Follicular Lymphoma
Conditions
Brief summary
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.
Detailed description
What the study is about: This study will evaluate whether surovatamig, a novel CD19 × CD3 bispecific T-cell engager, can improve outcomes for people with previously untreated, limited-stage nodal follicular lymphoma (FL). The trial will compare surovatamig with the current standard of care: involved-site radiotherapy (ISRT) with or without rituximab. The aim is to determine whether surovatamig can produce deeper and more durable responses, reduce the risk of disease relapse, and improve event-free survival. Who is it for: This study is for adults aged 18 years or older who have: 1. Histologically confirmed classical follicular lymphoma (Grade 1-3a), Ann Arbor stage I or II nodal, non-bulky disease ( less or equal to 7 cm) 2. PET-positive, measurable disease 3. No prior lymphoma-directed therapy Study details: This is an international, Phase III randomised clinical trial. Participants will be randomised 1:1 on either Surovatamig (6 doses over 12 weeks with an additional triple step-up dosing schedule over 14 days for cycle 1) or to the standard of care treatment (Involved-Site Radiotherapy (24 Gy) with or without 6 doses of rituximab, according to each site's predefined standard). Participants will be followed up for 5 years after treatment to assess long-term outcomes. A total of 140 participants will be enrolled across Australia, New Zealand, the United Kingdom, Ireland and Nordic countries. What is hoped from it: If successful, surovatamig could represent a new standard of care for patients with early-stage nodal follicular lymphoma that is highly effective, well-tolerated, non-radiation frontline option for patients with limited-stage FL.
Interventions
DRUGSurovatamig
Surovatamig is supplied as a concentrate for solution for intravenous administration (2mg/mL).
RADIATIONInvolved Site Radiotherapy (ISRT)
24 Gray of ISRT
RADIATIONInvolved-Site Radiotherapy (ISRT) + Rituximab
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.
Sponsors
Australasian Leukaemia and Lymphoma Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients or their legally authorised representative must voluntarily sign and date an informed consent, approved by an HREC, prior to the initiation of any screening or trial specific procedures. 2. Are willing and able to comply with procedures required in this protocol. 3. Age 18 years and older at the time of signing the ICF 4. Must have histologically confirmed classical 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 WHO Classification of Haematolymphoid Tumours (excluding cutaneous and duodenal FL). 5. Must have Ann Arbor Stage I or II, nodal, non-bulky disease (maximum tumour diameter ≤7cm) 6. Previously untreated disease (no prior systemic lymphoma-directed therapies) 7. Has one or more target lesions: 1. A PET/CT scan demonstrating PET-positive lesion(s), and 2. ≥ 1 measurable nodal lesion (long axis \> 1.5cm) on CT scan or MRI 8. ECOG performance status 0-2 9. Patient must have adequate haematologic function: 1. ANC ≥ 1.0 x 10\^9/L 2. Haemoglobin ≥ 90 g/L 3. Platelet count ≥ 100 x 10\^9/L 10. Patient must have adequate renal and liver function, unless values meeting the following criteria are related to lymphoma): 1. Serum AST or ALT ≤ 3.0 × ULN 2. Total Bilirubin ≤ 1.5 × ULN; subjects with Gilbert's syndrome may have total bilirubin levels \> 1.5 x ULN, but conjugated (direct) bilirubin must be ≤ 2 x ULN 3. Estimated CrCl ≥ 30 mL/min (as calculated by Cockcroft-Gault Formula) 11. 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 toC1D1. The pregnancy test must be sensitive to at least 25 mIU/ml. 12. Women of childbearing potential must agree to practice at least 2 protocol-specified methods of birth control, that are effective from 28 days prior to randomisation through at least 12 months after the last dose of trial therapy. Female patients of non-childbearing potential do not need to use birth control. 13. Male patients who are sexually active with female partner(s) of childbearing potential, must agree, from 28 days prior to randomisation through 12 months after the last dose of trial therapy, to practice the protocol-specified contraception, particularly 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
1. Has a history of prior systemic therapy or radiotherapy for FL. 2. Has prior or current Follicular large B-cell lymphoma (WHO 2022 classification), formerly Follicular lymphoma Grade 3B (WHO 2016 classification), histologic transformation to DLBCL or other aggressive lymphomas. 3. Inadequately staged follicular lymphoma (unable to perform staging imaging or bone marrow trephine length totalling \<20mm) 4. Known or suspected CNS involvement at screening based on clinical presentation or imaging findings. 5. Prior exposure to surovatamig or a history of severe allergic or anaphylactic reactions to any component or excipient of surovatamig 6. Has had major surgery within 14 days prior to the first dose of trial intervention (excluding biopsies) pr anticipation of the need for major surgery during trial intervention 7. Relative contraindications for radiotherapy 1. Non-rheumatoid collagen vascular disorders involving the potential radiation field 2. Radiation field that may impact on Cardiac implantable electronic devices (CIEDs). 3. Previous radiation therapy to the same site. 8. Clinically significant cardiovascular disease, such as: 1. Myocardial infarction within ≤ 12 weeks or stroke within 6 months prior to randomisation 2. Screening 12-lead ECG showing a baseline QT interval as corrected by Frederica's formula (QTcF) \> 480 msec 3. The following conditions within 3 months prior to randomisation: 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 9. History or presence of clinically relevant CNS pathology which, based on Investigator assessment, may prevent, limit, or confound the protocol-specified assessments of neurotoxicity. This may include current seizure disorder requiring therapy, major cerebrovascular ischemia/haemorrhage, aphasia, severe brain injuries, severe dementia, severe Parkinson's disease, or cerebellar disease. Note: patients with history of seizure disorder must have complete CNS workup 10. History of other prior malignancies, except: 1. Malignancy treated with curative intent and with no known active disease present for ≥2 years before the first dose of trial therapy and felt to be at low risk for recurrence by treating physician. 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. 3. Adequately treated carcinoma in situ without evidence of disease. 4. Localized prostate cancer, post-radical prostatectomy or with non-rising prostate-specific antigen levels \< 0.1 ng/mL. 11. Current autoimmune disease requiring immunosuppressive therapy other than prednisolone \<10 mg daily (or equivalent) 12. Known history of hemophagocytic lymphohistiocytosis / macrophage activation syndrome (HLH/MAS) or HLH-like syndrome. 13. Active bacterial, viral (including EBV infections), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) requiring systemic therapy or antibiotics within 2 weeks prior to randomisation. COVID-19 infection needs to resolve to Grade ≤1 before commencing on treatment. 14. HIV infection unless: 1. Patients with an HIV infection who are on effective anti-retroviral therapy with undetectable viral load within 6 months prior to trial entry are eligible for this trial. 2. HIV RNA will be monitored during the trial as clinically indicated. 15. Active hepatitis B infection (defined as the presence of detectable HBV DNA or HBs antigen). 1. Patients who are HBcAb positive but are HBV DNA and HBsAg negative are eligible. 2. If receiving surovatamig or rituximab, patients with HBcAb positive will have 12 weekly monitoring of HBV DNA for the duration of treatment and for 12 months following last dose of either therapy. These patients will receive appropriate anti-viral prophylaxis, with entecavir or similar, according to advice from the infectious disease service. 3. Patients who are HBcAb positive and received ISRT alone do not require HBV DNA monitoring. 4. Please note that patients who have received IVIG may have false positive HBcAb results. In such patients, if HBV DNA and HBsAg are negative, prophylaxis may be omitted if felt un-necessary by the infectious disease service, but monitoring of HBV DNA levels is still required. 16. Active hepatitis C, defined by the detection of hepatitis C RNA in plasma by PCR. Patients who have received treatment for hepatitis C that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable. 17. Received a live, attenuated vaccine within 28 days prior to initiation of trial treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg. FluMist) are live, attenuated vaccines and are not allowed. Experimental and/or non-authorized SARS-CoV-2 vaccinations are not allowed. a. NOTE: Patients should not receive live vaccine while receiving trial intervention and for a period of at least 6 months after the last dose of surovatamig or rituximab, and until B-cell recovery within a normal range is confirmed. 18. Active TB or history of completed treatment for active TB within the past 12 months - Note: IGRA testing must be performed if active or latent TB is suspected (e.g., clinical signs and symptoms of TB, contact history, or if the subject lives in or has travelled to or lived in the WHO high TB burden countries). For subjects with positive IGRA, active pulmonary TB must be excluded with clinical evaluation and radiologic imaging. Subjects with positive IGRA and no evidence of active disease may be enrolled after treatment for latent TB infection (recommend isoniazid monotherapy for a total of 6 months) has been initiated. 19. History of clinically significant medical conditions, psychiatric conditions or any other reason that the investigator determines would: 1. Interfere with individual participation in this trial OR 2. Places the patient at an unacceptably high risk for toxicities OR 3. Would make the patient an unsuitable candidate to receive trial therapy OR 4. could interfere with evaluation of the trial intervention or interpretation of patient safety or trial results 20. Participation in another clinical trial (for a separate medical comorbidity) with an investigational product administered within the last 28 days or 5 half-lives (of that agent), whichever shorter 21. Female patient who is pregnant or breastfeeding or is considering becoming pregnant or donating eggs during the trial or for approximately 12 months after the last dose of trial therapy. 22. Male patients who are considering fathering a child or donating sperm during the trial or for approximately 12 months after the last dose of trial therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival | Time from date of randomisation until disease progression until end of 5 year follow up. | Defined as death from any cause, failure to achieve complete response (CR) at End-of-Treatment ((EoT); defined as 18 weeks from start of treatment), initiation of new anti-lymphoma treatment (including new RT) or disease progression (based on Lugano 2014 Response Criteria), whichever comes first |
Contacts
PRINCIPAL_INVESTIGATORChan Cheah
Sir Charles Gairdner Hospital
Outcome results
None listed