Open-Label, Single Arm, Phase 3b, Multi-Center Study Evaluating the Efficacy of Venetoclax (ABT 199) in Relapsed/Refractory Subjects With Chronic Lymphocytic Leukemia (CLL)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 258
- 试验地点
- 67
- 主要终点
- Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Primary Analysis
研究概览
简要总结
The purpose of this study is to evaluate the efficacy of venetoclax monotherapy in participants with relapsed/refractory CLL with or without the 17p deletion or TP53 mutation, including those who have received prior treatment with a B-cell receptor inhibitor.
详细描述
Following the Screening period, all eligible participants initiate venetoclax on a once daily (QD) dosing schedule. To mitigate the risk for tumor lysis syndrome (TLS), dosing will start with a 5-week dose titration phase.
Participants may receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator assessment), do not have unacceptable toxicity and do not meet any of the criteria for subject discontinuation. In countries where venetoclax is not commercially available, participants who continued to derive benefit after 2 years of treatment may extend their treatment for up to 2 additional years in an extended access phase. Participants in the extended access phase of this study who continue to derive benefit from venetoclax after the 2-year extension and are transferring to the venetoclax extension study, Study M19-388 (NCT03844048), may remain in Extended Access for up to 1 additional year or until the extension study is approved and initiated at the site, whichever is sooner.
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant has Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2
- •Participant has relapsed/refractory disease (received at least 1 prior therapy)
- •Participant has diagnosis of CLL that meets published 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute Working Group (IWCLL NCI-WG) Guidelines and:
- •has an indication for treatment according to the 2008 Modified IWCLL NCI-WG criteria
- •has clinically measurable disease (lymphocytosis greater than 5 × 10^9/L and/or palpable and measurable nodes by physical exam and/or organomegaly assessed by physical exam)
- •In addition, participants:
- •with or without 17p deletion or TP53 mutation, assessed by a local laboratory in bone marrow or peripheral blood are eligible
- •may have been previously treated with a prior B-cell receptor inhibitor
- •Participant must have adequate bone marrow function, coagulation profile, renal, and hepatic function, per laboratory at Screening
排除标准
- •Participant has developed Richter's transformation or Prolymphocytic leukemia
- •Participant has previously received venetoclax
- •History of active malignancies other than CLL within the past 2 years prior to first dose of venetoclax, with the exception of:
- •adequately treated in situ carcinoma of the cervix uteri
- •adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
- •previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
- •Participant has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), including autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura despite low dose corticosteroids
- •Participant has undergone an allogeneic stem cell transplant
- •Treatment with any of the following within five half-lives or 14 days (if half-life unknown) as applicable prior to the first dose of venetoclax, or clinically significant adverse effect(s)/toxicity(s) of the previous therapy have not resolved to < National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 Grade 2:
- •Any anti-cancer therapy including chemotherapy, or radiotherapy;
- •Investigational therapy, including targeted small molecule agents
- •Participant is human immunodeficiency virus (HIV) positive
- •Participant has known allergy to both xanthine oxidase inhibitors and rasburicase
研究组 & 干预措施
Venetoclax
Venetoclax will be administered orally once daily (QD) beginning with a dose-titration phase. The initial venetoclax dose is 20 mg QD. After 1 week of treatment at 20 mg QD, the dose will be escalated to 50 mg QD followed by subsequent increases, each after 1 week, to 100 mg QD, 200 mg QD and the maximum dose of 400 mg QD. Participants may continue to receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator's assessment), do not have unacceptable toxicity, and do not meet any of the criteria for discontinuation.
In countries where venetoclax is not commercially available, participants who continue to derive benefit after 2 years of treatment may be able to extend their treatment for up to 2 additional years, plus one additional year until the venetoclax extension study was open, determined on a case by case basis.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Primary Analysis
时间窗: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: * Peripheral blood lymphocytes \< 4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly by physical examination * Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \> 1500/μL * Platelets \> 100,000/μL * Hemoglobin \> 110 g/L * Bone marrow at least normocellular for age, \< 30% lymphocytes. CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.
次要结局
- Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Primary Analysis(From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.)
- Time to Progression (TTP) - Primary Analysis(From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.)
- Progression-Free Survival (PFS) - Primary Analysis(From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue)(Baseline and Weeks 48 and 108)
- Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Health Index Score(Baseline and Weeks 48 and 108)
- Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Visual Analog Scale Score(Baseline and Weeks 48 and 108)
- Overall Response Rate (ORR) - Primary Analysis(From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.)
- Duration of Overall Response (DOR) - Primary Analysis(From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.)
- Overall Survival (OS) - Primary Analysis(From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.)
- Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu)(Baseline and Weeks 48 and 108)