Phase II Evaluation of Tislelizumab Efficacy and Safety in De Novo Hodgkin Lymphoma Patients Ineligible for Standard Chemotherapy

Trial ID: 2022-503090-11-00
Protocol: FIL_Tisle-HL
Sponsor: Fondazione Italiana Linfomi Ets

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Diseases & Conditions

Hodgkin's disease

Objectives

The primary objective of this study is to evaluate the **efficacy** of **tislelizumab** as a frontline treatment in patients with untreated **Hodgkin lymphoma** who are deemed unsuitable for standard chemotherapy. This is measured in terms of the overall response rate (ORR), which is clinically relevant as it provides insight into the initial effectiveness of the treatment in inducing a response in this specific patient population.

Secondary objectives include evaluating the efficacy of tislelizumab through various measures determined by the investigator:

Duration of response (DoR)
Progression-free survival (PFS)
Overall survival (OS)
Disease-free survival (DFS)

Additionally, the study aims to assess the safety and tolerability of tislelizumab. These secondary objectives are crucial for understanding the long-term benefits and potential risks associated with the treatment, thereby informing clinical decision-making and patient management strategies.

Participants

The clinical trial focuses on evaluating the efficacy of **tislelizumab** as a frontline treatment for patients with untreated **Hodgkin lymphoma** who are considered unsuitable for chemotherapy. The study population includes both male and female participants aged 65 years and older. These individuals are ineligible for standard chemotherapy primarily due to medical comorbidities. Participants must have a histologically confirmed diagnosis of de novo classical Hodgkin lymphoma and exhibit measurable disease. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less and adequate organ and marrow function. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include treatment-naïve status and a life expectancy of at least six months. The trial does not specify any exclusion criteria beyond the outlined inclusion parameters.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of **tislelizumab** as a frontline treatment in patients with untreated **Hodgkin lymphoma** who are unsuitable for standard chemotherapy. This is a Phase II, open-label study, which means that both the researchers and participants are aware of the treatment being administered. The trial aims to assess the overall response rate (ORR) as the primary endpoint, with secondary endpoints including duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease-free survival (DFS), and the incidence and severity of adverse events.

The trial is expected to commence recruitment on November 1, 2023, and is estimated to conclude by March 1, 2029. Participants will be involved in the study for a maximum treatment period of 24 months, during which they will receive **tislelizumab** intravenously. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. Participants must meet specific inclusion criteria, such as having a histologically confirmed diagnosis of de novo classical Hodgkin lymphoma, being treatment-naïve, and having a life expectancy of at least six months. They must also be able to adhere to the study schedule and return for follow-up visits.

Conditions that may lead to early termination from the study include the occurrence of severe adverse events, disease progression, or withdrawal of consent by the participant. The study will ensure that all participants provide informed consent before any study-specific procedures are initiated. The trial will be conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

Treatment

The clinical trial involves the administration of **Tislelizumab**, an experimental medication, as a frontline treatment for patients with untreated Hodgkin Lymphoma who are considered unsuitable for standard chemotherapy. **Tislelizumab** is provided in the form of a **solution for infusion** and is administered **intravenously**. The maximum daily dose of **Tislelizumab** is 200 mg, with a total maximum dose of 7 grams over the course of the treatment. The treatment period is set to a maximum of 24 weeks. **Tislelizumab** is classified as an orphan drug, indicating its use in rare conditions. The active substance in **Tislelizumab** is a protein of other origin, specifically designed for this therapeutic purpose.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the efficacy and safety of **Tislelizumab**. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The study is conducted as an open-label trial, allowing for direct observation of the treatment effects without the use of blinding.

Efficacy

The efficacy of **tislelizumab** as a frontline treatment in patients with untreated Hodgkin Lymphoma (HL) unsuitable for standard chemotherapy will be assessed primarily through the overall response rate (ORR). The ORR is defined as the sum of complete response (CR) and partial response (PR) rates. Secondary endpoints include the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and disease-free survival (DFS). Additionally, the incidence and severity of adverse events during therapy and up to 90 days post-treatment, as well as serious adverse events from the signing of informed consent to the end of the study, will be evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically confirmed diagnosis of de novo classical Hodgkin Lymphoma (cHL)
Patients >= 65 years ineligible for frontline standard chemotherapy (mainly due to medical comorbidities)
Treatment naïve
Measurable disease defined as presence of both fluorodeoxyglucose-avid nodal involvement and at least one nodal target lesion measurable in two diameters (and at least 1.5 cm in its major diameter)
Indication for systemic treatment, i.e., all stages except IA without a large tumor burden, as radiotherapy is regarded curative in those patients
Eastern Cooperative Oncology Group (ECOG) performance status (PS) <= 2
Adequate organ and marrow function as defined below: Absolute neutrophil count (ANC) > 10 x 10^9/L (without growth factor support within 7 days of ANC measurement), unless due to bone marrow involvment by lymphoma; Platelet > 50 x 10^9/L (without growth factor support or transfusion within 7 days of platelets measurement), unless due to bone marrow involvment by lymphoma; Hemoglobin > 8 g/dL (prior transfusion is acceptable); Creatinine clearance ≥ 30 ml/min (as estimated by the Cockcroft-Gault equation or as measured by nuclear medicine scan or 24-hour urine collection); Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase, and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase ≤ 3.0 × upper limit of normal (ULN); Serum total bilirubin < 1.5 × ULN (or < 3 x ULN in case of documented Gilbert’s syndrome)
Life expectancy ≥ 6 months
Men must agree to use effective contraception if sexually active. This applies for the time period between signing of the informed consent form and 4 months after last tislelizumab dose.
Subject voluntarily signs and dates an informed consent form approved by an National Ethics Committee prior to the initiation of any screening or study-specific procedures, indicating that they understand the purpose of and procedures required for the study and are willing to participate in it
Subject must be able to adhere to the study visit schedule and other protocol requirements, and to return to enrolling institution for follow-up (during the active monitoring phase of the study)

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Exclusion Criteria

Nodular lymphocyte predominant HL
Hypersensitivity to tislelizumab or any of its excipients
Active central nervous system (CNS) involvement or leptomeningeal metastases involvement
Evidence of other clinically significant uncontrolled and/or active systemic infection (viral, bacterial or fungal), including active ongoing infection from SARS-CoV-2
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
Major surgery within 4 weeks of the first dose of study drug
Vaccination with a live vaccine within 4 weeks prior to the first dose of study drug
Clinically significant cardiovascular disease including the following: Myocardial infarction within 6 months before screening; Unstable angina within 3 months before screening; New York Heart Association Classification III or IV congestive heart failure; History of clinically significant arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes); QTcF > 480 msecs based on Fridericia’s formula; History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place; Uncontrolled hypertension as indicated by a minimum of 2 consecutive blood pressure measurements showing systolic blood pressure > 170 mm Hg and diastolic blood pressure > 105 mm Hg at screening
Significant history of neurologic, psychiatric, endocrinological, metabolic, immunologic, or hepatic disease that would preclude participation in the study or compromise ability to give informed consent
Any history of other active malignancies within 3 years prior to study entry, with the exception of adequately treated in situ carcinoma of the cervix uterine, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, previous malignancy confined and surgically resected with curative intent
Any previous treatment (including radiation therapy) for HL
History of severe hypersensitivity reactions to other monoclonal antibodies
Concurrent participation in another therapeutic clinical trial
Any active autoimmune disease requiring systemic treatment (including disease-modifying agents, corticosteroids, immunosuppressants) in the past 2 years. Note: Patients with the following diseases are not excluded and may proceed to further screening: type I diabetes under control; Hypothyroidism (provided it is managed with hormone replacement therapy only); Controlled celiac disease
Has known history of interstitial lung disease, non-infectious pneumonitis, pulmonary fibrosis, acute lung diseases or evidence of dyspnea at rest or pulse oximetry of < 92% while breathing room air
A history of previous exposure to anti-PD1, anti-PDL1 or anti-PDL2 or anti-CTLA-4 agents for any disease other than HL
Use of systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications ≤14 days from registration; Note: Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
Known infection with HIV, human T-cell lymphotropic virus-1, -2
Serologic status reflecting active hepatitis B defined as presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) (mandatory testing). Patients with occult or prior HBV infection (respectively defined as patient with HBsAg-/HBcAb+ and patients HBsAg+ with HBV DNA undetectable) are eligible, provided that they are willing to undergo prophylactic antiviral medication according to local standard of care. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination are eligible
Presence of hepatitis C virus (HCV) antibody (mandatory HCV antibody serology testing). Patients with presence of HCV antibody are eligible only if PCR is negative for HCV RNA