Reduced Post-transplant Cyclophosphamide Dose in Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies

Phase 3Not Yet RecruitingNCT07193420

Assistance Publique - Hôpitaux de Paris180 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

NONE

Enrollment

180

Conditions

GVHD - Graft-Versus-Host Disease HSCT Haploidentical Stem Cell Transplantation

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

GVHD-free, relapse-free, event-free survival (GREFS)

Time frame: From Day 0 until the occurrence of any of the following: acute grade III-IV GVHD, severe chronic GVHD, relapse, death, grade 3-4 cardiac event, or grade 3-4 BK virus-associated HC, whichever occurs first, assessed up to 24 months after transplantation, f

Secondary Outcomes

Overall survival (OS)

Overall survival (OS) at 2 years is defined as survival irrespective of disease status

Time frame: From transplantation until death from any cause or up to 24 months, whichever occurs first

Quality of life FACT-BMT

Quality of life compared to baseline using questionnaire: FACT-BMT (Functional Assessment of Cancer Therapy - Bone Marrow Transplant, version 4)

Time frame: At 1, 3, 6, 12, and 24 months after HSCT

Toxicities, infection and hematogical recovery

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 109/L) or platelet recovery (platelet count \> 50 x 109/L) after HSCT

Time frame: 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

Cumulative incidence and severity of acute and chronic GVHD

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

Time frame: 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

Non-relapse mortality

Time frame: 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

Cumulative incidence functions (CIFs) will estimate outcomes such as relapse

Time frame: From transplantation until the occurrence of relapse or up to 24 months, whichever occurs first

Disease-free survival (DFS)

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

Time frame: At two years

GVHD-free, relapse-free survival (GRFS)

GRFS encompasses survival free from acute grade III-IV GVHD, chronic GVHD requiring systemic immunosuppression, or relapse

Time frame: From transplantation until the occurrence of acute grade III-IV GVHD, severe chronic GVHD, relapse, death, or up to 24 months, whichever occurs first

Cost-effectiveness

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.

Time frame: From transplantation until 2 years

Cytokine profiles

This ancillary study will evaluate cytokine profiles in relation to PTCy doses using a multiplex test based on fluorescence-coded beads

Time frame: Inclusion, Day 0, Day 15-35, Day 90, Day 365

Quality of life EQ-5D-5L

Quality of life compared to baseline using questionnaire: EQ-5D-5L (EuroQol 5-Dimension, 5-Level questionnaire).

Time frame: At 1, 3, 6, 12, and 24 months after HSCT

Gut microbiota

This ancillary study will evaluate gut microbiota: richness based on α-diversity indexes

Time frame: Inclusion, Day 0, Day 15-35, Day 90