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A Multicenter Phase 3, Open-Label Study of Bosutinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia

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ClinicalTrials.gov Identifier: NCT02130557
Recruitment Status : Active, not recruiting
First Posted : May 5, 2014
Results First Posted : November 14, 2018
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
Phase 3, 2-arm, randomized, open label trial. Patients will be randomized to receive bosutinib or imatinib for the duration of the study.

Condition or disease Intervention/treatment Phase
Leukemia, Myelogenous, Chronic, Breakpoint Cluster Region-Abelson Proto-oncogene (BCR-ABL) Positive Drug: Bosutinib Drug: Imatinib Phase 3

Detailed Description:
The study will be open for enrollment until the planned number of approximately 500 Philadelphia Chromosome Positive (Ph+) patients have been randomized (approximately 250 Ph+ patients in each treatment arm; a total of approximately 530 Ph+ and Ph- patients). All patients will be treated and/or followed for approximately 5 years (240 weeks) after randomization until the study has closed. Patients who discontinue study therapy early due to disease progression or intolerance to study medication will continue to be followed yearly for survival for up to approximately 5 years (240 weeks) after randomization.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 536 participants
Allocation: Randomized
Masking: None (Open Label)
Masking Description: NOTE: Value was Open Label in old format; This study has an open-label design. Although most efficacy studies have a double blind design, this is not feasible in this trial, due to the complexity of the dose reduction and dose escalation schemes with tablets of various sizes, dosage strengths, as well as the number of tablets that would be required daily. However, the opportunity for bias is mitigated by the use of objective outcome measures (MMR, CCyR, CHR). The Investigators will be instructed to ensure that laboratory/pathology personnel are blinded to treatment information. For these reasons, an open-label, randomized study is appropriate.
Primary Purpose: Treatment
Official Title: A Multicenter Phase 3 Randomized, Open-label Study Of Bosutinib Versus Imatinib In Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia
Actual Study Start Date : July 22, 2014
Actual Primary Completion Date : August 11, 2016
Estimated Study Completion Date : April 4, 2020


Arm Intervention/treatment
Experimental: Bosutinib
Bosutinib, 400 mg, oral administration once a day
Drug: Bosutinib
Bosutinib (Bosulif®) is an orally bioavailable, potent, multi-targeted, dual Src-Abl tyrosine kinase inhibitor (TKI) that has been approved for the treatment of adult patients with Philadelphia positive (Ph+) chronic phase (CP), accelerated phase (AP) and blast phase (BP) chronic myelogenous leukemia (CML) previously treated with other TKI inhibitor therapy.[1] This study will investigate the use of bosutinib as first-line treatment for patients with Ph+ CP CML.

Active Comparator: Imatinib
Imatinib, 400 mg, oral administration once a day
Drug: Imatinib

Imatinib mesylate (referred to in this protocol as imatinib) is an inhibitor of the BCR-ABL kinase and been the standard first-line therapy for patients with chronic-phase CML. Imatinib was granted approval by the European Commission in November 2001 and by the FDA in December 2002 for the treatment of newly diagnosed patients with CP Ph+ CML based on results from the IRIS trial.

Imatinib is considered the standard of care for both first-line and later line settings, and consequently is an appropriate active comparator.





Primary Outcome Measures :
  1. Percentage of Participants With Major Molecular Response (MMR) at Month 12 [ Time Frame: Month 12 ]
    MMR was defined as a ratio of breakpoint cluster region to abelson (Bcr-Abl/Abl) less than or equal to (<=) 0.1 percent (%) on the international scale (IS) (greater than or equal to [>=] 3 log reduction from standardized baseline in ratio of Bcr-Abl to Abl transcripts [>=3000 Abl required]) by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR).


Secondary Outcome Measures :
  1. Major Molecular Response (MMR) by Month 18 [ Time Frame: up to Month 18 ]

    MMR was defined as a ratio of Bcr-Abl/Abl <=0.1% on the international scale (>=3 log reduction from standardized baseline in ratio of Bcr-Abl to Abl transcripts [>=3000 Abl required]) by quantitative RT-qPCR.

    It will be tested at the 1-sided significance level of 0.0125.


  2. Duration of Major Molecular Response (MMR) [ Time Frame: From the date of first MMR until the date of confirmed loss of MMR or censoring (up to 752 days) ]
    It was defined as the time from the first date of MMR until the date of the confirmed loss of MMR or censoring. Confirmed Loss of MMR was Bcr-Abl/Abl IS ratio >0.1% in association with a >=5-fold increase in Bcr-Abl/Abl IS ratio from the lowest value achieved up to that time-point confirmed by a second assessment at least 28 days later. Treatment discontinuation due to progressive disease (PD) or death due to PD within 28 days of last dose were considered confirmed loss of MMR. PD was defined as disease progression to accelerated phase or blast phase CML. Kaplan-meier analysis was used for determation of duration of MMR. Duration of response will be analyzed for responders only therefore duration of response will be excluded from the long-term family of secondary outcome measures.

  3. Percentage of Participants With Complete Cytogenetic Response (CCyR) by Month 12 [ Time Frame: up to Month 12 ]
    Complete Cytogenetic Response (CCyR) was based on the prevalence of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a bone marrow (BM) aspirate. CCyR was achieved when there was 0 % Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analyzed, or MMR if no BM was available.

  4. Duration of Complete Cytogenetic Response (CCyR) [ Time Frame: From the date of first CCyR until the date of confirmed loss of CCyR or censoring (up to 752 days) ]
    It was defined as the time from the first date of CCyR until the date of the confirmed loss of CCyR or censoring. Confirmed Loss of CCyR was the presence of at least one Ph+ metaphase confirmed by a second assessment at least 28 days later. Treatment discontinuation due to progressive disease (PD) or death due to PD within 28 days of last dose were considered confirmed loss of CCyR. PD was defined as disease progression to accelerated phase or blast phase CML. Kaplan meier analysis was used for the determination of duration of CCyR. Duration of response will be analyzed for responders only therefore duration of response will be excluded from the long-term family of secondary outcome measures.

  5. Cumulative Incidence of Event Free Survival (EFS) Events at Month 12 [ Time Frame: Month 12 ]
    EFS was defined as the time from randomization to death due to any cause, transformation to AP or BP at any time, confirmed loss of complete hematologic response (CHR), confirmed loss of CCyR or censoring. Loss of CHR was defined as a hematologic assessment of non-CHR [chronic phase, AP, or BP] confirmed by 2 assessments at least 4 weeks apart). Loss of CCyR was defined as at least 1 Ph+ metaphase from analysis of <100 metaphases confirmed by a follow up cytogenetic analysis after 1 month. Cumulative incidence of EFS event at month 12 was adjusted for competing risk of treatment discontinuation without the event. The comparative analysis between the two arms for this member of the long-term secondary family will be done at the end of the study.

  6. Overall Survival (OS) at Month 12 [ Time Frame: Month 12 ]
    OS was defined as the time (in months) from randomization to the occurrence of death due to any cause or censoring. Kaplan-meier analysis was used for determination of OS. The comparative analysis between the two arms for this member of the long-term secondary family will be done at the end of the study. Percentage of participants with OS were estimated in this outcome measure.


Other Outcome Measures:
  1. Summary of Trough Plasma Concentration by Complete Cytogenetic Response (CCyR) [ Time Frame: Day 28, 56, 84 ]
    CCyR is based on the prevalence of Ph+ metaphases among cells in metaphase on a BM aspirate. CCyR was achieved when there was 0 % Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analyzed, or MMR if no BM was available. Trough plasma concentration of participants who had CCyR are presented in this outcome measure.

  2. Summary of Trough Plasma Concentration by Major Molecular Response (MMR) [ Time Frame: Day 28, 56, 84 ]
    MMR was defined as a ratio of Bcr-Abl/Abl <=0.1% on the international scale (>=3 log reduction from standardized baseline in ratio of Bcr-Abl to Abl transcripts) by quantitative RT-qPCR. Trough plasma concentration of participants who had MMR are presented in this outcome measure.

  3. Summary of Trough Plasma Concentration by Presence of Grade 1 or Higher Adverse Events (AEs) [ Time Frame: Day 28, 56, 84 ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Grade 1 =mild; Grade 2 =moderate; within normal limits, Grade 3 =severe or medically significant but not immediately life-threatening; Grade 4 =life-threatening or disabling; urgent intervention indicated; Grade 5 =death. Trough plasma concentration of participants who had grade 1 or higher AE are presented in this outcome measure. Data of plasma concentration is reported separately for each preferred term of AE.

  4. Summary of Trough Plasma Concentration by Presence of Grade 3 or Higher Adverse Events (AEs) [ Time Frame: Day 28, 56, 84 ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Grade 1 =mild; Grade 2 =moderate; within normal limits, Grade 3 =severe or medically significant but not immediately life-threatening; Grade 4 =life-threatening or disabling; urgent intervention indicated; Grade 5 =death. Trough plasma concentration of participants who had grade 3 or higher AE are presented in this outcome measure. Data of plasma concentration is reported separatley for each preferred term of AE.

  5. Number of Participants With Vital Signs Abnormalities [ Time Frame: Baseline up to 752 days ]
    Criteria for vital signs abnormalities: systolic blood pressure (SBP) <80 millimeter of mercury (mmHg), >210 mmHg; diastolic blood pressure (DBP) <40 mmHg, >130 mmHg; heart rate <40 beats per minute (bpm), >150 bpm; temperature <32 degree celsius, >40 degree celsius.

  6. Number of Participants With Laboratory Test Abnormalities Based on National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) Version 4.03 [ Time Frame: Baseline up to 752 days ]
    Laboratory parameters included hematological (haemoglobin, lymphocytes (absolute), neutrophils (absolute), platelets and leukocytes) and biochemistry (albumin, alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, amylase, bilirubin, creatinine kinase, calcium, creatinine, glucose, potassium, lipase, magnesium, phosphate, sodium, urate) parameters. Abnormalities in laboratory tests were graded by NCI CTCAE version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling.

  7. Number of Participants With Electrocardiogram (ECG) Abnormalities of Potential Clinical Concern [ Time Frame: Baseline up to 752 days ]
    Criteria for ECG abnormalities : heart rate: increase of >15 bpm from baseline value and >=120 bpm, decrease of >15 bpm from baseline value and <=45 bpm; PR interval: change of >=20 msec from baseline value and >=220 milliseconds (msec); QRS interval >=120 msec; QTcB interval >500 msec, increase of >60 msec from baseline; QT interval using Fridericia's correction (QTcF) >500 msec, increase of >60 msec from baseline, <=450 msec (Men) or <=470 msec (Women), >450 msec (Men) or >470 msec (Women).

  8. Number of Participants With Adverse Events (AEs) Leading to Study Drug Discontinuation [ Time Frame: Baseline up to 752 days ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.

  9. Number of Participants With Treatment-Emergent Adverse Events By National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) (Version 4.03) [ Time Frame: Baseline up to 752 days ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to severity grading based on NCI CTCAE version 4.03. Grade 1 =mild; Grade 2 =moderate; Grade 3 =severe or medically significant but not immediately life-threatening, hospitalization or prolongation of hospitalization indicated; Grade 4 =life-threatening or disabling, urgent intervention indicated; Grade 5 =death. Treatment-emergent events were events between first dose of study drug and up to 752 days that were absent before treatment that worsened relative to pretreatment state. If the same participant in a given treatment had more than 1 adverse event, only the maximum CTCAE was 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:

  1. Molecular diagnosis of CP CML of ≤ 6 months (from initial diagnosis).
  2. Adequate hepatic, renal and pancreatic function.
  3. Age ≥ 18 years.

Exclusion Criteria:

  1. Any prior medical treatment for CML, including tyrosine kinase inhibitors (TKIs), with the exception of hydroxyurea and/or anagrelide treatment, which are permitted for up to 6 months prior to study entry (signature of ICF) if suitably approved for use in the subject's region.
  2. Any past or current Central Nervous System (CNS) involvement, including leptomeningeal leukemia.
  3. Extramedullary disease only.
  4. Major surgery or radiotherapy within 14 days of randomization.
  5. History of clinically significant or uncontrolled cardiac disease.
  6. Known seropositivity to human immunodeficiency virus (HIV), current acute or chronic hepatitis B (hepatitis B surface-antigen positive), hepatitis C, cirrhosis or evidence of decompensated liver disease. Patients with resolved Hepatitis B can be included.
  7. Recent or ongoing clinically significant GI disorder, e.g. Crohn's Disease, Ulcerative Colitis, or prior total or partial gastrectomy.
  8. History of another malignancy within 5 years with the exception of basal cell carcinoma or cervical carcinoma in situ or stage 1 or 2 cancer that is considered adequately treated and currently in complete remission for at least l2 months.
  9. Current, or recent (within 30 days, or 5 half-lives of investigational product) participation in other clinical trials of investigational agents and/or containing interventional procedures deemed contrary to the objectives and conduct of this trial.

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): NCT02130557


  Show 193 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02130557     History of Changes
Other Study ID Numbers: AV001
2013-005101-31 ( EudraCT Number )
B1871053 ( Other Identifier: Alias Study Number )
First Posted: May 5, 2014    Key Record Dates
Results First Posted: November 14, 2018
Last Update Posted: November 14, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Pfizer:
Leukemia
Myelogenous
Chronic
BCR-ABL Positive
Bosutinib
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Pathologic Processes
Imatinib
Therapeutic Uses
Pharmacologic Actions
Molecular Mechanisms of Pharmacological Action

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Imatinib Mesylate
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors