A Prospective, Randomized, Open Label, Two Arm Phase III Study to Evaluate Treatment Free Remission (TFR) Rate in Patients With Philadelphia-positive CML After Two Different Durations of Consolidation Treatment With Nilotinib 300mg BID.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 620
- 试验地点
- 1
- 主要终点
- Percentage of Participants Who Remained in Treatment Free Remission (TFR) Without Molecular Relapse 12 Months After Entering the TFR Phase
研究概览
简要总结
This study aimed to assess the optimal duration of nilotinib 300 mg twice daily (BID) consolidation treatment in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), in order that patients remained in treatment-free remission (≥MR4.0) without molecular relapse 12 months after starting the Treatment-Free Remission (TFR) phase.
详细描述
This was a prospective, randomized, open-label, multicenter Phase III study. The study design was made up of 3 phases:
- Nilotinib induction phase: 12 months
- Nilotinib consolidation phase: 12 or 24 months, depending on randomization
- Nilotinib treatment-free remission (TFR) phase: 24 or 36 months, depending on randomization.
Subjects were enrolled into the study and were treated with nilotinib 300mg twice daily (BID) for 24 months, during the induction (12 months) and consolidation (12 months) phases. At the end of the first 24 months of treatment, participants achieving a sustained molecular response (defined as ≥ MR4.0, in 4 out of 5 real-time quantitative polymerase chain reaction (RQ-PCR) assessments, including the last assessment, in the last 12 months) were randomized on a 1:1 basis to either:
- suspend nilotinib treatment immediately and enter the TFR phase for 36 months (Nilotinib 24-month treatment arm), or
- continue nilotinib treatment for a further 12 months (post-randomization consolidation phase), then suspend treatment and enter the TFR phase for 24 months (Nilotinib 36-month treatment arm).
Participants not achieving a sustained molecular response at 24 months from treatment start were not eligible for randomization and were treated at the discretion of the investigator according to standard practice. Information on survival, stem cell transplantation, and status of the patient's disease was collected until death or until 5 years from study entry, whichever came first. Additionally, for Nilotinib 36-month treatment arm, participants who did not achieve a sustained molecular response at 36 months from treatment start, discontinued from the study and were treated according to standard practice and followed up until death or until 5 years from study entry, whichever came first.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Confirmed diagnosis of chronic phase Ph+ CML
- •Previous first-line treatment with imatinib for a minimum of 2 years;
- •Patient in complete cytogenetic response;
排除标准
- •Previous achievement of MR4.0 at study entry;
- •Previous treatment with other target cells inhibitors other than imatinib;
- •Patients with any history of detectable atypical Leukemia transcripts or patients with detectable atypical leukemia transcripts at screening;
- •Previous anticancer agents for Chronic myeloid leukemia other than imatinib except for cytoreduction;
- •Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol;
- •History of other active malignancies within the 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively;
- •Patients who have not recovered from prior surgery;
- •Treatment with other investigational agents within 4 weeks of Day 1;
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug
- •Other inclusion/exclusion criteria might apply.
研究组 & 干预措施
Nilotinib 24-month treatment
Participants were treated with nilotinib 300mg BID for 24 months and, thereafter, entered the 36-month TFR phase
干预措施: Nilotinib (Drug)
Nilotinib 36-month treatment
Participants were treated with nilotinib 300mg BID for 36 months and, thereafter, entered the 24-month TFR phase
干预措施: Nilotinib (Drug)
Not randomized
Participants were treated with nolotinib 300mg BID for 24 months, but did not achieve a sustained molecular response after 24 months of treatment.
干预措施: Nilotinib (Drug)
结局指标
主要结局
Percentage of Participants Who Remained in Treatment Free Remission (TFR) Without Molecular Relapse 12 Months After Entering the TFR Phase
时间窗: 12 months after entering the TFR phase, which is after 36 months from study treatment start for Nilotinib 24-month treatment arm and after 48 months from study treatment start for Nilotinib 36-month treatment arm
Number of participants who remained in TFR (≥molecular response (MR) 4.0) without molecular relapse 12 months after entering the TFR phase (without re-starting nilotinib therapy) divided by the number of participants who entered the TFR phase and multiplied by 100. Molecular relapse during TFR is defined as the loss of major molecular response (MMR), or the confirmed loss of MR4.0 (defined by 3 consecutive tests less than MR4.0 assessed at 3 consecutive visits during TFR phase). Participants dropping out early from the study during the TFR phase were considered as unsuccessful TFR. Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL. MR4.0 is defined as either detectable disease≤0.01% BCR-ABL or undetectable disease in cDNA with≥10,000 ABL transcripts
次要结局
- Cumulative Incidence of MMR During the Post-randomization Consolidation Phase Among Participants Without That Response at Study Entry(From randomization (month 24 after study treatment start) up to 36 months after study treatment start)
- Cumulative Incidence of MR4.0 During the Pre-randomization Induction/Consolidation Phase(From baseline up to 24 months after study treatment start)
- Cumulative Incidence of MR4.0 During the Post-randomization Consolidation Phase(From randomization (month 24 after study treatment start) up to 36 months after study treatment start)
- Cumulative Incidence of MR4.0 During the Post-randomization Consolidation Phase Among Participants Without That Response at Study Entry(From randomization (month 24 after study treatment start) up to 36 months after study treatment start)
- Cumulative Incidence of MMR During the Pre-randomization Induction/Consolidation Phase(From baseline up to 24 months after study treatment start)
- BCR-ABL Ratio (Expressed as a Percentage) During the TFR Phase(From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm)
- BCR-ABL Ratio (Expressed as a Percentage) During the Nilotinib Re-treatment Phase(From Day 1 after entering the re-treatment phase up to 24 months after entering re-treatment phase for Nilotinib 36-month treatment arm and 36 months after entering the re-treatment phase for Nilotinib 24-month treatment arm)
- Cumulative Incidence of MR4.0 During the Pre-randomization Induction/Consolidation Phase Among Participants Without That Response at Study Entry(From baseline up to 24 months after study treatment start)
- Cumulative Incidence of MMR During the Post-randomization Consolidation Phase(From randomization (month 24 after study treatment start) up to 36 months after study treatment start)
- BCR-ABL Ratio (Expressed as a Percentage) During the Induction/Consolidation Phase(From baseline up to 24 months after study treatment start for Nilotinib 24-month treatment arm and Not randomized participants; and up to 36 months after study treatment start for Nilotinib 36-month treatment arm.)
- Progression-free Survival (PFS) During the TFR Phase of the Study.(From the start of the TFR phase to progression to AP/BC or death up to 24 months after entering TFR phase for Nilotininb 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm)
- Cumulative Incidence of MMR During the Pre-randomization Induction/Consolidation Phase Among Participants Without That Response at Study Entry(From baseline up to 24 months after study treatment start)
- Cumulative Incidence of MR4.5 During the Post-randomization Consolidation Phase Among Participants Without That Response at Study Entry(From randomization (month 24 after study treatment start) up to 36 months after study treatment start)
- Cumulative Incidence of MR4.5 During the Pre-randomization Induction/Consolidation Phase(From baseline up to 24 months after study treatment start)
- Cumulative Incidence of MR4.5 During the Post-randomization Consolidation Phase(From randomization (month 24 after study treatment start) up to 36 months after study treatment start)
- Treatment -Free Survival (TFS) During the TFR Phase of the Study(From the start of the TFR phase to the date of occurrence of treatment-free survival event, up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm)
- Cumulative Incidence of MR4.5 During the Pre-randomization Induction/Consolidation Phase Among Participants Without That Response at Study Entry(From baseline up to 24 months after study treatment start)
- Percentage of Participants Who Were in MMR During TFR Phase(From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm)
- Overall Survival (OS) Rate During the TFR Phase of the Study.(From the start of the TFR phase to death due to any cause, assessed up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm)
- Percentage of Participants Who Were in MR4.0 During the TFR Phase(From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotininb 36-months treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-months treatment arm)
- Percentage of Participants Who Were in MR4.5 During the TFR Phase(From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotininb 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm)