A study aimed at Optimise and Personalise Immunological Therapy of relapsed chronic lymphocytic leukaemia patients (OPTIC)

Prior treatment

• Vaccination with a live vaccine < 28 days before starting treatment.
• Patients who received strong and moderate CYP3A inhibitors and/or CYP3A inducers within 7 days prior to the first dose of venetoclax; patients who consumed grapefruit, grapefruit products, Seville oranges (including Seville orange marmalade), or star fruit within 3 days prior to the first dose of venetoclax.
• Patients who require warfarin (due to potential drug-drug interactions that could potentially increase warfarin exposure). Patients may be eligible if it is possible to discontinue warfarin and initiate treatment with an alternative anticoagulant.
• Patients with any of the following conditions: ● New York Heart Association functional classification III or IV for congestive heart failure. ● History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment. ● Recent infection requiring systemic therapy; antibiotic treatment must be discontinued > 14 days before the first dose of study drug. ● Ischemic or hemorrhagic stroke or transient ischemic attack within the last 6 months prior to the screening visit. ● Diagnosed active chronic hepatitis C infection. ● Positive hepatitis B serology, defined as a positive hepatitis B surface antigen (HBsAg) test result. In addition, if the HBsAg test is negative but the hepatitis B core antibody (HBcAb) test is positive (regardless of hepatitis B surface antibody [HBsAb] status), a hepatitis B deoxyribonucleic acid (DNA) test will be performed, and if the test is positive, the participant will be ineligible for the study; if the hepatitis B DNA test is negative (i.e., undetectable viral load), the participant will be ineligible for the study. If the patient is HBsAg negative, HBcAb positive, and hepatitis B DNA negative, prophylactic antiviral therapy or careful monitoring for HBV reactivation should be considered. Patients who have a protective HBsAb titer after vaccination or who have previously had but recovered from hepatitis B may be eligible.

Other illness

• Known positive serological test results for human immunodeficiency virus (HIV), due to potential drug interactions between antiretroviral medications and the drugs used in the study.
• Active hepatitis C, defined by detectable hepatitis C ribonucleic acid (RNA) in plasma by polymerase chain reaction (PCR).
• Malabsorption syndrome or other condition that prevents enteral administration of the drug.
• Impairment of specific organ/system function on a scale of 4 as defined by the CIRS, limiting the ability to follow the treatment regimen in this study, excluding eyes, ears, nose, throat (note that patient symptoms related to CLL should not be included in the screening CIRS score). When assigning points for certain disease states (e.g., pulmonary embolism), investigators should familiarize themselves with the general principles of severity grading and organ categories and consider the level of disease severity associated with the patient's condition.
• Diagnosed chronic obstructive pulmonary disease (COPD) (defined as forced expiratory volume in 1 second [FEV1] <50% of predicted normal).
• History of persistent asthma or poorly controlled asthma within the last 2 years (controlled intermittent asthma or controlled mild persistent asthma are acceptable).
• Active systemic infection (viral, bacterial and fungal).

Lab values

• Other serious acute or chronic medical or psychiatric conditions or laboratory abnormalities that, in the opinion of the investigator, may pose a risk associated with participation in the study or with the administration of the study medication or may affect the interpretation of the study results and/or cause the patient to be ineligible for the study.

Age

• History of other malignancies that could affect protocol adherence or interpretation of results. ● Patients who have previously undergone surgical treatment for basal or squamous cell carcinoma, stage 1 melanoma, or carcinoma in situ of the cervix are eligible. ● Patients with malignancies that have been treated solely with surgical intervention with curative intent will be included. Individuals with documented treatment-free remission for ≥2 years prior to study entry may be included at the investigator's discretion.

Other

• Richter's transformation confirmed by biopsy.
• The patient is pregnant or breastfeeding.
• Central nervous system involvement in the course of CLL.

• Age> 18 years old.
• Normal liver function, according to the local laboratory reference range for screening, as indicated by: ● AST and ALT ≤ 2.5 × ULN ● Total bilirubin ≤ 1.5 × ULN (or ≤ 3 × ULN in patients with documented Gilbert's syndrome).
• No active hemolytic anemia requiring immunosuppressive or other pharmacological treatment. Patients with a positive Coombs test but no evidence of hemolysis are NOT excluded from the study.
• No current use of corticosteroids. EXCEPTION: Low-dose steroids (< 10 mg prednisone or equivalent dose of another steroid) are permitted for the treatment of non-hematological conditions (e.g., chronic adrenal insufficiency).
• No prior autoimmune complications (e.g., autoimmune hemolytic anemia or immune thrombocytopenia) that have developed since the initial diagnosis of CLL and required treatment with high-dose corticosteroids (e.g., equivalent to > 20 mg of prednisone daily), monoclonal antibody-based therapy, or chemotherapy. Previous use of corticosteroids for reasons other than the treatment of autoimmune complications of CLL is permitted.
• No major surgery within 4 weeks (28 days) of the first dose of study drug or minor surgery within 3 days of the first dose of study drug.
• No radiotherapy ≤ 4 weeks prior to study treatment.
• The patient must be able to take a xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis.
• A negative pregnancy test result (serum βHCG concentration) is required for women of reproductive age (including premenopausal women who have had tubal ligation) and for all women who do not meet the definition of postmenopausal (≥ 24 months of amenorrhea) and who have not undergone surgical sterilization through hysterectomy and/or bilateral oophorectomy for other medical reasons. For all other women, documentation confirming that the patient is not of reproductive age must be provided in the medical history. ● Patients who are not surgically sterile or postmenopausal must agree to the simultaneous use of two reliable forms of contraception or to complete abstinence from heterosexual intercourse during the study. ● Men must agree to use a latex condom during sexual contact with women of reproductive age during participation in the study and for at least 18 months after discontinuation or completion of the study, even if they have undergone a successful vasectomy.
• Obtaining the patient's informed voluntary consent to participate in the study.
• Ability and willingness to comply with study protocol requirements
• The patient must have a diagnosis of CLL (CLL or SLL) that meets the criteria published in 2018 iwCLL.
• Prior treatment for CLL or SLL, including chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling inhibitor, or monoclonal antibody therapy with a response to previous venetoclax treatment > 36 months from last dose.
• The patient must have an indication for treatment according to the criteria published in the 2018 iwCLL NCI-WG.
• The patient must have an Eastern Cooperative Oncology Group (ECOG) stage score of ≤ 2.
• Adequate hematologic function independent of growth factors or transfusion support, according to the local laboratory reference range at screening (unless due to underlying disease, as evidenced by extensive bone marrow involvement or hypersplenism secondary to splenic lymphoma according to the investigator), defined as follows: ● Hemoglobin ≥ 9 g/dL ● Absolute neutrophil count ≥ 1.0 × 109/L ● Platelet count ≥ 75 × 109/L
• Adequate renal function, according to the local laboratory reference range at screening, as indicated by: ● Calculated creatinine clearance ≥ 30 mL/min using 24-hour creatinine clearance or the modified Cockcroft-Gault equation (eCCR; using ideal body weight [IBM] instead of weight).