A Multicenter Study of Ibrutinib Resistance Development and Intervention With Venetoclax (Phase II)
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 发起方
- Kerry Rogers
- 主要终点
- Overall response rate (ORR) (intervention cohort)
研究概览
简要总结
This phase II trial studies how well the combination of ibrutinib and venetoclax works in treating patients with chronic lymphocytic leukemia whose cancer has stopped responding to ibrutinib alone. Both ibrutinib and venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving ibrutinib and venetoclax together after development of ibrutinib resistance may work better than discontinuing ibrutinib and switching to other chemotherapy drugs.
详细描述
PRIMARY OBJECTIVES:
I. Overall response rate to combination ibrutinib and venetoclax after 12 cycles (intervention cohort).
II. Rate of mutation negative status after 12 cycles of combination venetoclax and ibrutinib (intervention cohort ).
SECONDARY OBJECTIVES:
I. Incidence of BTK C481S mutations during ibrutinib treatment (observation cohort).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Diagnosis of chronic lymphocytic leukemia (CLL) meeting criteria established by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL).
- •Currently taking ibrutinib and first took ibrutinib > 12 months ago.
- •At high risk for the development of ibrutinib resistance. Patients are considered at high risk for ibrutinib resistance if they have had >= 2 prior therapies for CLL prior to ibrutinib and have either del(17p)(13.1) and/or a complex CLL karyotype.
- •Able to continue taking ibrutinib.
- •Willing to enter the intervention cohort if clinical disease progression as defined by IWCLL 2018 criteria develops.
- •Eastern Cooperative Oncology Group (ECOG) performance status =<
- •Absolute neutrophil count (ANC) >= 1000/mm^3 independent of growth factor support.
- •Platelets >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement independent of transfusion support in either situation.
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN).
- •Total bilirubin =< 1.5 x ULN unless bilirubin rise is due to Gilbert?s syndrome or of non-hepatic origin.
- •Creatinine clearance (CLcr) >30 ml/min.
- •Able to take an absorb pill form oral medications.
- •Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug.
- •Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
- •Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.
- •CRITERIA FOR ENTERING THE INTERVENTION COHORT: Clinical disease progression as defined by IWCLL 2018 criteria AND presence of an ibrutinib resistance mutation as defined.
- •CRITERIA FOR ENTERING THE INTERVENTION COHORT: No evidence of a non-CLL/small lymphocytic lymphoma (SLL) lymphoma (Richter?s syndrome).
- •CRITERIA FOR ENTERING THE INTERVENTION COHORT: No contraindication to taking venetoclax.
- •CRITERIA FOR ENTERING THE INTERVENTION COHORT: Able to continue taking ibrutinib.
排除标准
- •Inability to continue taking ibrutinib for any reason.
- •Presence of a known ibrutinib resistance mutation as defined.
- •Clinical disease progression while taking ibrutinib as defined by IWCLL 2018 criteria.
- •Major surgery or a wound that has not fully healed within 4 weeks of randomization.
- •Known central nervous system lymphoma.
- •Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon).
- •Requires chronic treatment with strong CYP3A inhibitors.
- •Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
- •Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection.
- •Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator?s opinion, could compromise the subject?s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
- •Uncontrolled autoimmune hemolytic anemia or thrombocytopenia.
- •History of lymphoma (Richter?s syndrome) unless in complete remission > 2 years without relapse.
- •History of active malignancies other than CLL within the past 3 years prior to study entry, with the exception of:
- •Adequately treated in situ carcinoma or the cervix or breast
- •Basal cell or localized squamous cell carcinoma of the skin
- •Previous malignancy treated with curative therapy and not expected to relapse.
- •Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease, etc.).
- •Prior allogeneic stem cell transplant with Day 0 < 12 months prior and/or with chronic graft versus host disease (GVHD) requiring current use of immunosuppression. Patients with prior allogeneic stem cell transplant with Day 0 > 12 months prior who do not require immunosuppression for GVHD will be eligible.
- •Patients in the observation cohort who develop clinical disease progression and do NOT have a known ibrutinib resistance mutation will be taken off study and may not enter the intervention cohort.
研究组 & 干预措施
Treatment (venetoclax, ibrutinib)
OBSERVATION COHORT: Patients who are taking ibrutinib enter observation cohort and undergo screening every 3 months for development for genetic mutations. If mutations develop, patients undergo increased screening for development of clinical disease progression. Patients who develop clinical disease progression with or without mutations enter the Intervention cohort.
INTERVENTION COHORT: Patients receive venetoclax PO daily and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve MRD negative CR after 12 or 24 cycles continue receiving ibrutinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.
干预措施: Ibrutinib (Drug)
Treatment (venetoclax, ibrutinib)
OBSERVATION COHORT: Patients who are taking ibrutinib enter observation cohort and undergo screening every 3 months for development for genetic mutations. If mutations develop, patients undergo increased screening for development of clinical disease progression. Patients who develop clinical disease progression with or without mutations enter the Intervention cohort.
INTERVENTION COHORT: Patients receive venetoclax PO daily and ibrutinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who achieve MRD negative CR after 12 or 24 cycles continue receiving ibrutinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Overall response rate (ORR) (intervention cohort)
时间窗: After 12 cycles of combination therapy, assessed up to 3 years
Defined as the percentage of patients who have achieved any response better than stable disease after 12 cycles of combination ibrutinib and venetoclax treatment. All eligible patients who take one study dose of venetoclax will be considered evaluable and included in the denominator when calculating the ORR. ORR will be estimated with a 95% exact binomial confidence interval at the response assessment after 12 cycles of combination ibrutinib and venetoclax therapy, and 24 if applicable.
Rate of mutation negative status (intervention cohort)
时间窗: After 12 cycles of combination therapy, assessed up to 3 years
Rate of mutation negative status will be estimated with a 95% exact binomial confidence interval at the response assessment after 12 cycles of combination ibrutinib and venetoclax therapy, and 24 if applicable.
次要结局
- Incidence of BTK C481S mutations (observation cohort)(Up to 3 years)
- Progression-free survival (PFS) after development of a BTK C481S mutation (observation cohort)(Up to 3 years)
- Overall survival (OS) after adding venetoclax to ibrutinib (intervention cohort)(Up to 3 years)
- PFS after adding venetoclax to ibrutinib (intervention cohort)(Up to 3 years)
- Incidence of adverse events (intervention cohort)(Up to 3 years)
研究者
Kerry Rogers
Principal Investigator
Ohio State University Comprehensive Cancer Center