Phase I/IIb Study of Atezolizumab with BEGEV Regimen in Relapsed/Refractory Hodgkin's Lymphoma for Autologous Stem-Cell Transplantation Candidates

The primary objective of this study is to determine the **maximum tolerated dose (MTD)** of atezolizumab in combination with the BEGEV regimen during the first cycle of therapy. This will establish the recommended phase II dose (RP2D). Additionally, the study aims to assess the complete response rate (CRR) before autologous stem-cell transplantation (ASCT) according to the Lugano classification response criteria (2014) and the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC 2016) through an independent radiologic review committee (IRRC) assessment. These objectives are clinically relevant as they aim to optimize the dosing regimen and evaluate the efficacy of the treatment in patients with relapsed or refractory Hodgkin’s lymphoma, potentially improving patient outcomes.

The secondary objectives include: - Assessing the overall response rate (ORR), partial response (PR), stable disease (SD), and progression disease (PD) rates. - Evaluating the rate of PR converted to complete response (CR) at the end of consolidation treatment with atezolizumab in the experimental arm. - Assessing peripheral blood stem-cell mobilization in patients receiving atezolizumab combined with the BEGEV schedule. - Evaluating engraftment in patients who received ASCT after salvage treatment with atezolizumab combined with BEGEV. - Assessing the duration of response (DoR). - Evaluating progression-free survival (PFS) and overall survival (OS) for all patients and for those achieving CR, with measurements also taken during long-term follow-up to better assess prognosis. - Assessing the safety and tolerability of a first salvage treatment based on the combination of intravenous (IV) atezolizumab and the BEGEV regimen in patients with relapsed or refractory Hodgkin’s lymphoma. - Evaluating the correlation of quantitative baseline PET parameters with other clinical parameters, response to treatment, and outcome.

The clinical trial involves participants diagnosed with **Hodgkin’s lymphoma**, specifically those who have experienced a first disease relapse or are refractory to first-line treatment. The study population includes both male and female subjects aged between 18 and 60 years, with the upper age limit applicable only to Phase I of the trial. Participants are required to have a performance status of 2 or less on the Eastern Cooperative Oncology Group (ECOG) scale, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial does not include a vulnerable population. Participants must have adequate hematological function unless affected by bone marrow involvement due to lymphoma. The sponsor has not provided information regarding the total number of participants. Selection criteria include eligibility for autologous stem cell transplantation (ASCT) and a history of only one prior systemic therapy for Hodgkin’s lymphoma. Participants are expected to comply with effective contraception measures and adhere to the study visit schedule and protocol procedures. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, controlled, phase I/IIb** study to evaluate the combination of **atezolizumab** with the BEGEV regimen in patients with relapsed or refractory **Hodgkin's lymphoma** who are candidates for autologous stem-cell transplantation. The trial aims to determine the maximum tolerated dose (MTD) of atezolizumab in phase I and assess the complete response rate (CRR) before transplantation in phase IIb. The study is expected to run from February 2023 to August 2031, with participant involvement lasting until the end of the study or until early termination criteria are met.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of Hodgkin's lymphoma, and performance status. Follow-up visits will occur throughout the treatment cycles to monitor safety, efficacy, and any adverse events. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment. The expected length of participant involvement is contingent upon the treatment response and any adverse events that may necessitate early withdrawal from the study.

Conditions that may lead to early termination from the study include significant adverse events, lack of compliance with study procedures, or disease progression. The trial will employ a double-blind methodology to ensure unbiased results, with an independent radiologic review committee assessing responses according to the Lugano classification and LYRIC criteria. The primary endpoints include the determination of MTD in phase I and CRR in phase IIb, while secondary endpoints will evaluate overall response rate, progression-free survival, and overall survival, among others.

The clinical trial involves the administration of **atezolizumab**, a monoclonal antibody, as part of the experimental treatment regimen. Atezolizumab is administered in the form of an intravenous infusion. The pharmaceutical form is designated as PHF00231MIG. The specific dosage and frequency of administration are determined during the trial to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Participant compliance with the dosing schedule is monitored throughout the study.

**Bendamustine hydrochloride** is utilized as a comparator treatment in the trial. It is an antineoplastic agent provided as a powder for concentrate for solution for infusion. The administration route is intravenous infusion. The pharmaceutical form is PHF00230MIG. The dosing schedule and frequency are aligned with standard clinical practices for its use in oncology, and compliance is monitored accordingly.

**Vinorelbine** is included in the trial as a chemotherapeutic agent. It is administered via intravenous infusion, with the pharmaceutical form being PHF00230MIG. The dosing schedule is determined based on established protocols for its use in cancer treatment, and participant adherence to the regimen is closely monitored.

**Gemcitabine** is another antineoplastic agent used in the trial, provided as a powder for solution for infusion. It is administered intravenously, with the pharmaceutical form being PHF00230MIG. The dosing schedule follows standard oncology guidelines, and compliance is tracked throughout the study.

**Vinorelbine tartrate** is used as a comparator treatment, classified as an antineoplastic agent - Vinca alkaloid. It is administered via intravenous infusion. The dosing schedule is consistent with its use in clinical practice, and participant adherence is monitored.

**Gemcitabine hydrochloride** is also included as a comparator treatment. It is an antineoplastic agent administered through intravenous infusion, with the pharmaceutical form being PHF00230MIG. The dosing schedule is based on standard treatment protocols, and compliance is monitored to ensure adherence.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. In Phase I, the primary endpoint is the determination of the maximum tolerated dose (MTD) of **atezolizumab** in combination with the BEGEV regimen, established during the first cycle of therapy. In Phase IIb, the primary endpoint is the complete response rate (CRR) before autologous stem-cell transplantation (ASCT), evaluated according to the Lugano classification response criteria (2014) and the LYmphoma Response to Immunomodulatory Therapy Criteria (LYRIC 2016) by an independent radiologic review committee (IRRC).

Secondary endpoints in Phase IIb include overall response rate (ORR), partial response (PR), stable disease (SD), and progressive disease (PD) rates, defined according to the Lugano 2014 and LYRIC 2016 criteria. Additional secondary endpoints involve the conversion of PR to CR, adequate stem cell mobilization, engraftment in patients receiving ASCT, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). The study will also measure patient withdrawal rates, incidence, type, and grade of adverse events (AEs) and serious adverse events (SAEs), and hospitalization rates throughout the study. Furthermore, imaging parameters such as SUVmax, total Metabolic Tumor Volume (tMTV), Total Lesion Glycolysis (TLG), Dmax, and radiomics features will be extrapolated from PET scans.