Objectives: Primary: Chronic Phase Cohort: To assess the rate of major cytogenetic response (MCyR) of an alternating schedule of axitinib and bosutinib in patients with chronic myeloid leukemia, chronic phase (CML-CP) after failure of/intolerance to >/= 3 tyrosine kinase inhibitors (TKIs) using standard response criteria. Advanced Phase Cohort - Phase I Portion: To determine the recommended phase II doses (RPTDs) of axitinib and bosutinib in combination in patients with CML in accelerated phase (CML-AP) or blast phase (CML-BP). (AP patients must have received >1 prior TKI). Advanced Phase Cohort - Phase II Portion: To evaluate the rate of major hematologic response (MaHR) of combined treatment with axitinib and bosutinib in patients with CML-AP or CML-BP using standard response criteria. (AP patients must have received >1 prior TKI). Secondary: Chronic Phase Cohort: To determine the rate of complete cytogenetic response (CCyR), BCR-ABL/ABL <10% and <1%, major molecular response (MMR), molecular response 4-log (MR4), molecular response 4.5-log (MR4.5), and complete molecular response (CMR), overall and at different time points. To determine the duration of response (DOR), event-free survival (EFS), transformation-free survival (TFS), failure-free survival (FFS) and overall survival (OS) for patients with CML-CP treated with alternating axitinib and bosutinib after failure of/intolerance to >3 TKIs. To determine the safety and tolerability of alternating therapy with axitinib and bosutinib after failure of/intolerance to >3 TKIs. Advanced phase cohort - Phase I Portion: To establish the response rate of concurrent administration of axitinib and bosutinib to patients with CML-AP or CML-BP. (AP patients must have received >1 prior TKI). Advanced phase cohort - Phase II Portion: To determine the rate of complete hematologic response (CHR), complete cytogenetic response (CCyR), BCR-ABL/ABL <10% and <1%, major molecular response (MMR), molecular response 4-log (MR4), molecular response 4.5-log (MR4.5), and complete molecular response (CMR), overall and at different time points of combined treatment with axitinib and bosutinib in patients with CML-AP or CML-BP. (AP patients must have received >1 prior to TKI). To determine the DOR, EFS, TFS, FFS and OS for patients with CML-AP or -BP treated with combined axitinib and bosutinib. (AP patients must have received >1 prior to TKI). To evaluate the probability of developing Abl kinase domain and other somatic mutations in patients with CML treated with alternating (CP) or concurrent (AP/BP) axitinib and bosutinib. To analyze differences in response rates, duration and survival according to pre-treatment mutations and patient characteristics in both the CP and AP/BP cohorts. To characterize mechanisms of resistance in patients who develop resistance to alternating (CP) or concomitant (AP/BP) therapy with axitinib and bosutinib. To evaluate symptom burden in patients with CML receiving axitinib and bosutinib, whether alternating (CP) or in combination (AP/BP).
Name: Axitinib
Description: Chronic Phase CML with T315I Mutation Group and Chronic Phase CML with No T315I Mutation Group: Axitinib 5 mg twice a day by mouth. Blast Phase or Accelerated Phase CML Group: Phase I Dose Escalation Phase Starting Dose of Axitinib 3 mg/day by mouth twice daily. Phase II Dose Expansion Phase Starting Dose of Axitinib is maximum tolerated dose from Phase I Dose Escalation Phase.Type: DrugAdvanced Phase CML Group - (CML-AP) or CML-BP Chronic Phase CML Group
Name: Bosutinib
Description: Chronic Phase CML with T315I Mutation Group and Chronic Phase CML with No T315I Mutation Group: Bosutinib 500 mg by mouth daily. Blast Phase or Accelerated Phase CML Group: Phase I Dose Escalation Phase Starting Dose of Bosutinib 400 mg/day by mouth once daily. Phase II Dose Expansion Phase Starting Dose of Bosutinib is maximum tolerated dose from Phase I Dose Escalation Phase.Type: DrugAdvanced Phase CML Group - (CML-AP) or CML-BP Chronic Phase CML Group
Description: Cytogenetic response classified according to suppression of the Philadelphia chromosome (Ph) by conventional karyotyping (FISH if cytogenetic analysis not informative, e.g., insufficient metaphases). Target response rate is 30%. The Bayesian approach of Thall, Simon, Estey implemented for the futility monitoring.
Measure: Rate of Major Cytogenetic Response (MCyR) of an Alternating Schedule of Axitinib and Bosutinib in Participants with Chronic Myeloid Leukemia, Chronic Phase (CML-CP) Time: 12 monthsDescription: Maximum tolerated dose (MTD) is highest dose level in which <2 patients of 6 develop first cycle dose limiting toxicity (DLT). DLT defined by adverse events occurring during the first month (1 cycle) of therapy that are clinically significant and are not related to CML.
Measure: Recommended Phase II Doses (RPTDs) of Axitinib and Bosutinib in Combination in Participants with CML in Accelerated Phase (CML-AP) or Blast Phase (CML-BP) Time: 1 monthDescription: Complete Hematologic Remission (CHR) - non-palpable spleen and normalization of the bone marrow (≤5% blasts) and peripheral blood with white blood cell count (WBC) <10 x 109/L and absolute neutrophil count (ANC) ≥1 x 109/L, <5% basophils, no peripheral myeloblasts or promyelocytes, <5% myelocytes plus metamyelocytes, and platelet count 100-450 x 109/L. This is in addition to disappearance of all signs and symptoms of the disease. Target response rate is 30%. The Bayesian approach of Thall, Simon, Estey implemented for the futility monitoring.
Measure: Complete Hematologic Response (MaHR) of Combined Treatment with Axitinib and Bosutinib in Participants with CML in Accelerated Phase (CML-AP) or Blast Phase (CML-BP). Time: 3 monthsAllocation: Non-Randomized
Parallel Assignment
There is one SNP
At least 10 CP patients with the T315I mutation affecting the kinase domain of Bcr-Abl will be enrolled in cohort 1, as well as in the phase II portion of cohort 2. 3. Age >/=18 years. --- T315I ---