Chronic lymphocytic leukemia MedDRA version: 21.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Venclyxto
Product Name: Venetoclax
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Venetoclax
CAS Number: 1257044-40-8
Concentration unit: mg milligram(s)
Concentration type:
Sponsors
POLISH ADULT LEUKEMIA GROUP
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed Informed Consent Form. 2. Ability and willingness to comply with the requirements of the study protocol. 3. Patient must have diagnosis of CLL or SLL that meets published 2018 IWCLL NCI-WG criteria. 4. No prior treatment for CLL or SLL including chemotherapy, BTK inhibitor therapy, venetoclax, small molecule signaling inhibitor, or monoclonal antibody therapy. 5. Patient must have an indication for treatment according to published 2018 IWCLL NCI-WG criteria. 6. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance score of = 2. 7. Adequate hematologic function independent of growth factor or transfusion support, per local laboratory reference range at screening (unless caused by underlying disease, as established by extensive bone marrow involvement or as a result of hypersplenism secondary to the involvement of the spleen by lymphoma per the investigator) defined as follows: o Hemoglobin = 9 g/dL o Absolute neutrophil count = 1.0 x 109/L o Platelet count = 50 × 109/L 8. Adequate renal function, per local laboratory reference range at screening, as indicated by: o Calculated creatinine clearance = 30 mL/min using 24-hour creatinine clearance or modified Cockcroft-Gault equation (eCCR; with the use of ideal body mass [IBM] instead of mass). 9. Adequate liver function, per local laboratory reference range at screening, as indicated by: o AST and ALT = 2.5 × ULN o Total bilirubin = 1.5 × ULN (or = 3 × ULN for patients with documented Gilbert syndrome). 10. No active hemolytic anemia requiring immunosuppressive therapy or other pharmacologic treatment. Patients who have a positive Coombs test but no evidence of hemolysis are NOT excluded from participation. 11. No current use of corticosteroids. EXCEPTION: Low doses of steroids ( 20 mg/day of prednisone), monoclonal antibody-based therapy, or chemotherapy. Prior use of corticosteroids for reasons other than treatment of autoimmune complications of CLL is allowed. 13. No major surgery within 4 weeks (28 days) of first dose of study drug or minor surgery within 3 days of first dose of study drug. 14. No radiation therapy = 4 weeks prior to study treatment initiation. 15. Patient must be able to receive xanthine oxidase inhibitor or rasburicase for tumor lysis syndrome (TLS) prophylaxis. 16. Negative pregnancy test (serum ßHCG) for women of childbearing potential (including pre-menopausal women who have had a tubal ligation) and for all women not meeting the definition of postmenopausal (= 24 months of amenorrhea), and who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy. For all other women, documentation must be present in medical history confirming that the patient is not of childbearing potential. o Female patients who are not surgically sterile or postmenopausal must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the study. o Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential w
Exclusion criteria
Exclusion criteria: 1. Richter's transformation confirmed by biopsy. 2. History of other malignancy that could affect compliance with the protocol or interpretation of results o Patients with a history of curatively treated basal or squamous cell carcinoma or Stage 1 melanoma of the skin or in situ carcinoma of the cervix are eligible. o Patients with a malignancy that has been treated with surgery alone with curative intent will be included. Individuals in documented remission without treatment for = 2 years prior to enrollment may be included at the discretion of the investigator. 3. Uncontrolled active systemic infection (viral, bacterial, and fungal). 4. Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection confirmed by polymerase chain reaction (PCR) test from respiratory tract specimen (e.g. nasopharyngeal swab). 5. Known positive serology for human immunodeficiency virus (HIV), due to potential drug-drug interactions between anti-retroviral medications and the study drugs. 6. Active hepatitis C, defined by the detectable hepatitis C ribonucleic acid (RNA) in plasma by polymerase chain reaction (PCR). 7. Patient is pregnant or breast-feeding. 8. Malabsorption syndrome or other condition that precludes enteral route of administration. 9. An individual organ/system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system (note that symptoms related to CLL should not be included in the patient’s screening CIRS score). Investigators should consult the General Rules for Severity Rating as well as the Organ-Specific Categories when assigning scores for certain conditions (i.e., pulmonary embolism) and consider the level of morbidity associated with a patient’s condition. 10. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and/or would make the patient inappropriate for enrollment into this study. 11. Patients who have 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 marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax. 12. Patients require use of warfarin (due to potential drug-drug interactions that may potentially increase the exposure of warfarin). Patients may be eligible if able to be taken off warfarin and started on an alternative anticoagulant. 13. Patients with evidence any of the following conditions: o New York Heart Association Functional Classification III or IV congestive heart failure o History of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to registration o Recent infection requiring systemic treatment; need to have completed anti-biotic therapy > 14 days before the first dose of study drug o Cerebral vascular accident or intracranial bleed within the last 6 months o Known active chronic hepatitis C Positive serology for hepatitis B defined as a positive test for hepatitis B surface antigen (HBsAg); in addition, if negative for HBsAg but hepatitis B core antibody (HBcAb) positive (regardless of hepatitis B surface an
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To demonstrate that VR treatment strategy leads to 35% of complete response (CR) or complete response with incomplete hematological recovery (CRi) according to IWCLL 2018 guidelines with undetectable (<10-4) MRD in bone marrow (as determined by flow cytometry) at the completion of therapy.;Secondary Objective: 1. To evaluate rates of ORR (defined as CR , CRi PR), PR, and CR and CRi at disease assessment time points 2. To determine PFS, DOR and TTNT 3. To evaluate OS. 4. To evaluate OR, PR, CR, and CRi rates, PFS, DOR, TTNT and OS in patients with TP53 deletion/mutation 5. To estimate the rate of uMRD (MRD < 10-4) in the peripheral blood at 12 months from treatment completion. 6. To evaluate the safety and tolerability of treatment. 7. To evaluate quality of life (QoL) of subjects during therapy. 8. To evaluate potential biomarkers including but not limited to FISH-detected cytogenetic abnormalities, IGVH gene mutational status and TP53 mutations assessed by NGS 9.To develop innovative, machine-learning-based algorithms to assess the prediction of response to VR treatment in CLL. 10. To identify gut microbiota associated biomarkers;Primary end point(s): The proportion of patients who will achieve a CR or CRi with bone marrow MRD assessed by flow cytometry less than 10-4 at the end of treatment.;Timepoint(s) of evaluation of this end point: Cycle 12 ( at 12 months from the start of treatment with the VR regimen), Cycle 18 (at 18 months from the start of treatment with the VR regimen), Cycle 24 (at 24 months from the start of treatment with the VR scheme). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Overall Response Rate (ORR) Percentage of Participants with Best Overall Response (ORR)(defined as complete response [CR], CR [CRi], nodular partial response [nPR], PR) as assessed by investigator determined using iwCLL guidelines 2. Percentage of participants with MRD less than 10-4 in peripheral blood at 12 months following end of treatment 3. Duration of Responses (DOR) [time frame: response up to disease progression or death, whichever occurs first (up to approximately 5 years)]. 4. Progression-Free Survival (PFS) [ time frame: baseline up to disease progression or death, whichever occurs first (up to approximately 5 years)] Investigator-Assessed Progression-Free Survival (PFS) determined using standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines 5. Overall Survival (OS) [time Frame: Baseline up to death (up to approximately 5 years)] 6. Time to Next Anti-CLL Treatment (TTNT) [time frame: baseline up to next treatment or death from any cause, whichever occurs first (up to approximately 5 years)] 7. Quality of life (QOL) of subjects during therapy. Changes from baseline in QOL measures assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). 8. Evaluation of safety of VR treatment comprising all grades adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE, v.5.0). 9. To develop innovative, machine-learning-based algorithms to assess the prediction of response to VR treatment in CLL (as a probability of selected categories of response supported by rationale) based on patients’ electronic health records. 10. To identify gut microbiota associated biomarkers that predict risk of development treatment-related toxicities (mainly infections) and kinetics and depth of response including undetectable MRD.;Timepoint(s) of evaluation of this end point: 1. C12 (in 12 month f | — |
Countries
Poland
Contacts
Public ContactPolish Adult Leukemia Group
Polish Adult Leukemia Group
Outcome results
None listed