Phase III Multicenter Trial of Allogeneic CD4+ and CD8+ T Lymphocytes for Chemo-Refractory CMV, EBV, and AdV Infections Post-Allogeneic Stem Cell Transplantation

The primary objective of this clinical trial is the evaluation of the **efficacy** of multispecific T-cell transfer in patients with chemo-refractory viral infections following allogeneic stem cell transplantation. This is clinically relevant as it addresses the treatment of patients who have not responded to standard antiviral therapies, specifically targeting infections caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (AdV). The study aims to provide an alternative therapeutic option for these patients, potentially improving outcomes and reducing morbidity associated with these persistent infections.

Secondary objectives include:

• Incidence and severity of newly occurring graft-versus-host disease (GvHD).
• Incidence and severity of acute toxicity.
• Effect on viral load of underlying viral infection.
• Clinical response/resolution of symptoms of underlying viral infection.
• Overall survival.
• Necessity and duration of antiviral chemotherapy.
• Incidence of viral infections other than the underlying viral infection, evaluating the putative prophylactic effect of treatment.
• Days of hospitalization.
• Quality of life.
• Effect on the patients’ T-cell immunity in vivo.
• Quality of the investigational medicinal product (IMP) and performance of the CliniMACS® Prodigy system.
• Evaluation of the drop-out rate.
• Evaluation of time from inclusion to administration of the IMP.
• Overall safety evaluation.
• Concomitant medication.

The clinical trial involves a **vulnerable population** of both male and female participants, including adult and pediatric patients over 2 months of age, who have undergone allogeneic stem cell transplantation (HSCT). These participants are suffering from new or reactivated infections of cytomegalovirus (CMV), Epstein-Barr virus (EBV), or adenovirus (AdV) that are refractory to standard antiviral treatment. The study population was selected based on the presence of these viral infections, confirmed by quantitative blood PCR analysis, and the availability of the original HSCT donor with an immune response to the virus causing the therapy-refractory infection. The sponsor has not provided the total number of participants. Participants' general health status is compromised due to their post-transplant condition and viral infections. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the requirement for written informed consent from the patient or their legal representative.

The clinical trial is a **phase III**, prospective, multicentre study designed to evaluate the efficacy of multispecific T-cell transfer in patients with chemo-refractory viral infections following allogeneic stem cell transplantation. The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The study is expected to run from February 2020 to March 2028, with participant involvement lasting up to 15 weeks from the initial treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, previous stem cell transplantation, and viral infection status. The primary inclusion criteria require patients to have a new or reactivated **CMV**, **EBV**, or **AdV** infection that is refractory to standard antiviral treatment. Following the screening, eligible participants will be randomized to receive either the investigational product, allogeneic multivirus-specific T cells, or a placebo, both administered via **intravenous infusion**.

Subsequent follow-up visits will occur weekly from Day 7 to Week 8, with an additional visit at Week 15. These visits are designed to monitor the primary endpoints, which include the percentage of patients achieving viral clearance and the progression of the infection. Secondary endpoints will assess the incidence and severity of acute and chronic **GvHD**, changes in viral load, and overall survival rates, among other factors. The end-of-study visit will occur at Week 15, marking the conclusion of the participant's involvement in the trial.

Participants may be withdrawn from the study early if they experience severe adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial's rigorous design and comprehensive monitoring aim to provide valuable insights into the potential benefits of T-cell therapy for patients with refractory viral infections post-transplantation.

The clinical trial involves the administration of **Allogeneic multivirus (CMV, EBV, AdV-) specific T cells** as the experimental treatment. This investigational product is composed of **allogeneic CD4+ and CD8+ T lymphocytes** that have been ex vivo incubated with synthetic peptides of the viral antigens of **cytomegalovirus (CMV)**, **adenovirus (AdV)**, and **Epstein-Barr virus (EBV)**. The pharmaceutical form of this treatment is an infusion, and it is administered via **intravenous bolus injection/IV infusion**. The maximum daily dose is 20 ml, with a total dose not exceeding 20 ml over the treatment period, which is limited to one day. The product is classified as a structurally diverse substance used in cell therapy, and it is not formulated for pediatric use.

The study also includes a **placebo** group, which receives a **Multivirus-specific T cells placebo**. The placebo is used as a comparator to evaluate the efficacy of the experimental treatment. The pharmaceutical form and route of administration for the placebo are not specified in the trial data. The placebo serves as a control to ensure the reliability of the trial results by providing a baseline for comparison against the active treatment group.

The efficacy of the investigational medicinal product in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the percentage of patients achieving **viral clearance**, defined as two consecutive negative PCR tests, and the percentage of patients experiencing disease progression between Day 7 and Week 8 following the investigational medicinal product (IMP) transfer. Secondary endpoints encompass a range of clinical and laboratory measures, including the incidence and severity of acute and chronic graft-versus-host disease (GvHD), changes in viral load as determined by quantitative PCR analysis, and overall survival rates from Day 0 to the end of follow-up.

Additional secondary endpoints involve the assessment of acute toxicity, measured by vital signs and specific adverse events from 1 hour prior to 4 hours post-IMP infusion, and the evaluation of clinical symptoms reduction or clearance from Day 7 to Week 8 post-IMP transfer. The trial will also monitor the number of days requiring antiviral chemotherapy, the time to last administration of antiviral medication, and the number of new viral reactivations. Patient-reported outcomes will be collected using EQ-5D and FACT-BMT for adults and PEDS-QL for pediatric patients at Screening and Week 8. T-cell phenotyping and analysis of virus-specific T cells will be conducted at multiple timepoints, including Screening, Day 0, and each visit from Day 7 to Week 15 post-IMP transfer.