A Phase I/II Open-label, Multi-center Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD7789, an anti-PD-1 and anti-TIM-3 Bispecific Antibody, in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma

The primary objective of this study is to evaluate the **safety** and **tolerability** of sabestomig in participants with relapsed or refractory classical Hodgkin lymphoma (r/r cHL). This includes establishing the maximum tolerated dose or optimal biological dose and recommending a Phase 2 dose. The clinical relevance of this objective lies in determining the appropriate dosing regimen that maximizes therapeutic benefit while minimizing adverse effects, which is crucial for the development of effective treatment strategies for r/r cHL.

Secondary objectives include:

• Part A Dose Escalation: Assessing the preliminary antitumor activity of sabestomig in participants with r/r cHL.
• Part B Dose Expansion: Further assessing the preliminary antitumor activity of sabestomig and evaluating patient-reported treatment-related symptoms, overall side-effect impact, and global health status during treatment.
• Part A Dose Escalation and Part B Dose Expansion: Assessing the pharmacokinetics (PK) and immunogenicity of sabestomig in participants with r/r cHL.

These secondary objectives aim to provide insights into the therapeutic potential and patient experience associated with sabestomig, as well as its pharmacological profile, which are essential for understanding its overall efficacy and safety in the target population.

The clinical trial involves a total of **112 participants** diagnosed with **Relapsed/Refractory Classical Hodgkin Lymphoma**. The study population includes both male and female subjects, aged 16 years and older, with an Eastern Cooperative Oncology Group performance status of 0 or 1. Participants were selected based on their confirmed histological diagnosis of active relapse/refractory classical Hodgkin lymphoma and must have failed at least two prior lines of systemic therapy. The trial includes individuals who have adequate organ and bone marrow function and a minimum body weight of 40 kg. Both genders are represented, and the trial population includes vulnerable groups. Participants are required to adhere to specific lifestyle considerations, such as avoiding pregnancy or fathering children through highly effective methods of contraception. The selection criteria ensure that the study population is appropriate for assessing the safety and tolerability of the investigational drug, sabestomig, in this specific patient group.

The clinical trial is designed to evaluate the **safety**, tolerability, pharmacokinetics, and preliminary efficacy of AZD7789, a bispecific antibody targeting PD-1 and TIM-3, in patients with relapsed or refractory classical Hodgkin lymphoma. This study is structured as a Phase I/II open-label, multi-center trial. The trial is divided into two parts: Part A involves dose escalation to determine the maximum tolerated dose or optimal biological dose, while Part B focuses on dose expansion to further assess safety and preliminary antitumor activity. The trial is expected to conclude by September 30, 2025, with recruitment having commenced on March 10, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and prior treatment history. Follow-up visits will be scheduled to monitor safety, collect pharmacokinetic data, and assess treatment efficacy. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted. The expected duration of participant involvement will vary depending on individual response and tolerance to the treatment.

Participants may be withdrawn from the study early if they experience unacceptable adverse events, fail to comply with study procedures, or if the investigator deems it in the participant's best interest. The primary endpoints include the incidence of adverse events, dose-limiting toxicities, and changes in vital signs and laboratory parameters. Secondary endpoints focus on response rates, progression-free survival, and overall survival. The trial will also evaluate pharmacokinetic parameters and the incidence of anti-drug antibodies against sabestomig.

The clinical trial involves the administration of **AZD7789**, a bispecific IgG1 kappa/lambda monoclonal antibody targeting PD-1 and TIM-3, developed by AstraZeneca AB. This investigational drug is provided as a **solution for infusion** and is administered intravenously. The dosing schedule for AZD7789 is determined based on the phase of the trial, with the primary objective being to establish the maximum tolerated dose or optimal biological dose during the dose escalation phase. Participant compliance is monitored through regular assessments and infusion records.

**Paracetamol** is utilized as an auxiliary treatment in the trial. It is an **oral solution** administered orally, serving as an analgesic and antipyretic agent. The dosage and frequency of administration are aligned with standard clinical guidelines for pain and fever management, ensuring participant comfort and safety during the trial.

**Diphenhydramine** is also included as an auxiliary treatment, provided in the form of a **coated tablet** for oral administration. As an antihistamine, it is used to manage allergic reactions that may occur during the trial. The dosing schedule follows established protocols for antihistamine use, with participant adherence monitored through pill counts and participant diaries.

**Infliximab** is administered as a **powder for concentrate for solution for infusion**, delivered via intravenous infusion. This immunosuppressant is used to manage inflammatory responses and is dosed according to standard medical practices for its use in clinical settings. Infusion records and participant monitoring ensure compliance and safety.

**Tocilizumab** is provided as a **concentrate for solution for infusion** and is administered intravenously. It functions as an interleukin inhibitor, playing a role in managing immune responses. The dosing regimen is consistent with clinical guidelines for tocilizumab, with compliance monitored through infusion logs and participant assessments.

**Epinephrine** is included as an auxiliary treatment in the form of a **solution for injection**, administered intramuscularly. It serves as a hormone and neurotransmitter, primarily used for emergency management of severe allergic reactions. The administration is on an as-needed basis, with usage documented in participant records to ensure proper management of any adverse events.

The clinical trial aims to assess the efficacy of **sabestomig**, a bispecific antibody targeting PD-1 and TIM-3, in patients with relapsed or refractory classical Hodgkin lymphoma (cHL). Efficacy will be evaluated through several primary and secondary endpoints. In Part B Dose Expansion, the primary endpoints include the Objective Response Rate (ORR) for cohort B1, defined as the proportion of patients achieving complete or partial remission, and the Complete Response Rate (CRR) for cohort B2, defined as the proportion of patients achieving complete remission.

Secondary endpoints for both Part A Dose Escalation and Part B Dose Expansion include the Duration of Response (DoR), Duration of Complete Response (DoCR), and Progression-Free Survival (PFS) with landmarks at 12 and 24 months. Overall Survival (OS) will also be assessed at these timepoints. Patient-reported outcomes will be measured using tools such as the PRO-CTCAE or Peds-PROCTCAE for symptoms like diarrhea, rash, and fatigue, and the EORTC ILXX QL2 for quality of life and health status. Pharmacokinetic parameters, including maximum observed concentration, area under the concentration-time curve, clearance, and terminal elimination half-life, will be analyzed. Additionally, the incidence of anti-drug antibodies against sabestomig in serum will be monitored.