NCT03874858终止2 期
A Phase II, Single-arm Study of De-escalation and Treatment-free Remission in Patients With Chronic Myeloid Leukemia Treated With Nilotinib in First-line Therapy Followed by a Second Attempt After Nilotinib and Asciminib Combination: DANTE Study
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 135
- 试验地点
- 27
- 主要终点
- Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation period of TFR1 stage
研究概览
简要总结
This study is constituted of two stage: Treatment-Free Remission 1 (TFR1) stage and Treatment-Free Remission 2 (TFR2) stage.
The purpose of the TFR1 stage is to assess the effect of nilotinib reduced to half the standard dose for 12 months on treatment-free remission in patients with Chronic Myeloid Leukemia - Chronic Phase (CML-CP) treated with first-line nilotinib who reached a sustained deep molecular response before entering the study.
The purpose of the TFR2 stage is to evaluate whether the use of asciminib in combination with nilotinib after failure of a first attempt at TFR can lead to higher and more durable TFR rates after a second attempt at TKI discontinuation than those reported in other studies.
详细描述
This is a prospective, single arm, phase II study constituted of two stage: Treatment-Free Remission 1 (TFR1) stage and Treatment-Free Remission 2 (TFR2) stage.
The TFR1 stage is made up of 4 periods:
- Screening (week -4 - week 0)
- Nilotinib consolidation (week 0 - week 48): Patients will be treated with nilotinib 300 mg QD. At the end or during the consolidation period, patients will proceed as follows:
- Patients with sustained DMR at the end of the consolidation phase will enter the treatment-free remission (TFR1) and nilotinib will be discontinued. If two or more consecutive quarterly BCR-ABL RQ-PCR assessments are not performed or results are not available, the patient will not be eligible for TFR1 period and will be treated with nilotinib 300 mg QD until the end of the TFR1 stage (week 144).
- Patients with loss of major molecular response (MMR) at any time during the consolidation phase will enter the follow-up period and will return to the standard nilotinib administration regimen (nilotinib 300 mg BID) until the end of the TFR1 stage (week 144).
- Patients with more than MMR, but without meeting the definition of sustained DMR, will remain in the consolidation phase and will be treated with nilotinib 300 mg QD until the end of the TFR1 stage (week 144).
- Nilotinib treatment-free remission (TFR1) (week 48 - week 144): During the TFR1 period, BCR-ABL levels will be monitored until the end of the TFR1 stage (week 144)
- Follow up: Patients who remain on half-dose nilotinib after week 48 and patients with loss of MMR at any time during the study will enter follow-up until week 144.
Patients discontinued from the treatment for any reason will be followed for survival information until week 144. All patients still on study treatment at the end of the study will be transitioned to prescription nilotinib.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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
- •TFR1 stage:
- •Male and female patients 18 years or older.
- •Diagnosis of CML-CP according to the World Health Organization (WHO).
- •Patients with CML-CP under first-line treatment with nilotinib at the approved daily dose of 300 mg BID mg for at least 3 calendar years.
- •Note: At study entry, an ongoing treatment at a dose ≥400 mg per day is allowed.
- •Sustained DMR defined as ≥ MR 4.0 (BCR-ABL level ≤0.01% IS) in all of the last 4 BCR-ABL RQ-PCR assessments with a minimum interval between each assessment of 3 months and a maximum interval of 6 months.
- •Patient must meet the following laboratory values at the screening visit:
- •Absolute Neutrophil Count ≥1.0 x 109/L
- •Platelets ≥75 x 109/L
- •Hemoglobin (Hgb) ≥ 9 g/dL
- •Serum creatinine < 1.5 mg/dL
- •Aspartate transaminase (AST) ≤ 3.0 x ULN
- •Alanine transaminase (ALT) ≤ 3.0 x ULN
- •Serum lipase ≤ 2 x ULN
- •Eastern Cooperative Oncology Group performance status (ECOG) 0-
- •Study subjects must be able to comply with study procedures and follow-up examinations.
- •Signed informed consent to the TFR1 stage from the patient or from his/her legal representative.
排除标准
- •TFR1 stage:
- •Patients with known atypical transcript.
- •CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past).
- •Dose reductions/interruptions due to neutropenia or thrombocytopenia in the past 6 months.
- •Patient ever attempted to permanently discontinue nilotinib treatment.
- •Known impaired cardiac function including any one of the following:
- •Inability to determine QT interval on ECG
- •Complete left bundle branch block
- •Long QT syndrome or a known family history of long QT syndrome
- •History of or presence of clinically significant ventricular or atrial tachyarrhythmias
- •Clinically significant resting bradycardia
- •QTcF > 480 msec
- •History or clinical signs of myocardial infarction within 1 year prior to study entry
- •History of unstable angina within 1 year prior to study entry
- •Other clinically significant heart disease (e.g. uncontrolled congestive heart failure or uncontrolled hypertension)
- •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 acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis.
- •Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer.
- •History of other active malignancy within 5 years prior to study entry except for previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ treated curatively.
- •Patients who have not recovered from prior surgery.
- •Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
- •Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry.
- •Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to study entry. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo.
- •Pregnant or nursing (lactating) women.
- •Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for at least 14 days after stopping medication. There is a limited amount of data on pregnancies in patients while attempting treatment-free remission (TFR). If pregnancy is planned during the TFR phase, the patient must be informed of a potential need to re-initiate treatment with nilotinib during pregnancy.
- •Highly effective contraception methods include:
- •Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- •Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
- •Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject.
- •Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
- •In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before starting the study.
- •Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago.
- •In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential.
- •Inclusion Criteria TFR2 stage:
- •Signed informed consent to the TFR2 stage from the patient or from his/her legal representative.
- •Male and female patients 18 years or older.
- •Diagnosis of CP-CML according to the WHO and no previous history of progression to AP/BP CML.
- •First-line treatment with nilotinib for at least 3 calendar years, followed by first TFR attempt.
- •Failed first TFR attempt followed by at least 1 year of nilotinib retreatment before enrollment in TFR2 stage.
- •MR4 or better (BCR-ABL ≤ 0.01% IS) assessed at screening.
- •Patient must meet the following laboratory values at the reinduction screening visit:
- •Absolute neutrophil count ≥1.0 x 109/L
- •Platelets ≥75 x 109/L
- •Hemoglobin (Hgb) ≥ 9 g/dL
- •Serum creatinine < 1.5 mg/dL
- •Total bilirubin ≤ 2 x ULN except for patients with Gilbert's syndrome who may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
- •AST ≤ 3.0 x ULN
- •ALT ≤ 3.0 x ULN
- •Alkaline phosphatase ≤ 2.5 x ULN
- 另有 37 项未显示
研究组 & 干预措施
TFR2 stage- Nilotinib+Asciminib
Experimental
During the TFR2 stage, participants will be treated with nilotinib and asciminib for up to 96 weeks (reinduction period).
- Patients with sustained DMR at the end of reinduction will enter TFR2 and asciminib + nilotinib will be discontinued.
- Patients with ≥ MMR, but without sustained DMR, at the end of the reinduction, will be treated with nilotinib monotherapy at 300 mg BID until the end of the TFR2 stage.
- Patients with loss of MMR at any time during reinduction or during nilotinib monotherapy will be discontinued from the study.
干预措施: Asciminib (Drug)
TFR1 stage- Nilotinib
Experimental
During TFR1 stage, all patients will be treated with nilotinib 300 mg QD for up to 48 weeks (consolidation period).
- Patients with sustained DMR at the end of the consolidation period will enter the TFR1 period and nilotinib will be discontinued.
- Patients with loss of MMR will return to the standard nilotinib administration
- Patients with ≥ MMR, but without sustained DMR at the end of the consolidation period will be treated with nilotinib 300 mg QD
干预措施: Nilotinib (Drug)
TFR2 stage- Nilotinib+Asciminib
Experimental
During the TFR2 stage, participants will be treated with nilotinib and asciminib for up to 96 weeks (reinduction period).
- Patients with sustained DMR at the end of reinduction will enter TFR2 and asciminib + nilotinib will be discontinued.
- Patients with ≥ MMR, but without sustained DMR, at the end of the reinduction, will be treated with nilotinib monotherapy at 300 mg BID until the end of the TFR2 stage.
- Patients with loss of MMR at any time during reinduction or during nilotinib monotherapy will be discontinued from the study.
干预措施: Nilotinib (Drug)
结局指标
主要结局
Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation period of TFR1 stage
时间窗: Baseline of consolidation phase up to 96 weeks of TFR1 stage
Full Treatment-Free Remission (FTFR) is defined as patients with Major Molecular Response (MMR) or better (i.e. BCR-ABL ≤ 0.1% IS), including those who have totally discontinued treatment during the Treatment-Free Remission (TFR) stage and those who are treated with half the standard dosage. Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation period of TFR1 stage is calculated by dividing the number of patients with no loss of MMR-Major Molecular Response (BCR-ABL ≤ 0.1% (IS) after 96 weeks by the number of patients who entered consolidation of TFR1 stage.
Percentage of patients in treatment-free remission 48 weeks after starting a second attempt at treatment-free remission during TFR2 stage.
时间窗: Baseline TFR2 phase (week 96 of TFR2 stage) up to week 144 of TFR2 stage
Treatment-Free Remission (TFR) is defined as patients with MMR or better (i.e. BCR-ABL ≤ 0.1% IS). Percentage of patients in TFR 48 weeks after the start of TFR2 phase during TFR2 stage is calculated by dividing the number of patients with no loss of MMR after 48 weeks by the number of patients who entered TFR2 during TFR2 stage. Patients who require re-initiation of nilotinib during TFR2 for loss of MMR, and those discontinued from the study will be considered failures.
次要结局
- Percentage of patients who remain in sustained Deep Molecular Response (DMR) at the end of the consolidation period (week 48 TFR1 stage).(Baseline of consolidation period up to 48 weeks (TFR1 stage))
- Percentage of patients who remain in DMR at the end of the consolidation period (week 48 of TFR1 stage), at 96 weeks and at 144 weeks after the start of the consolidation period of TFR1 stage.(Baseline of consolidation period, week 48, week 96 and week 144 (TFR1 stage))
- Percentage of patients in full treatment-free remission 144 weeks after the start of consolidation ( end of the TFR1 stage.)(Baseline of consolidation period, week 144 of TFR1 stage)
- Percentage of patients with MMR or better at 48, 96, 144 weeks after starting the consolidation period of TFR1 stage(Baseline of consolidation period, week 48, 96 and 144 of TFR1 stage)
- Change in BCR-ABL transcript levels after re-start of nilotinib therapy in patients who failed Treatment Free Remission Phase during TFR1 stage.(Restart of nilotinib therapy up to 144 weeks of TFR1 stage)
- Change in BCR-ABL transcript levels after discontinuation of nilotinib therapy in TFR1 period in TFR1 stage.(Discontinuation of nilotinib therapy in patients in TFR phase up to 144 weeks of TFR1 stage)
- Change in BCR-ABL transcript levels during the consolidation period of TFR1 stage.(Baseline of consolidation period up to 48 weeks of TFR1 stage)
- Full Treatment-Free Survival (FTFS) in TFR1 stage(Baseline of consolidation period up to 144 weeks of TFR1 stage)
- Treatment-Free Remission rate (TFR rate) after the start of consolidation of TFR1 stage(Baseline of consolidation, week 96 and week 144 of TFR1 stage)
- Treatment-free survival (TFS) in TFS1 stage(From the start of the TFR phase up to 144 weeks of TFR1 stage.)
- Progression-free survival (PFS) after the start of the consolidation period of TFR1 stage(Baseline of consolidation up to 144 weeks of TFR1 stage)
- Progression Free Survival (PFS) after the start of TFR1 period of TFR1 stage(From the start of the TFR1 period up to week 144 of TFR1 stage.)
- Overall Survival (OS) in TFR1 stage(Baseline of consolidation up to 144 weeks of TFR1 stage)
- Correlation between clinical and laboratory factors and clinical outcome(Baseline of reinduction up to 144 weeks of TFR2 stage)
- Number of patients stratified by risk of cardiovascular disease through the Framingham risk score (TFR1 stage)(Baseline of TFR1 stage)
- Number of patients stratified by risk of cardiovascular disease through the Systemic Coronary Risk Evaluation (SCORE) (TFR1 stage)(Baseline of TFR1 stage)
- Percentage of patients eligible for the TFR2 period among patients entering reinduction with asciminib + nilotinib in TFR2 stage(Baseline of TFR2 stage up to week 96 of TFR2 stage)
- Number of patients with loss of MMR in TFR2 who regain MMR/DMR by the end of the TFR2 stage(Baseline TFR2 phase (week 96 of TFR2 stage) up to week 144 of TFR2 stage)
- Change in BCR-ABL transcript levels during reinduction of TFR2 stage.(Baseline of TFR2 stage up to week 96 of TFR2 stage)
- Change in BCR-ABL transcript levels after restart of nilotinib therapy in patients who failed TFR2 period in TFR2 stage.(Restart of nilotinib therapy up to week 144 of TFR2 stage)
- Change in BCR-ABL transcript levels after restart of nilotinib therapy in patients who were not eligible for entering the TFR2 period in TFR2 stage.(Restart of nilotinib therapy up to week 144 of TFR2 stage)
- Change in BCR-ABL transcript levels after discontinuation of asciminib + nilotinib therapy in TFR2 stage.(Discontinuation of asciminib + nilotinib (week 96 of TFR2 stage) up to week 144 of TFR2 stage)
- Treatment-free survival (TFS) in TFR2 stage(From the start of the TFR period of TFR2 stage up to Week 144 of TFR2 stage.)
- Progression Free Survival (PFS) after the start of TFR2 period of TFR2 stage(From the start of the TFR2 period of TFR2 stage up to week 144 of TFR2 stage.)
- Overall Survival (OS) in TFR2 stage(Baseline of reinduction period up to week 144 of TFR2 stage)
- Number of patients stratified by risk of cardiovascular disease through the Framingham risk score (TFR2 stage)(Baseline of TFR2 stage)
- Number of patients stratified by risk of cardiovascular disease through the Systemic Coronary Risk Evaluation (SCORE) (TFR2 stage)(Baseline of TFR2 stage)
- Correlation between clinical and laboratory factors and clinical outcome(Baseline of consolidation phase up to 96 weeks of TFR1 stage)
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