Evaluation of Glofitamab Monotherapy and Combination with R-ICE in Pediatric and Young Adult Relapsed/Refractory CD20+ B-Cell Non-Hodgkin Lymphoma

The primary objective of this study is to evaluate the **efficacy** of glofitamab in combination with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) chemoimmunotherapy in pediatric and young adult participants with relapsed/refractory mature B-cell non-Hodgkin lymphoma. This is assessed by the investigator based on the achievement of a complete response (CR). Additionally, the study aims to evaluate the safety and tolerability of glofitamab in combination with R-ICE chemoimmunotherapy and to determine the pharmacokinetics of glofitamab alone and in combination with R-ICE chemoimmunotherapy. The clinical relevance of this objective lies in its potential to improve treatment outcomes for patients with this aggressive form of lymphoma, offering insights into the therapeutic benefits and safety profile of the combination therapy.

Secondary objectives include:

• Evaluating the anti-tumor activity of glofitamab in combination with R-ICE chemoimmunotherapy and glofitamab monotherapy.
• Assessing the safety and tolerability of glofitamab monotherapy.
• Determining the pharmacokinetics of obinutuzumab and rituximab.
• Evaluating the immune response to glofitamab.

The clinical trial involves a total of **40 participants** diagnosed with **CD20 positive B-Cell Non-Hodgkin Lymphoma**. The study population includes both male and female subjects, with an age range from 6 months to less than 18 years for Cohort A Part 1 and Cohort B, and up to 30 years for Cohort A Part 2. Participants were selected based on a histologically re-confirmed diagnosis of aggressive mature B-cell non-Hodgkin lymphoma, including subtypes such as Burkitt lymphoma, Burkitt leukemia, diffuse large B-cell lymphoma, and primary mediastinal large B-cell lymphoma. The trial includes individuals with refractory or relapsed disease following prior chemoimmunotherapy regimens. Participants are required to have adequate performance status and organ function, and must test negative for hepatitis B, hepatitis C, HIV, and SARS-CoV-2. The trial population is considered vulnerable, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is designed to evaluate the **safety**, tolerability, pharmacokinetics, and anti-tumor activity of **glofitamab** in monotherapy and in combination with chemoimmunotherapy in pediatric and young adult participants with relapsed/refractory mature B-cell non-Hodgkin lymphoma. This trial is structured as a Phase I/II, open-label, single-arm, two-part study. The trial is expected to commence on January 15, 2023, and conclude by November 30, 2027. Participants will be involved in the study for a duration that includes multiple cycles of treatment, with the potential for early termination based on specific criteria such as adverse events or lack of efficacy.

The trial involves a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment history. Participants must have a histologically confirmed diagnosis of aggressive mature B-cell non-Hodgkin lymphoma expressing CD20. The study will include follow-up visits to monitor the participants' response to treatment and assess any adverse events. The end-of-study visit will evaluate the overall outcomes and gather final data on the participants' health status.

Participants will be randomly assigned to receive either glofitamab monotherapy or glofitamab in combination with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) chemoimmunotherapy. The primary endpoints include the achievement of a complete response after up to three cycles of treatment and the incidence and severity of adverse events. Secondary endpoints focus on objective response rate, duration of response, progression-free survival, and overall survival. The trial will also assess the pharmacokinetics of glofitamab and the prevalence of anti-drug antibodies.

Participant involvement is expected to last through the treatment cycles, with regular assessments to ensure safety and efficacy. Conditions for early termination from the study include the occurrence of severe adverse events, disease progression, or withdrawal of consent. The trial aims to provide comprehensive data on the potential benefits and risks of glofitamab in this patient population, contributing to the understanding of its role in treating relapsed/refractory mature B-cell non-Hodgkin lymphoma.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Etoposide** is utilized in this study in the form of a pharmaceutical formulation identified as PHF675. It is administered via **IV infusion**. The frequency and specific dosage are determined based on the trial protocol, and participant compliance is monitored through regular assessments.

**Ifosfamide** is another experimental medication used in this trial. It is provided in the pharmaceutical form PHF00230MIG and is administered through **intravenous use**. The administration schedule is aligned with the trial's chemoimmunotherapy regimen, and adherence is tracked by the clinical team.

**Obinutuzumab**, marketed as Gazyvaro, is included as a concentrate for solution for infusion. It is administered via **IV infusion**. The dosing schedule is designed to optimize therapeutic outcomes while ensuring participant safety, with compliance monitored throughout the trial.

**Glofitamab**, known as CD20 CD3 TCB, is administered as a solution for infusion through **IV infusion**. This medication is part of the trial's investigational regimen, and its administration is carefully controlled and monitored to assess its safety and efficacy in combination with other treatments.

**Carboplatin** is utilized in the trial in the form PHF00230MIG and is administered via **IV infusion**. The dosing regimen is integrated into the overall chemoimmunotherapy protocol, with participant adherence closely monitored by the research team.

**Rituximab**, marketed as MabThera, is provided as a 500 mg concentrate for solution for infusion. It is administered through **intravenous use**. The administration schedule is part of the trial's combination therapy approach, and compliance is ensured through systematic monitoring.

**Tocilizumab**, marketed as RoActemra, is included as a 20 mg/mL concentrate for solution for infusion. It is administered via **IV infusion**. The dosing and administration are tailored to the trial's objectives, with participant compliance being a key focus of the clinical team.

In addition to the experimental medications, the trial includes a standard-of-care therapy regimen, which may involve the use of placebo or comparator treatments as necessary. The trial protocol outlines the specific dosing schedules and administration routes for each medication, ensuring a comprehensive approach to participant treatment and monitoring. Compliance with the treatment regimen is assessed through regular follow-ups and adherence checks, ensuring the integrity of the trial data.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary efficacy endpoint for Cohort A involves the achievement of a **complete response (CR)** after up to three cycles of treatment with glofitamab in combination with R-ICE chemoimmunotherapy. This will be determined by the investigator using the International Pediatric NHL Response Criteria for pediatric participants and the Lugano Classification for young adult participants. Additionally, the incidence, nature, frequency, severity, and timing of adverse events will be evaluated, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 (NCI CTCAE v5.0).

Secondary efficacy endpoints include the objective response rate (ORR), duration of complete response (DOCR), progression-free survival (PFS), event-free survival (EFS), overall survival (OS), and the percentage of patients who proceed to hematopoietic stem cell transplantation (HSCT) after up to three cycles of treatment. For glofitamab monotherapy, ORR, duration of response (DOR), and OS will be assessed. The trial will also monitor the serum concentrations of obinutuzumab and rituximab at specified timepoints, as well as the prevalence of anti-drug antibodies (ADAs) at baseline and the incidence of ADAs against glofitamab during the study.