Evaluation of Chemotherapy with Nivolumab in Early-Stage Classical Hodgkin Lymphoma with Low Metabolic Tumor Volume and Negative Interim PET

The primary objective of this study is to explore the efficacy of **chemotherapy** alone in terms of 3-year progression-free survival (3-Y PFS) in patients with low-risk early-stage I-IIA classical Hodgkin Lymphoma (cHL), characterized by a low Metabolic Tumor Volume (MTV) and a negative interim PET scan after two courses of ABVD chemotherapy. This objective is clinically relevant as it aims to determine the potential of a less intensive treatment regimen to maintain disease control in a specific subset of cHL patients, potentially reducing treatment-related toxicity.

Secondary objectives include: - Evaluating the efficacy of a triple combination therapy (chemotherapy, involved-node radiotherapy (INRT), and **Nivolumab**) in high-risk early-stage cHL patients, defined by a positive PET-2 or high baseline MTV, in terms of 3-Y PFS. - Assessing the efficacy of chemotherapy followed by INRT "on demand" and Nivolumab maintenance in patients with a "limited relapse" pattern, in terms of 3-year freedom from second treatment failure (3-Y FF2TF), for low-risk patients with low MTV and negative PET-2. - Exploring the safety of chemotherapy alone in low-risk early-stage cHL patients, in terms of 3-year overall survival (3-Y OS), defined by low MTV and negative interim PET after two ABVD courses. - Evaluating the ability of cell-free DNA (cfDNA) assays to detect impending relapse during follow-up in low-risk patients treated with chemotherapy alone.

The clinical trial involves participants diagnosed with **early stage classical Hodgkin Lymphoma** (cHL) without bulky lesions and constitutional symptoms. The study population includes both male and female patients aged between 18 and 70 years. Participants are required to have a good general health status, as indicated by specific laboratory criteria such as total bilirubin, ALT, AST, hemoglobin, absolute neutrophil count, platelet count, and serum creatinine levels within defined limits. The trial population was selected based on their treatment-naïve status and histologically confirmed classical HL according to the World Health Organization Classification. Participants are expected to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. The sponsor has not provided the total number of participants involved in the study. Lifestyle considerations include the requirement for female participants to practice effective contraception or abstinence if fertile, and for male participants to agree to barrier contraception or abstinence. The trial does not specifically address dietary or physical activity habits. Key inclusion criteria focus on the disease stage and health parameters, while exclusion criteria are not detailed in the provided data.

The clinical trial is designed to evaluate the efficacy of chemotherapy alone in patients with **early stage classical Hodgkin Lymphoma** (cHL) without bulky lesions and constitutional symptoms. This study is a Phase II, randomized, double-blind, controlled trial. The trial aims to assess the three-year progression-free survival (3-Y PFS) in low-risk early-stage I-IIA Hodgkin Lymphoma patients, defined by a low Metabolic Tumor Volume (MTV) and a negative interim PET scan after two courses of ABVD chemotherapy. The trial is expected to conclude by May 31, 2026, with recruitment having started on February 1, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, performance status, and laboratory values. Following the screening, eligible participants will be randomized to receive the investigational treatment. The study includes follow-up visits to monitor the participants' response to treatment and any adverse events. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

The expected length of participant involvement is up to 12 months, with conditions for early termination including disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is to achieve a 3-Y PFS equal to or greater than 90%. Secondary endpoints include evaluating the efficacy of combined modality therapy plus **Nivolumab** in high-risk patients and assessing the safety and overall survival (3-Y OS) of delayed radiotherapy followed by Nivolumab maintenance. The trial will also explore the accuracy of cell-free DNA in detecting impending relapse during follow-up.

The clinical trial involves the administration of **Nivolumab**, a monoclonal antibody used as an experimental medication. **Nivolumab** is provided in the form of a **concentrate for solution for infusion**. The active substance, **Nivolumab**, is of chemical origin. The medication is administered via **intravenous use**. The dosing regimen specifies a maximum daily dose of 240 mg, with a total maximum dose of 5760 mg over the course of the treatment. The treatment period is limited to a maximum of 12 months. The trial does not involve a pediatric formulation, and **Nivolumab** is not classified as an orphan drug for this study.

In addition to the experimental treatment, the study protocol includes the use of standard-of-care chemotherapy, specifically the ABVD regimen, which consists of **doxorubicin, bleomycin, vinblastine, and dacarbazine**. This regimen is administered as part of the standard treatment for patients with early-stage Hodgkin Lymphoma (HL). The trial aims to evaluate the efficacy of chemotherapy alone in patients with low-risk early-stage I-IIA HL, characterized by a low metabolic tumor volume and a negative interim PET scan after two courses of ABVD. Compliance with the dosing schedule and administration of both the experimental and standard treatments will be monitored throughout the study to ensure adherence to the protocol.

Efficacy in this clinical trial will be assessed primarily through the evaluation of the three-year **Progression-Free Survival** (3-Y PFS) rate. This endpoint is defined as the time from registration until the first occurrence of disease progression, relapse, or death for any reason. The primary focus is on patients with early-stage I-IIA non-bulky Hodgkin Lymphoma (HL) who are considered to have a very low risk of treatment failure, characterized by a low Metabolic Tumor Volume (MTV) and a negative interim PET scan after two cycles of ABVD chemotherapy.

Secondary efficacy endpoints include the exploration of 3-Y PFS in high-risk HL patients, defined by either a positive interim PET scan after two cycles of ABVD or a high baseline MTV, or both. Additionally, the trial will evaluate the three-year freedom from second treatment failure (3-Y FF2TF), measured from the date of registration to the date of second relapse after radiotherapy "on demand" for low-risk patients. The safety and efficacy of delayed radiotherapy followed by Nivolumab maintenance in rescuing patients who relapsed after chemotherapy alone will also be assessed in terms of three-year overall survival (3-Y OS). Furthermore, the trial will assess the overall accuracy, sensitivity, specificity, negative predictive value, and positive predictive value of cell-free DNA in detecting impending relapse during follow-up.