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

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

Sponsors

Lead Sponsor: Prof. Tobias Feuchtinger

Collaborator: 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

Source Klinikum der Universitaet Muenchen
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.

Overall Status Recruiting
Start Date 2019-08-27
Completion Date 2022-12-01
Primary Completion Date 2022-05-01
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Viral clearance 8 weeks after treatment
Disease Progression day 7 until week 8 after treatment
Secondary Outcome
Measure Time Frame
Incidence of acute GvHD 15 weeks after treatment
Incidence of chronic GvHD 15 weeks after treatment
Time to newly occuring GvHD 15 weeks after treatment
Severity of GvHD week 8 and 15 week after treatment
Incidence of acute toxicity 15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer
Severity of acute toxicity 15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer
Change in viral load of underlying viral infection 8 weeks after treatment
Time to viral load change of underlying viral infection 15 weeks after treatment
Percentage of viral decrease 8 weeks after treatment
Viral reactivations 15 weeks after treatment
Clinical response/resolution of symptoms of underlying viral infection 8 weeks after treatment
Overall survival 15 weeks after treatment
Necessity of antiviral chemotherapy Day 7 until Week 8
Duration of antiviral chemotherapy 8 weeks after treatment
Incidence of viral infections other than underlying viral infection 15 weeks
Days of hospitalization 8 weeks
Life quality in adults Screening and Week 8.
Life quality in adults Screening and Week 8
Life quality in children Screening and Week 8
Effect on the patient's T-cell phenotype in vivo Screening until Week 15
Effect on the patient's number of expanded T cells Screening until Week 15
Quality of the IMP and performance of the CliniMACS® Prodigy Before IMP release (between Screening and Day 0)
Quality of the IMP and performance of the CliniMACS® Prodigy Before IMP release (between Screening and Day 0)
Evaluation of the drop-out rate at Day 0 (planned treatment day)
Time from inclusion to administration of the IMP Screening until Day 0 (treatment day)
Adverse events 15 weeks
Physical examination Screening to Week 8
Vital Sign - blood pressure Screening to Week 8
Vital Signs - heart rate Screening to Week 8
Vital Signs - body temperature Screening to Week 8
Vital Signs - body temperature Screening to Week 8
Vital Signs - body weight Screening to Week 8
Vital Signs - respiratory rate Screening to Week 8
Incidence of abnormal laboratory values Screening to Week 8
Concomitant medication until Week 8 8 weeks after treatment
Concomitant medication until Week 15 15 weeks after treatment
Enrollment 149
Condition
Intervention

Intervention Type: Other

Intervention Name: Multivirus (CMV, EBV, AdV)-specific T cells

Description: Cell therapy product which is individually produced for each patient and administered via IV bolus injection.

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 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.

Gender:

All

Minimum Age:

2 Months

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Tobias Feuchtinger, Prof Principal Investigator Klinikum der Universität München
Overall Contact

Last Name: Tobias Feuchtinger, Prof

Phone: 0049 (0)89 4400

Phone Ext.: 57945

Email: [email protected]

Location
Facility: Status:
Jules Bordet Institut (JBI) | Brussels, 1000, Belgium Active, not recruiting
Ghent Universal Hospital (UZG) | Ghent, 9000, Belgium Active, not recruiting
Center Hospitalier Universitaire de Liège (CHU) | Liège, 4000, Belgium Active, not recruiting
Universitätsklinikum Tübingen, Center for Pediatric Clinical Studies (CPCS) | Tübingen, Baden-Württemberg, 72076, Germany Active, not recruiting
Klinikum der Universität München - Medizinische Klinik und Poliklinik III | München, Bayern, 81377, Germany Active, not recruiting
Klinikum rechts der Isar der Technischen Universität | München, Bayern, Germany Active, not recruiting
Universitätsklinikum Würzburg | Würzburg, Bayern, 97080, Germany Active, not recruiting
Medizinische Hochschule Hannover | Hannover, Niedersachsen, 30625, Germany Active, not recruiting
Universitätsklinikum Berlin | Berlin, 13353, Germany Recruiting Johannes Schulte, Prof 0049 30450666658 [email protected] Johannes Schulte, Prof Principal Investigator
Universitätsklinikum Düsseldorf - Klinik für Kinder-Onkologie, -Hämatologie und klinische Immunologie | Düsseldorf, 40225, Germany Recruiting Roland Meisel, Prof [email protected] Roland Meisel, Prof Principal Investigator
Klinikum der Universität München - Dr. v. Haunersches Kinderspital | Munich, 80337, Germany Recruiting Tobias Feuchtinger, Prof 0049894400 57945 [email protected] Tobias Feuchtinger, Prof Principal Investigator
Leiden University Medical Centre (LUMC) | Leiden, ZA, 2333, Netherlands Recruiting Peter van Balen, Dr 003171526 2267 [email protected] Peter van Balen, Dr Principal Investigator
Location Countries

Belgium

Germany

Netherlands

Verification Date

2021-06-01

Responsible Party

Type: Sponsor-Investigator

Investigator Affiliation: Klinikum der Universitaet Muenchen

Investigator Full Name: Prof. Tobias Feuchtinger

Investigator Title: Prof. Dr. med Tobias Feuchtinger

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Multivirus (CMV, EBV, AdV)-specific T cells

Type: Experimental

Description: 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

Label: Sodium chloride

Type: Placebo Comparator

Description: Suspension of multivirus-specific T cells in 20 mL of 0.9% NaCl + 0.5% HSA

Acronym TRACE
Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Intervention Model Description: 2 (verum): 1 (Placebo) randomization

Primary Purpose: Treatment

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.

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