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Trial record 1 of 1 for:    2018-000853-29
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Multivirus-specific T-cell Transfer Post SCT vs AdV, CMV and EBV Infections (TRACE)

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ClinicalTrials.gov Identifier: NCT04832607
Recruitment Status : Recruiting
First Posted : April 6, 2021
Last Update Posted : June 15, 2021
Sponsor:
Collaborators:
European Commission
Simbec Orion
Miltenyi Biotec B.V. & Co. KG
Leiden University Medical Center
Central Hospital, Nancy, France
University Hospital, Ghent
Bambino Gesù Hospital and Research Institute
University of Newcastle Upon-Tyne
Information provided by (Responsible Party):
Prof. Tobias Feuchtinger, LMU Klinikum

Brief Summary:
Haematopoietic stem cell transplantation (HSCT) can expose patients to a transient but marked immunosuppression, during which viral infections are an important cause of morbidity and mortality. Adoptive transfer of virus-specific T cells is an attractive approach to restore protective T-cell immunity in patients with refractory viral infections after allogeneic HSCT. The aim of this Phase III trial is to confirm efficacy of this treatment in children and adults.

Condition or disease Intervention/treatment Phase
AdV Infection EBV Infection CMV Infection Stem Cell Transplant Complications Other: Multivirus (CMV, EBV, AdV)-specific T cells Phase 3

Detailed Description:

For a growing number of patients suffering from various conditions as, e.g., haematological malignancies or diverse genetic disorders, haematopoietic stem cell transplantation (HSCT) or bone marrow transplantation offer the only possible curative options. However, HSCT is associated with three major risks: graft rejection, graft-versus-host disease (GvHD) and opportunistic, mostly viral, infections or reactivations resulting from delayed immune reconstitution. Delayed immune reconstitution, however, often is the direct result of the severe pre-transplantation conditioning treatment and T-cell depletion of the transplant necessary to fight the risks of graft rejection and GvHD. Therefore, the risk for life-threatening opportunistic, mostly viral, infections is increased in post-transplantation patients. The most common infections after HSCT are Cytomegalovirus (CMV), Epstein-Barr virus (EBV) and Adenovirus (AdV).

The standard treatment approach for viral infections/reactivations is chemotherapy which shows limited efficacy and does not restore immunity. Therefore, effective new treatment options are required for this condition.

Previous investigations have shown that sufficient T-cell immunity is essential for the control and prevention of viral reactivations and newly occurring infections after HSCT. The infusion of T-cells is therefore a promising new approach to treat immune-comprised patients. However, infusion with unselected T cells is associated with an increased risk for GvHD due to the high content of alloreactive T cells. A very promising approach to minimize this problem is to remove alloreactive T cells and enrich, isolate and purify virus-specific T cells.

This approach has been studied for nearly two decades and the data published up to date indicate that virus-specific T-cell responses after adoptive T-cell transfer protect against virus-related complications post HSCT and restore T-cell immunity, in particular for AdV-, CMV- and EBV-infections. Despite these promising results, virus-specific T-cell transfer is not yet translated into daily clinical practice due to the lack of prospective clinical trials confirming the efficacy of this treatment approach.

The overall goal of this Phase III, double-blind placebo-controlled study is to test efficacy of multivirus-specific T cells to bring this treatment method in clinical routine. Multivirus-specific T cells generated in this study will be directed against all three most common post-HSCT viral infections: AdV, CMV and EBV. Thus, T-cell immunity will be restored to fight and prevent new viral infections.

After an initial screening visit, patients eligible to participate in the study will be treated within 28 days after screening. Patients will be randomized in a 2:1 (treatment: placebo) ratio and receive a single infusion with either multivirus-specific T cells or placebo. Patients will be followed up on the day of treatment, 1 day after and 1, 2, 4, 8 and 15 weeks after treatment. Treatment success will be measured by assessing different parameters including symptoms, quality of life, viral load and T-cell immunity in blood samples.

Patients eligible to participate in this study are adult and paediatric patients who have received allogeneic stem cell transplantation and suffer from new or reactivated EBV, AdV or CMV infection refractory to standard antiviral treatment for two weeks. Patients from the six European countries Germany, Belgium, Netherlands, UK, France and Italy will be enrolled. In total 130 patients plus 19 screening failures are expected to participate in the study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 149 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 2 (verum): 1 (Placebo) randomization
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Randomization will be stratified with respect to three age groups: Children up to 6 years, children >6 and up to 18 years, and adults >18 years. Accordingly, for each stratum, a separate randomization list will be provided. Randomization will be performed by a representative of the Simbec-Orion Group who will be independent in the sense that he / she will otherwise not be involved in the TRACE trial.
Primary Purpose: Treatment
Official Title: Treatment of Chemo-refractory Viral Infections After Allogeneic Stem Cell Transplantation With Multispecific T Cells Against CMV, EBV and AdV: A Phase III, Prospective, Multicentre Clinical Trial
Actual Study Start Date : August 27, 2019
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Multivirus (CMV, EBV, AdV)-specific T cells

Allogeneic CD4+ and CD8+ T lymphocytes ex vivo incubated with synthetic peptides of the viral antigens of Cytomegalovirus, Adenovirus and Epstein-Barr Virus

Max dose:

  • HLA-matched (8/8) donors: 1.0 x 10e5 T cells/kg recipient BW
  • HLA-mismatched donors: 2.5 x 10e4 T cells/kg recipient BW

Min. dose:

- 10 T cells/kg recipient BW

Other: Multivirus (CMV, EBV, AdV)-specific T cells
Cell therapy product which is individually produced for each patient and administered via IV bolus injection.

Placebo Comparator: Sodium chloride
Suspension of multivirus-specific T cells in 20 mL of 0.9% NaCl + 0.5% HSA
Other: Multivirus (CMV, EBV, AdV)-specific T cells
Cell therapy product which is individually produced for each patient and administered via IV bolus injection.




Primary Outcome Measures :
  1. Viral clearance [ Time Frame: 8 weeks after treatment ]
    Percentage of patients with viral clearance (defined as two consecutive negative PCRs) to determine efficacy of multispecific T-cell transfer in patients with chemo-refractory viral infections after allogeneic stem cell transplantation

  2. Disease Progression [ Time Frame: day 7 until week 8 after treatment ]
    Percentage of patients with progression between Day 7 and Week 8 after T-cell Transfer to determine efficacy of multispecific T-cell transfer in patients with chemo-refractory viral infections after allogeneic stem cell transplantation


Secondary Outcome Measures :
  1. Incidence of acute GvHD [ Time Frame: 15 weeks after treatment ]
    Incidence of newly occurring acute GvHD grade I from Day 0 to Week 8 and Week 15.

  2. Incidence of chronic GvHD [ Time Frame: 15 weeks after treatment ]
    Incidence of chronic GvHD from Day 7 to Week 8 and to Week 15 after treatment.

  3. Time to newly occuring GvHD [ Time Frame: 15 weeks after treatment ]
    Time to newly occurring acute and chronic GvHD.

  4. Severity of GvHD [ Time Frame: week 8 and 15 week after treatment ]
    Severity of acute GvHD ≥ grade II until Week 8 and Week 15.

  5. Incidence of acute toxicity [ Time Frame: 15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer ]
    Acute maximum toxicity on the day of T-cell transfer evaluated by measuring vital signs prior to and at different times after the T-cell transfer from 1 hour prior to T-cell transfer to 4 hours post infusion.

  6. Severity of acute toxicity [ Time Frame: 15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer ]
    Monitoring of adverse events infusion.

  7. Change in viral load of underlying viral infection [ Time Frame: 8 weeks after treatment ]
    Change in viral load of underlying viral infection as assessed by quantitative PCR analysis of peripheral blood; samples taken weekly from Day 7 to Week 8 after T-cell transfer as compared to samples taken at Day 0.

  8. Time to viral load change of underlying viral infection [ Time Frame: 15 weeks after treatment ]
    Time to 1 log change in viral load.

  9. Percentage of viral decrease [ Time Frame: 8 weeks after treatment ]
    Percentage of patients with ≥1 log decrease in CMV, EBV or AdV viral load at Week 8.

  10. Viral reactivations [ Time Frame: 15 weeks after treatment ]
    Number of reactivations of the underlying viral infection following initial viral clearance until end of follow-up.

  11. Clinical response/resolution of symptoms of underlying viral infection [ Time Frame: 8 weeks after treatment ]
    Number of patients with reduction or clearance of clinical symptoms of underlyingviral infection from Day 7 to Week 8 after T-cell transfer as compared to Day 0.

  12. Overall survival [ Time Frame: 15 weeks after treatment ]
    Overall survival rate (OS): From Day 0 to end of follow-up.

  13. Necessity of antiviral chemotherapy [ Time Frame: Day 7 until Week 8 ]
    Number of days requiring antiviral chemotherapy after T-cell transfer from Day 7 to Week 8 after T-cell transfer.

  14. Duration of antiviral chemotherapy [ Time Frame: 8 weeks after treatment ]
    Time to last administration of defined antiviral medication or switch to prophylactic treatment from Day 0 to Week 8 after T-cell transfer.

  15. Incidence of viral infections other than underlying viral infection [ Time Frame: 15 weeks ]
    Number of new viral reactivations (CMV, AdV or EBV) other than the underlying viral infection per patient as assessed by PCR analysis and clinical symptoms throughout the study to evaluate the putative prophylactic effect of the treatment.

  16. Days of hospitalization [ Time Frame: 8 weeks ]
    Number of days hospitalized after T-cell transfer from Day 7 to Week 8.

  17. Life quality in adults [ Time Frame: Screening and Week 8. ]
    EQ-5D for adult patients (≥18 years) at Screening and Week 8 to evaluate life quality in adults. A scale from 0 to 100 is used with 100 being best value and 0 the worst.

  18. Life quality in adults [ Time Frame: Screening and Week 8 ]

    FACT-BMT for adult patients (≥18 years) at Screening and Week 8 to evaluate life quality in adults.

    The patients have to answer questions about their physicial, social, emotional and functional wellbeing. A scale from 0 to 4 is used with 0= not at all, 1= a little bit, 2=somewhat, 3=quite a bit, 4=very much.


  19. Life quality in children [ Time Frame: Screening and Week 8 ]

    PEDS-QL for paediatric patients (<18 years) at Screening and Week 8 to evaluate life quality in children.

    The patients and /or their parents have to answer questions about pain and hurt, fatigue and sleep, nausea, worry, Nutrition, thinking and communication.

    A scale from 0 to 4 is used with 0=never a Problem, 1=almost never a problem, 2= sometimes a problem, 3=often a problem, 4= almost always a problem.


  20. Effect on the patient's T-cell phenotype in vivo [ Time Frame: Screening until Week 15 ]
    T-cell phenotyping, samples taken at Screening, Day 0 and each visit from Day 7 to Week 15 after treatment.

  21. Effect on the patient's number of expanded T cells [ Time Frame: Screening until Week 15 ]
    Analysis of virus-specific T cells: number of in vivo expanded virus-specific T cells in peripheral blood samples taken at Screening, Day 0, Day 7 to Week 15 after treatment.

  22. Quality of the IMP and performance of the CliniMACS® Prodigy [ Time Frame: Before IMP release (between Screening and Day 0) ]
    Assessment of the number of viable CD3+ cells.

  23. Quality of the IMP and performance of the CliniMACS® Prodigy [ Time Frame: Before IMP release (between Screening and Day 0) ]
    Assessment of the cellular composition, in particular the percentage of IFN-gamma+ cells, in the IMP.

  24. Evaluation of the drop-out rate [ Time Frame: at Day 0 (planned treatment day) ]
    Drop-out rate at Day 0 and reasons for drop-out.

  25. Time from inclusion to administration of the IMP [ Time Frame: Screening until Day 0 (treatment day) ]
    Number of days from Screening to Day 0 (day of T-cell transfer) to evaluate the required time frame.

  26. Adverse events [ Time Frame: 15 weeks ]
    Documentation of incidence, severity and type of adverse events from Day 0 to Week 8 and serious adverse events throughout the study to evaluate safety.

  27. Physical examination [ Time Frame: Screening to Week 8 ]
    Physical examinations will be conducted to identify possible clinically significant pathologies. These findings will be recorded at each visit. The Karnofsky/Lansky index will be included in the physical examination at Screening and at Week 8 only.

  28. Vital Sign - blood pressure [ Time Frame: Screening to Week 8 ]
    supine systolic and diastolic blood preasure in mm Hg

  29. Vital Signs - heart rate [ Time Frame: Screening to Week 8 ]
    The resting heart rate in beats/min

  30. Vital Signs - body temperature [ Time Frame: Screening to Week 8 ]
    Body temperature in °C (aural), body weight in kg, respiratory rate in breaths/min.

  31. Vital Signs - body temperature [ Time Frame: Screening to Week 8 ]
    Body temperature in °C (aural)

  32. Vital Signs - body weight [ Time Frame: Screening to Week 8 ]
    body weight in kg

  33. Vital Signs - respiratory rate [ Time Frame: Screening to Week 8 ]
    respiratory rate in breaths/min.

  34. Incidence of abnormal laboratory values [ Time Frame: Screening to Week 8 ]

    haemoglobin, leukocytes, thrombocytes, dirfferential blood count (neutrophil granulocytes, lymphocytes, monocytes and easinophil granulocytes), total and conjugated Bilirubin, C reactive Protein (CRP), creatinine, Alanin aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma glutamyl Transferase (GGT), Lactate Dehydrase (LDH), Urea.

    A list of normal ranges will be provided from each site.


  35. Concomitant medication until Week 8 [ Time Frame: 8 weeks after treatment ]
    All concomitant medication will be recorded from Screening until Week 8. The generic name, indication, route of administration, dose/ unit, start and stop date or ongoing, way of application will be documented.

  36. Concomitant medication until Week 15 [ Time Frame: 15 weeks after treatment ]

    During follow-up Week 15, only antiviral therapy, immunosuppression and SAE-related concomitant medication as well as chemotherapy will be documented.

    The generic name, indication, route of administration, dose/ unit, start and stop date or ongoing, way of application will be documented.

    Cellular treatment also has to be documented as concomitant medication.




Information from the National Library of Medicine

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Ages Eligible for Study:   2 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult or paediatric patients (> 2 months of age) after allogeneic stem cell transplantation (SCT) (no time restrictions apply) suffering from new or reactivated CMV or EBV or AdV infection refractory to standard antiviral treatment for two weeks (defined as no decrease or insignificant decrease of less than 1log in viral load over two weeks) as confirmed by quantitative blood PCR analysis.
  2. Original HSCT-donor available with an immune response at least to the virus causing the therapy-refractory infection.
  3. Written informed consent given (patient or legal representative) prior to any study-related procedures.

Exclusion Criteria:

  1. Patient with acute GvHD > grade II or extensive chronic GvHD at the time of T-cell transfer
  2. Patient receiving steroids (>1 mg/kg BW Prednisone equivalent) at Screening.
  3. Therapeutic donor lymphocyte infusion (DLI) from 4 weeks prior to IMP infusion until 8 weeks post IMP infusion. Prescheduled prophylactic DLI ≤3x105 T cells/kg BW in case of T-cell depleted HSCT is not considered an exclusion criterion.
  4. Patient with organ dysfunction or failure as determined by Karnofsky (patients >16 years) or Lansky (patients ≤16 years) score ≤30%
  5. Concomitant enrolment in another clinical trial interfering with the endpoints of this study
  6. Any medical condition which could compromise participation in the study according to the investigator's assessment
  7. Progression of underlying disease (disease that has led to the indication of HSCT, e.g. leukaemia) that will limit the life expectance below the duration of the study
  8. Second line or experimental antiviral treatment other than Ganciclovir/Valganciclovir, Foscarnet, Cidofovir and Rituximab until 8 weeks after IMP study.
  9. Known HIV infection. In case patients do not have a negative HIV test performed within 6 months before enrolment in the study, HIV negativity has to be confirmed by a negative laboratory test.
  10. Female patient who is pregnant or breast-feeding. Female patient of child-bearing potential (i.e. post menarche and not surgically sterilized) or male patient of reproductive potential not willing to use an effective method of birth control from Screening until the last follow-up visit (FU6, Visit 8).

    Note: Women of childbearing potential must have a negative serum pregnancy test at study entry ≤7 days before IMP administration on Day 0. Acceptable birth control methods are hormonal oral contraceptive ('pill'), contraceptive injection or patch, intrauterine pessar or the combination of two barrier methods. The combination of female and male condomes is NOT acceptable. If the male partner is sterilized, no further contraceptive is required. Women of post-menopausal status (no menses for 12 months without an alternative medical cause) are also not required to use contraceptives during the study.

  11. Known hypersensitivity to iron dextran
  12. Patients unwilling or unable to comply with the protocol or unable to give informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04832607


Contacts
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Contact: Tobias Feuchtinger, Prof 0049 (0)89 4400 ext 57945 onkostudien.hauner@med.uni-muenchen.de
Contact: Theresa Käuferle, Dr 0049 (0)89 4400 ext 52338 info@trace-study.de

Locations
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Belgium
Jules Bordet Institut (JBI) Active, not recruiting
Brussels, Belgium, 1000
Ghent Universal Hospital (UZG) Active, not recruiting
Ghent, Belgium, 9000
Center Hospitalier Universitaire de Liège (CHU) Active, not recruiting
Liège, Belgium, 4000
Germany
Universitätsklinikum Tübingen, Center for Pediatric Clinical Studies (CPCS) Active, not recruiting
Tübingen, Baden-Württemberg, Germany, 72076
Klinikum der Universität München - Medizinische Klinik und Poliklinik III Active, not recruiting
München, Bayern, Germany, 81377
Klinikum rechts der Isar der Technischen Universität Active, not recruiting
München, Bayern, Germany
Universitätsklinikum Würzburg Active, not recruiting
Würzburg, Bayern, Germany, 97080
Medizinische Hochschule Hannover Active, not recruiting
Hannover, Niedersachsen, Germany, 30625
Universitätsklinikum Berlin Recruiting
Berlin, Germany, 13353
Contact: Johannes Schulte, Prof    0049 30450666658    johannes.schulte@charite.de   
Principal Investigator: Johannes Schulte, Prof         
Universitätsklinikum Düsseldorf - Klinik für Kinder-Onkologie, -Hämatologie und klinische Immunologie Recruiting
Düsseldorf, Germany, 40225
Contact: Roland Meisel, Prof       meisel@med.uni-duesseldorf.de   
Principal Investigator: Roland Meisel, Prof         
Klinikum der Universität München - Dr. v. Haunersches Kinderspital Recruiting
Munich, Germany, 80337
Contact: Tobias Feuchtinger, Prof    0049894400 ext 57945    info@trace-study.de   
Principal Investigator: Tobias Feuchtinger, Prof         
Netherlands
Leiden University Medical Centre (LUMC) Recruiting
Leiden, ZA, Netherlands, 2333
Contact: Peter van Balen, Dr    003171526 ext 2267    P.van_Balen@lumc.nl   
Principal Investigator: Peter van Balen, Dr         
Sponsors and Collaborators
Prof. Tobias Feuchtinger
European Commission
Simbec Orion
Miltenyi Biotec B.V. & Co. KG
Leiden University Medical Center
Central Hospital, Nancy, France
University Hospital, Ghent
Bambino Gesù Hospital and Research Institute
University of Newcastle Upon-Tyne
Investigators
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Principal Investigator: Tobias Feuchtinger, Prof Klinikum der Universität München
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Responsible Party: Prof. Tobias Feuchtinger, Prof. Dr. med Tobias Feuchtinger, LMU Klinikum
ClinicalTrials.gov Identifier: NCT04832607    
Other Study ID Numbers: TRACE
2018-000853-29 ( EudraCT Number )
DRKS00018985 ( Other Identifier: Deutsches Register Klinischer Studien )
First Posted: April 6, 2021    Key Record Dates
Last Update Posted: June 15, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Infection
Communicable Diseases
Cytomegalovirus Infections
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections