Comparison Between Local Radiotherapy Alone or Combined With Obinutuzumab in Early Stage Follicular Lymphoma: the GAZEBO Trial From the Fondazione Italiana Linfomi

Prospective, multicenter, open label, phase III randomized clinical trial in previously untreated Follicular Lymphoma in early stage (I-II non-bulky).

Patients will be randomized to receive:

• Involved-Site Radiation Therapy at standard dose 24Gy - standard arm

OR

• Involved-Site Radiation Therapy at standard dose 24Gy followed by Obinutuzumab 4 infusions weekly + 4 infusions every 3 weeks (8 total doses) - experimental arm

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 (Appendix 2)
• 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), 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 Independent 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

• 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 pre-pared 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

• practice effective barrier contraception during the entire study treatment period and through 3 months after the last dose of study drug, or
• 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)

Exclusion criteria

• Histological diagnosis of Follicular lymphoma grade IIIb
• 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 HC 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 HBVDNA 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
• 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.