Trial of GVHD Prophylasxis With PTCy or Thymoglobulin in Unrelated SCT

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

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.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes; Leukemia, Chronic Myeloid; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: Thymoglobulin; Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: Busulfan; Drug: Fludarabine monophosphate; Procedure: Unrelated allogeneic stem cell transplantation

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• Russian Federation
  • Saint-Petersburg, Russian Federation, 197089
    • First Pavlov State Medical University of St. Petersburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Thymoglobulin; Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: Busulfan; Drug: Fludarabine monophosphate; Procedure: Unrelated allogeneic stem cell transplantation
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	Drug: Cyclophosphamide; Drug: Tacrolimus; Drug: Mycophenolate mofetil; Drug: Busulfan; Drug: Fludarabine monophosphate; Procedure: Unrelated allogeneic stem cell transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence of primary graft failure	60 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Non-relapse mortality analysis		365 days
Overall survival analysis		365 days
Event-free survival analysis		365 days
Relapse rate analysis		365 days
Infectious complications, including analysis of severe bacterial, fungal and viral infections incidence		100 days
Incidence of chronic GVHD, moderate and severe (NIH criteria)		365 days
Toxicity (NCI CTCAE 4.03)	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	100 days
Incidence of acute GVHD, grades II-IV		365 days

Collaborators and Investigators

• Sponsor: St. Petersburg State Pavlov Medical University
• Investigators: Principal Investigator: Boris V. Afanasyev, Professor, First Pavlov State Medical University of St. Petersburg

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2015
• Primary Completion (Actual): April 3, 2019
• Study Completion (Actual): April 3, 2019

Study Registration Dates

• First Submitted: December 4, 2015
• First Submitted That Met QC Criteria: December 10, 2015
• First Posted (Estimate): December 11, 2015

Study Record Updates

• Last Update Posted (Actual): April 5, 2019
• Last Update Submitted That Met QC Criteria: April 3, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Immune System Diseases; Cyclophosphamide; Tacrolimus; Thymoglobulin; Myelodysplastic Syndromes; Hematopoietic Stem Cell Transplantation; Fludarabine; Allogeneic Transplantation; Busulfan; Immunosuppressive Agents; Mycophenolate mofetil; Antineoplastic Agents, Alkylating; Myeloablative Agonists; Leukemia, Chronic Myeloid; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Preleukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Tacrolimus; Mycophenolic Acid; Busulfan; Thymoglobulin
• Other Study ID Numbers: 06/15-n

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO