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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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AdV Infection, EBV Infection, CMV Infection, Stem Cell Transplant Complications

Intervention / Treatment
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* Other: Multivirus (CMV, EBV, AdV)-specific T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Original HSCT-donor available with an immune response at least to the virus causing the therapy-refractory (=underlying) infection. Written informed consent given (patient or legal representative) prior to any study-related procedures. Exclusion Criteria: Patient with acute GvHD > grade II or extensive chronic GvHD at the time of IMP transfer Patient receiving steroids (>1 mg/kg BW Prednisone equivalent) at Screening. 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. Patient with organ dysfunction or failure as determined by Karnofsky (patients >16 years) or Lansky (patients ≤16 years) score ≤30% Concomitant enrolment in another clinical trial interfering with the endpoints of this study Any medical condition which could compromise participation in the study according to the investigator's assessment 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 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 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. 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. Known hypersensitivity to iron dextran Patients unwilling or unable to comply with the protocol or unable to give informed consent.

Ages Eligible for Study
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Minimum Age: 2 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2 (verum): 1 (Placebo) randomization
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multivirus (CMV, EBV, AdV)-specific T cells<br>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<br>* Cell therapy product which is individually produced for each patient and administered via IV bolus injection.<br>|
| Placebo Comparator: Sodium chloride<br>Suspension of multivirus-specific T cells in 20 mL of 0.9% NaCl + 0.5% HSA | Other: Multivirus (CMV, EBV, AdV)-specific T cells<br>* Cell therapy product which is individually produced for each patient and administered via IV bolus injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Incidence of chronic GvHD | Incidence of chronic GvHD from Day 7 to Week 8 and to Week 15 after treatment. | 15 weeks after treatment | 
| Time to newly occuring GvHD | Time to newly occurring acute and chronic GvHD. | 15 weeks after treatment | 
| Severity of GvHD | Severity of acute GvHD ≥ grade II until Week 8 and Week 15. | week 8 and 15 week after treatment | 
| 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 | 
| Severity of acute toxicity | Monitoring of adverse events infusion. | 15 minutes, 30 minutes, 2 hours and 4 hours post T-cell/placebo transfer | 
| 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 | 
| Time to viral load change of underlying viral infection | Time to 1 log change in viral load. | 15 weeks after treatment | 
| 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 | 
| Viral reactivations | Number of reactivations of the underlying viral infection following initial viral clearance until end of follow-up. | 15 weeks after treatment | 
| 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 | 
| Overall survival | Overall survival rate (OS): From Day 0 to end of follow-up. | 15 weeks after treatment | 
| 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 | 
| 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 | 
| 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 | 
| Days of hospitalization | Number of days hospitalized after IMP transfer from Day 7 to Week 8. | 8 weeks | 
| 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. | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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) | 
| Evaluation of the drop-out rate | Drop-out rate at Day 0 and reasons for drop-out. | at Day 0 (planned treatment day) | 
| 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) | 
| 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 | 
| 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 | 
| Vital Sign - blood pressure | supine systolic and diastolic blood preasure in mm Hg | Screening to Week 8 | 
| Vital Signs - heart rate | The resting heart rate in beats/min | Screening to Week 8 | 
| Vital Signs - body temperature | Body temperature in °C (aural) | Screening to Week 8 | 
| Vital Signs - body weight | body weight in kg | Screening to Week 8 | 
| Vital Signs - respiratory rate | respiratory rate in breaths/min. | Screening to Week 8 | 
| 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 | 
| 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 | 
| 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 |