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Altretamine

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

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

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

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

Tobias Feuchtinger, Prof

Theresa Käuferle, Dr

Philippe Lewalle, Prof

Ann De Becker, Dr.

Tessa Kerre, Prof

Johan Maertens, Prof. Dr.

Johan Maertens, Prof.

Yves Beguin, Prof.

Bénédicte Bruno, Dr.

Marie Ouachée-Chardin, Dr.

Daniele Bensoussan, Prof.

Maud D'Aveni-Piney, Dr.

Stéphanie Nguyen Quoc, Prof.

Bendedicte Neven, Prof.

Jean Hugues Dalle, Prof.

Johannes Schulte, Prof.

Martin Bornhäuser, Prof.

Roland Meisel, Prof.

Stefan Schönberger, Dr.

Brigitte Strahm, PD Dr.

Britta Maecker-Kolhoff, Prof.

Vladan Vucinic, Dr.

Tobias Feuchtinger, Prof.

Irene Teichert von Lüttichau, PD Dr.

Johanna Tischer, Dr.

Mareike Verbeek, Dr.

Jürgen Föll, Prof.

Peter Lang, Prof.

Hermann Einsele, Prof.

Matthias Wölfl, Prof.

Franco Locatelli, Prof.

Franca Fagioli, Prof.

Peter van Balen, Dr.

Pere Barba, Dr.

María Laura Fox, Dr.

Antonio Pérez-Martinez, Dr.

José Antonio Pérez Simón, Dr.

Juan Montoro Gómez, Dr.

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.

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.

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.

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

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

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

Incidence of newly occurring acute GvHD grade I from Day 0 to Week 8 and Week 15.

Incidence of chronic GvHD from Day 7 to Week 8 and to Week 15 after treatment.

Time to newly occurring acute and chronic GvHD.

Severity of acute GvHD ≥ grade II until Week 8 and Week 15.

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.

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.

Percentage of patients with ≥1 log decrease in CMV, EBV or AdV viral load at Week 8.

Number of reactivations of the underlying viral infection following initial viral clearance until end of follow-up.

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.

Overall survival rate (OS): From Day 0 to end of follow-up.

Number of days requiring antiviral chemotherapy after T-cell transfer from Day 7 to Week 8 after T-cell transfer.

Time to last administration of defined antiviral medication or switch to prophylactic treatment from Day 0 to Week 8 after IMP transfer.

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.

Number of days hospitalized after IMP transfer from Day 7 to 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.

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.

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.

T-cell phenotyping, samples taken at Screening, Day 0 and each visit from Day 7 to Week 15 after treatment.

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.

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

Drop-out rate at Day 0 and reasons for drop-out.

Number of days from Screening to Day 0 (day of IMP transfer) to evaluate the required time frame.

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.

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.

supine systolic and diastolic blood preasure in mm Hg

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.

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.

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.

Spots Global Cancer Trial Database for adv infection