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

Stem Cell Transplant Complications Clinical Trial

— TRACE  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04832607
• Other study ID #: TRACE
• Secondary ID: 2018-000853-29DR
• Status: Recruiting
• Phase: Phase 3
• Start date: August 27, 2019
• Est. completion date: December 2024

Study information

• Verified date: October 2023
• Source: LMU Klinikum
• Contact: Tobias Feuchtinger, Prof
• Phone: 0049 (0)89 4400
• Email: onkostudien.hauner[@]med.uni-muenchen.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 149
• Est. completion date: December 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Months and older

Eligibility

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.

Related Conditions & MeSH terms

• AdV Infection
• CMV Infection
• Communicable Diseases
• Cytomegalovirus Infections
• EBV Infection
• Epstein-Barr Virus Infections
• Infections
• Stem Cell Transplant Complications

Intervention

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

Locations

Country	Name	City	State
Belgium	Institut Jules Bordet (JBI)	Brussels
Belgium	UZ Brussel	Brussels
Belgium	Ghent Universal Hospital (UZG)	Ghent
Belgium	UZ Leuven	Leuven
Belgium	Université de Liège (ULG)	Liège
France	Hôpital Jeanne de Flandre, CHU Lille	Lille
France	Institut d'Hématologie et Oncologie Pédiatrique (IHOPe)	Lyon
France	Centre Hospitalier Régional Universitaire de Nancy (CHRU)	Nancy
France	Hôpital de la Pitie-Salpêtrière	Paris
France	Hôpital Necker - Enfants Malades	Paris
France	Hôpital Robert Debré	Paris
Germany	Charité Berlin (Campus Virchow-Klinikum) - Klinik für Pädiatrie mit Schwerpunkt Onkologie und Hämatologie	Berlin
Germany	Universitätsklinikum Dresden	Dresden
Germany	Universitätsklinikum Düsseldorf - Klinik für Kinder-Onkologie, -Hämatologie und klinische Immunologie	Düsseldorf
Germany	Universitätsklinikum Essen - Pädiatrische Hämatologie-Onkologie	Essen
Germany	Universitätsklinikum Freiburg - Klinik für Pädiatrische Hämatologie und Onkologie	Freiburg
Germany	Medizinische Hochschule Hannover - Zentrum für Kinderheilkunde und Jugendmedizin	Hannover
Germany	Universitäsklinikum Leipzig - Medizinische Klinik und Poliklinik I	Leipzig
Germany	Klinikum rechts der Isar der Technischen Universität - Klinik und Poliklinik für Innere Medizin III	München
Germany	LMU Klinikum - Medizinische Klinik und Poliklinik III	München
Germany	Klinikum rechts der Isar der Technischen Universität - Kinderklinik Schwabing	Munich
Germany	LMU Klinikum - Dr. v. Haunersches Kinderspital	Munich
Germany	Universitätsklinikum Regensburg - Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation	Regensburg
Germany	Universitätsklinikum Tübingen, Center for Pediatric Clinical Studies (CPCS)	Tübingen
Germany	Universitätsklinikum Würzburg - Medizinische Klinik und Poliklinik II & Zentrum Innere Medizin (ZIM)	Würzburg
Germany	Universitätsklinikum Würzburg - Pädiatrische Hämatologie, Onkologie und Stammzelltransplantation	Würzburg
Italy	Ospedale Pediatrico Bambino Gesù (OPBG)	Rom
Italy	Ospedale Infantile Regina Margherita - Oncoematologie Pediatrica	Turin
Netherlands	Leiden University Medical Centre (LUMC) - Department of Hematology	Leiden
Spain	Vall d'Hebron Institute of Oncology (VHIO)	Barcelona
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Virgen del Rocío	Sevilla
Spain	Hospital Universitario Politécnico La Fe	Valencia

Sponsors (10)

Lead Sponsor

Collaborator

Prof. Tobias Feuchtinger

Centre Hospitalier Universitaire de Nancy, CHU, Vandoeuvre-Lès-Nancy, France, European Commission, Ghent University Hospital, UZG, Ghent, Belgium, Leiden University Medical Center, LUMC, Leiden, The Netherlands, Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany, Newcastle University, UNEW, Newcastle, UK, Ospedale Pediatrico Bambino Gesù, OPBG, Rome, Italy, Simbec-Orion Group Ltd, Merthyr Tydfil, UK, Vall d'Hebron Institute of Oncology (VHIO) and Banc de Sang I Teixits (BST), Barcelona, Spain

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Italy,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Viral clearance	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	8 weeks after treatment
Primary	Disease Progression	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	day 7 until week 8 after treatment
Secondary	Incidence of acute GvHD	Incidence of newly occurring acute GvHD grade I from Day 0 to Week 8 and Week 15.	15 weeks after treatment
Secondary	Incidence of chronic GvHD	Incidence of chronic GvHD from Day 7 to Week 8 and to Week 15 after treatment.	15 weeks after treatment
Secondary	Time to newly occuring GvHD	Time to newly occurring acute and chronic GvHD.	15 weeks after treatment
Secondary	Severity of GvHD	Severity of acute GvHD = grade II until Week 8 and Week 15.	week 8 and 15 week after treatment
Secondary	Incidence of acute toxicity	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.	15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer
Secondary	Severity of acute toxicity	Monitoring of adverse events infusion.	15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer
Secondary	Change in viral load of underlying viral infection	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 weeks after treatment
Secondary	Time to viral load change of underlying viral infection	Time to 1 log change in viral load.	15 weeks after treatment
Secondary	Percentage of viral decrease	Percentage of patients with =1 log decrease in CMV, EBV or AdV viral load at Week 8.	8 weeks after treatment
Secondary	Viral reactivations	Number of reactivations of the underlying viral infection following initial viral clearance until end of follow-up.	15 weeks after treatment
Secondary	Clinical response/resolution of symptoms of underlying viral infection	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.	8 weeks after treatment
Secondary	Overall survival	Overall survival rate (OS): From Day 0 to end of follow-up.	15 weeks after treatment
Secondary	Necessity of antiviral chemotherapy	Number of days requiring antiviral chemotherapy after T-cell transfer from Day 7 to Week 8 after T-cell transfer.	Day 7 until Week 8
Secondary	Duration of antiviral chemotherapy	Time to last administration of defined antiviral medication or switch to prophylactic treatment from Day 0 to Week 8 after IMP transfer.	8 weeks after treatment
Secondary	Incidence of viral infections other than underlying viral infection	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.	15 weeks
Secondary	Days of hospitalization	Number of days hospitalized after IMP transfer from Day 7 to Week 8.	8 weeks
Secondary	Life quality in adults	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.	Screening and Week 8.
Secondary	Life quality in adults	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.	Screening and Week 8
Secondary	Life quality in children	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.	Screening and Week 8
Secondary	Effect on the patient's T-cell phenotype in vivo	T-cell phenotyping, samples taken at Screening, Day 0 and each visit from Day 7 to Week 15 after treatment.	Screening until Week 15
Secondary	Effect on the patient's number of expanded T cells	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.	Screening until Week 15
Secondary	Quality of the IMP and performance of the CliniMACS® Prodigy	Assessment of the cellular composition, in particular the percentage of IFN-gamma+ cells, in the IMP.	Before IMP release (between Screening and Day 0)
Secondary	Evaluation of the drop-out rate	Drop-out rate at Day 0 and reasons for drop-out.	at Day 0 (planned treatment day)
Secondary	Time from inclusion to administration of the IMP	Number of days from Screening to Day 0 (day of IMP transfer) to evaluate the required time frame.	Screening until Day 0 (treatment day)
Secondary	Adverse events	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.	15 weeks
Secondary	Physical examination	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.	Screening to Week 8
Secondary	Vital Sign - blood pressure	supine systolic and diastolic blood preasure in mm Hg	Screening to Week 8
Secondary	Vital Signs - heart rate	The resting heart rate in beats/min	Screening to Week 8
Secondary	Vital Signs - body temperature	Body temperature in °C (aural)	Screening to Week 8
Secondary	Vital Signs - body weight	body weight in kg	Screening to Week 8
Secondary	Vital Signs - respiratory rate	respiratory rate in breaths/min.	Screening to Week 8
Secondary	Incidence of abnormal laboratory values	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.	Screening to Week 8
Secondary	Concomitant medication until Week 8	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.	8 weeks after treatment
Secondary	Concomitant medication until Week 15	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.	15 weeks after treatment