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JOURNAL ONKOLOGIE – STUDIE
TRACE

Multivirus-specific T-cell Transfer Post SCT vs AdV, CMV and EBV Infections

Rekrutierend

NCT-Nummer:
NCT04832607

Studienbeginn:
August 2019

Letztes Update:
04.10.2023

Wirkstoff:
-

Indikation (Clinical Trials):
Infections, Communicable Diseases, Cytomegalovirus Infections, Epstein-Barr Virus Infections

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
Phase 3

Sponsor:
Prof. Tobias Feuchtinger

Collaborator:
European Commission, Simbec-Orion Group Ltd, Merthyr Tydfil, UK, Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany, Leiden University Medical Center, LUMC, Leiden, The Netherlands, Centre Hospitalier Universitaire de Nancy, CHU, Vandoeuvre-Lès-Nancy,

Studienleiter

Tobias Feuchtinger, Prof
Principal Investigator
Klinikum der Universität München

Kontakt

Tobias Feuchtinger, Prof
Kontakt:
Phone: 0049 (0)89 4400
Phone (ext.): 57945
E-Mail: onkostudien.hauner@med.uni-muenchen.de» Kontaktdaten anzeigen

Studienlocations
(3 von 33)

Charité Berlin (Campus Virchow-Klinikum) - Klinik für Pädiatrie mit Schwerpunkt Onkologie und Hämatologie
13353 Berlin
(Berlin)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Johannes Schulte, Prof.
E-Mail: johannes.schulte@charite.de» Ansprechpartner anzeigen
Universitätsklinikum Düsseldorf - Klinik für Kinder-Onkologie, -Hämatologie und klinische Immunologie
40225 Düsseldorf
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Roland Meisel, Prof.
E-Mail: meisel@med.uni-duesseldorf.de» Ansprechpartner anzeigen
Universitätsklinikum Essen - Pädiatrische Hämatologie-Onkologie
45147 Essen
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Stefan Schönberger, Dr.
E-Mail: Stefan.Schoenberger@uk-essen.de» Ansprechpartner anzeigen
Universitätsklinikum Freiburg - Klinik für Pädiatrische Hämatologie und Onkologie
79106 Freiburg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Brigitte Strahm, PD Dr.
E-Mail: brigitte-strahm@uniklinik-freiburg.de» Ansprechpartner anzeigen
Medizinische Hochschule Hannover - Zentrum für Kinderheilkunde und Jugendmedizin
30625 Hannover
(Niedersachsen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Britta Maecker-Kolhoff, Prof.
E-Mail: Maecker.Britta@MH-Hannover.de» Ansprechpartner anzeigen
Universitäsklinikum Leipzig - Medizinische Klinik und Poliklinik I
04103 Leipzig
(Sachsen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Vladan Vucinic, Dr.
E-Mail: Vladan.Vucinic@medizin.uni-leipzig.de» Ansprechpartner anzeigen
Klinikum rechts der Isar der Technischen Universität - Kinderklinik Schwabing
80804 Munich
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Irene Teichert von Lüttichau, PD Dr.
E-Mail: Irene.Teichert-vonluettichau@mri.tum.de» Ansprechpartner anzeigen
LMU Klinikum - Medizinische Klinik und Poliklinik III
81377 München
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Johanna Tischer, Dr.
E-Mail: johanna.tischer@med.uni-muenchen.de» Ansprechpartner anzeigen
Klinikum rechts der Isar der Technischen Universität - Klinik und Poliklinik für Innere Medizin III
81675 München
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Mareike Verbeek, Dr.
E-Mail: Mareike.Verbeek@tum.de» Ansprechpartner anzeigen
Universitätsklinikum Regensburg - Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation
93053 Regensburg
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Jürgen Föll, Prof.
E-Mail: juergen.foell@klinik.uni-regensburg.de» Ansprechpartner anzeigen
Universitätsklinikum Tübingen, Center for Pediatric Clinical Studies (CPCS)
72076 Tübingen
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Peter Lang, Prof.
E-Mail: peter.lang@med.uni-tuebingen.de» Ansprechpartner anzeigen
Universitätsklinikum Würzburg - Medizinische Klinik und Poliklinik II & Zentrum Innere Medizin (ZIM)
97080 Würzburg
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Hermann Einsele, Prof.
E-Mail: einsele_h@klinik.uni-wuerzburg.de» Ansprechpartner anzeigen
Universitätsklinikum Würzburg - Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation
97080 Würzburg
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Matthias Wölfl, Prof.
E-Mail: Woelfl_M@kw.de» Ansprechpartner anzeigen
Vall d'Hebron Institute of Oncology (VHIO)
119-129 Barcelona
SpainRekrutierend» Google-Maps
Ansprechpartner:
Pere Barba, Dr.
E-Mail: pbarba@vhio.net

María Laura Fox, Dr.
E-Mail: mlfox@vhio.net» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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 (=underlying) 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 IMP

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 Infusion or prophylactic

Treatment other than Aciclovir or Letermovir throughout the study except approved by

sponsor

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.

Studien-Rationale

Primary outcome:

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:

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 IMP 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 IMP 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 IMP 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 IMP 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: frequencies 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 cellular composition, in particular the percentage of IFN-gamma+ cells, in the IMP.

23. 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.

24. 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 IMP transfer) to evaluate the required time frame.

25. 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.

26. 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.

27. Vital Sign - blood pressure (Time Frame - Screening to Week 8):
supine systolic and diastolic blood preasure in mm Hg

28. Vital Signs - heart rate (Time Frame - Screening to Week 8):
The resting heart rate in beats/min

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

30. Vital Signs - body weight (Time Frame - Screening to Week 8):
body weight in kg

31. Vital Signs - respiratory rate (Time Frame - Screening to Week 8):
respiratory rate in breaths/min.

32. 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.

33. 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.

34. 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.

Studien-Arme

  • 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
  • Placebo Comparator: Sodium chloride
    Suspension of multivirus-specific T cells in 20 mL of 0.9% NaCl + 0.5% HSA

Geprüfte Regime

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

Quelle: ClinicalTrials.gov


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