Phase 2 Evaluation of Nanatinostat and Valganciclovir in Epstein-Barr Virus-Positive Relapsed/Refractory Lymphomas

The primary objective of this study is to evaluate the **anti-tumor activity** of the combination treatment of nanatinostat (Nstat) with valganciclovir (VGCV) in patients with **Epstein-Barr Virus-Positive (EBV+) Relapsed/Refractory Lymphomas**. This is assessed based on objective tumor response rates, which is clinically relevant as it provides insight into the efficacy of the treatment regimen in controlling tumor progression in this patient population.

Secondary objectives include:

• To determine the duration of tumor control, which is important for understanding the long-term effectiveness of the treatment.
• To determine survival outcomes, providing data on the potential impact of the treatment on patient longevity.
• To describe the safety profile of the combination treatment of Nstat with VGCV, which is crucial for assessing the risk-benefit ratio of the therapy.
• To generate pharmacokinetic (PK) data, which aids in understanding the absorption, distribution, metabolism, and excretion of the drugs involved.

The clinical trial involves a total of **418 participants** diagnosed with **Epstein-Barr Virus-Positive (EBV+) Relapsed/Refractory Lymphomas**. The study population includes both male and female subjects, with an age range starting from 18 years and above, as well as specific criteria for patients with post-transplant lymphoproliferative disorder (PTLD) aged 12 years and weighing at least 40 kg. Participants were selected based on their relapsed or refractory status following two or more prior systemic therapies, including at least one course of anti-CD20 immunotherapy and anthracycline-based chemotherapy. The trial includes individuals with measurable disease per Lugano 2007 criteria and an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, indicating a general health status that allows for participation in clinical trials. Adequate bone marrow function is required, and participants must be able to swallow whole tablets. The trial population is considered vulnerable, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **anti-tumor activity** of a combination treatment involving **nanatinostat** and **valganciclovir** in patients with **Epstein-Barr Virus-Positive (EBV+) Relapsed/Refractory Lymphomas**. This is a Phase II, open-label study, which will assess the objective tumor response rates as the primary endpoint. The trial employs a randomized, controlled design to ensure the reliability of the results. The estimated duration of the trial is approximately four years, with recruitment starting in June 2021 and expected completion by June 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and previous treatment history. Eligible participants must be adults aged 18 years or older, with specific criteria for those with post-transplant lymphoproliferative disorder (PTLD). The trial will include follow-up visits to monitor the **objective response rate (ORR)**, duration of response, progression-free survival, and other secondary endpoints such as overall survival and pharmacokinetic parameters. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment.

The expected length of participant involvement is up to 168 weeks, depending on individual response and disease progression. Conditions that may lead to early termination from the study include adverse reactions to the treatment, disease progression, or withdrawal of consent by the participant. The trial aims to provide comprehensive data on the efficacy and safety of the combination therapy, contributing valuable insights into the management of EBV+ relapsed/refractory lymphomas.

The clinical trial involves the administration of **Nanatinostat**, an experimental medication, in the form of a **coated tablet**. Nanatinostat is chemically derived and is administered orally. The maximum daily dose is 20 mg, with a total maximum dose of 1920 mg over a treatment period of 168 days. The primary objective of the trial is to evaluate the anti-tumor activity of Nanatinostat in combination with other treatments in patients with Epstein-Barr Virus-Positive (EBV+) relapsed/refractory lymphomas.

**Valganciclovir** is used as a non-experimental treatment in this study. It is also of chemical origin and is administered orally. The pharmaceutical form is denoted as PHF00169MIG. The maximum daily dose for Valganciclovir is 900 mg, with a total maximum dose of 151200 mg over the same treatment period of 168 days. Valganciclovir serves as a standard-of-care therapy in combination with Nanatinostat to assess the objective tumor response rates.

Additionally, **Ganciclovir Sodium** is included as a comparator treatment. It is administered intravenously, with the pharmaceutical form identified as PHF00230MIG. The dosing regimen allows for a maximum daily dose of 5 mg/kg, with a total maximum dose of 840 mg/kg over 168 days. Ganciclovir Sodium is also of chemical origin and is used to provide a comparative analysis of treatment efficacy in the trial.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial is designed to provide comprehensive data on the efficacy and safety of the combination treatment in the specified patient population.

The efficacy of the combination treatment of **nanatinostat** with valganciclovir in patients with Epstein-Barr Virus-Positive (EBV+) relapsed/refractory lymphomas will be assessed primarily through the **Objective Response Rate (ORR)**. This will be evaluated by an Independent Review Committee (IRC) using the 2007 International Working Group (IWG) criteria. Secondary endpoints for efficacy assessment include the **Duration of Response (DOR)**, **Time to Next Anti-Lymphoma Treatment**, **Progression-Free Survival**, **Time to Progression**, and **Overall Survival (OS)**. Additionally, pharmacokinetic parameters such as time to maximum plasma concentration (tmax), maximum plasma concentration (Cmax), and area under the plasma concentration-time curve (AUC) will be measured.