A Prospective, Multicenter, Phase-II Trial of Ibrutinib Plus Venetoclax in Patients With Creatinine Clearance >= 30 ml/Min Who Have Relapsed or Refractory Chronic Lymphocytic Leukemia (RR-CLL) With or Without TP53 Aberrations
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 230
- 试验地点
- 49
- 主要终点
- Number of patients with progression free survival 27 months after starting treatment
研究概览
简要总结
The aim of the current trial is to evaluate if combination treatment with venetoclax + ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL) can lead to MRD negativity, which may induce long lasting remissions for MRD-negative patients randomized to stopping treatment after 15 induction cycles.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 /μL 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) ≥ 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 nonhepatic 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.
排除标准
- •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.
研究组 & 干预措施
Ibrutinib until progression/relapse
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles.
MRDpositive patients (PB and BM) will continue on Ibrutinib maintenance (non-randomized group) until progression/relapse
干预措施: Ibrutinib + Venetoclax 15 cycles (Drug)
Ibrutinib until progression/relapse
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles.
MRDpositive patients (PB and BM) will continue on Ibrutinib maintenance (non-randomized group) until progression/relapse
干预措施: Ibrutinib until progression/relapse (Drug)
Arm A
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles.
MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm A: Ibrutinib until progression/relapse (Continuous ibrutinib treatment until toxicity or progression)
干预措施: Ibrutinib + Venetoclax 15 cycles (Drug)
Arm A
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles.
MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm A: Ibrutinib until progression/relapse (Continuous ibrutinib treatment until toxicity or progression)
干预措施: Ibrutinib until progression/relapse (Drug)
Arm B
All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles.
MRD negative patients (PB and BM) will be randomized to Arm A or Arm B. Arm B: Observation until event.
Patients randomized to Arm B will get reinitiation of therapy during the observation period in case of:
- progression according to IWCLL criteria or
- MRD≥10-3 (PB) and at least one month later MRD ≥10-2 (PB).
Treatment reinitiation will consist of ibrutinib and venetoclax (with ramp up of venetoclax from cycle 1) for 12 cycles
干预措施: Ibrutinib + Venetoclax 15 cycles (Drug)
结局指标
主要结局
Number of patients with progression free survival 27 months after starting treatment
时间窗: 27 months after last patient in trial
arm B of the study
次要结局
- Number of patients with progression free survival(7 years after last patient in)
- Number of patients initiating new CLL treatment(7 years after last patient in)
- Number of patients with treatment failure after reinitiating treatment(7 years after last patient in)
- Number of patients with MRD negativity 27 months after starting treatment(27 months after last patient in trial)
- Number of patients reinitiating treatment(7 years after last patient in)
- Number of patients with MRD negativity 12 (peripheral blood) and 15 months (peripheral blood and bone marrow) after starting treatment(15 months after last patient in trial)
- Number and grading of adverse events, serious adverse events and adverse events of special interest (bleeding, atrial fibrillation and tumorlysis)(7 years after last patient in)
- Number of patients with improved quality of life (by EORTC QLQ-C30 and QLQ-CLL16 questionnaires)(51 months after last patient in trial)
- Number of patients alive(7 years after last patient in)
- Number of patients with complete remission, partial remission and stable disease and the duration of remission for each group(7 years after last patient in)