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Clinical picture: CLL (Chronical Lymfatic Leukemia)
Trial: HOVON 141 CLL
2. Patient eligibility criteria
3. Registration (& randomization) of patients
4. Participating parties
5. Participating sites
6. Instruction videos
7. Download documentation / forms
A prospective, multicenter, phase-II trial of ibrutinib plus venetoclax in physically fit (CIRS ≤ 6) and unfit (CIRS > 6) patients with creatinine clearance ≥ 30 ml/min who have relapsed or refractory chronic lymphocytic leukemia (RR-CLL) with or without TP53 aberrations
HOVON, Nordic CLL Group
Type of study
Prospective randomized Phase II study
Type of monitoring for this study
Target number of patients
The primary objective:
Evaluate efficacy of ibrutinib + venetoclax (VI) in terms of progression free survival (PFS, reinitiated treatment not considered progression) 12 months after stopping treatment for patients achieving MRD negativity at 12 and 15 months in previously treated patients with CLL.
Evaluation of the efficacy in terms of MRD at 12 months after stopping treatment (month 27)
Evalution of efficacy in terms of PFS (IWCLL criteria)
number of patients reinitiating treatment, time to treatment failure after reinitiated treatment, time to next treatment, MRD month 12 (PB) and 15 (PB and BM) and at later time points in PB, QoL, OS, CR/PR/SD at month 3, 9, 12, 15, 27 and end of study
– all secondary endpoints for patients MRD negative randomized to stopping treatment at 15 months, patients randomized to ibrutinib maintenance and patients MRD positive at month 12/15 continuing on ibrutinib maintenance.
– To evaluatie safety with regards to type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment.
– To evaluate patient related outcomes, measured in terms of health-related quality of life by EORTC QLQ-C30 and QLQ-CLL17 questionnaires.
2. Patient eligibility 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 hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening defined as:
Absolute neutrophil count (ANC) >750/µL (750 cells/mm3 or 0.75 x 109/L)
Platelet count >30,000 /µL (30,000 cells/mm3 or 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 ≥ 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) ≤ 3.0 x upper limit of normal (ULN)
Bilirubin ≤1.5 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 upper limit of normal (ULN) and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are unrelated 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 6 weeks prior to registration.
ECOG/ WHO performance status 0-3 (appendix C).
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 (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence , or sterilized partner) and a barrier method (eg, 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.
Any prior therapy with ibrutinib and/or venetoclax.
Transformation of CLL (Richter’s transformation).
Patients with a history of confirmed 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 (eg, von Willebrand’s disease or hemophilia).
Uncontrolled or active infection.
Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix X).
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 randomization.
Major surgery within 4 weeks of first dose of study drug.
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
Pregnant women and nursing mothers.
Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.