An open-label, randomized phase III trial comparing local radiotherapy alone or combined with Obinutuzumab in early stage Follicular Lymphoma: the GAZEBO Trial from the Fondazione Italiana Linfomi

Trial ID: 2022-502775-29-01
Sponsor: Fondazione Italiana Linfomi Ets

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Diseases & Conditions

Follicular lymphoma

Objectives

The primary objective of this study is to evaluate the **superiority** in terms of Progression-Free Survival (PFS) for the combination of radiotherapy and obinutuzumab (experimental arm) compared to radiotherapy alone (standard arm) in patients with early stage Follicular Lymphoma. This is clinically relevant as it aims to determine whether the addition of obinutuzumab can enhance treatment efficacy, potentially leading to improved patient outcomes in terms of delaying disease progression.

Secondary objectives include:

Comparing the response rate and the duration of response between the two treatment arms.
Assessing the toxicity and safety profile of the experimental treatment arm.
Evaluating the risk of transformation in both arms.
Investigating the presence or absence of t(14;18) rearrangement by FISH and the expression of selected tumor and microenvironment-related genes.
Exploring the role in survival and response of conventional Minimal Residual Disease (MRD) and MRD on plasmatic circulating tumor deoxyribonucleic acid (ctDNA) at different time points.
Investigating the role on survival of different thresholds of the quantitative PET indexes (QPI) at baseline, including SUVmax, Metabolic Tumor Volume (MTV), and Total Lesion Glycolysis (TLG).
Exploring the role of liquid biopsy, specifically lymphoma mutations on plasmatic ctDNA, at different time points.
Assessing the survival and response associated with radiomic analysis, evaluated on both CT and PET images (multimodal analysis).
Correlating the MRD results with radiomics results and survival.
Evaluating the role of the genotype at diagnosis and at relapse.
Investigating the role of liquid biopsy in anticipating clonal evolution.
Assessing the long-term outcome of the patients.

Participants

The clinical trial focuses on individuals diagnosed with **early stage Follicular Lymphoma**, specifically targeting those with histologically documented Follicular Lymphoma grade I-IIIA. The study population includes both male and female participants aged 18 years and older. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, ensuring they are in a relatively stable health condition. The trial does not involve a vulnerable population. The selection criteria emphasize adequate renal and hepatic function, as well as a life expectancy of at least three months. Participants must have a negative bone marrow biopsy and meet specific fertility and pregnancy prevention criteria. The trial does not provide information on the total number of participants, as this data was not disclosed by the sponsor. Lifestyle considerations such as diet and physical activity are not specified in the available data. The trial population was selected based on specific medical and diagnostic criteria, including the presence of measurable nodal disease and a negative pregnancy test for women of childbearing potential.

Plans and Procedures

The clinical trial is designed as an open-label, randomized, phase III study to evaluate the efficacy of combining local radiotherapy with **obinutuzumab** versus radiotherapy alone in patients with early-stage **Follicular Lymphoma**. The primary objective is to assess the superiority of the combination therapy in terms of progression-free survival (PFS). The trial is expected to commence recruitment in December 2023 and conclude by March 2031. Participants will be randomly assigned to either the experimental arm receiving both radiotherapy and obinutuzumab or the standard arm receiving only radiotherapy. The study is not categorized as low intervention due to the investigational medicinal product not being authorized for monotherapy in this indication.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as histological diagnosis, performance status, and adequate organ function. The inclusion visit will involve baseline assessments, including imaging and laboratory tests. Follow-up visits will be scheduled at regular intervals to monitor treatment response, adverse events, and compliance with the study protocol. The end-of-study visit will occur after the completion of the treatment period, which is a maximum of 16 weeks, to evaluate the final outcomes and collect data on secondary endpoints such as complete response rate and overall response rate.

The expected duration of participant involvement is approximately 16 weeks, with additional follow-up for long-term outcomes. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. Participants must adhere to the study visit schedule and protocol requirements, including contraceptive measures for those of childbearing potential. The trial will utilize intravenous administration of the investigational product, with a maximum daily dose of 1000 mg. The study aims to provide valuable insights into the potential benefits of combining radiotherapy with obinutuzumab in this patient population.

Treatment

The clinical trial involves the use of **Gazyvaro**, a **concentrate for solution for infusion** containing the active substance **obinutuzumab**. This experimental medication is a **monoclonal antibody** designed for intravenous administration. The pharmaceutical form is a solution for infusion, and the maximum daily dose is 1,000 mg. The treatment period extends up to 16 weeks, with the dosing schedule determined by the study protocol. Obinutuzumab is a protein-based therapeutic agent, and its administration is monitored to ensure participant compliance. The product is not a pediatric formulation and is authorized under the marketing authorization number EU/1/14/937/001 by Roche Registration GmbH.

In this trial, the experimental arm involves the combination of local radiotherapy with obinutuzumab, while the standard arm consists of local radiotherapy alone. The objective is to evaluate the superiority of the combination therapy in terms of Progression-Free Survival (PFS) in patients with early-stage **Follicular Lymphoma**. The trial is open-label and randomized, ensuring that the allocation of treatments is unbiased and that the outcomes are assessed objectively. Compliance with the dosing schedule and administration route is critical for the integrity of the trial results.

Efficacy

The efficacy of the clinical trial will be assessed primarily through **Progression-Free Survival (PFS)**, comparing the experimental arm, which combines radiotherapy with obinutuzumab, against the standard arm of radiotherapy alone. Secondary endpoints include a range of measures to provide a comprehensive evaluation of treatment impact. These include the Complete Response (CR) rate according to international criteria, Overall Response Rate (ORR) at each treatment phase, Disease-Free Survival (DFS), and Event-Free Survival (EFS). Additionally, the trial will assess Molecular Response, reported as Minimal Residual Disease (MRD) negativity at the end of treatment for patients who were positive at baseline, and the Rate of Adverse Events categorized by the latest version of NCI CTCAE.

Further secondary endpoints involve the prognostic and predictive impact on PFS in the presence or absence of the t(14;18) rearrangement, expression of selected tumor and microenvironment-related genes, and the prognostic role of conventional MRD and MRD on plasmatic circulating tumor DNA (ctDNA) at various time points. The trial will also evaluate the prognostic and predictive value of different thresholds of metabolic response expressed as quantitative PET indexes at baseline, the role of liquid biopsy at different time points, and the value of radiomic analysis on CT and PET images. Correlations between MRD results, radiomics, and clinical outcomes, as well as associations between genotype at diagnosis and relapse, and between liquid biopsy in anticipating clonal evolution, will also be explored.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histological documented diagnosis of Follicular Lymphoma grade I-IIIA as defined in the 2017 edition of World Health Organization (WHO).
Ann Arbor Stage IA or IIA (includible in one radiation field), or IE, non-bulky (<7 cm). Stage must be determined by PET/CT scan.
Patients performing PET before surgery can also be enrolled without repeating PET after surgery.
No previous treatment except for steroid pre-treatment.
FLIPI < 2, FLIPI2 ≤ 2.
Age ≥ 18 years.
Negative bone marrow biopsy.
Qualitative/quantitative PCR centralized assessment of BCL2/IGH positive cells in peripheral blood (PB) and bone marrow (BM).
Centralized revision of the lymph node biopsy with FISH for t(14;18).
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.
At least one site of measurable nodal disease pre-biopsy ≥ 2.0 cm in the longest transverse diameter as determined by CT scan or ultrasonography.
Adequate renal function defined as follows: • Creatinine clearance ≥ 40 mL/min (Cockcroft–Gault formula).
Adequate hepatic function per local laboratory reference range as follows: • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x UNL • Bilirubin ≤1.5 x UNL (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin).
Subject understands and voluntarily signs an informed consent form approved by an National Ethics Committee (NEC), prior to the initiation of any screening or study-specific procedures.
Subject must be able to adhere to the study visit schedule and other protocol requirements.
Life expectancy ≥ 3 months.
Fertility and pregnancy prevention criteria a. Women must be: • postmenopausal for at least 1 year (must not have had a natural menses for at least 12 months) • surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), • completely abstinent (periodic abstinence from intercourse is not permitted) or if sexually active, be practicing a highly effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method (e.g.: condoms, diaphragm, or cervical cap, with spermicidal foam, cream, or gel, male partner sterilization) as local regulations permit, before entry, and must agree to continue to use the same method of contraception throughout the study. They must also be prepared to continue birth control measures for at least 18 months after terminating treatment. • Women of childbearing potential must have a negative pregnancy test at screening • Men with female partners of childbearing potential: men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of study treatment. Men must refrain from donating sperm for the same period • Male even if surgically sterilized (i.e., status post vasectomy) must agree to 1 of the following o practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of study drug, or o agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence e.g., calendar, ovulation, symptothermal, post ovulation methods for the female partner] and withdrawal are not acceptable methods of contraception).

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Exclusion Criteria

Histological diagnosis of Follicular lymphoma grade IIIb.
Any history of other active malignancies within 3 years prior to study entry, except for 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.
Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: • Uncontrolled and/or active systemic infection (viral, bacterial or fungal) • Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.
If female, the patient is pregnant or breast-feeding.
Patients participating in other clinical studies.
Staging >II or B symptoms or bulky disease (> 7 cm).
Stage II with distant involved sites, not includible in a single radiation field.
Primary cutaneous follicular lymphoma.
Known HIV positivity.
Positive serology for hepatitis C (HC) defined as a positive test for HCAb, in which case reflexively perform a HCV RNA on the same sample to confirm the result, if negative, the patient is eligible.
Positive serology for hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a quantitative HBV-DNA test will be performed and if positive the subject will be excluded. Patients with HBcAb positivity and negative HBV DNA should be prophylactically treated with oral Lamivudine (100 mg /day). Note: subjects with serologic evidence of prior vaccination to HBV (i.e., hepatitis B surface (HBs) antigen negative, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
Central Nervous System (CNS) involvement with lymphoma.
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.
History of severe or life-threatening allergic or anaphylactic reactions to humanized or murine monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
Known hypersensitivity to biopharmaceuticals produced in Chinese Hamster Ovary cells or any component of Obinutuzumab
Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to start of treatment, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities
Active autoimmune disease requiring treatment