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

The Primary objective of this study was to determine the percentage of patients who were in Major Molecular Response (MMR) at 48 weeks after starting the Treatment-Free Remission (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 Treatment-Free Remission (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.

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:

• 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.
• Placement of an intrauterine device (IUD) or intrauterine system (IUS)
• 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.