Clinical trial NCT04832607: Multivirus-specific T-cell Transfer Post SCT vs AdV, CMV and EBV Infections
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: AdV Infection
EBV Infection
CMV Infection
Stem Cell Transplant Complications
Lead sponsor: LMU Klinikum
Sponsor class: OTHER
Collaborators: name: European Commission
name: Simbec-Orion Group Ltd, Merthyr Tydfil, UK
name: Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany
name: Leiden University Medical Center, LUMC, Leiden, The Netherlands
name: Central Hospital, Nancy, France
name: Ghent University Hospital, UZG, Ghent, Belgium
name: Ospedale Pediatrico Bambino Gesù, OPBG, Rome, Italy
name: Newcastle University, UNEW, Newcastle, UK
name: Vall d'Hebron Institute of Oncology
First posted: 2021-04-06
Enrollment: 149
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 2 (verum): 1 (Placebo) randomization
Primary purpose: TREATMENT

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.

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.

Eligibility 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 (=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.

Primary outcomes:
measure: Viral clearance
timeFrame: 8 weeks after treatment
measure: Disease Progression
timeFrame: day 7 until week 8 after treatment
Secondary outcomes:
measure: Incidence of acute GvHD
timeFrame: 15 weeks after treatment
measure: Incidence of chronic GvHD
timeFrame: 15 weeks after treatment
measure: Time to newly occuring GvHD
timeFrame: 15 weeks after treatment
measure: Severity of GvHD
timeFrame: week 8 and 15 week after treatment
measure: Incidence of acute toxicity
timeFrame: 15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer
measure: Severity of acute toxicity
timeFrame: 15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer
measure: Change in viral load of underlying viral infection
timeFrame: 8 weeks after treatment
measure: Time to viral load change of underlying viral infection
timeFrame: 15 weeks after treatment
measure: Percentage of viral decrease
timeFrame: 8 weeks after treatment
measure: Viral reactivations
timeFrame: 15 weeks after treatment
measure: Clinical response/resolution of symptoms of underlying viral infection
timeFrame: 8 weeks after treatment
measure: Overall survival
timeFrame: 15 weeks after treatment
measure: Necessity of antiviral chemotherapy
timeFrame: Day 7 until Week 8
measure: Duration of antiviral chemotherapy
timeFrame: 8 weeks after treatment
measure: Incidence of viral infections other than underlying viral infection
timeFrame: 15 weeks
measure: Days of hospitalization
timeFrame: 8 weeks
measure: Life quality in adults
timeFrame: Screening and Week 8.
measure: Life quality in adults
timeFrame: Screening and Week 8
measure: Life quality in children
timeFrame: Screening and Week 8
measure: Effect on the patient's T-cell phenotype in vivo
timeFrame: Screening until Week 15
measure: Effect on the patient's number of expanded T cells
timeFrame: Screening until Week 15
measure: Quality of the IMP and performance of the CliniMACS® Prodigy
timeFrame: Before IMP release (between Screening and Day 0)
measure: Evaluation of the drop-out rate
timeFrame: at Day 0 (planned treatment day)
measure: Time from inclusion to administration of the IMP
timeFrame: Screening until Day 0 (treatment day)
measure: Adverse events
timeFrame: 15 weeks
measure: Physical examination
timeFrame: Screening to Week 8
measure: Vital Sign - blood pressure
timeFrame: Screening to Week 8
measure: Vital Signs - heart rate
timeFrame: Screening to Week 8
measure: Vital Signs - body temperature
timeFrame: Screening to Week 8
measure: Vital Signs - body weight
timeFrame: Screening to Week 8
measure: Vital Signs - respiratory rate
timeFrame: Screening to Week 8
measure: Incidence of abnormal laboratory values
timeFrame: Screening to Week 8
measure: Concomitant medication until Week 8
timeFrame: 8 weeks after treatment
measure: Concomitant medication until Week 15
timeFrame: 15 weeks after treatment
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Institut Jules Bordet (JBI)
city: Brussels
country: Belgium
facility: UZ Brussel
city: Ghent
country: Belgium
facility: Ghent Universal Hospital (UZG)
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: Université de Liège (ULG)
city: Lille
country: France
facility: Hôpital Jeanne de Flandre, CHU Lille
city: Lyon
country: France
facility: Institut d'Hématologie et Oncologie Pédiatrique (IHOPe)
city: Nancy
country: France
facility: Centre Hospitalier Régional Universitaire de Nancy (CHRU)
city: Paris
country: France
facility: Hôpital de la Pitie-Salpêtrière
city: Paris
country: France
facility: Hôpital Necker - Enfants Malades
city: Paris
country: France
facility: Hôpital Robert Debré
city: Berlin
country: Germany
facility: Charité Berlin (Campus Virchow-Klinikum) - Klinik für Pädiatrie mit Schwerpunkt Onkologie und Hämatologie
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf - Klinik für Kinder-Onkologie, -Hämatologie und klinische Immunologie
city: Essen
country: Germany
facility: Universitätsklinikum Essen - Pädiatrische Hämatologie-Onkologie
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg - Klinik für Pädiatrische Hämatologie und Onkologie
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover - Zentrum für Kinderheilkunde und Jugendmedizin
city: Leipzig
country: Germany
facility: Universitäsklinikum Leipzig - Medizinische Klinik und Poliklinik I
city: Munich
country: Germany
facility: LMU Klinikum - Dr. v. Haunersches Kinderspital
city: Munich
country: Germany
facility: Klinikum rechts der Isar der Technischen Universität - Kinderklinik Schwabing
city: München
country: Germany
facility: LMU Klinikum - Medizinische Klinik und Poliklinik III
city: München
country: Germany
facility: Klinikum rechts der Isar der Technischen Universität - Klinik und Poliklinik für Innere Medizin III
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg - Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen, Center for Pediatric Clinical Studies (CPCS)
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg - Medizinische Klinik und Poliklinik II & Zentrum Innere Medizin (ZIM)
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg - Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation
city: Rom
country: Italy
facility: Ospedale Pediatrico Bambino Gesù (OPBG)
city: Turin
country: Italy
facility: Ospedale Infantile Regina Margherita - Oncoematologie Pediatrica
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre (LUMC) - Department of Hematology
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology (VHIO)
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Universitario Politécnico La Fe
Study officials:
affiliation: Klinikum der Universität München
name: Tobias Feuchtinger, Prof
role: PRINCIPAL_INVESTIGATOR
References: