The goal of this clinical trial is to learn if surovatamig works better than standard of care involved-site radiotherapy (ISRT) with or without rituximab to treat patients with limited-stage follicular lymphoma. It will also learn about the safety of the drug.
The main questions it aims to answer is whether surovatamig can produce deeper and more durable responses, reduce the risk of disease relapse, and improve event-free survival.
Participants will:
1) Take surovatamig for 4 cycles. The first cycle will have a dose ramp up in 3 steps over a period of 14 days. Cycle 2-4 are for 28 days with drug administered every fortnight.
OR 2a) Undergo radiotherapy only for 3 weeks OR 2b) Radiotherapy + rituximab weekly for 6 doses (6 weeks)
Visit the clinic once every cycle, at the end of treatment, and be monitored every 3 months in year 1, every 6 months in year 2, and once a year from year 3-5 for checkups and tests.
Inclusion Criteria:
Patients or their legally authorised representative must voluntarily sign and date an informed consent form (ICF), approved by a Human Research Ethics Committee (HREC), prior to the initiation of any screening or trial-specific procedures.
Provide samples for optional genetic research that supports the Genomic Initiative.
Are willing and able to comply with procedures required in this protocol.
Age 18 years and older at the time of signing the informed consent form (ICF).
Must have histologically confirmed classical follicular lymphoma (FL) (previously Grade 1 to 3a FL) at the most recent representative tumour biopsy based on the local pathology report, according to the 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours.
Must have Ann Arbor Stage I or II, nodal, non-bulky disease (maximum tumour diameter less than or equal to 7 cm).
Previously untreated disease (no prior systemic lymphoma-directed therapies).
Has one or more target lesions:
Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
Patient must have adequate renal and liver function, unless values meeting the following criteria are related to lymphoma:
Patient must have adequate haematologic function:
Patients of child-bearing potential must have a negative serum pregnancy test 10 to 14 days prior to randomisation and again within 24 hours prior to Cycle 1 Day 1 (C1D1). The pregnancy test must be sensitive to at least 25 mIU/mL.
Women of child-bearing potential must agree to practise at least two protocol-specified methods of birth control, effective from 28 days prior to randomisation through at least 12 months after the last dose of trial drug. Female patients of non-child-bearing potential do not need to use birth control.
Male patients who are sexually active with female partners of child-bearing potential must agree, from 28 days prior to randomisation through 12 months after the last dose of trial drug, to practise the protocol-specified contraception, particularly using a latex or synthetic condom every time they have sexual intercourse with a partner of reproductive potential, even if they have undergone a successful vasectomy.
Exclusion Criteria:
Has a history of prior systemic or radiotherapy therapy for follicular lymphoma (FL).
Has prior or current follicular large B-cell lymphoma (World Health Organization [WHO] 2022 classification), formerly follicular lymphoma Grade 3B (WHO 2016 classification), histologic transformation to diffuse large B-cell lymphoma (DLBCL) or other aggressive lymphomas.
Known or suspected central nervous system (CNS) involvement at screening based on clinical presentation or imaging findings.
A history of severe allergic or anaphylactic reactions to any component or excipient of AZD486.
Has had major surgery within 14 days prior to the first dose of trial intervention (excluding biopsies) or anticipation of the need for major surgery during trial intervention.
Clinically significant cardiovascular disease, such as:
i. Uncontrolled unstable angina ii. New York Heart Association (NYHA) Class III-IV congestive heart failure iii. Uncontrolled life-threatening cardiac arrhythmia iv. Other clinically significant ECG abnormalities in the opinion of the investigator
History or presence of clinically relevant CNS pathology (based on investigator assessment) such as epilepsy, seizure, paresis, aphasia, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
Active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) requiring systemic therapy or antibiotics within 2 weeks prior to randomisation.
Human immunodeficiency virus (HIV) infection unless:
Active hepatitis B infection (detectable hepatitis B virus [HBV] deoxyribonucleic acid (DNA) or hepatitis B surface antigen [HBsAg]).
Active hepatitis C, defined by detectable hepatitis C RNA in plasma by polymerase chain reaction (PCR). Patients with resolved infection may participate if hepatitis C RNA is undetectable.
Received a live, attenuated vaccine within 28 days prior to initiation of trial treatment.
a. Patients must not receive live vaccines while receiving trial intervention and for at least 6 months after the last dose of surovatamig or rituximab, and until B-cell recovery is confirmed.
Active tuberculosis (TB) or history of completed treatment for active TB within the past 12 months.
a. Interferon-gamma release assay (IGRA) testing must be performed if TB is suspected.
History of other prior malignancies, except defined low-risk cases.
Current autoimmune disease requiring immunosuppressive therapy other than prednisolone less than 20 mg daily (or equivalent).
Current seizure disorder requiring therapy (patients with history must have complete CNS workup).
History of clinically significant medical or psychiatric conditions interfering with trial participation or safety.
Participation in another clinical trial with an investigational product within the last 28 days or 5 half-lives.
Female patient who is pregnant, breastfeeding, or planning pregnancy or egg donation during or 12 months after treatment.
Male patients planning to father a child or donate sperm during or 12 months after treatment.
This arm involves treatment with Surovatamig only with no radiotherapy. Treatment is in 3 phases. 1. Cycle 1 is a 14 day cycle including a triple step-up dosing: Day 1 of cycle 1: 0.09 mg, Day 4 of cycle 1: 0.27 mg, Day 8 of cycle 1: 1.0 mg. 2. Cycle 2-4 are 28 day cycles with a dose administered every 2 weeks: Cycles 2-4 (28-day cycle): Surovatamig treatment doses administered on days 1 and 15 of each cycle at 7.2mg. 3\. At the end of cycle 4, patients will enter the post-treatment period.
This arm is the standard of care (SOC): Involved-Site Radiotherapy (ISRT) at 24Gy and involves radiotherapy for 3 weeks.
This arm is another standard of care (SOC): Involved-Site Radiotherapy (ISRT) at 24Gy with 6 doses of rituximab administered weekly by intravenous (IV) at 375 mg/m\^2. 1 week = 1 cycle.
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