questionnaire: FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant, version 4) |
| Quality of life EQ-5D-5L | At 1, 3, 6, 12, and 24 months after HSCT | Quality of life compared to baseline using questionnaire: EQ-5D-5L (EuroQol 5-Dimension, 5-Level questionnaire). |
| Cumulative incidence and severity of acute and chronic GVHD assessed according to the 2014 NIH criteria | From transplantation until the occurrence of GVHD or death from any cause, or up to 180 days after transplantation for acute GVHD, or up to 24 months for chronic GVHD, whichever occurs first | Acute GVHD grading should be performed by the MAGIC criteria, for chronic GVHD; the time of onset of chronic GVHD will be recorded, as well as the requirement for a systemic immunosuppressive therapy and the maximum grade achieved according to the NIH Consensus Criteria |
| Toxicities, infection and hematogical recovery | From transplantation until the occurrence of the event, day +60 for hematological recovery, or up to 24 months for organ damage toxicities and infections, whichever occurs first | Organ damage toxicities assessed by the common terminology criteria for adverse events (CTCAE) v5.0, cumulative incidences of bacterial, viral, and fungal infections, and failure to achieve neutrophil recovery (absolute neutrophil count \> 0.5 x 10\^9/L) or platelet recovery (platelet count \> 50 x 10\^9/L) after HSCT |
Countries
France
Contacts
CONTACTMohamad MOHTY, PU-PH
CONTACTRemy DULERY
PRINCIPAL_INVESTIGATORMohamad MOHTY, PU-PH
Assistance Publique - Hôpitaux de Paris
Outcome results
None listed