Overview

This trial is active, not recruiting.

Condition chronic myelogenous leukemia
Treatment nilotinib followed by treatment-free
Phase phase 2
Targets BCR-ABL, KIT, PDGF
Sponsor Novartis Pharmaceuticals
Start date March 2013
End date November 2018
Trial size 215 participants
Trial identifier NCT01784068, CAMN107I2201

Summary

The main purpose of the study is to investigate whether nilotinib treatment can be safely suspended with no recurrence of CML in selected patients who responded optimally on this treatment

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Arm
(Experimental)
Patients who have received a minimum of 2 years of first line nilotinib treatment and with pre-screen PCR results in ≥ MR4.5 will enter the consolidation phase of the study (52 weeks - nilotinib 300 mg BID). Patients with Minimal Residual Disease (MRD) at the end of this phase will enter the Treatment-Free Remission (TFR) phase where no treatment is given. Non eligible patients will enter the continuation phase of the study. Patients with MRD at the end of the continuation phase will enter the TFR-2 phase of the study where no treatment is given. Non eligible patients will enter the prolonged continuation phase of the study. If at any time during TFR or TFR-2 the patient loses MMR, nilotinib treatment will be immediately re-initiated (nilotinib 300 mg BID).
nilotinib followed by treatment-free
Nilotinib will be used as commercial available capsules (except in Japan where clinical supplies is used) of 150 mg and 200 mg strength. treatment occurs during consolidation, continuation, prolonged continuation, re-initiation and re-initiation-2 phases of the study.

Primary Outcomes

Measure
Percentage of patients who are in MMR (major molecular response) at 48 weeks after starting the treatment-free remission (TFR) phase
time frame: 48 weeks

Secondary Outcomes

Measure
Percentage of patients who are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 weeks after starting the TFR phase
time frame: 48 weeks
Percentage of patients who are in MMR at 96, 144 and 192 weeks after starting the TFR phase
time frame: 96, 144 and 192 weeks
Percentage of patients who are in MR4.5 at 96, 144 and 192 weeks after starting the TFR phase
time frame: 96, 144 and 192 weeks
Percentage of patients in MMR at 48, 96, 144 and 192 weeks after starting the TFR phase of nilotinib
time frame: 48, 96, 144 and 192 weeks
Percentage of patients in MR4.5 at 48, 96, 144 and 192 weeks after starting the TFR phase of nilotinib
time frame: 48, 96, 144 and 192 weeks
Percentage of patients who achieve MMR within 12 weeks of re-treatment with nilotinib
time frame: 12 weeks
Kinetics of BCR-ABL transcript after re-start of nilotinib therapy
time frame: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 192 after last patient has entered the TFR
Duration of re-initiated treatment required to regain MMR after loss of MMR
time frame: Every 4 weeks up to week 24 and every 12 weeks therefater up to 192 weks after the last patient has entered TFR
Duration of re-initiated treatment required to regain MR4.5 after loss of MMR
time frame: Every 4 weeks up to week 24 and every 12 weeks thereafter up to 192 weks after the last patient has entered TFR
Treatment-free survival (TFS) after the start of the TFR phase
time frame: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks in TFR and every 12 weeks in the last period of 96 weeks of the TFR
Progression-free survival (PFS) after the start of the TFR phase
time frame: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 96 weeks of the TFR
Overall survival (OS) after the start of the TFR phase
time frame: Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 96 weeks of the TFR
Safety profile during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation treatment with nilotinib
time frame: Every 4 weeks in the treatment consolidation and during the first 24 weeks of the re-initaion phase, every 12 weeks thereafter. Every 4, 6 and 12 weeks respectively in the first and second period of 48 weeks and in the last period of 96 weeks of the TFR
Proportion of patients who develop T3151, E255K/V, Y253H, F359V/C/I mutations on study or any other BCR-ABL mutations in patients who lost MMR after nilotinib suspension
time frame: Every 3 months in patients who lost MMR until the result is negative or up to 192 weeks after the last patient entered TFR. On average 3 analyses (every 3 months or up to 192 weeks after the last patient has entered TFR.)

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: - Minimum of 2 calendar years of nilotinib treatment with at least the last 12 months of nilotinib treatment prior to pre-screening at approved total dialy dose of 600 mg BID or at a reduced dose of 400 mg QD if required from the perspective of tolerance for BCR-ABL positive CML in documented chronic phase at the time of diagnosis - Evidence of typical BCR-ABL transcripts (b3a2 and/or b2a2) at the time of CML-CP diagnosis i.e. prior to first start of TKI treatment which are amenable to standardized RT-PCR quantification" - Patient in MR4.5 at prescreening at Novartis designated lab - ECOG performance status of 0-2 - Adequate end organ function as defined by: - Direct bilirubin ≤ 1.5 x ULN except for i) patients 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 i.e. equivalent to ≤ Grade 1 NCI-CTCAE v.4.03 - Serum lipase ≤ 2 x ULN i.e. equivalent to ≤ Grade 2 NCI-CTCAE v.4.03 - Alkaline phosphatase ≤ 2.5 x ULN - Serum creatinine < 1.5 x ULN - Patients must have the following electrolyte values within normal limits or corrected to be within normal limits with supplements prior to first dose of study medication: - Potassium (suggested keep to prevent issues with QT and/or rhythm abnormalities) - Magnesium (suggested keep to prevent issues with QT and/or rhythm abnormalities) - Total calcium (corrected for serum albumin) - Patients must have normal marrow function as defined: - Absolute Neutrophil Count (ANC) ≥ 1.5 x 10E9/L - Hemoglobin ≥ 9.0 g/dL - Platelets ≥ 100 x 10E9/L Exclusion Criteria: - Previous treatment with BCR-ABL inhibitors other than nilotinib for more than a total cumulative duration of 4 weeks - Previous treatment with alpha-interferon of any duration - Previous anticancer agents for CML other than nilotinib except for cytoreduction after CML diagnosis until up to 4 weeks after first dose of nilotinib - Known second chronic phase of CML after previous progression to AP/BC - Poorly controlled diabetes mellitus (defined as HbA1c > 9%) - Impaired cardiac function including any one of the following: - LVEF < 45% or below the institutional lower limit of the normal range (whichever is higher) - Inability to determine the QT interval on ECG, except for patients with evidence of measurable QT interval at the time of CML diagnosis (e.g. prior to first start of TKI treatment) and who have no documented clinical signs of cardiovascular disease and/or clinical signs of conduction abnormality. - Complete left bundle branch block - Right bundle branch block plus left anterior or posterior hemiblock - Use of a ventricular-paced pacemaker - Congenital 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 - QTc > 450 msec on the average of three serial baseline ECG (using the QTcF formula). If QTcF > 450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-tested for QTc.This exclusion criterion is not applicable for patients with non-measurable QT interval who have evidence of measurable QT interval at the time of CML diagnosis (e.g. prior to first start of TKI treatment) and who have no documented clinical signs of cardiovascular disease and/or clinical signs of conduction abnormality. - History or clinical signs of myocardial infarction within 1 year of study entry - History of unstable angina within 1 year of study entry - Other clinically significant heart disease (e.g. congestive heart failure, cardiomyopathy or uncontrolled hypertension) - History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis - Known presence of significant congenital or acquired bleeding disorder unrelated to cancer - History of another active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively - 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 starting study drug. See Appendix 1 for a list of these medications. This list may not be exhaustive. - 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 starting study drug. 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 starting study drug. (Please see http://www.torsades.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, unless they are using highly effective methods of contraception during the study and for 14 days after the final dose of nilotinib. Highly effective contraception is defined as either: - 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) 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 enrolling). For female patients on the study the vasectomized male partner should be the sole partner for that patient. - Use of a combination of any two of the following: 1. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. 2. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository In case of use of oral contraception women should have been 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) 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 suspects being pregnant during the study or within 30 days after the final dose of nilotinib, the Study Doctor needs to be informed immediately and ongoing study treatment with nilotinib has to be stopped immediately. Other protocol-defined inclusion/exclusion criteria may apply.

Additional Information

Official title A Single-arm, Multicenter, Nilotinib Treatment-free Remission Study in Patients With BCR-ABL1 Positive Chronic Myelogenous Leukemia in Chronic Phase Who Have Achieved Durable Minimal Residual Disease (MRD) Status on First Line Nilotinib Treatment.
Trial information was received from ClinicalTrials.gov and was last updated in September 2016.
Information provided to ClinicalTrials.gov by Novartis.
Location data was received from the National Cancer Institute and was last updated in September 2016.