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

Official title

Reduced Post-transplant Cyclophosphamide Dose in Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation for Hematological Malignancies: a Phase III Randomized Study

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.

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

• Drug Cyclophosphamide 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).
• Drug Cyclophosphamide 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).

Primary outcome measures

• GVHD-free, relapse-free, event-free survival (GREFS) [Time frame: 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]

Secondary outcome measures (12)

• Overall survival (OS) [Time frame: From transplantation until death from any cause or up to 24 months, whichever occurs first]
• Quality of life FACT-BMT [Time frame: At 1, 3, 6, 12, and 24 months after HSCT]
• Quality of life EQ-5D-5L [Time frame: At 1, 3, 6, 12, and 24 months after HSCT]
• Toxicities, infection and hematogical recovery [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 assessed according to the 2014 NIH 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 [Time frame: From transplantation until the occurrence of relapse or up to 24 months, whichever occurs first]
• Disease-free survival (DFS) [Time frame: At two years]
• GVHD-free, relapse-free survival (GRFS) [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 [Time frame: From transplantation until 2 years]
• Cytokine profiles [Time frame: Inclusion, Day 0, Day 15-35, Day 90, Day 365]
• Gut microbiota [Time frame: Inclusion, Day 0, Day 15-35, Day 90]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

France · 1 center

• Saint Antoine Hospital - Hematology Department — Paris

Identifiers

NCT: NCT07193420 · APHP241012 · 2024-519986-23-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗