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

Primary Purpose

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

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Bosutinib
Laboratory Biomarker Analysis
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Blasts Under 15 Percent of Bone Marrow Nucleated Cells

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (bosutinib)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Number of Participants With Treatment Interruptions and Dose Reductions
Will be summarized.
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%).
Rates of BCR-ABL/ABL <10%
Will be assessed using the international scale. Will be estimated along with the exact 95% confidence intervals.
Rates of BCR-ABL/ABL < 1%
Will be assessed using the international scale. Will be estimated along with the exact 95% confidence intervals.
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.
Event-free Survival
Time from date of treatment start until the date of first objective documentation of disease-relapse.
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.
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.

Full Information

First Posted
September 15, 2016
Last Updated
April 22, 2020
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI), Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT02906696
Brief Title
Bosutinib in Treating Patients With Chronic Myeloid Leukemia in Chronic Phase After Frontline TKI Failure
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Terminated
Why Stopped
Terminated per PI's request due to competing priorities.
Study Start Date
October 28, 2016 (Actual)
Primary Completion Date
August 8, 2019 (Actual)
Study Completion Date
August 8, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI), Pfizer

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
8 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (bosutinib)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Bosutinib
Other Intervention Name(s)
Bosulif, SKI 606, SKI-606
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Response Rate
Description
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.
Time Frame
Up to 6 months
Secondary Outcome Measure Information:
Title
Number of Participants With Treatment Interruptions and Dose Reductions
Description
Will be summarized.
Time Frame
Up to 2 years
Title
Rates of Major Molecular Response (MR), MR4, MR4.5 and Complete Molecular Response
Description
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%).
Time Frame
Up to 2 years
Title
Rates of BCR-ABL/ABL <10%
Description
Will be assessed using the international scale. Will be estimated along with the exact 95% confidence intervals.
Time Frame
At 3 months
Title
Rates of BCR-ABL/ABL < 1%
Description
Will be assessed using the international scale. Will be estimated along with the exact 95% confidence intervals.
Time Frame
At 6 months
Title
Overall Survival
Description
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.
Time Frame
Up to 2 years
Title
Event-free Survival
Description
Time from date of treatment start until the date of first objective documentation of disease-relapse.
Time Frame
Up to 2 years
Title
Transformation-free Survival
Description
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.
Time Frame
Up to 2 years
Title
Change of ABL Kinase Domain Mutation Status
Description
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.
Time Frame
Baseline up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Philip A Thompson
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
University of Texas MD Anderson Cancer Center Website

Learn more about this trial

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

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