Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients (ENESTfreedom)

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.

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

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Myelogenous Leukemia
• Intervention / Treatment: Drug: Nilotinib followed by treatment-free

Detailed Description

The Primary objective of this study was to determine the percentage of patients who were in MMR at 48 weeks after starting the TFR phase (patients who required re-initiation of treatment were considered as non-responders).

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. All patients were treated with the planned nilotinib dose 300 mg BID (or at a reduced dose level of 400 mg QD if required from the perspective of toxicity). In order for patients to be eligible for the TFR phase, they had to fulfill the protocol specific definition of durable MRD. The four last quarterly performed PCR assessments must have fulfilled the following criteria:

• The last assessment was MR4.5 (BCR-ABL ≤ 0.0032% IS)
• No assessment worse than MR4.0 (BCR-ABL >0.01% IS) and
• No more than two assessments between MR4.0 and MR4.5 (0.0032% IS<BCR-ABL ≤ 0.01% IS)

Nilotinib TFR phase: Patients who were eligible to enter in the TFR phase after completing the 52 weeks consolidation phase, stopped taking nilotinib on the first day of the TFR phase. Duration of this phase was up to 10 years after the last patient enters in the TFR phase. BCR-ABL levels were monitored every four weeks during the first 48 weeks, every six weeks for the following 48 weeks and every 12 weeks during the last period.

Nilotinib treatment re-initiation (NTRI) phase: If a patient had a loss of MMR (BCR-ABL >0.1% IS) in the TFR phase, the patient restarted nilotinib treatment. Patients were on nilotinib treatment for up to 10 years after the last patient entered the nilotinib TFR phase. Patients who required re-initiation of nilotinib treatment were monitored for the BCR-ABL level every four weeks for the first 24 weeks and then every 12 weeks thereafter in patients who regained MMR. The frequency of BCR-ABL monitoring in patients not regaining MMR within the first 24 weeks after re-initiation of treatment was at least every 12 weeks or more frequently as clinically indicated.

• Study Type: Interventional
• Enrollment (Actual): 215
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1114AAN
    • Novartis Investigative Site
• Austria
  • Graz, Austria, A-8036
    • Novartis Investigative Site
  • Rankweil, Austria, A-6830
    • Novartis Investigative Site
  • Salzburg, Austria, 5020
    • Novartis Investigative Site
  • Wien, Austria, 1140
    • Novartis Investigative Site
• Belgium
  • Bruxelles, Belgium, 1200
    • Novartis Investigative Site
  • Charleroi, Belgium, 6000
    • Novartis Investigative Site
  • Gent, Belgium, 9000
    • Novartis Investigative Site
  • Kortrijk, Belgium, 8500
    • Novartis Investigative Site
  • Liege, Belgium, 4000
    • Novartis Investigative Site
  • Brussel
    • Jette, Brussel, Belgium, 1090
      • Novartis Investigative Site
  • Oost Vlaanderen
    • Sint Niklaas, Oost Vlaanderen, Belgium, 9100
      • Novartis Investigative Site
• Bulgaria
  • Varna, Bulgaria, 9000
    • Novartis Investigative Site
• Colombia
  • Monteria, Colombia, 230004
    • Novartis Investigative Site
  • Cundinamarca
    • Bogota, Cundinamarca, Colombia, 111411
      • Novartis Investigative Site
• Denmark
  • Aarhus, Denmark, 8000
    • Novartis Investigative Site
• France
  • Bordeaux, France, 33076
    • Novartis Investigative Site
  • Brest, France, 29200
    • Novartis Investigative Site
  • Corbeil Essonnes, France, 91100
    • Novartis Investigative Site
  • Dunkerque, France, 59240
    • Novartis Investigative Site
  • Grenoble, France, 38043
    • Novartis Investigative Site
  • Nantes Cedex 1, France, 44093
    • Novartis Investigative Site
  • Rouen, France, 76038
    • Novartis Investigative Site
  • Saint Priest en Jarez, France, 42271
    • Novartis Investigative Site
  • Strasbourg, France, 67000
    • Novartis Investigative Site
  • Strasbourg cedex, France, 67085
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
  • Bayonne Cedex
    • Bayonne, Bayonne Cedex, France, 64109
      • Novartis Investigative Site
• Germany
  • Aachen, Germany, 52074
    • Novartis Investigative Site
  • Bayreuth, Germany, 95445
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Bonn, Germany, 53105
    • Novartis Investigative Site
  • Bottrop, Germany, 46236
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Duesseldorf, Germany, 40225
    • Novartis Investigative Site
  • Duesseldorf, Germany, 40479
    • Novartis Investigative Site
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Freiburg, Germany, 79106
    • Novartis Investigative Site
  • Goslar, Germany, 38642
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Hamburg, Germany, 22417
    • Novartis Investigative Site
  • Jena, Germany, 07740
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Magdeburg, Germany, 39104
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Stuttgart, Germany, 70376
    • Novartis Investigative Site
  • Ulm, Germany, 89081
    • Novartis Investigative Site
  • Baden Wuerttemberg
    • Mannheim, Baden Wuerttemberg, Germany, 68305
      • Novartis Investigative Site
  • Schleswig-Holstein
    • Luebeck, Schleswig-Holstein, Germany, 23563
      • Novartis Investigative Site
• Greece
  • Athens, Greece, 115 27
    • Novartis Investigative Site
  • Athens, Greece, 106 76
    • Novartis Investigative Site
  • GR
    • Athens, GR, Greece, 115 27
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1085
    • Novartis Investigative Site
  • Budapest, Hungary, H-1097
    • Novartis Investigative Site
  • Szeged, Hungary, H 6725
    • Novartis Investigative Site
• Ireland
  • Dublin, Ireland, DUBLIN 8
    • Novartis Investigative Site
  • Galway, Ireland, 12074
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80132
    • Novartis Investigative Site
  • Novara, Italy, 28100
    • Novartis Investigative Site
  • AN
    • Ancona, AN, Italy, 60126
      • Novartis Investigative Site
  • BS
    • Brescia, BS, Italy, 25123
      • Novartis Investigative Site
  • FE
    • Cona, FE, Italy, 44124
      • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • NU
    • Nuoro, NU, Italy, 08100
      • Novartis Investigative Site
  • PG
    • Perugia, PG, Italy, 06129
      • Novartis Investigative Site
  • RC
    • Reggio Calabria, RC, Italy, 89124
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00161
      • Novartis Investigative Site
  • TO
    • Orbassano, TO, Italy, 10043
      • Novartis Investigative Site
  • TR
    • Terni, TR, Italy, 05100
      • Novartis Investigative Site
• Japan
  • Akita, Japan, 010-8543
    • Novartis Investigative Site
  • Chiba
    • Kashiwa-city, Chiba, Japan, 277-8567
      • Novartis Investigative Site
  • Hokkaido
    • Sapporo city, Hokkaido, Japan, 060 8648
      • Novartis Investigative Site
  • Kanagawa
    • Sagamihara, Kanagawa, Japan, 252-0375
      • Novartis Investigative Site
  • Kumamoto
    • Kumamoto City, Kumamoto, Japan, 860-8556
      • Novartis Investigative Site
  • Osaka
    • Osaka Sayama, Osaka, Japan, 589 8511
      • Novartis Investigative Site
    • Suita, Osaka, Japan, 565 0871
      • Novartis Investigative Site
  • Saga
    • Saga-city, Saga, Japan, 849-8501
      • Novartis Investigative Site
  • Saitama
    • Kawagoe, Saitama, Japan, 350 8550
      • Novartis Investigative Site
  • Tochigi
    • Shimotsuga Gun, Tochigi, Japan, 321-0293
      • Novartis Investigative Site
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8519
      • Novartis Investigative Site
    • Shinjuku-ku, Tokyo, Japan, 160-0023
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Novartis Investigative Site
• Poland
  • Gdansk, Poland, 80-952
    • Novartis Investigative Site
  • Warszawa, Poland, 02 106
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08041
    • Novartis Investigative Site
  • Las Palmas de Gran Canaria, Spain, 35010
    • Novartis Investigative Site
  • Madrid, Spain, 28041
    • Novartis Investigative Site
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Madrid, Spain, 28006
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Asturias
    • Oviedo, Asturias, Spain, 33006
      • Novartis Investigative Site
  • Catalunya
    • Tarragona, Catalunya, Spain, 43005
      • Novartis Investigative Site
    • Terrassa, Catalunya, Spain, 08221
      • Novartis Investigative Site
  • Galicia
    • Orense, Galicia, Spain, 32005
      • Novartis Investigative Site
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Novartis Investigative Site
  • Santa Cruz De Tenerife
    • La Laguna, Santa Cruz De Tenerife, Spain, 38320
      • Novartis Investigative Site
  • Vizcaya
    • Baracaldo, Vizcaya, Spain, 48903
      • Novartis Investigative Site
• Sweden
  • Lund, Sweden, SE-221 85
    • Novartis Investigative Site
  • Stockholm, Sweden, SE-171 76
    • Novartis Investigative Site
  • Uppsala, Sweden, SE-751 85
    • Novartis Investigative Site
• United Kingdom
  • Cardiff, United Kingdom, CF14 4XW
    • Novartis Investigative Site
  • Oxford, United Kingdom, OX3 7LJ
    • Novartis Investigative Site
• United States
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Novartis Investigative Site
    • Miami Lakes, Florida, United States, 33014
      • Lakes Research SC
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Center and Research Institute SC - 5
  • Kansas
    • Wichita, Kansas, United States, 67214-3728
      • Cancer Center of Kansas SC
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute SC - 8
  • New York
    • New York, New York, United States, 10017
      • Novartis Investigative Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University SC-6
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Novartis Investigative Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute Sarah Cannon Research
  • Utah
    • Ogden, Utah, United States, 84405
      • Community Cancer Trials of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female patients ≥ 18 years of age
• 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 daily 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

• Documented chronic phase CML must meet all the criteria defined by:

  • < 15% blasts in peripheral blood and bone marrow,
  • < 30% blasts plus promyelocytes in peripheral blood and bone marrow,
  • < 20% basophils in the peripheral blood,
  • ≥ 100 x 109/L (≥ 100,000/mm3) platelets,
  • No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
• Patients must tolerate a minimum total daily dose of nilotinib of 400 mg

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
• 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, uncontrolled infection)
• 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 who have not recovered from prior 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 starting study drug.
• 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. (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Nilotinib followed by treatment-free; Patients who received a minimum of 2 years of first line nilotinib treatment and with pre-screen PCR results in ≥ MR4.5 entered the consolidation phase of the study (52 weeks - nilotinib 300 mg BID). Patients with Minimal Residual Disease (MRD) at the end of this phase entered the Treatment-Free Remission (TFR) phase where no treatment was 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).

Drug: Nilotinib followed by treatment-free; Nilotinib is being 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.; Other Names: AMN107

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Who Are in MMR (Major Molecular Response) at 48 Weeks After Starting the Treatment-free Remission (TFR) Phase	Primary endpoint was the percentage of participants who were in MMR at 48 weeks after starting the TFR phase and is calculated by dividing the number of patients with MMR at 48 weeks after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment were considered as non-responders.	48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Who Are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 Weeks After Starting the TFR Phase	Proportion of patients who are in MR4.5 at 48 weeks after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48 weeks after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders. MR4.5 = log reductions of the BCR-ABR transcript load in blood as a measurement of deep molecular response of the CML clone to treatment.	48 weeks
Percentage of Patients Who Are in MMR at 96, 144,192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase	Proportion of patients who are in MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders	96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years
Percentage of Patients Who Are in MR4.5 at 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase	Proportion of patients who are in MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders	96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years
Percentage of Patients in MMR at 48, 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase of Nilotinib	Proportion of patients who are in MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MMR at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis	48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years
Percentage of Patients in MR4.5 at 48, 96, 144, 192, 264 Weeks and at the End of 6, 7, 8, 9 and 10 Years After Starting the TFR Phase of Nilotinib	Proportion of patients who are in MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48, 96, 144, 192, 264 weeks and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis	48, 96, 144, 192, 264 weeks, end of 6, 7, 8, 9 and 10 years
Percentage of Patients Who Achieve MMR Within 12 Weeks of Re-treatment With Nilotinib	Proportion of patients who achieve MMR within 12 weeks of re-initiation of nilotinib is calculated by dividing the number of patients who are in MMR at least at one assessment within 12 weeks after re-start of nilotinib treatment by the number of patients who are re-initiated for at least 12 weeks	12 weeks
Kinetics of BCR-ABL Transcript After Re-start of Nilotinib Therapy	Descriptive statistics of BCR-ABL levels (IS) over time after re-start of nilotinib therapy up to 528 weks after the last patient has entered TFR	Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after last patient has entered the TFR
Duration of Re-initiated Treatment Required to Regain MMR After Loss of MMR	Defined as time from date of start of re-initiation of treatment after loss of MMR to the date of first achievement of MMR. Patients who do not regain MMR after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment	Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after the last patient has entered TFR
Duration of Re-initiated Treatment Required to Regain MR4.5 After Loss of MMR	Defined as the time from start of re-initiation of treatment after loss of MMR to the first achievement of MR4.5. Patients who do not regain MR4.5 after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment	Every 4 weeks up to week 24 and every 12 weeks thereafter up to 528 weeks after the last patient has entered TFR
Treatment-free Survival (TFS) After the Start of the TFR Phase	TFS is defined as the time from the start of the TFR phase to the earliest occurrence of loss of MMR, re-initiation of treatment due to any cause, progression of AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (PCR, cytogenetic, hematologic or extramedullary). A TFS sensitivity analysis will be conducted to consider discontinuation from TFR phase due to any reason as a TFS event, in addition to the TFS events as defined above.	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 432 weeks of the TFR
Progression-free Survival (PFS) After the Start of the TFR Phase	PFS is defined as the time from the start of the TFR phase to the earliest occurrence of progression to AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (cytogenetic, hematologic or extramedullary) for patients who are still on study and at the date of last contact for patients who are in follow-up	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 432 weeks of the TFR
Overall Survival (OS) After the Start of the TFR Phase	OS is defined as the time from start of the TFR phase to death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment for patients who are still on study and at the date of last contact for patients who are in follow-up	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 432 weeks of the TFR
Safety Profile During the Nilotinib Treatment Consolidation Phase, During the TFR Phase and During Re-initiation Treatment With Nilotinib	Safety profile includes type, frequency and severity of adverse events, laboratory abnormalities and clinically notable ECG and other safety parameters during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation of treatment with nilotinib	Every 4 weeks in treatment consolidation and during the first 24 weeks of the re-initiation 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 432 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	Proportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR	Every 3 months in patients who lost MMR until the result is negative or up to 528 weeks after the last patient entered TFR. On average 3 analyses (every 3 months or up to 264 weeks after the last patient has entered TFR.)
Percentage of Patients Who Are in Stable Response (MMR and MR4.5) After Achievement of That Response in Nilotinib Re-initiation Phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 Weeks, Based on Availability of Appropriate Data	Proportion of patients who are in stable MMR/MR4.5 after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks, based on availability of appropriate data, is calculated by dividing the number of patients achieving MMR/MR4.5 any time during the nilotinib re-initiation phase and having the same response 48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks after the first achievement of MMR/MR4.5, irrespective of whether there is loss of MMR in between, by the number of patients who achieved MMR/MR4.5 at any time during the nilotinib re-initiation phase	48, 96, 144, 192, 240, 288, 336, 384 and 432 weeks

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2013
• Primary Completion (Actual): May 31, 2016
• Study Completion (Estimated): February 20, 2025

Study Registration Dates

• First Submitted: January 30, 2013
• First Submitted That Met QC Criteria: February 4, 2013
• First Posted (Estimated): February 5, 2013

Study Record Updates

• Last Update Posted (Estimated): February 29, 2024
• Last Update Submitted That Met QC Criteria: February 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: CML; AMN107; Ph+ CML-CP; chronic phase; nilotinib treatment; 2 years treatment; MR 4.5; Loss of MR 4; Loss of MMR
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chronic Disease; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: CAMN107I2201; 2012-004092-40 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No