Chronic Lymfocytic Leukemia (CLL) CLL
Conditions
Interventions
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. Patients not achieving MRD negativity after cycle 12 (PB) AND/OR cycle 15 (PB
Sponsors
HOVON Data Center
Nordic CLL group
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: ? Documented CLL or SLL requiring treatment according to IWCLL criteria after either being refractory to first line therapy or relapse after initial therapy. ? Age at least 18 years. ? Adequate bone marrow function defined as: - Absolute neutrophil count (ANC) >0.75 x 109/L - Platelet count >30,000 /¦ÌL 30 x 109/L. - Hemoglobin >8.0 g/dL (5 mmol/L) Unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy ? Creatinine clearance (CrCL) ¡Ý 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection. ? Adequate liver function as indicated - Serum aspartate transaminase (AST) or alanine transaminase (ALT) ¡Ü 3.0 x upper limit of normal (ULN) - Bilirubin ¡Ü1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) - Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are related to coagulopathy or bleeding disorder). ? 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 dose), negative testing for hepatitis C RNA within 42 days prior to registration. ? WHO/ECOG performance status 0-3 (appendix C), stage 3 only if attributable to CLL. ? Negative pregnancy test at study entry (for women of childbearing potential). ? Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence , or sterilized partner) and a barrier method (e.g., condoms, cervical ring, sponge, etc.) during the period of therapy and for 90 days after the last dose of study drug. ? Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements. ? Written informed consent.
Exclusion criteria
Exclusion criteria: ? Any prior therapy with ibrutinib and/or venetoclax. ? Transformation of CLL (Richter¡¯s transformation). ? Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML). ? Malignancies other than CLL currently requiring systemic therapies or not being treated in curative intention before or showing signs of progression after curative treatment. ? Known allergy to xanthine oxidase inhibitors and/or rasburicase. ? Known bleeding disorders (e.g., von Willebrand¡¯s disease or hemophilia). ? Uncontrolled or active infection. ? Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see appendix K). or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. Please note: Patients being treated with NOACs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib. ? History of stroke or intracranial hemorrhage within 6 months prior to registration. ? Major surgery within 28 days prior to registration. ? Use of investigational agents which might interfere with the study drug within 28 days prior to registration. ? Vaccination with live vaccines within 28 days prior to registration ? Steroid therapy within 7 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 25 mg of prednisolone daily to control autoimmune phenomenon¡¯s, or replacement/stress corticosteroids. ? Pregnant women and nursing mothers. ? Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| (Only considered for arm B of the study) - Proportion of patients fulfilling the criteria for progression free survival (PFS) at 12 months after stopping therapy (27 months after starting treatment) for patients randomized to stop treatment (arm B of the study), reinitiated treatment due to MRD positivity not considered progression (see section 13.1 for details). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary endpoints (for all treatment groups): - Minimal residual disease (MRD) at 12 months after stopping treatment (month 27) for patients randomized to stop treatment. - PFS (IWCLL criteria). - Time to and number of patients reinitiating treatment - Time to treatment failure after reinitiated treatment - Time to next CLL treatment - MRD after cycle 12 (PB) and 15 (PB and BM) and at later time points in PB - Overall survival (OS) - Complete response (CR)/ Partial Response (PR)/ Stable disease (SD) after cycle 3, 9, 12, 15 and month 27 and 51 (3 years after stopping treatment - Duration of response - Safety parameters: Type, frequency, and severity of o adverse events (AEs) and o adverse events of special interest (AESI) and their relationship to study treatment - Health-related quality of life by EORTC QLQ-C30 and QLQ-CLL16 questionnaires Exploratory endpoints: - Evaluation of relationship between various baseline markers and clinical outcome parameters - Various markers at time of progression - Correlation between MRD in BM and PB - Correlation between MRD in BM and PFS//OS - Correlation between MRD in PB and PFS/OS | — |
Contacts
Public ContactA.P. Kater
Academic Medical Center, Amsterdam Secretariaat Hematologie F4-224 Meibergdreef 9
Outcome results
None listed