VENETOCLAX for Chronic lymphocytic leukemia

Inclusion criteria

• {"criterion_text":"- CLL diagnosed according to IWCLL criteria within one year prior to randomization\n- Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration (signature date on informed consent).\n- Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.\n- Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 30 days after the last dose of investigational drugs.\n- Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.\n- Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information.\n- High risk of infection and/or progressive treatment within 2 years according to CLL-TIM\n- IWCLL treatment indication not fulfilled\n- Life expectancy > 2 years\n- Age at least 18 years\n- Ability and willingness to provide written informed consent and adhere to study procedures and treatment\n- Adequate bone marrow function as indicated by platelets above 100 x 10E9, hemoglobin above 10 g/dL and neutrophils above 1 x 10E9\n- Creatinine clearance above 30 mL/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault\n- Adequate liver function as indicated by a total bilirubin≤ 2 x, AST or ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome."}

Exclusion criteria

• {"criterion_text":"- Prior CLL treatment (including monoclonal antibodies, chemotherapy, small molecules, including CD20 antibodies, BTK inhibitors and bcl-2 inhibitors for any indication)\n- History of clinically significant cardiovascular disease such as arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening (counting from signature date on informed consent), or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening.\n- History of stroke or intracranial hemorrhage within 6 months prior to (signature date on informed consent).\n- Use of investigational agents which might interfere with the study drug within 28 days prior to first day of treatment/C1D1.\n- Vaccination with live vaccines within 28 days prior to first day of treatment/C1D1.\n- Major surgery less than 30 days before start of treatment. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.\n- Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.\n- Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly).\n- Fertile men or women of childbearing potential unless: surgically sterile or ≥ 2 years after the onset of menopause or willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 30 days after the end of study treatment.\n- Legal incapacity.\n- Persons who are in dependence to the sponsor or an investigator\n- Transformation of CLL (Richter’s transformation)\n- Persons not considered fit for the trial by the investigator\n- Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.\n- Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) > 2x ULN.\n- Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.\n- Previous autoimmune disease as AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura) treated with immune suppression or uncontrolled AIHA or ITP\n- History of progressive multifocal leukoencephalopathy\n- HIV infection (a negative test required)\n- Known active infection\n- Malignancies other than CLL requiring systemic therapies (except anti-hormonal therapies) or considered to impact survival\n- Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonists\n- History of bleeding disorders or current platelet inhibitors or anticoagulant therapy"}

Primary endpoints

• {"endpoint_text":"- Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm 12 weeks after finishing treatment (24 weeks after treatment initiation). This is a non-inferiority analysis as detailed in statistical analysis plan to assure safety of the combination treatment in this preemptive trial population.","definition_or_measurement_approach":"Measured as grade ≥3 infection-free survival comparing treatment vs observation at 12 weeks after finishing treatment (24 weeks after treatment initiation); analysed as a non-inferiority comparison according to the statistical analysis plan."}

Secondary endpoints

• {"endpoint_text":"- Grade ≥3-infection free, CLL-treatment-free survival at end of treatment, 1 year and 2 years after enrollment","definition_or_measurement_approach":"Measured as grade ≥3 infection-free and CLL-treatment-free survival assessed at end of treatment, at 1 year and at 2 years after enrollment."}
• {"endpoint_text":"- Overall survival and cause of death","definition_or_measurement_approach":"Overall survival measured as time to death; cause of death recorded."}
• {"endpoint_text":"- Treatment free survival","definition_or_measurement_approach":"Measured as time from randomization/enrollment to start of subsequent CLL treatment."}
• {"endpoint_text":"- Rate and CTCAE grade of infections","definition_or_measurement_approach":"Infection incidence and severity graded using CTCAE v5.0."}
• {"endpoint_text":"- Response rate and duration according to IWCLL criteria","definition_or_measurement_approach":"Response rate and duration assessed per IWCLL response criteria."}
• {"endpoint_text":"- Treatment related adverse events, type, frequency and severity during and for 2 years after treatment","definition_or_measurement_approach":"Adverse events recorded, categorized by type, frequency and severity (likely CTCAE) during treatment and for 2 years post-treatment."}
• {"endpoint_text":"- Immune function as assessed by immune phenotyping, functional TruCulture assays and measurements of cytokine levels","definition_or_measurement_approach":"Immune function assessed using immune phenotyping, TruCulture functional assays and cytokine quantification."}

Other endpoints

• {"endpoint_text":"- MRD levels in bone marrow and peripheral blood\n- Quality of life during and for 2 years after treatment, QLQC30 and CLL16","definition_or_measurement_approach":"MRD measured in bone marrow and peripheral blood (method not specified); QoL assessed using EORTC QLQ-C30 and CLL16 questionnaires at specified timepoints during treatment and up to 2 years after treatment."}

Denmark

Earliest CTIS Part Ii Submission Date

24-05-2024

Latest Decision Or Authorization Date

10-03-2025

Processing Time Days

290

Number Of Sites

3

Number Of Participants

30

Sweden

Earliest CTIS Part Ii Submission Date

24-05-2024

Latest Decision Or Authorization Date

11-03-2025

Processing Time Days

291

Number Of Sites

2

Number Of Participants

15

Netherlands

Earliest CTIS Part Ii Submission Date

24-05-2024

Latest Decision Or Authorization Date

17-03-2025

Processing Time Days

297

Number Of Sites

3

Number Of Participants

5

Primary sponsor

Full Name

Rigshospitalet

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Denmark

Third parties

• {"country":"Denmark","full_name":"GCP-unit at Copenhagen University Hospital","duties_or_roles":"sponsorDuties code 1","organisation_type":"Health care"}
• {"country":"Denmark","full_name":"GCP-enheden ved Aalborg og Aarhus Universitetshospitaler","duties_or_roles":"sponsorDuties code 1","organisation_type":"Health care"}