Phase II Evaluation of Lacutamab Monotherapy and Combination Chemotherapy in Advanced T-Cell Lymphomas, Including Sézary Syndrome and Mycosis Fungoides

The primary objective of this study is to evaluate the **objective response rate (ORR)** in patients with advanced T-cell lymphomas, specifically focusing on cutaneous T-cell lymphomas (CTCL) subtypes such as relapsed/refractory Sézary Syndrome (SS) and stage IB to IV Mycosis Fungoides (MF). This is clinically relevant as ORR is a critical measure of the efficacy of the treatment, providing insights into the potential benefits of the investigational drug, **Lacutamab** (IPH4102), in managing these aggressive lymphomas.

Secondary objectives include:

• Characterizing the safety and tolerability of IPH4102, which is essential for understanding the risk-benefit profile of the treatment.
• Assessing the quality of life (QoL) of patients, which is important for evaluating the overall impact of the treatment on patient well-being.
• Evaluating other clinical activity endpoints such as duration of response (DOR), progression-free survival (PFS), and overall survival (OS), which provide comprehensive data on the treatment's long-term efficacy and survival benefits.
• Evaluating the pharmacokinetics (PK) and immunogenicity of IPH4102, which are crucial for understanding the drug's behavior in the body and its potential to elicit an immune response.

The clinical trial involves a total of **70 participants** diagnosed with **Advanced T-Cell Lymphomas (TCL)**, specifically focusing on subtypes such as relapsed/refractory Sézary Syndrome (SS) and stage IB to IV Mycosis Fungoides (MF). The study population includes both male and female subjects, aged 18 years and older, who have previously undergone at least two systemic therapies. Participants were selected based on their relapsed or refractory status and the feasibility of obtaining skin biopsies. The trial includes individuals with an **ECOG performance status** of 2 or less, ensuring they are capable of basic self-care. Participants are required to have adequate baseline laboratory data, including specific hematology and biochemistry parameters. Lifestyle considerations such as the use of contraception are mandated for women of childbearing potential and sexually active men. The trial population is considered vulnerable, reflecting the advanced stage of the disease and the specific medical conditions under investigation.

The clinical trial is designed to evaluate the efficacy and safety of **Lacutamab**, a **monoclonal antibody**, in patients with advanced T-cell lymphomas, specifically focusing on relapsed or refractory Sézary Syndrome and Mycosis Fungoides. This is a phase II, open-label, multi-cohort, multi-center study. The trial employs a non-randomized design, with participants receiving **Lacutamab** either alone or in combination with chemotherapy. The primary objective is to assess the objective response rate (ORR), defined as the proportion of patients achieving complete or partial response. Secondary endpoints include safety assessments, quality of life evaluations, pharmacokinetic assessments, and immunogenic potential of the drug.

The trial is expected to run from May 22, 2019, to July 31, 2025. Participants will be involved in the study for a maximum treatment period of 25 weeks, with a maximum daily dose of 750 mg and a total dose not exceeding 11,250 mg. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor response and safety, and an end-of-study visit to assess final outcomes. Participants must meet specific inclusion criteria, such as having received at least two prior systemic therapies and having an ECOG performance status of ≤2. Conditions for early termination from the study include significant adverse events, disease progression, or withdrawal of consent.

The clinical trial involves the administration of **Lacutamab**, a monoclonal antibody, as the experimental medication. Lacutamab is provided in the pharmaceutical form of a **solution for injection/infusion**. The active substance, also known as **anti-KIR3DL2 monoclonal antibody** or **IPH-4102**, is a humanized IgG1 monoclonal antibody targeting the human KIR3DL2 receptor. The medication is administered via **intravenous infusion**. The dosing regimen specifies a maximum daily dose of 750 mg, with a cumulative maximum dose of 11,250 mg over a treatment period of up to 25 weeks. The trial does not include a pediatric formulation of Lacutamab.

In addition to the experimental treatment, the study may involve the use of standard-of-care therapies or comparator treatments as deemed necessary by the study protocol. These non-experimental treatments are not specified in the provided data but are typically used to evaluate the efficacy and safety of the experimental medication in comparison to existing therapeutic options. Participant compliance with the dosing schedule and administration route will be monitored throughout the trial to ensure adherence to the study protocol.

The efficacy of the clinical trial will be assessed primarily through the **Objective Response Rate (ORR)**, which is defined as the proportion of patients achieving a complete or partial response to the treatment. This primary endpoint will be evaluated to determine the effectiveness of Lacutamab, also known as IPH4102, in patients with advanced T-cell lymphoma. The ORR will be measured by central review, specifically for Cohort 1, to ensure consistent and unbiased assessment of disease response.

Secondary endpoints will include various measures to provide a comprehensive evaluation of the treatment's efficacy and safety. These include the duration of response, progression-free survival (PFS), and overall survival (OS). The duration of response will be calculated from the first documentation of objective response to the event of disease progression or death. PFS will be measured from the start of IPH4102 administration to documented progression or death from any cause, while OS will be measured from the start of IPH4102 administration to death from any cause.

Additional secondary endpoints will assess safety through adverse events (AEs), serious adverse events (SAEs), and changes in clinical laboratory evaluations and vital signs. Quality of life will be evaluated using patient-reported outcomes, including the VAS score for pruritus and the SkinDex29 questionnaire. Pharmacokinetic assessments will involve measuring individual IPH4102 serum concentrations, and the immunogenic potential of IPH4102 will be evaluated through immunogenicity results for each patient.