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Axitinib and Bosutinib in Treating Patients With Chronic, Accelerated, or Blastic Phase Chronic Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02782403
Recruitment Status : Active, not recruiting
First Posted : May 25, 2016
Last Update Posted : October 4, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase I/II trial studies the side effects and best dose of axitinib and bosutinib and how well they work in treating patients with chronic, accelerated, or blastic phase chronic myeloid leukemia. Axitinib and bosutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Accelerated Phase Chronic Myelogenous Leukemia (CML) Blast Phase Chronic Myelogenous Leukemia (CML) Chronic Phase Phase Chronic Myelogenous Leukemia (CML) Philadelphia Chromosome Positive (Ph+) Phase Chronic Myelogenous Leukemia (CML) Drug: Axitinib Drug: Bosutinib Other: Laboratory Biomarker Analysis Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Alternating or Combined Therapy With Axitinib and Bosutinib for Patients With Chronic Myeloid Leukemia in Chronic, Accelerated, or Blastic Phases
Actual Study Start Date : March 20, 2017
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : August 31, 2021


Arm Intervention/treatment
Experimental: Treatment (alternating therapy)
Patients with chronic phase CML receive either bosutinib PO QD or axitinib PO BID alone for 3 months. Patients then switch to the other drug for 3 months and alternate between the two every 3 months in the absence of disease progression or unacceptable toxicity.
Drug: Axitinib
Given PO
Other Names:
  • AG-013736
  • AG013736
  • Inlyta

Drug: Bosutinib
Given PO
Other Names:
  • Bosulif
  • SKI 606
  • SKI-606

Other: Laboratory Biomarker Analysis
Correlative studies

Experimental: Treatment (combined therapy)
Patients with accelerated or blastic phase CML receive bosutinib PO QD and axitinib PO BID for 3 months. Courses repeat every 3 months in the absence of disease progression or unacceptable toxicity.
Drug: Axitinib
Given PO
Other Names:
  • AG-013736
  • AG013736
  • Inlyta

Drug: Bosutinib
Given PO
Other Names:
  • Bosulif
  • SKI 606
  • SKI-606

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Rate of major cytogenetic response (MCyR) among patients with chronic myeloid leukemia, chronic phase status post (s/p) failure of/intolerance to >= 3 tyrosine kinase inhibitors treated with alternating axitinib and bosutinib (Chronic Phase Cohort) [ Time Frame: Up to 4 years ]
  2. Maximum tolerated doses of the combination of axitinib and bosutinib among patients with chronic myeloid leukemia (CML)-advanced phase (AP) or -blast phase (BP) (AP patients must have received >= 1 prior TKI) (Advanced phase cohort - Phase I Portion) [ Time Frame: Up to 4 years ]
  3. Complete hematologic response (CHR) rate to the combination of axitinib and bosutinib among patients with CML-AP or -BP (AP patients must have received >= 1 prior TKI) (Advanced phase cohort - Phase II Portion) [ Time Frame: Up to 4 years ]

Secondary Outcome Measures :
  1. Clinical rates analysis (Chronic Phase Cohort) [ Time Frame: Up to 4 years ]
    Rates of CHR, complete cytogenetic response (CCyR), major molecular response (MMR), molecular response 4-log (MR4), molecular response 4.5-log (MR4.5), complete molecular response (CMR), BCR-ABL/ABL =< 10% and =< 1%, duration of response (DOR), event-free survival (EFS), transformation-free survival (TFS), failure-free survival (FFS) and overall survival (OS) among patients with CML-CP after resistance and/or intolerance to >= 2 TKIs treated with alternating axitinib and bosutinib.

  2. Incidence and severity of adverse events (AEs) (Advanced phase cohort - Phase I Portion) [ Time Frame: Up to 4 years ]
    Will be determined by history and physical examination and laboratory assessment, seen with the combination of axitinib and bosutinib among patients with CML-AP or -BP.

  3. Rates of CHR, CCyR, MMR, MR4, MR4.5, CMR, BCR-ABL/ABL =< 10% and =< 1%, DOR, EFS, TFS, FFS and OS among patients with CML-AP or -BP receiving combined therapy with axitinib and bosutinib (Advanced phase cohort - Phase II Portion) [ Time Frame: Up to 4 years ]
  4. Percentage of participants with mutations in BCR-ABL and other genes in all patients receiving study drugs [ Time Frame: Baseline up to 4 years ]

    Measured by analysis of each patient's multigene profile using Next Generation Sequencing (NGS) panel and/or ABL kinase domain sequencing performed at baseline.

    Following the analysis of each patient's mutation profile, the number of each somatic mutation identified will be reported.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of Philadelphia chromosome positive (Ph+) (by cytogenetics or FISH) or BCR-ABL+ (by polymerase chain reaction [PCR]) CML in CP (cohort 1), AP (cohort 2) or BP (cohort 2)
  • Patients should have failed (demonstrated resistance, intolerance or treatment discontinuation for any other reason of) at least 3 Food and Drug Administration (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 Leukemia Net (ELN); 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
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless due to Gilbert syndrome, in which case it should be =< 3.0 x ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
  • Serum creatinine =< 1.5 x ULN
  • Patients must sign the Institutional Review Board (IRB)-approved informed consent document for this trial
  • Reliable telephone access so as to be able to receive calls from an interactive voice response (IVR) system (only applicable to patients participating in the optional symptom burden assessment portion)
  • 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)
  • 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:

  • 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
  • Active gastrointestinal conditions that are expected to impair absorption of orally administered medications
  • 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
  • Patients with active, uncontrolled psychiatric disorders including: psychosis, major depressive, and bipolar disorders
  • Patients with uncontrolled hypertension (defined as sustained systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg)
  • Pregnant or breast-feeding women are excluded
  • Inability to understand a written informed consent document
  • Patients receiving anticoagulants that are unable to be discontinued
  • Patients with active, uncontrolled infection
  • Patients with a history of hypersensitivity to bosutinib or axitinib
  • 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 principal investigator (PI) and the rationale documented; these patients, if enrolled on study, may require dose modifications for both axitinib and bosutinib

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02782403


Locations
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United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Prithviraj Bose M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02782403    
Other Study ID Numbers: 2015-0787
NCI-2016-01188 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2015-0787 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: May 25, 2016    Key Record Dates
Last Update Posted: October 4, 2019
Last Verified: October 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Blast Crisis
Leukemia, Myeloid, Accelerated Phase
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Cell Transformation, Neoplastic
Carcinogenesis
Neoplastic Processes
Axitinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action