A Phase II, Single Arm, Open Label Study of Treatment-free Remission in Chronic Myeloid Leukemia (CML) Chronic Phase (CP) Patients After Achieving Sustained MR4.5 on Nilotinib
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 163
- 试验地点
- 68
- 主要终点
- Percentage of Patients in Treatment Free Remission (TFR) Within 48 Weeks
研究概览
简要总结
A clinical research study to find out if it is safe to stop the drug nilotinib (Tasigna) in chronic myeloid leukemia (CML) patients. Patients who started treatment with imatinib (Gleevec) when they were first diagnosed with CML, then switched to nilotinib (Tasigna) for at least 2 years with the combined time on imatinib (Gleevec) and nilotinib (Tasigna) for at least 3 years and have very small amount of leukemia cells remaining after the nilotinib (Tasigna) treatment will qualify for the study.
详细描述
The Primary objective was to evaluate the percentage of patients in TFR within 48 weeks following nilotinib cessation.
This study originally consisted of seven phases (five treatment phases and two treatment-free phases) from which two were the focus of this primary analysis report (consolidation, TFR and treatment re-initiation) The study consisted of 2 main phases: Consolidation and TFR
Nilotinib treatment consolidation phase (NTCS): Patients who satisfied all inclusion/exclusion criteria were enrolled in the consolidation phase and continued to receive nilotinib for 52 weeks at the dose which the patient was receiving prior to study entry. If a patient maintained MR4.5 throughout the consolidation phase, he/she was eligible to enter in the TFR phase. If a patient had confirmed loss of MR4.5 during the consolidation phase, he/she was not eligible to enter in the TFR phase and continued nilotinib treatment.
Nilotinib TFR phase: Patients who were eligible to enter in the TFR phase after completing the 52 week consolidation phase stopped taking nilotinib on the first day of the TFR phase. Duration of this phase was up to 520 weeks after the last patient enters in the TFR phase.
Nilotinib treatment re-initiation phase (NTRI): If a patient had a confirmed loss of MR4 (two consecutive BCR-ABL >0.01% IS) or loss of MMR (BCR-ABL >0.1% IS) in the TFR phase, the patient restarted nilotinib treatment. Patients will be on nilotinib treatment for up to 520 weeks after the last patient entered the nilotinib TFR phase, or until a patient experience unacceptable toxicity, disease progression and/or treatment discontinued at the discretion of the Investigator or if the patient withdrew consent. Nilotinib cessation was not attempted for a second time in the patient who reinitiated treatment or discontinued following the TFR phase.
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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female patients >= 18 years of age
- •ECOG Performance Status of 0, 1, or 2
- •Patient with diagnosis of BCR-ABL positive CML CP
- •Patient has received a minimum of 3 years of tyrosine kinase inhibitor treatment (first with imatinib (> 4 weeks) and then switched to nilotinib) since initial diagnosis
- •Patient has at least 2 years of nilotinib treatment prior to study entry.
- •Patient has achieved MR4.5 (local laboratory assessment) during nilotinib treatment, and determined by a Novartis designated central PCR lab assessment at screening
- •Adequate end organ function as defined by:
- •Direct bilirubin ≤ 1.5 x ULN except for i) patient with documented Gilbert's syndrome for whom any bilirubin value is allowed and ii) for patients with asymptomatic hyperbilirubinemia (liver transaminases and alkaline phosphatase within normal range)
- •SGOT(AST) and SGPT(ALT) < 3 x ULN (upper limit of normal)
- •Serum lipase ≤ 2 x ULN
- •Alkaline phosphatase ≤ 2.5 x ULN
- •Serum creatinine < 1.5 x ULN
- •Patients must have the following electrolyte values ≥ LLN (lower limit of normal) limits or corrected to within normal limits with supplements prior to the first dose of study medication:
- •Potassium
- •Magnesium
- •Total calcium (corrected for serum albumin)
- •Patients must have normal marrow function as defined below:
- •Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
- •Platelets ≥ 100 x 109/L
- •Hemoglobin ≥ 9.0 g/dL
- •Written informed consent obtained prior to any screening procedures
排除标准
- •Prior AP, BC or allo-transplant
- •Patient has documented MR4.5 at the time when switched from imatinib to nilotinib
- •Patients with known atypical transcript
- •CML treatment resistant mutation(s) (T315I, E255K/V, Y253H, F359C/V) detected if a 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 due to neutropenia or thrombocytopenia in the past 6 months
- •Patient ever attempted to permanently discontinue imatinib or nilotinib treatment
- •Known impaired cardiac function including any one of the following:
- •Inability to determine the 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 (e.g. uncontrolled diabetes (defined as HbA1c > 9%), uncontrolled infection)
- •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 with the exception of 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 1
- •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. See Appendix 14.1 for a list of these medications. This list may not be comprehensive.
- •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.
- •Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to study entry. (Please see www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm for a list of agents that prolong the QT interval.)
- •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)
- •Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
- •Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must have a negative serum pregnancy test before initiation of study treatment and must also use highly effective methods of contraception while enrolled in the study. The use of highly effective contraception should continue for at least 14 days after the last dose of study treatment or until the last day of TFR/TFR-2, or for the duration of a monthly cycle of oral contraception, whichever is longer. Acceptable forms of highly effective contraception methods include:
- •Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 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 be stable on the same pill for a minimum of 3 months before taking study treatment. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. 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 prior to enrolling. 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 child bearing potential. If a study patient becomes pregnant or is suspected of being pregnant during the study or within 30 days as part of safety evaluations after the final dose of nilotinib, the Study Doctor needs to be informed immediately and any ongoing study treatment with nilotinib has to be stopped immediately.
研究组 & 干预措施
Nilotinib
Patients with minimum 3 years of tyrosine kinase inhibitor treatment (first with imatinib and then switched to nilotinib) since initial diagnosis, at least 2 years of nilotinib treatment prior to study entry and who achieved MR4.5 (local laboratory assessment) during nilotinib treatment, and determined by a Novartis designated central PCR lab assessment at screening
干预措施: nilotinib (Drug)
结局指标
主要结局
Percentage of Patients in Treatment Free Remission (TFR) Within 48 Weeks
时间窗: First 48 weeks following nilotinib cessation.
TFR is defined as no confirmed loss of MR4 (Molecular response 4.0 log reduction from baseline) or loss of MMR (major molecular response) and no re-starting of nilotinib therapy within 12 months following cessation of nilotinib. Confirmed loss of MR4 is two consecutive BCR-ABL \> 0.01% IS. Loss of MMR does not require confirmation. Percentage of patients in TFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, no documented loss of MMR and no re-starting of nilotinib therapy in the first 48 weeks after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase, and multiplied by 100.
Percentage of Participants in TFR Within 48-weeks Following Nilotinib Cessation
时间窗: first 48 weeks following nilotinib cessation
TFR is defined as no confirmed loss of MR4 (Molecular response 4.0 log reduction from baseline) or loss of MMR (major molecular response) and no re-starting of nilotinib therapy within 12 months following cessation of nilotinib. Confirmed loss of MR4 is two consecutive BCR-ABL \> 0.01% IS. Loss of MMR does not require confirmation.
次要结局
- Progression Free Survival (PFS) to Accelerated Phase/Blast Crisis (AP/BC) or Death(nilotinib cessation up to approximately 580 weeks)
- Change in BCR-ABL (Oncoprotein Product of BCR-ABL Fusion Gene) Transcripts After Re-start of Nilotinib Therapy(re-start of nilotinib up to approximately 48 weeks)
- Percentage of Patients in Treatment Free Remission (TFR) Within 96, 144, 192, 264 Weeks and Within 6,7,8,9 and 10 Years(96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years following nilotinib cessation)
- Treatment Free Survival (TFS)(nilotinib cessation up to approximately 580 weeks)
- Overall Survival (OS)(nilotinib cessation up to approximately 580 weeks)
- Percentage of Patients With Stable MR4.5 in Nilotinib Re-initiation Phase(start of nilotinib in re-initiation phase up to approximately 432 weeks)
- Percentage of Patients With Stable MMR in Nilotinib Re-initiation Phase(start of nilotinib in re-initiation phase up to approximately 432 weeks)
- Percentage of Patients With Stable MR4 in Nilotinib Re-initiation Phase(start of nilotinib in re-initiation phase up to approximately 432 weeks)
- Percentage of Participants in TFR Within 96, 144, 192, 264 Weeks, and Within the End of Years 6, 7, 8, 9 and 10 Following Nilotinib Cessation(first 96, 144, 192, 264 weeks, and within the end of years 6, 7, 8, 9 and 10 following nilotinib cessation.)
- Progression Free Survival (PFS) After the Start of the TFR Phase(nilotinib cessation up to approximately 580 weeks)
- Treatment Free Survival (TFS) After the Start of the TFR Phase(nilotinib cessation up to approximately 580 weeks)
- Overall Survival (OS) After the Start of the TFR Phase(nilotinib cessation up to approximately 580 weeks)
- BCR-ABL Ratio (%) Over Time in Nilotinib Treatment Re-initiation Phase (NTRI)(re-start of nilotinib up to approximately 48 weeks)
- Percentage of Participants With Stable MMR in Nilotinib Re-initiation Phase(at 48 weeks, 96 weeks, 144 weeks, 192 weeks, 240 weeks, 288 weeks, 336 weeks, 384 weeks and 432 weeks after re-initiating Nilotinib in the NTRI Phase)
- Proportion of Participants With Stable MR4.5 in Nilotinib Re-initiation Phase(at 48 weeks, 96 weeks, 144 weeks, 192 weeks, 240 weeks, 288 weeks, 336 weeks, 384 weeks and 432 weeks)
- Percentage of Participants With Stable MR4 in Nilotinib Re-initiation Phase(at 48 weeks, 96 weeks, 144 weeks, 192 weeks, 240 weeks, 288 weeks, 336 weeks, 384 weeks and 432 weeks)