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

Sponsor
M.D. Anderson Cancer Center (Other)
Overall Status
Terminated
CT.gov ID
NCT02906696
Collaborator
National Cancer Institute (NCI) (NIH), Pfizer (Industry)
8
1
1
33.3
0.2

Study Details

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:
  1. 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:
  1. Safety of dosing schedule. II. Frequency of treatment interruptions and dose reductions.

  2. 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.

  3. Determine the cumulative rate of CCyR. V. Determine the rate of major molecular response, molecular response (MR)4, MR4.5 and complete molecular response.

  4. Determine long-term outcomes, including progression-free survival, event-free survival, and overall survival.

  5. Investigate the correlation between ABL kinase domain mutations, if present at the time of enrollment, with outcome.

  6. 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.

Study Design

Study Type:
Interventional
Actual Enrollment :
8 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Oct 28, 2016
Actual Primary Completion Date :
Aug 8, 2019
Actual Study Completion Date :
Aug 8, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (bosutinib)

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
Given PO
Other Names:
  • Bosulif
  • SKI 606
  • SKI-606
  • Other: Laboratory Biomarker Analysis
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Response Rate [Up to 6 months]

      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

    1. Number of Participants With Treatment Interruptions and Dose Reductions [Up to 2 years]

      Will be summarized.

    2. Rates of Major Molecular Response (MR), MR4, MR4.5 and Complete Molecular Response [Up to 2 years]

      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%).

    3. Rates of BCR-ABL/ABL <10% [At 3 months]

      Will be assessed using the international scale. Will be estimated along with the exact 95% confidence intervals.

    4. Rates of BCR-ABL/ABL < 1% [At 6 months]

      Will be assessed using the international scale. Will be estimated along with the exact 95% confidence intervals.

    5. Overall Survival [Up to 2 years]

      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.

    6. Event-free Survival [Up to 2 years]

      Time from date of treatment start until the date of first objective documentation of disease-relapse.

    7. Transformation-free Survival [Up to 2 years]

      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.

    8. Change of ABL Kinase Domain Mutation Status [Baseline up to 2 years]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 109/L platelets (>= 100,000/mm3);

    • 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)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 M D Anderson Cancer Center Houston Texas United States 77030

    Sponsors and Collaborators

    • M.D. Anderson Cancer Center
    • National Cancer Institute (NCI)
    • Pfizer

    Investigators

    • Principal Investigator: Philip A Thompson, M.D. Anderson Cancer Center

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT02906696
    Other Study ID Numbers:
    • 2016-0081
    • NCI-2016-01954
    • 2016-0081
    • P30CA016672
    First Posted:
    Sep 20, 2016
    Last Update Posted:
    May 11, 2020
    Last Verified:
    Apr 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Recruitment Period: October 2016 to November 2018
    Pre-assignment Detail
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Period Title: Overall Study
    STARTED 8
    COMPLETED 8
    NOT COMPLETED 0

    Baseline Characteristics

    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Overall Participants 8
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    6
    75%
    >=65 years
    2
    25%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    44
    Sex: Female, Male (Count of Participants)
    Female
    3
    37.5%
    Male
    5
    62.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    3
    37.5%
    White
    5
    62.5%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    8
    100%

    Outcome Measures

    1. Primary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Measure Participants 8
    Count of Participants [Participants]
    6
    75%
    2. Secondary Outcome
    Title Number of Participants With Treatment Interruptions and Dose Reductions
    Description Will be summarized.
    Time Frame Up to 2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Measure Participants 8
    Interruptions
    6
    75%
    Reductions
    4
    50%
    3. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Measure Participants 8
    Complete Molecular Response (CMR)
    2
    25%
    MR4.5
    3
    37.5%
    MR4
    3
    37.5%
    Major Molecular Response (MMR)
    5
    62.5%
    4. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Measure Participants 8
    Count of Participants [Participants]
    3
    37.5%
    5. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Measure Participants 8
    Count of Participants [Participants]
    2
    25%
    6. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Measure Participants 8
    Median (Full Range) [Months]
    20.26
    7. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Measure Participants 8
    Median (Full Range) [Months]
    13.97
    8. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Measure Participants 8
    Median (Full Range) [Months]
    13.97
    9. Secondary Outcome
    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

    Outcome Measure Data

    Analysis Population Description
    There were not any at the start of treatment so there were not any mutation status to follow. These were not done.
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    Measure Participants 0

    Adverse Events

    Time Frame up to 2 years
    Adverse Event Reporting Description
    Arm/Group Title Treatment (Bosutinib)
    Arm/Group 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. Bosutinib: Given PO Laboratory Biomarker Analysis: Correlative studies
    All Cause Mortality
    Treatment (Bosutinib)
    Affected / at Risk (%) # Events
    Total 0/8 (0%)
    Serious Adverse Events
    Treatment (Bosutinib)
    Affected / at Risk (%) # Events
    Total 4/8 (50%)
    Cardiac disorders
    Chest Pain 1/8 (12.5%) 1
    Gastrointestinal disorders
    Diarrhea 1/8 (12.5%) 1
    Gastrointestinal Bleed 1/8 (12.5%) 1
    General disorders
    Viral Infection 1/8 (12.5%) 1
    Injury, poisoning and procedural complications
    Arterial Rupture 1/8 (12.5%) 1
    Other (Not Including Serious) Adverse Events
    Treatment (Bosutinib)
    Affected / at Risk (%) # Events
    Total 8/8 (100%)
    Blood and lymphatic system disorders
    Angioedema 1/8 (12.5%) 1
    Anemia 2/8 (25%) 2
    Eye disorders
    Periorbital Edema 1/8 (12.5%) 1
    Gastrointestinal disorders
    Diarrhea 7/8 (87.5%) 7
    Mucositis 1/8 (12.5%) 1
    Nausea 1/8 (12.5%) 1
    Vomiting 1/8 (12.5%) 1
    General disorders
    Abdominal Pain 2/8 (25%) 2
    Chest Pain 1/8 (12.5%) 1
    Fatigue 5/8 (62.5%) 5
    Fever of Unknown origin 1/8 (12.5%) 1
    Headache 2/8 (25%) 2
    Infections and infestations
    Upper Respiratory Infection 1/8 (12.5%) 1
    Yeast Infection 1/8 (12.5%) 1
    Injury, poisoning and procedural complications
    Bruising 1/8 (12.5%) 1
    Investigations
    Elevated Alanine transaminase 4/8 (50%) 11
    Aspartate transaminase 2/8 (25%) 4
    Elevated Creatinine 1/8 (12.5%) 1
    Metabolism and nutrition disorders
    Hyperglycemia 1/8 (12.5%) 1
    Sodium 1/8 (12.5%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 2/8 (25%) 2
    Nervous system disorders
    Sensory Neuropathy 1/8 (12.5%) 1
    Reproductive system and breast disorders
    Irregular Menstration 1/8 (12.5%) 1
    Skin and subcutaneous tissue disorders
    Pruritis 1/8 (12.5%) 1
    Rash 3/8 (37.5%) 3

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Philip Thompson, MD/Assistant Professor
    Organization The University of Texas MD Anderson Cancer Center
    Phone 713-792-7430
    Email PAThompson2@mdanderson.org
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT02906696
    Other Study ID Numbers:
    • 2016-0081
    • NCI-2016-01954
    • 2016-0081
    • P30CA016672
    First Posted:
    Sep 20, 2016
    Last Update Posted:
    May 11, 2020
    Last Verified:
    Apr 1, 2020