Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib (ENESTop)
Condition: Chronic Myeloid Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Intervention: nilotinib
Intervention description: Nilotinib was dosed by weight or body surface area.
Nilotinib 300 mg BID or 400 mg BID was be administered orally at approximately 12 hour intervals, and must not have been taken with food. The capsules were to be swallowed whole with water.
No food should have been consumed for at least 2 hours before the dose was taken and no additional food should have been consumed for at least one hour after the dose was taken. Patients were also allowed to enter this study on the same dose they were taking prior to study entry. Patients who required permanent dose reduction from their original starting dose were to be allowed to enter this study on the same dose only if the patient maintained this dose for a minimum of 6 months prior to study entry.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 163.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: AMN107; CML; Phase II; single arm; open label; nilotinib; treatment-free remission; MR4.5; confirmed loss of MR4; loss of MMR; Ph+ CML-CP

Summary:

      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.
    

Eligibility criteria:

        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.