Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients
Condition: Chronic Myelogenous Leukemia
MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Intervention: Nilotinib followed by treatment-free
Intervention description: 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Other
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 215.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: AMN107; Ph+ CML-CP; chronic phase; nilotinib treatment; 2 years treatment; MR 4.5; Loss of MR 4; Loss of MMR; CML

Summary:

      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
    

Eligibility criteria:

        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.