GvHD Prophylaxis in Unrelated Donor HCT: Randomized Trial Comparing PTCY Versus ATG (GRAPPA)

Graft vs Host Disease Prophylaxis in Unrelated Donor Transplantation: a Randomized Clinical Trial Comparing PTCY vs ATG (GRAPPA)

Post-transplantation cyclophosphamide (PTCY) has become increasingly popular in the haploidentical HCT setting because it overcomes the HLA-mismatch barrier and levels GVHD risk. This advantage may also prove useful in the context of unrelated donor (UD) transplantation. GVHD prophylaxis for matched unrelated donor hematopoietic cell transplantation (alloHCT) in Europe is mainly conducted with ATG. Still, the burden of acute and chronic GVHD and especially of relapse remains high with both approaches for GVHD prevention.

PTCY has not been tested against the current standard ATG for GvHD prophylaxis in large randomized trials. The goal of this trial is to compare the outcomes of PTCY and ATG for patients receiving unrelated donor PBSCT. PTCY-based prophylaxis promises to have beneficial net effects on immune reconstitution, GVHD and disease control, and thus might impact on patient survival.

Study Overview

• Status: Recruiting
• Conditions: AML; MDS; Peripheral Blood Stem Cell Transplantation; Graft Vs Host Disease; CMML; MDS/MPN
• Intervention / Treatment: Drug: Cyclophosphamide; Biological: ATG

• Study Type: Interventional
• Enrollment (Estimated): 540
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sarah Trost, MSc; Phone Number: 28 +49 351 210 798; Email: grappa@dkms.de

Study Locations

• Germany
  • Aachen, Germany, 52074
    • Recruiting
    • Uniklinik RWTH Aachen
    • Principal Investigator: Edgar Jost, Prof Dr med
  • Augsburg, Germany, 86156
    • Recruiting
    • Univeristätsklinikum Augsburg
    • Principal Investigator: Christoph Schmid, Prof Dr med
  • Chemnitz, Germany, 09113
    • Recruiting
    • Klinikum Chemnitz gGMbH
    • Principal Investigator: Mathias Hänel, PD Dr med habil
  • Dortmund, Germany, 44137
    • Recruiting
    • St.-Johannes-Hospital Dortmund
    • Principal Investigator: Ralf Meyer, PD Dr med
  • Dresden, Germany, 01307
    • Recruiting
    • Universitätsklinikum Dresden
    • Principal Investigator: Johannes Schetelig, Prof Dr med
  • Düsseldorf, Germany, 40225
    • Not yet recruiting
    • Uniklinikum Düsseldorf
    • Principal Investigator: Guido Kobbe, Prof Dr med
  • Essen, Germany, 45147
    • Recruiting
    • Universitätsklinikum Essen (AöR)
    • Principal Investigator: Thomas Schröder, PD Dr med
  • Frankfurt am Main, Germany, 60595
    • Recruiting
    • Universitätsklinikum Frankfurt
    • Principal Investigator: Gesine Bug, Dr med
  • Halle, Germany, 06120
    • Recruiting
    • Universitätsklinikum Halle (Saale)
    • Principal Investigator: Lutz Peter Müller, PD Dr med
  • Homburg, Germany, 66421
    • Recruiting
    • Universitätsklinikum des Saarlandes
    • Principal Investigator: Lorenz Thurner, PD Dr med
  • Jena, Germany, 07747
    • Recruiting
    • Universitätsklinikum Jena
    • Principal Investigator: Inken Hilgendorf, PD Dr med
  • Kiel, Germany, 24105
    • Recruiting
    • Universitätsklinikum Schleswig-Holstein
    • Principal Investigator: Friedrich Stölzel, Prof Dr med
  • Köln, Germany, 50937
    • Recruiting
    • Universitätsklinikum Köln
    • Principal Investigator: Udo Holtick, PD Dr med
  • Lübeck, Germany, 23538
    • Recruiting
    • Universitätsklinikum Schleswig-Holstein
    • Principal Investigator: Friederike Wortmann, Dr med
  • Mainz, Germany, 55131
    • Recruiting
    • Universitätsmedizin Mainz
    • Principal Investigator: Eva Maria Wagner-Drouet, Dr med
  • Mannheim, Germany, 68167
    • Recruiting
    • Universitätsmedizin Mannheim
    • Principal Investigator: Stefan Klein, PD Dr med
  • Marburg, Germany, 35043
    • Recruiting
    • Philipps Universität Marburg
    • Principal Investigator: Andreas Burchert, Prof Dr med
  • Münster, Germany, 48149
    • Recruiting
    • Universitätsklinikum Münster
    • Principal Investigator: Matthias Stelljes, Prof Dr med
  • Nürnberg, Germany, 90419
    • Recruiting
    • Klinikum Nürnberg Nord
    • Principal Investigator: Kerstin Schäfer-Eckart, Dr med
  • Rostock, Germany, 18057
    • Recruiting
    • Universitatsmedizin Rostock
    • Principal Investigator: Christian Junghanß, Prof Dr med
  • Stuttgart, Germany, 70376
    • Recruiting
    • Robert-Bosch-Krankenhaus
    • Principal Investigator: Martin Kaufmann, Dr med
  • Tübingen, Germany, 72076
    • Recruiting
    • Universitatsklinikum Tubingen
    • Principal Investigator: Wolfgang Bethge, Prof Dr med
  • Würzburg, Germany, 97080
    • Recruiting
    • Universitätsklinikum Würzburg
    • Principal Investigator: Jochen Frietsch, Dr med

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed written Informed Consent and able to understand the nature of the trial and the trial related procedures and to comply with them.
• Age ≥ 18 years.
• One of the following eligible diagnoses: AML in CR1 with intermediate or adverse risk genetic abnormalities (according to the ELN 2017 guidelines), or undefined risk. AML of any ELN risk category after hematological or molecular relapse, or with primary refractory disease. AML arising from myelodysplastic syndrome (MDS) or a myeloproliferative neoplasia, except if favourable genetic abnormalities (according to ELN 2017 guidelines) are present. Therapy-related myeloid neoplasia (t-MN), except if favourable genetic abnormalities (according to ELN 2017 guidelines) are present. MDS with intermediate risk, high risk or very high risk disease (according to the IPSS-R Score) regardless of treatment status. MDS/MPN and CMML-1/CMML-2 regardless of treatment status.
• The left ventricular ejection fraction (LVEF) was assessed ≥40% at last echocardiography.
• Transplantation with Peripheral Blood Stem Cells (PBSC) scheduled to be performed 4 to 14 days after date of randomization.
• The scheduled donor is unrelated to the patient, and matched or partially matched (with not more than one allele or antigen mismatch) at HLA-A, -B, -C, or -DRB1.
• Absence of pregnancy confirmed by highly sensitive pregnancy test for WOCBP. Test must not date back more than 3 days prior to randomization, or more than 3 days prior to start of conditioning, if it started before randomization.

Exclusion Criteria:

• Anamnestic intravenous or subcutaneous exposure to rabbit immunoglobin-preparations (e.g. Grafalon or Thymoglobulin)
• Known hypersensitivity to ATG-Grafalon or its excipients.
• Known hypersensitivity to cyclophosphamide, its metabolites or excipients.
• Prior allogeneic hematopoietic transplantation.
• Patients who receive supplementary continuous oxygen at the time of randomization.
• Symptomatic heart failure (NYHA ≥2) at the time of randomization.
• Uncontrolled viral, bacterial or fungal infection with progression or no clinical improvement at the time of randomization.
• Symptomatic cystitis or known obstruction of urine flow at the time of randomization.
• Breast-feeding women.
• WOCBP and fertile male patients unable or unwilling to follow highly effective contraception methods from enrollment to minimum six months after the last dose of the IMP.
• Simultaneous participation in another interventional clinical trial with an investigational medicinal product.

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: Cyclophosphamide; Cyclophosphamide 50 mg/kg (AIBW) i.v. d+3, d+4 post transplant	Drug: Cyclophosphamide; 50 mg/kg (AIBW) i.v. d+3, d+4 post transplant; Other Names: all brands
Active Comparator: ATG; ATG Grafalon 10 mg/kg i.v. d-3, d-2, d-1 pre-transplant	Biological: ATG; 10 mg/kg i.v. d-3, d-2, d-1 pre-transplant; Other Names: ATG Grafalon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival from HCT	1 year
Relapse- and Immunosuppression-free Survival (RIFS)	1 year after HCT

Secondary Outcome Measures

Outcome Measure	Time Frame
GVHD-and relapse-free survival (GRFS)	1 year
Cumulative incidence of relapse	1 year
Cumulative incidence of non-relapse mortality	1 year
Cumulative incidences of acute and chronic GVHD	180 days and 2 years after HCT
Event-free survival	1 year

Collaborators and Investigators

• Sponsor: DKMS gemeinnützige GmbH
• Investigators: Study Chair: Johannes Schetelig, Prof Dr med, Universitätsklinikum Dresden

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2022
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: November 26, 2021
• First Submitted That Met QC Criteria: December 9, 2021
• First Posted (Actual): December 10, 2021

Study Record Updates

• Last Update Posted (Estimated): December 15, 2023
• Last Update Submitted That Met QC Criteria: December 14, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Graft vs Host Disease; Peripheral Blood Stem Cell Transplantation; Cyclophsophamide; Anti-thymocyte globulin (rabbit)
• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: DKMS-21-01; 2021-000853-17 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No