Stem Cell Monitoring for CML Patients Undergoing Nilotinib Therapy

The study is an open-label phase 2 clinical and translational trial designed to evaluate the effects of nilotinib on the leukemic stem cell population in subjects with newly diagnosed chronic phase chronic myeloid leukemia (Ph+ CML in CP). Nilotinib is FDA-approved to treat subjects with Ph+ CML in CP. Subjects on study will be monitored according to accepted National Cancer Comprehensive Network \[NCCN\] clinical guidelines for 24 months. After 24 months, if continued therapy is needed subjects will be transitioned to commercial supply of study drug.

Patients with newly diagnosed Ph+ CML in chronic phase will be eligible for enrollment in this trial. Prior treatment with nilotinib for less than 2 weeks and hydroxyurea is allowed.

Before therapy and during therapy, peripheral blood and bone marrow samples will be obtained for cytogenetic and molecular evaluations. During study, blood will be collected at approximately month 1, month 3, and every 3 months thereafter; aspirate samples will be collected at approximately month 1, month 3, and month 12. These samples will be collected to analyze the quantitative and qualitative changes in the leukemic stem cell population before and during therapy with nilotinib. The study is intended as a hypothesis finding analysis in order to establish whether in response to nilotinib therapy, defined differences in the baseline or therapy-induced changes in the characteristics of the stem cell population will be predictive of the ability to successfully discontinue therapy in subjects with CML.

In order to determine the effect of nilotinib in stem and progenitor populations we will evaluate 40 newly diagnosed CML subjects undergoing treatment with nilotinib at different time points. We will evaluate the levels of expression of Breakpoint Cluster Region-Abelson protooncogene (BCR-ABL) in purified stem cell populations during the course of treatment. In addition, we will compare the stem and progenitor populations present during the course of treatment in peripheral blood and bone marrow. We will perform transcriptional profiling of such populations to determine changes in signaling pathways driving survival, self-renewal or proliferation. Whole exome sequencing will be also performed in all diagnostic samples to determine whether there are novel cooperating mutations.

Eligibility Criteria:
Inclusion Criteria:

1. Patients 18 years or older
2. Eastern Cooperative Oncology Group (ECOG) Performance status 0,1, or 2
3. Documented diagnosis of Ph+ Chronic phase CML:

   * Chronic phase: None of the criteria for accelerated or blastic phase
   * Accelerated phase

     1. Blasts ≥ 15% in blood or BM
     2. Blasts plus progranulocytes ≥ 30% in blood or bone marrow (BM)
     3. Basophilia ≥ 20% in blood or BM
     4. Platelets \< 100 × 109/L unrelated to therapy
     5. Cytogenetic clonal evolution
   * Blast phase

     1. ≥ 30% blasts in blood or BM
     2. Extramedullary disease with localized immature blasts
4. Adequate end organ function, defined as the following:

   * Creatinine \< 1.5 x upper limit of normal (ULN)
   * Absolute neutrophil count (ANC) \> 1.5 x 109/L
   * Platelets \> 100 x 109/L
   * Total bilirubin \< 1.5 x ULN (Does not apply to patients with isolated hyperbilirubinemia \[e.g., Gilbert's disease\] grade \<3)
   * Aspartate aminotransferase (AST) (SGOT) and Alanine aminostransferase (ALT) (SGPT) \< 3 x ULN
   * Serum amylase and lipase ≤ 2 x ULN
   * Alkaline phosphatase ≤ 2.5 x ULN
   * Patients must have the following laboratory values (WNL = within normal limits at the local institution lab) or corrected to within normal limits with supplements prior to the first dose of study medication:

     1. Potassium (WNL)
     2. Magnesium (WNL)
     3. Phosphorus (WNL)
     4. Calcium (WNL)

Exclusion Criteria:

1. Previous treatment with any other tyrosine kinase inhibitor except for up to 2 weeks of nilotinib
2. Impaired cardiac function including any one of the following:

   * Inability to monitor the QT interval on ECG
   * Congenital long QT syndrome or a known family history of long QT syndrome.
   * Clinically significant resting brachycardia (\<50 beats per minute)
   * Q-T Corrected (corrected Q-T interval) (QTc) \> 450 msec on baseline ECG. If QTc \>450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc
   * Myocardial infarction within 12 months prior to starting study Other clinically significant uncontrolled heart disease (e.g. unstable angina, congestive heart failure or uncontrolled hypertension)
   * History of or presence of clinically significant ventricular or atrial tachyarrhythmias
   * Complete left bundle branch block
   * Right bundle branch block plus left anterior/posterior hemiblock
   * Use of ventricular-paced pacemaker
   * History of unstable angina within 1 year of study entry
3. Patients currently receiving treatment with strong CYP3A4 inhibitors and treatment cannot be either discontinued or switched to a different medication prior to starting study drug. (http://medicine.iupui.edu/clinpharm/ddis/) ).
4. Patients currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug (http://crediblemeds.org/)
5. Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery).
6. History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
7. 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)
8. 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
9. Known presence of significant congenital or acquired bleeding disorder unrelated to cancer
10. Major surgery within 4 weeks prior to Day 1 of the study or who have not recovered from prior surgery
11. Treatment with other investigational agents within 30 days of Day 1.
12. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of female after conception and until the termination of gestation, confirmed by a positive Human chorionic gonadotropin (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.