Phase 3 Multicenter Open-Label RCT of Duvelisib vs. Gemcitabine or Bendamustine in Relapsed/Refractory Nodal T-Cell Lymphoma with TFH Phenotype

The primary objective of this study is to evaluate the **progression-free survival (PFS)** benefit of duvelisib monotherapy as determined by an Independent Review Committee, compared to the investigator's choice of gemcitabine or bendamustine in patients with relapsed/refractory nodal T cell lymphoma with T follicular helper (TFH) phenotype. This is clinically relevant as PFS is a critical endpoint in assessing the efficacy of cancer treatments, providing insights into the duration a patient lives without disease progression.

Secondary objectives include:

• Evaluating the overall survival (OS) benefit of duvelisib monotherapy compared to gemcitabine or bendamustine.
• Assessing additional efficacy parameters such as investigator-assessed PFS, objective response rate (ORR), complete response rate (CRR), duration of response (DOR), the proportion of patients proceeding to stem cell transplantation (SCT), and PFS in patients who proceed to SCT.
• Evaluating the safety profile of duvelisib monotherapy compared to gemcitabine or bendamustine.
• Assessing the impact of duvelisib monotherapy on quality of life (QoL) compared to gemcitabine or bendamustine.

The clinical trial involves a total of **46 participants** diagnosed with **relapsed/refractory nodal T cell lymphoma with T follicular helper (TFH) phenotype**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as having a pathologically confirmed nodal T cell lymphoma with TFH phenotype and having relapsed or refractory disease following at least one prior systemic, cytotoxic therapy. The trial population is characterized by a measurable disease as defined by the Lugano 2014 criteria and an ECOG Performance Status of 0, 1, or 2. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating a careful selection process to ensure the safety and appropriateness of the study for all participants.

The clinical trial is a **randomized controlled** study designed to evaluate the efficacy of **duvelisib** monotherapy compared to the investigator's choice of **gemcitabine** or **bendamustine** in patients with **relapsed/refractory nodal T cell lymphoma with T follicular helper (TFH) phenotype**. The trial is open-label and conducted in multiple centers, with a primary objective to assess the progression-free survival (PFS) as determined by an Independent Review Committee (IRC). The study is expected to last until July 31, 2030, with recruitment starting on April 1, 2025. The trial will include a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as pathologically confirmed nodal T cell lymphoma with TFH phenotype and measurable disease as per Lugano 2014 criteria. Participants will be randomly assigned to receive either duvelisib or the investigator's choice of comparator drugs. The trial will involve regular follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, which is anticipated to last up to 36 months, depending on individual response and treatment tolerance. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will measure several secondary endpoints, including overall survival, objective response rate, and quality of life assessments, all evaluated over a period of up to three years. The study is not classified as low intervention and is categorized as a Phase 3 trial. Participants will be monitored for adverse events and laboratory abnormalities throughout the study duration to ensure safety and efficacy of the treatment regimen.

The clinical trial involves the administration of **Copiktra** in two different dosages as the experimental medication. **Copiktra 15 mg hard capsules** and **Copiktra 25 mg hard capsules** contain the active substance **duvelisib**, a phosphatidylinositol-3-kinase (Pi3K) inhibitor. These capsules are administered orally. The maximum daily dose is 150 mg, with a total maximum dose of 60,350 mg over a treatment period of up to 36 months. The capsules are provided in study-specific packaging, with each blister containing 32 capsules. The packaging includes child-resistant paper backing and push-through laminate blister lidding, with no secondary packaging. Compliance with the dosing schedule is monitored throughout the trial.

In addition to the experimental treatment, the trial includes comparator treatments, which are administered based on the investigator's choice. One such comparator is **Bendamustine hydrochloride**, an alkylating agent used as an antineoplastic treatment. It is administered intravenously, with a maximum daily dose of 120 mg/m² and a total maximum dose of 1,440 mg/m² over a treatment period of up to 18 months. The pharmaceutical form is denoted as PHF00230MIG.

Another comparator treatment is **Gemcitabine hydrochloride**, a pyrimidine analogue used in chemotherapy. This medication is also administered intravenously, with a maximum daily dose of 1,200 mg/m² and a total maximum dose of 21,600 mg/m² over a treatment period of up to 24 months. The pharmaceutical form is similarly denoted as PHF00230MIG. Both comparator treatments are monitored for participant compliance and efficacy throughout the trial.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-free Survival (PFS)**, as determined by the Independent Review Committee (IRC) according to the Lugano 2014 criteria. This primary endpoint will be evaluated up to 3 years and includes the time until disease progression or death from any cause. Secondary endpoints include Overall Survival (OS), Objective Response Rate (ORR), Complete Response Rate (CRR), and Duration of Response (DOR), all assessed by the IRC over the same period. Additionally, the trial will evaluate the proportion of participants proceeding to Stem Cell Transplantation (SCT) and investigator-assessed PFS in these participants. The incidence and frequency of Adverse Events (AEs) and abnormal laboratory values will also be monitored. Quality of Life (QoL) will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 Score, EQ5D Score, and QLQ-NHL-HG29 Score, all evaluated up to 3 years. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial duration, ensuring a comprehensive assessment of the treatment's impact on patients with relapsed/refractory nodal T cell lymphoma with T follicular helper (TFH) phenotype.