OASIS II - A randomized phase II trial evaluating Ibrutinib plus CD20 Ab and Ibrutinib-Venetoclax plus CD20 Ab in patients with untreated mantle cell lymphoma

Prior treatment

• 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. Note: subjects with serologic evidence of prior vaccination to HBV (i.e. HBs antigen negative, anti-HBs antibody + and antiHBc antibody -) and subjects with anti- HB-core antibody that are HBV DNA negative may participate
• Severe prior reactions to monoclonal antibodies or with prior significant toxicity (other than thrombocytopenia) from Bcl-2 inhibitor
• Anti-cancer therapies including chemotherapy, radiotherapy or other investigational therapy, including targeted small molecule agents
• Biological agents (e.g. monoclonal antibodies) for anti-neoplastic intent: excluded 30 days prior to first dose of venetoclax
• Major surgery within 28 days before enrollment
• History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
• Requires treatment with strong CYP3A inhibitors

Other illness

• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
• Known history of human immunodeficiency virus (HIV)
• Psychiatric illness or condition which could interfere with their ability to understand the requirements of the study
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’ opinion, could compromise the patient safety, interfere with the absorption or metabolism of treatment (Ibrutinib, CD20 Ab, venetoclax) or put the study outcomes at undue risk
• Known hypersensitivity to study treatment (CD20 Ab, Ibrutinib, Venetoclax) or to any of the excipients
• Known allergy to xanthine oxidase inhibitors or rasburicase
• Known bleeding disorders
• History of prior other malignancy with the exception of: - curatively treated basal cell carcinoma - curatively treated squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study - other curatively treated cancer and patient disease-free for over 5 years
• Vaccinated with live, attenuated vaccines within 6 months of enrollment (except COVID vaccine)

Lab values

• Hemoglobin level < 10g/dL; Neutrophil count <1 G/L; Platelets < 75 G/L (except if related to lymphoma then platelet must be >50),

Other

• Pregnant, planning to become pregnant, or lactating woman
• Known G6DP deficiency
• Impaired organ function (other than liver and renal) which will interfere with the treatment
• Person deprived of his/her liberty by a judicial or administrative decision
• Adult person under legal protection
• Known central nervous system lymphoma
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumone)

• Patient is ≥ 18 years and < 80 years of age at the time of signing the informed consent form (ICF).
• Stage II-IV disease, measurable with at least lymph node > 1.5 cm and requiring treatment in the opinion of the treating clinician
• ECOG performance status of 0 – 2.
• Life expectancy of more than 3 months.
• For France: patient affiliated to any social security system
• Patient understood and voluntarily signed and dated an ICF prior to any studyspecific assessments/procedures being conducted.
• Patient willing and able to adhere to the study visit schedule and other protocol requirements
• Women of childbearing potential must have negative results for pregnancy test prior to study treatment start and agree to abstain from breastfeeding during study participation and at least 18 months after the last drug administration
• Men or women of reproductive potential agree to use highly effective method of contraception (failure rate of less than 1%) during treatment and for eighteen months after the last drug administration.
• Histologically confirmed (according to the WHO classification) mantle cell lymphoma. The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cyclin D1 or the t(11;14) translocation (by cytogenetics and/or FISH and/or BCL1-IgH PCR)
• Untreated MCL
• Adequate renal function as demonstrated by a creatinine clearance > 50 mL/min; calculated by Cockcroft Gault formula or MDRD
• Adequate hepatic function per local laboratory reference range as follow: o Aspartate transaminase (AST) and alanine transaminase (ALT) < 3.0 x upper limit of normal (ULN) o Bilirubin < 1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin)