Trial of GVHD Prophylasxis With PTCy or Thymoglobulin in Unrelated SCT

Overview

Purpose There is a growing evidence of high efficacy of post-transplantation cyclophocphomide (PTCy)-based GVHD prophylaxis in haploidentical and matched related and unrelated bone marrow transplantation. There is limitted, but growing data on safety and efficacy of this prophylaxis in unrelated and peripheral blood stem cell transplantations. Use of PTCy in chronic myeloproliferative neoplasms and myelodisplatic syndrome is of particular interest. On the one hand, PTCy could reduce the incidence of chronic GVHD and long-term bormidity. On the other hand, there is a concern, that PTCy can increase the incidence of graft failures in this group of patients. Currently published data indicate that low-dose Thymoglobulin-based prophylaxis is the most promissing compatitor in terms of acute and chronic GVHD control. So there is a rationale to randomize Thymoglobulin and PTCy as GVHD prophilaxis. Pre-transplant assesment of moratlity (PAM)-index will be used as the strata for randomization, as it is the paramter that takes into account the most important factors effecting survival. The conditioning regimen and the other two components of GVHD prophylaxis (mycophenolate mofetil and tacrolimus) will be identical in the two arms of the study.

Full Title of Study: “Randomized Trial of GVHD Prophylasxis With Post-transplantation Cyclophocphomide (PTCy) or Thymoglobulin in Unrelated SCT Recepients With Chronic Myeloproliferative Neoplasms and Myelodisplatic Syndrome”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: None (Open Label)
  • Study Primary Completion Date: April 3, 2019

Interventions

  • Procedure: Unrelated allogeneic stem cell transplantation
  • Drug: Busulfan
  • Drug: Fludarabine monophosphate
  • Drug: Tacrolimus
  • Drug: Mycophenolate mofetil
  • Drug: Cyclophosphamide
  • Drug: Thymoglobulin

Arms, Groups and Cohorts

  • Experimental: Thymoglobulin
    • Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -6 through -5 Busulfan 1 mg/kg po qid x 2 days Days -4 through -3 Thymoglobulin 2,5 mg/kg po qd x 2 days Days -1 through +30: Mycophenolate mofetil 30 mg/kg/day, maximum 2 g/day, iv or po x 30 days Days -1 through +150: Tacrolimus 0.03 mg/kg/day with further correction by concentration
  • Experimental: PTCy
    • Days -7 through -2: Fludarabine 30 mg/m2/day iv x 6 days Days -4 through -3: Busulfan 1 mg/kg po qid x 2 days Day 0: Infusion of unmanipulated graft Day +3 and +4: Cyclophosphamide 50 mg/kg/day iv Days +5 through +35: Mycophenolate mofetil 30 mg/kg/day, maximum 2 g/day, iv or po x 30 days Days +5 through +120: Tacrolimus 0.03 mg/kg/day with further correction by concentration

Clinical Trial Outcome Measures

Primary Measures

  • Incidence of primary graft failure
    • Time Frame: 60 days

Secondary Measures

  • Incidence of acute GVHD, grades II-IV
    • Time Frame: 365 days
  • Incidence of chronic GVHD, moderate and severe (NIH criteria)
    • Time Frame: 365 days
  • Non-relapse mortality analysis
    • Time Frame: 365 days
  • Event-free survival analysis
    • Time Frame: 365 days
  • Overall survival analysis
    • Time Frame: 365 days
  • Relapse rate analysis
    • Time Frame: 365 days
  • Toxicity (NCI CTCAE 4.03)
    • Time Frame: 100 days
    • Toxicity parameters based on NCI CTCAE 4.03 grades: hepatotoxicity (liver function tests), nephrotoxicity (creatinine), neurotoxicity (attending physician assessment), mucositis (attending physician assessment), hemorrhagic cystitis (attending physician assessment), cardiotoxicity (ECG, echocardiography). Additional toxicity parameters: incidence and severity of veno-occlusive disease, incidence of transplant-associated microangiopathy
  • Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence
    • Time Frame: 100 days

Participating in This Clinical Trial

Inclusion Criteria

  • Patients must have an indication for allogeneic hematopoietic stem cell transplantation – Diagnosis: Chronic myeloid leukemia Myelodysplastic Syndromes Myeloprolipherative neoplsm unclassified Atypical chronic myelogenous leukemia – Signed informed consent – Patients with 10/10 HLA-matched unrelated donor available. The donor and recipient must be identical by the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. Mismatches in these loci are not allowed. – Peripheral blood stem cells as graft source – No second tumors – No prior history of Thymoglobulin exposure or no history of anaphylactic shock after Thymoglobulin administration – No severe concurrent illness Exclusion Criteria:

  • Moderate or severe cardiac dysfunction, left ventricular ejection fraction <50% – Moderate or severe decrease in pulmonary function, FEV1 <70% or DLCO<70% of predicted – Respiratory distress >grade I – Severe organ dysfunction: AST or ALT >5 upper normal limits, bilirubin >1.5 upper normal limits, creatinine >2 upper normal limits – Creatinine clearance < 60 mL/min – Uncontrolled bacterial or fungal infection at the time of enrollment – Requirement for vasopressor support at the time of enrollment – Karnofsky index <30% – Pregnancy – Somatic or psychiatric disorder making the patient unable to sign informed consent

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • St. Petersburg State Pavlov Medical University
  • Provider of Information About this Clinical Study
    • Principal Investigator: Ivan S Moiseev, Head of adolescent and adult department of oncology, heamatology and transplantation – St. Petersburg State Pavlov Medical University
  • Overall Official(s)
    • Boris V. Afanasyev, Professor, Principal Investigator, First Pavlov State Medical University of St. Petersburg

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