IBRUTINIB for Mantle cell lymphoma

Inclusion criteria

• {"criterion_text":"- Patient is ≥ 18 years and < 80 years of age at the time of signing the informed consent form (ICF).\n- Stage II-IV disease, measurable with at least lymph node > 1.5 cm and requiring treatment in the opinion of the treating clinician\n- ECOG performance status of 0 – 2.\n- Life expectancy of more than 3 months.\n- For France: patient affiliated to any social security system\n- Patient understood and voluntarily signed and dated an ICF prior to any studyspecific assessments/procedures being conducted.\n- Patient willing and able to adhere to the study visit schedule and other protocol requirements\n- 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\n- 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.\n- 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)\n- Untreated MCL\n- Adequate renal function as demonstrated by a creatinine clearance > 50 mL/min; calculated by Cockcroft Gault formula or MDRD\n- 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)"}

Exclusion criteria

• {"criterion_text":"- 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.\n- Known history of human immunodeficiency virus (HIV)\n- 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\n- Psychiatric illness or condition which could interfere with their ability to understand the requirements of the study\n- 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\n- Pregnant, planning to become pregnant, or lactating woman\n- Known hypersensitivity to study treatment (CD20 Ab, Ibrutinib, Venetoclax) or to any of the excipients\n- Known allergy to xanthine oxidase inhibitors or rasburicase\n- Known G6DP deficiency\n- Known bleeding disorders\n- Severe prior reactions to monoclonal antibodies or with prior significant toxicity (other than thrombocytopenia) from Bcl-2 inhibitor\n- Impaired organ function (other than liver and renal) which will interfere with the treatment\n- 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\n- Anti-cancer therapies including chemotherapy, radiotherapy or other investigational therapy, including targeted small molecule agents\n- Biological agents (e.g. monoclonal antibodies) for anti-neoplastic intent: excluded 30 days prior to first dose of venetoclax\n- Person deprived of his/her liberty by a judicial or administrative decision\n- Adult person under legal protection\n- Hemoglobin level < 10g/dL; Neutrophil count <1 G/L; Platelets < 75 G/L (except if related to lymphoma then platelet must be >50),\n- Major surgery within 28 days before enrollment\n- Known central nervous system lymphoma\n- History of stroke or intracranial hemorrhage within 6 months prior to enrollment.\n- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumone)\n- Requires treatment with strong CYP3A inhibitors\n- Vaccinated with live, attenuated vaccines within 6 months of enrollment (except COVID vaccine)"}

Primary endpoints

• {"endpoint_text":"- The primary endpoint is the MRD negativity rate at the end of induction (after 6 cycles) in the informative MRD set using ddPCR technique. We expect to have an increase of 12% of the MRD negativity rate in each arm.","definition_or_measurement_approach":"MRD negativity rate at the end of induction (after 6 cycles) in the informative MRD set measured by droplet digital PCR (ddPCR)."}

Secondary endpoints

• {"endpoint_text":"- MRD response in PB and BM at the following timepoints: o C6 (qPCR +/- NGS +/- any other technique recommended by state of art) o C12 (ddPCR +/- NGS +/- any other technique recommended by state of art) o C24 (ddPCR +/- NGS +/- any other technique recommended by state of art) o Permanent treatment discontinuation (due to progression/relapse)","definition_or_measurement_approach":"MRD response in peripheral blood and bone marrow at specified cycles measured using qPCR, ddPCR, NGS or other recommended techniques as stated."}
• {"endpoint_text":"- MRD response in PB (ddPCR / NGS or any other technique recommended by state of art at the time of the analysis) at the following timepoints: C3 – C18 – C30 – C36 – C42","definition_or_measurement_approach":"MRD response in peripheral blood at specified cycles measured by ddPCR/NGS or other recommended technique."}
• {"endpoint_text":"- Overall response rate (Lugano response criteria 2014)","definition_or_measurement_approach":"Overall response rate assessed using Lugano 2014 response criteria."}
• {"endpoint_text":"- Complete response rate (Lugano response criteria 2014)","definition_or_measurement_approach":"Complete response rate assessed using Lugano 2014 response criteria."}
• {"endpoint_text":"- Overall Survival","definition_or_measurement_approach":"Overall survival measured from randomization to death from any cause."}
• {"endpoint_text":"- Progression Free Survival","definition_or_measurement_approach":"Progression-free survival measured from randomization to progression or death."}
• {"endpoint_text":"- Response duration","definition_or_measurement_approach":"Duration of response measured from initial documented response to progression or relapse."}
• {"endpoint_text":"- Duration of MRD negativity and delay from MRD positivity to clinical relapse","definition_or_measurement_approach":"Time duration of MRD-negative status and interval between MRD positivity and clinical relapse as measured by ddPCR/NGS or other technique."}
• {"endpoint_text":"- Disease free survival","definition_or_measurement_approach":"Disease-free survival measured from remission to relapse or death."}
• {"endpoint_text":"- Tolerability and safety of Ibrutinib/CD20 Ab and Ibrutinib/CD20 Ab/Venetoclax","definition_or_measurement_approach":"Safety and tolerability assessed by adverse event reporting and clinical/laboratory evaluations."}
• {"endpoint_text":"- Investigate peripheral blood stem cell collection after at least 12 cycles and a washout period of 4 weeks for venetoclax","definition_or_measurement_approach":"Assessment of feasibility/collection of peripheral blood stem cells after ≥12 cycles and 4-week venetoclax washout."}
• {"endpoint_text":"- The key secondary objective is to evaluate the Progression Free Survival at 3 years from randomization to progression or death from any cause.","definition_or_measurement_approach":"PFS at 3 years measured from randomization to progression or death from any cause."}

Belgium

Earliest CTIS Part Ii Submission Date

04-04-2024

Latest Decision Or Authorization Date

07-08-2025

Processing Time Days

490

Number Of Sites

5

Number Of Participants

8

France

Earliest CTIS Part Ii Submission Date

04-04-2024

Latest Decision Or Authorization Date

14-04-2026

Processing Time Days

740

Number Of Sites

34

Number Of Participants

60

Primary sponsor

Full Name

LYSARC

Organisation Type

Laboratory/Research/Testing facility

Country Of Registered Address

France