Topic: Cancer
Conditions
Interventions
Ibrutinib: Continuous Ibrutinib treatment of 420mg once daily
Venetoclax: Venetoclax treatment for a maximum of 24 months
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Aged 18 and over 2. Able to give informed consent 3. Diagnosis of CLL, requiring therapy according to IWCLL criteria (appendix 1) 4. CLL should be assessable for MRD by flow cytometry (CD19, CD5 and CD23 and CD43 co-expression with weak CD20, CD79b/sIg & CD81 expression; to be confirmed by HMDS) 5. Refractory/relapsed CLL defined as any of the following: 5.1. Failure to achieve a response (CR or PR by IWCLL Criteria) to a purine analogue alone or in combination with chemotherapy 5.2. Relapse within 6 months of responding to a purine analogue alone or in combination with chemotherapy 5.3. Relapse at any time after the combination of fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine plus rituximab (or other equivalent monoclonal anti-CD20 antibodies) 5.4. Patients with CLL with deletion of chromosome 17p who have progressed after at least one previous therapy 6. ECOG performance status (PS) of 0, 1, or 2 7. Prepared to undergo the stipulated investigations within the trial (including bone marrow examinations) 8. Adequate bone marrow function (defined below) independent of growth factor or transfusion support, within 2 weeks of screening unless cytopenia is clearly due to marrow involvement of CLL: 8.1. Platelet count = 75 x 109/L; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator), platelet count should be = 30 109/L independent of transfusion 8.2. Absolute neutrophil count (ANC) = 1.0 x 109/L unless neutropenia is clearly due to marrow involvement of CLL (per the discretion of the investigator) 8.3. Total haemoglobin = 90 g/L unless anaemia is due to marrow involvement of CLL (per the discretion of the investigator) 9. Adequate renal and hepatic function at screening: 9.1. Calculated creatinine clearance = 50 mL/min using 24-hour creatinine clearance or modified Cockcroft-Gault equation (using ideal body mass [IBM] instead of mass): eCCR=((140-Age)>IBM (kg).[0.85 if female])/(72.Serum creatinine (mg/dL)) Or, if serum creatinine is in µmol/L: eCCR=((140-Age)>IBM (kg).[1.23 if male,1.04 if female])/( Serum creatinine (µmol/L)) IBM (kg) = ([height in cm-154] × 0.9)] + (50 if male, 45.5 if female) 10. AST or ALT= 3.0 times the upper limit of normal (ULN) of the institution's normal range 11. Bilirubin = 1.5 × ULN. Patients with known Gilbert's syndrome may have a bilirubin level > 1.5 × ULN 12. Prothrombin time (or international normalised ratio) and partial thromboplastin time not to exceed 1.2 times the institution’s normal range
Exclusion criteria
Exclusion criteria: 1. Transformation of CLL to aggressive NHL (e.g. Richter’s transformation, prolymphocytic leukaemia, or diffuse large B-cell lymphoma or CNS involvement by CLL) 2. A history of any severe, concurrent renal, neurological, psychiatric, endocrine, metabolic, immunologic, cardiac, pulmonary or hepatic diseases that could interfere with the patient’s ability to participate in the study 3. Use of prior investigational agents within 28 days of planned treatment 4. Females who are pregnant or lactating 5. Females of childbearing potential (or males whose partners are of childbearing potential) who are unwilling to use appropriate contraception during and for 3 months following treatment 6. Mantle cell lymphoma 7. Known to be HIV positive 8. Positive test results for chronic hepatitis B infection (defined as positive HBsAg serology) 9. Positive test results for hepatitis C (HCV antibody serology testing). Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 10. Active secondary malignancy excluding basal cell carcinoma 11. Patients requiring or who have received anticoagulation treatment with warfarin or vitamin K antagonists within 1 week of registration 12. Patients requiring concomitant use of strong CYP3A4/5 inhibitors/inducers within 7 days prior to registration 13. Previous treatment with Ibrutinib, venetoclax or an alternative Btk or Bcl-2 inhibitor 14. Inability to tolerate uric acid reducing medications • Undergone an allogeneic stem cell transplant unless beyond 6 months post-transplant and off immune suppressive therapy with no evidence of Graft-versus-Host disease 15. Known hypersensitivity to either of the compounds or to its excipients 16. Patients who have received an anti-CLL monoclonal antibody within 8 weeks prior to registration 17. A cardiovascular disability status of New York Heart Association Class = 3 (Class 3 is defined as cardiac disease in which patients are comfortable at rest but have marked limitation of physical activity due to fatigue, palpitations, dyspnoea or angina pain) 18. Major surgery within 30 days prior to registration 19. Vaccination with a live vaccine within 28 days prior to registration 20. Steroid therapy for anti-neoplastic intent will not be allowed either during or within 7 days prior to registration with the exception of inhalational steroids for the treatment of asthma or COPD, topical steroids, replacement corticosteroid therapy for an inherited or acquired deficiency
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proportion of patients with <0.01% MRD in the blood and bone marrow at 12 months. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Biological response is monitored throughout the duration of the trial 2. Overall Survival is determined from the date of registration to date of death 3. Progression-free survival (PFS) is monitored throughout the duration of the trial 4. Proportion of patients with <0.01% MRD in the blood and bone marrow is measured after 6 and 24 months of combination therapy 5. Response rate is determined using the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) criteria after 12 and 24 months of combination therapy 6. Toxicity of combination therapy is measured throughout the duration of trial | — |
Countries
England, Northern Ireland, Scotland, United Kingdom, Wales
Contacts
Public ContactRebecca Bishop
Outcome results
None listed