Clinical Trials /

Axitinib and Bosutinib for Patients With Chronic Myeloid Leukemia in Chronic, Accelerated or Blastic Phases

NCT02782403

Description:

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).

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Axitinib and Bosutinib for Patients With Chronic Myeloid Leukemia in Chronic, Accelerated or Blastic Phases
  • Official Title: Alternating or Combined Therapy With Axitinib and Bosutinib for Patients With Chronic Myeloid Leukemia in Chronic, Accelerated or Blastic Phases

Clinical Trial IDs

  • ORG STUDY ID: 2015-0787
  • SECONDARY ID: NCI-2016-01188
  • NCT ID: NCT02782403

Conditions

  • Leukemia

Interventions

DrugSynonymsArms
AxitinibAG-013736, InlytaAdvanced Phase CML Group - (CML-AP) or CML-BP
BosutinibSKI-606Advanced Phase CML Group - (CML-AP) or CML-BP

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Chronic Phase CML GroupExperimentalAt least 10 participants with the T315I mutation included in group. Participants with BCR-ABL T315I begin therapy with Axitinib, whereas those without this KD mutation begin therapy with Bosutinib. Participants receive starting dose of Axitinib 5 mg twice a day by mouth daily, and starting dose of Bosutinib 500 mg by mouth daily in alternating, 3-month cycles. At the end of 3 months, participants switch to the other drug for 3 months. This continues every 3 months while on the study. Participants may continue taking the study drugs for as long as the doctor thinks it is in their best interest.
  • Axitinib
  • Bosutinib
Advanced Phase CML Group - (CML-AP) or CML-BPExperimentalParticipants have either blast phase (BP) or accelerated phase (AP) chronic myeloid leukemia (CML). Phase I: Starting dose level of Axitinib 3 mg twice a day by mouth daily, and Bosutinib 400 mg by mouth daily. Phase II Dose Expansion Phase: Starting Dose of Axitinib and Bosutinib is maximum tolerated dose from Phase I Dose Escalation Phase.
  • Axitinib
  • Bosutinib

Eligibility Criteria

        Inclusion Criteria:

          1. Diagnosis of Ph+ (by cytogenetics or FISH) or BCR-ABL+ (by PCR) CML in CP (cohort 1),
             AP (cohort 2) or BP (cohort 2).

          2. Patients should have failed (demonstrated resistance, intolerance or treatment
             discontinuation for any other reason of) at least 3 FDA-approved TKIs if in CP (cohort
             1), or at least 1 FDA-approved TKI if in AP (cohort 2). Resistance will be defined as
             meeting the criteria for failure or warning by the European LeukemiaNet (ELN,
             Appendix)1. No prior therapy is necessary for patients in BP (cohort 2). Patients in
             CP who have failed <3 TKIs, but are ineligible to receive other FDA-approved TKIs, may
             also be enrolled in cohort 1. 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.

          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

          5. Adequate end organ function, defined as the following: total bilirubin </= 1.5 x ULN
             (unless due to Gilbert syndrome, in which case it should be </= 3.0 x ULN), ALT and
             AST </= 2.5 x ULN, serum creatinine </= 1.5 x ULN.

          6. Patients must sign the IRB-approved informed consent document for this trial.

          7. Reliable telephone access so as to be able to receive calls from an IVR system (only
             applicable to patients participating in the optional symptom burden assessment
             portion).

          8. Women of childbearing potential (WOCBP) must practice 2 effective methods of birth
             control during the course of the study. Male patients who are partners of WOCBP should
             also practice an effective method of contraception: Postmenopausal women must be
             amenorrheic for >/= 12 months to be considered of non-childbearing potential. Women
             and men must continue birth control for the duration of the trial and >/= 3 months
             after the last dose of study drug. All WOCBP MUST have a negative pregnancy test prior
             to first receiving study medication(s).

          9. Patients should have discontinued therapy with imatinib, dasatinib, nilotinib,
             ponatinib, omacetaxine or other anti-leukemia therapy (except hydroxyurea) >/= 48
             hours prior to start of study therapy and recovered from any toxicity due to these
             therapies to grade </= 1. Hydroxyurea may be received up to the time of enrollment and
             for the first 6 weeks of study treatment if necessary.

        Exclusion Criteria:

          1. Prior therapy with axitinib. Prior therapy with bosutinib is allowed, except in the
             following circumstances: the subject is currently on bosutinib; bosutinib is the
             subject's most recent TKI for CML; the subject has a history of intolerance to
             bosutinib.

          2. Active gastrointestinal conditions that are expected to impair absorption of orally
             administered medications.

          3. Patients who currently have or have a history of the following within 6 months
             preceding study entry are not eligible: Unstable angina (UA), myocardial infarction
             (MI), transient ischemic attack (TIA), stroke, deep vein thrombosis (DVT), acute
             peripheral or pulmonary arterial thromboembolism (PE). Clinically significant
             ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or
             torsades de pointes). New York Heart Association class III or IV heart failure.

          4. Patients with active, uncontrolled psychiatric disorders including: psychosis, major
             depressive, and bipolar disorders.

          5. Patients with uncontrolled hypertension (defined as sustained systolic blood pressure
             > 160 mmHg or diastolic blood pressure >100 mmHg).

          6. Pregnant or breast-feeding women are excluded.

          7. Inability to understand a written informed consent document.

          8. Patients receiving anticoagulants that are unable to be discontinued.

          9. Patients with active, uncontrolled infection.

         10. Patients with a history of hypersensitivity to bosutinib or axitinib.

         11. Patients on proton pump inhibitors, potent CYP3A or P-glycoprotein substrates,
             inhibitors or inducers a minimum 7 day period washout required unless discontinuation
             or substitution is not in the best interests of the patient as determined by the
             investigator. In instances where use of these agents is felt to be required for
             optimal management, inclusion of such patients should be discussed with the PI and the
             rationale documented. These patients, if enrolled on study, may require dose
             modifications for both axitinib and bosutinib. The list of drugs that interact with
             cytochrome P450 enzymes can be found online at:
             http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable.aspx
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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 Frame:12 months
Safety Issue:
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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Leukemia
  • Chronic Myeloid Leukemia
  • CML
  • Chronic Myeloid Leukemia, Chronic Phase
  • CML-CP
  • Chronic Myeloid Leukemia in Accelerated Phase
  • CML-AP
  • Chronic Myeloid Leukemia in Blast Phase
  • CML-BP
  • Axitinib
  • AG-013736
  • Inlyta
  • Bosutinib
  • SKI-606

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