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Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00261846
First Posted: December 5, 2005
Last Update Posted: July 27, 2017
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.
Information provided by (Responsible Party):
Pfizer
Results First Submitted: October 4, 2012  
Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition: Chronic Myeloid Leukemia
Intervention: Drug: Bosutinib

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Bosutinib 400 mg (Part 1) Single oral dose of bosutinib 400 milligram (mg) on Day 1 and then bosutinib 400 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in chronic phase second-line (CP2L) chronic myelogenous leukemia (CML) Part 2 of the study.
Bosutinib 500 mg (Part 1) Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily continuously from Day 3 up to Week 4. All participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study.
Bosutinib 600 mg (Part 1) Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily continuously from Day 3 up to Week 4. Eleven participants who completed treatment in Part 1 were continued in CP2L-CML Part 2 of the study and 1 participant was continued in advanced phase (AP) CML Part 2 of the study.
Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
AP-CML Total (Part 2) All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I.
BP-CML Total (Part 2) All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I.
Bosutinib 500 mg, Ph+ ALL (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL

Participant Flow for 2 periods

Period 1:   Period 1: Part 1 (Dose Escalation)
    Bosutinib 400 mg (Part 1)   Bosutinib 500 mg (Part 1)   Bosutinib 600 mg (Part 1)   Bosutinib 500 mg, CP2L-CML IM-R (Part 2)   Bosutinib 500 mg, CP2L-CML IM-I (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)   AP-CML Total (Part 2)   BP-CML Total (Part 2)   Bosutinib 500 mg, Ph+ ALL (Part 2)
STARTED   3   3   12   0   0   0   0   0   0   0   0   0 
COMPLETED   0   0   0   0   0   0   0   0   0   0   0   0 
NOT COMPLETED   3   3   12   0   0   0   0   0   0   0   0   0 
Continued in to Part 2                3                3                12                0                0                0                0                0                0                0                0                0 

Period 2:   Period 2: Part 2 (Efficacy)
    Bosutinib 400 mg (Part 1)   Bosutinib 500 mg (Part 1)   Bosutinib 600 mg (Part 1)   Bosutinib 500 mg, CP2L-CML IM-R (Part 2)   Bosutinib 500 mg, CP2L-CML IM-I (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)   AP-CML Total (Part 2)   BP-CML Total (Part 2)   Bosutinib 500 mg, Ph+ ALL (Part 2)
STARTED   0   0   0   195 [1]   89   5   38   50   26   79 [2]   64   24 
COMPLETED   0   0   0   60   39   3   16   21   12   30   15   1 
NOT COMPLETED   0   0   0   135   50   2   22   29   14   49   49   23 
Discontinuation of study by sponsor                0                0                0                1                0                0                0                0                1                0                0                0 
Withdrawal by Subject                0                0                0                9                8                1                3                3                0                2                0                0 
Lost to Follow-up                0                0                0                12                4                0                4                0                1                4                4                0 
Other                0                0                0                15                4                0                1                5                4                4                0                0 
Death                0                0                0                37                7                1                10                12                3                30                44                22 
Extension study                0                0                0                61                27                0                4                9                5                9                1                1 
[1] 17 participants from Part 1 (Bosutinib 400mg, 500mg, 600mg cohort) continued in Part 2 of the study.
[2] 1 participant from Part 1 (Bosutinib 600mg cohort) continued in Part 2 of the study.



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All-treated population - included all enrolled participants who received at least one dose of bosutinib.

Reporting Groups
  Description
Bosutinib 500 mg, CP2L-CML IM-R (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-R CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg, CP2L-CML IM-I (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP2L IM-I CML; who had no prior proto-oncogene tyrosine-protein kinase Src, Abl, or Src-Abl inhibitor exposure other than IM.
Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I, D and NI R/I or IM R/I and NI-I CML.
Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-R CML.
Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and D-I CML.
Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with CP3L IM R/I and NI-R CML.
AP-CML Total (Part 2) All participants who received bosutinib 500 mg orally once daily in AP CML who were IM R/I or multiple tyrosine kinase inhibitor (Multi-TKI): IM, D and/or NI R/I.
BP-CML Total (Part 2) All participants who received bosutinib 500 mg orally once daily in blast phase (BP) CML who were IM R/I or Multi-TKI: IM, D and/or NI R/I.
Bosutinib 500 mg, Ph+ ALL (Part 2) Bosutinib 500 mg was administered orally once-daily in participants with Ph+ ALL
Total Total of all reporting groups

Baseline Measures
   Bosutinib 500 mg, CP2L-CML IM-R (Part 2)   Bosutinib 500 mg, CP2L-CML IM-I (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I, (D+NI) R/I or NI-I (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I + D-R (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I + D-I (Part 2)   Bosutinib 500 mg, CP3L-CML IM R/I + NI-R (Part 2)   AP-CML Total (Part 2)   BP-CML Total (Part 2)   Bosutinib 500 mg, Ph+ ALL (Part 2)   Total 
Overall Participants Analyzed 
[Units: Participants]
 195   89   5   38   50   26   79   64   24   570 
Age, Customized 
[Units: Participants]
                   
<18 years   0   0   0   0   0   0   0   0   0   0 
Between 18 and 44 years   73   22   1   5   7   10   26   29   6   179 
Between 45 and 64 years   86   40   3   23   29   14   45   25   7   272 
>=65 years   36   27   1   10   14   2   8   10   11   119 
Sex: Female, Male 
[Units: Participants]
Count of Participants
                   
Female      82  42.1%      53  59.6%      3  60.0%      20  52.6%      31  62.0%      12  46.2%      35  44.3%      22  34.4%      12  50.0%      270  47.4% 
Male      113  57.9%      36  40.4%      2  40.0%      18  47.4%      19  38.0%      14  53.8%      44  55.7%      42  65.6%      12  50.0%      300  52.6% 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Number of Participants With Dose Limiting Toxicity (DLT)   [ Time Frame: Part 1 Baseline up to Day 28 ]

2.  Primary:   Maximum Tolerated Dose (MTD)   [ Time Frame: Part 1 Baseline up to Day 28 ]

3.  Primary:   Maximum Observed Plasma Concentration (Cmax) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1 ]

4.  Primary:   Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1 ]

5.  Primary:   Plasma Decay Half-Life (t1/2) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1 ]

6.  Primary:   Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1 ]

7.  Primary:   Area Under the Concentration-Time Curve (AUC) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1 ]

8.  Primary:   Apparent Oral Clearance (CL/F) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1 ]

9.  Primary:   Apparent Volume of Distribution (Vz/F) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1 ]

10.  Primary:   Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15 ]

11.  Primary:   Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15 ]

12.  Primary:   Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15 ]

13.  Primary:   Area Under the Concentration-Time Curve at Steady State (AUCss) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15 ]

14.  Primary:   Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15 ]

15.  Primary:   Accumulation Ratio (R)   [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15 ]

16.  Primary:   Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2   [ Time Frame: Week 24 ]

17.  Secondary:   Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1   [ Time Frame: Weeks 12, 24, 36, 48 and the end of active treatment phase of Part 1 (Week 52) ]

18.  Secondary:   Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1   [ Time Frame: Baseline, Weeks 4, 8, 12, 24, 36, 48 and the end of the active treatment phase of Part 1 (Week 52) ]

19.  Secondary:   Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1   [ Time Frame: 0 (pre-dose) on Day 1 (Baseline) ]

20.  Secondary:   Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1   [ Time Frame: 6 hours post-dose on Day 1, 0 (pre-dose), 6 hours post-dose on Day 8, 15 ]

21.  Secondary:   Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2   [ Time Frame: Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L) or Year 5 (CP2L) ]

22.  Secondary:   Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2   [ Time Frame: From first MCyR to loss of MCyR or censoring, assessed every 12 weeks up to 2 years and then every 24 weeks thereafter up to Year 5 ]

23.  Secondary:   Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2   [ Time Frame: Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 5 ]

24.  Secondary:   Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) - Part 2   [ Time Frame: From date of first confirmed CHR to loss of CHR or censoring, assessed at Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L) ]

25.  Secondary:   Duration of Complete Hematologic Response (CHR) - Part 2   [ Time Frame: From date of first confirmed CHR to loss of CHR or censoring, assessed at Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L) ]

26.  Secondary:   Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2   [ Time Frame: Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L) ]

27.  Secondary:   Cumulative Incidence of Progression/Death - Part 2   [ Time Frame: Years 1, 2, 3, 4, and 5 (CP2L only) ]

28.  Secondary:   Progression Free Survival (PFS) - Part 2   [ Time Frame: Years 1, 2, 3, 4, and 5 (CP2L only) ]

29.  Secondary:   Kaplan-Meier Estimate of Overall Survival (OS) - Part 2   [ Time Frame: Years 1, 2, 3, 4, and 5 (CP2L only) ]

30.  Secondary:   Overall Survival (OS) - Part 2   [ Time Frame: Years 1, 2, 3, 4, and 5 (CP2L only) ]

31.  Secondary:   Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2   [ Time Frame: Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L) ]

32.  Secondary:   Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Population - Part 2   [ Time Frame: Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 1 year ]

33.  Secondary:   Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)   [ Time Frame: Baseline up to follow up visit (30 days after last dose of study treatment) ]

34.  Secondary:   Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)   [ Time Frame: Baseline up to follow-up visit (30 days after last dose of study treatment) ]

35.  Secondary:   Percentage of Participants With Change From Baseline in Laboratory Tests Results   [ Time Frame: Week 1, 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter ]

36.  Secondary:   Percentage of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings   [ Time Frame: Baseline, 0 (pre-dose), 2, 4, 6 hours on Day 1, 0 (pre-dose), 2, 4, 6, 20-23 hours on Day 21, and end of treatment visit ]

37.  Secondary:   Number of Participants With Change From Baseline in Findings of Chest X-ray   [ Time Frame: Baseline, Week 8, and end of treatment ]

38.  Secondary:   Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs)   [ Time Frame: Baseline and Weeks 1, 2, 3, 4, 8, 12, then every 12 weeks thereafter until end of treatment, for a mean duration of 28 months ]

39.  Secondary:   Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)   [ Time Frame: Baseline, Week 1, 2, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter ]

40.  Secondary:   Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs   [ Time Frame: Screening, Baseline, and end of treatment ]

41.  Secondary:   Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs and Number of Participants With PCI Values   [ Time Frame: Post-therapy ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Analyses of progression free survival and overall survival was based on all-treated population, instead of evaluable population which was the primary efficacy population as per planned analyses.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
phone: 1-800-718-1021
e-mail: ClinicalTrials.gov_Inquiries@pfizer.com


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):


Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00261846     History of Changes
Other Study ID Numbers: 3160A4-200
B1871006, 3160A4-200-WW
2005-004230-40 ( EudraCT Number )
B1871006 ( Other Identifier: Alias Study Number )
First Submitted: December 2, 2005
First Posted: December 5, 2005
Results First Submitted: October 4, 2012
Results First Posted: March 12, 2013
Last Update Posted: July 27, 2017