Bosutinib in Treating Patients With Chronic Myeloid Leukemia in Chronic Phase After Frontline TKI Failure

Study Overview
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Brief Summary
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This phase II trial studies how well bosutinib works in treating patients with chronic myeloid leukemia in chronic phase after frontline tyrosine kinase inhibitor (TKI) failure. Bosutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the response rate within 24 weeks in patients in chronic phase receiving bosutinib with the starting dose of 300 mg per day, with potential escalation to 400 mg, 500 mg and 600 mg per day. SECONDARY OBJECTIVES: I. Safety of dosing schedule. II. Frequency of treatment interruptions and dose reductions. III. Determine the rate of BCR-ABL/ABL < 10% at 3 months and < 1% at 6 months on the international scale and the rate of complete cytogenetic response (CCyR) at 6 months after the start of treatment. IV. Determine the cumulative rate of CCyR. V. Determine the rate of major molecular response, molecular response (MR)4, MR4.5 and complete molecular response. VI. Determine long-term outcomes, including progression-free survival, event-free survival, and overall survival. VIII. Investigate the correlation between ABL kinase domain mutations, if present at the time of enrollment, with outcome. IX. Determine the rate of development and type of ABL kinase domain mutations during therapy with bosutinib. OUTLINE: Patients receive bosutinib orally (PO) daily on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 12 weeks for up to 2 years, every 24 weeks for 2 years.

Official Title
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An Open-Label Phase II Dose Optimization Study of Bosutinib at a Starting Dose of 300 Mg Daily for Adult Patients With Chronic Myeloid Leukemia (CML) in Chronic Phase Post Frontline TKI Failure

Conditions
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Blasts Under 15 Percent of Bone Marrow Nucleated Cells, Blasts Under 15 Percent of Peripheral Blood White Cells, Blasts Under 30 Percent of Bone Marrow Nucleated Cells, Blasts Under 30 Percent of Peripheral Blood White Cells, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Intervention / Treatment
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* Drug: Bosutinib
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with chronic myeloid leukemia (CML) in chronic phase who have resistance and/or intolerance to frontline TKI therapy; resistance is defined as lack (lack defined as response not achieved or lost by the given dates mentioned hereafter) of CHR (complete hematologic response) within 3 months, lack of major cytogenetic response (MCyR) within 6 months, and lack of CCyR within 12 months of therapy with frontline TKIs; in addition, loss of MCyR, CCyR or MMR at any time during the course of therapy is also considered resistance to therapy; intolerance is defined as persistent or severe toxicity that is unacceptable to the patient Chronic phase disease is defined as: < 15% blasts in peripheral blood and bone marrow; < 30% blasts plus promyelocytes in peripheral blood and bone marrow; < 20% basophils in peripheral blood; >= 100 x 10^9/L platelets (>= 100,000/mm^3); No evidence of extramedullary disease except hepatosplenomegaly; and No prior diagnosis of accelerated phase (AP) or blastic phase-chronic myeloid leukemia (BP-CML); patients with clonal evolution but no other criteria for accelerated phase are eligible Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Creatinine less than or equal to 2.0 mg/dl Bilirubin less than or equal to 2.0 mg/dl Alanine aminotransferase (ALT) less than or equal to 3 times institutional upper limit of normal Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotrophin (beta-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use one of the following effective contraception methods during the study and for 30 days following the last dose of study drug; effective methods of birth control include: Birth control pills, shots or implants (placed under the skin by a health care provider) or patches (placed on the skin); Intrauterine devices (IUDs); Condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide; females of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug Patients or their legally authorized representative must provide written informed consent Exclusion Criteria: Women who are pregnant or lactating Known to be human immunodeficiency virus (HIV)+ Active and uncontrolled disease/infection that in the opinion of the treating physician and principal investigator may affect the ability to participate in the trial or put the patient at unduly high risk Unable or unwilling to sign the informed consent document Received no other investigational therapy within the past 14 days Presence of T315I mutation by ABL1 sequencing Patient is currently in complete cytogenetic remission (CCyR)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bosutinib)<br>Patients receive bosutinib PO daily on days 1-28. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. | Drug: Bosutinib<br>* Given PO<br>* Other names: SKI-606;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Response is defined as follows: 1) For patients who do not currently have a partial cytogenetic response (PCyR), achievement of major cytogenetic response is considered a response. 2) For patients who are currently in PCyR, achievement of CCyR is considered a response. The Simon's optimal two-stage design will be used for interim futility monitoring. Will be estimated along with the 95% credible interval. | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Interruptions and Dose Reductions | Will be summarized. | Up to 2 years | 
| Rates of Major Molecular Response (MR), MR4, MR4.5 and Complete Molecular Response | Will be estimated along with the exact 95% confidence intervals. Molecular assessments are based on quantitative reverse transcriptase polymerase chain reaction for Bcr-Abl in peripheral blood. Molecular response is categorized as MMR (Bcr-Abl/Abl ratio of </= 0.1% in the international scale), MR4 (Bcr-Abl/Abl </= 0.01%), and MR4.5 (BCR-ABL/ABL </=0.0032%). | Up to 2 years | 
| Rates of BCR-ABL/ABL <10% | Will be assessed using the international scale. Will be estimated along with the exact 95% confidence intervals. | At 3 months | 
| Rates of BCR-ABL/ABL < 1% | Will be assessed using the international scale. Will be estimated along with the exact 95% confidence intervals. | At 6 months | 
| Overall Survival | Will be assessed by Kaplan-Meier methods. Cox proportional hazards regression models will be fit to assess the association between patient characteristics including survival outcome. Time from date of treatment start until date of death due to any cause or last Follow-up. | Up to 2 years | 
| Event-free Survival | Time from date of treatment start until the date of first objective documentation of disease-relapse. | Up to 2 years | 
| Transformation-free Survival | Will be assessed by Kaplan-Meier methods. Transformation-free survival is defined as the time from treatment initiation until either progression to AP/BP or death from any cause. | Up to 2 years | 
| Change of ABL Kinase Domain Mutation Status | Will be summarized and its association with survival outcomes will be analyzed through landmark analyses. Cox proportional hazards regression models will be fit to assess the association between patient characteristics including ABL kinase domain mutation status. | Baseline up to 2 years |