The Primary objective was to evaluate the proportion 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.
Nilotinib treatment continuation phase (NTCT) and Nilotinib treatment prolonged continuation
phase (NTCT-P): Patients who were not eligible to enter into the TFR phase after completing
the 52-week NTCS phase entered the nilotinib treatment continuation (NTCT) phase and would
continue treatment with nilotinib for another 52 weeks (a total of 104 weeks of treatment).
Patients who were not able to maintain MR4.5 and had a confirmed loss of MR4.5 during the
NTCT phase were not eligible to enter the TFR-2 phase. These patients entered into the
nilotinib prolonged treatment continuation phase (NTCT-P) and continued nilotinib treatment
until 520 weeks after the last patient entered the nilotinib TFR phase, or until the patients
experience unacceptable toxicity, disease progression and/or treatment would be discontinued
at the discretion of the Investigator or withdrawal of consent.
Nilotinib TFR-2 phase: Patients who maintained MR4.5 during the NTCT phase were eligible to
cease nilotinib treatment and enter the TFR-2 phase. The duration of the nilotinib TFR-2
phase is up to 520 weeks after the last patient entered the TFR phase. Patients stopped
taking nilotinib therapy on the day they entered the TFR-2 phase.
Nilotinib treatment re-initiation-2 (NTRI-2): If a patient had a loss of MMR or a confirmed
loss of MR4 during the TFR-2 phase, he/she entered the nilotinib treatment re-initiation-2
(NTRI-2) phase and resumed nilotinib treatment at a dose of either 300 mg or 400 mg bid.
Safety follow-up was performed within 30 days after the last dose of study treatment or the
last day in TFR/TFR-2.
Post-treatment follow-up visits were performed every 12 weeks up to 520 weeks after the last
patient entered the nilotinib TFR phase.
Inclusion Criteria:
1. Male or female patients >= 18 years of age
2. ECOG Performance Status of 0, 1, or 2
3. Patient with diagnosis of BCR-ABL positive CML CP
4. 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
5. Patient has at least 2 years of nilotinib treatment prior to study entry.
6. Patient has achieved MR4.5 (local laboratory assessment) during nilotinib treatment,
and determined by a Novartis designated central PCR lab assessment at screening
7. 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
8. 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)
9. 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
10. Written informed consent obtained prior to any screening procedures
Exclusion Criteria:
1. Prior AP, BC or allo-transplant
2. Patient has documented MR4.5 at the time when switched from imatinib to nilotinib
3. Patients with known atypical transcript
4. 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)
5. Dose reductions due to neutropenia or thrombocytopenia in the past 6 months
6. Patient ever attempted to permanently discontinue imatinib or nilotinib treatment
7. 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)
8. 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)
9. History of acute pancreatitis within 1 year prior to study entry or past medical
history of chronic pancreatitis
10. Known presence of a significant congenital or acquired bleeding disorder unrelated to
cancer
11. 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
12. Patients who have not recovered from prior surgery
13. Treatment with other investigational agents (defined as not used in accordance with
the approved indication) within 4 weeks of Day 1
14. 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.
15. 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.
16. 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.)
17. 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)
18. 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.
19. 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.
