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CompletedNCT00811070Updated Jun 28, 2016Results posted

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

A Phase 2 interventional study of SKI-606 (Bosutinib) in Chronic Myelogenous Leukemia, sponsored by Pfizer. Completed at 23 sites in Japan. Open to participants aged 20 Years to 74 Years. Per ClinicalTrials.gov, last updated 2016-06-28.

Sponsored by Pfizer · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
63
Allocation
Non-randomized
Ages
20 Years to 74 Years
Sex
All
01

Study summary

This is a two-part safety and efficacy study of SKI-606 in subjects who have Philadelphia chromosome positive leukemias (CML). Part 1 will be a dose-escalation study, in which an escalating dose of SKI-606 (Bosutinib), up to 600 mg, will be studied in subjects with imatinib resistant/refractory or imatinib intolerant chronic phase CML. Part 2 will evaluate the safety and efficacy of the maximum tolerated dose (MTD) of SKI-606 (Bosutinib)identified in Part 1 of the study.

02

Conditions studied

  • Chronic Myelogenous Leukemia

Keywords

  • CML. Chronic myelocytic leukemia. Philadelphia Chromosome. Japanese. SKI-606. Bosutinib. Imatinib resistant. Imatinib intolerant
03

In context

Leukemia

5,441 studies on the registry are indexed under Leukemia; 636 are open to participants now.

This study's enrollment of 63 is above the median of 38 across 4,247 interventional studies indexed under Leukemia.

Browse Leukemia studies →

Lead sponsor

Pfizer is the lead sponsor of 3,244 studies on the registry; 139 are open to participants now.

Of its 582 completed or terminated interventional studies of FDA-regulated products, 381 (65%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
20 Years to 74 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  • Cytogenetic or Polymerase Chain Reaction based diagnosis of Chronic phase of Philadelphia Chromosome Positive Chronic Myelogenous Leukemia:

(Part 1), any phase of Philadelphia Chromosome Positive Chronic Myelogenous Leukemia (Part 2), whose disease is resistant/refractory to full-dose imatinib (400 mg for chronic phase subjects/600 mg for advanced leukemia subjects), or are intolerant of any dose of imatinib.

  • Adequate duration of prior imatinib therapy.
  • No prior exposure to Src, Abl, or Src/Abl kinase inhibitors other than imatinib.
  • Eastern Cooperative Oncology Group Performance Status of 0 or 1 for chronic phase subjects, and 0, 1 or 2 for Advanced Stage subjects.
  • At least 7 days since any anti-proliferative treatment (including intrathecal chemotherapy) before the first dose of SKI-606, (except hydroxyurea).
  • Recovered to National Cancer Institute grade 0-1, or to baseline, from any toxicities of prior anti-tumor treatment, other than alopecia or thrombocytopenia due to active prior treatment (intolerant subjects).
  • At least 3 months post allogeneic stem cell transplantation before the first dose of SKI-606.
  • Able to take daily oral capsules reliably.
  • Absolute neutrophil count greater than 1,000/mL (Part 1)
  • Adequate hepatic, and renal function.
  • Documented normal INR if not on oral anticoagulant therapy, or, if on oral anticoagulant therapy consistent target INR less than 3.
  • Age should be greater than 20 years and less than 75 years (Part 1), greater than 20 years (Part 2), including women of childbearing potential.
  • Willingness of male and female subjects, who are not surgically sterile or postmenopausal, must agree and commit to the use of reliable methods of birth control (oral contraceptives, intrauterine devices, or barrier methods used with a spermicide) for the duration of the study and for 30 days after the last dose of SKI-606.

Exclusion criteria

Exclusion Criteria:

  • Subjects with Philadelphia chromosome negative Chronic Myelogenous Leukemia.
  • Overt leptomeningeal leukemia. Subjects must be free of CNS involvement according to the symptoms for a minimum of 2 months before the first dose of SKI-606. Subjects with CNS symptoms must have a diagnostic lumbar puncture prior to study enrollment.
  • Subjects with extramedullary disease only.
  • Ongoing requirement for warfarin or other oral anticoagulant therapy (Part 1).
  • Ongoing requirement for hydroxyurea (Part 1).
  • Graft Versus Host Disease. a. no previous Graft Versus Host Disease allowed (Part 1). b. no treated or untreated Graft Versus Host Disease within 60 days of first dose (Part 2).
  • Major surgery within 14 days or radiotherapy within 7 days before the first dose of SKI-606 (recovery from any previous surgery should be complete before day 1).
  • Ongoing clinical requirement for administration of a strong inhibitor or inducer of CYP-3A4 (Part 1).
  • History of clinically significant or uncontrolled cardiac disease including: a. history of a clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) b. diagnosed or suspected congenital or acquired prolonged QT syndrome c. history of prolonged QTc d. unexplained syncope e. history of or active congestive heart failure f. myocardial infarction within 12 months. g. Uncontrolled angina or hypertension within 3 months.
  • Baseline QTcF greater than 0.45 sec (average of triplicate readings).
  • Concomitant use of or need for medications known to prolong the QT interval.
  • Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.
  • Recent (within 14 days before the first dose of SKI-606) or ongoing clinically significant gastrointestinal disorder.
  • Pregnant or breastfeeding women.
  • Evidence of serious active infection, or significant medical or psychiatric illness.
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Single group
Masking
None (open label)
Enrollment
63 participants (actual)

Study arms

  • Experimental
    1

    Drug: SKI-606 (Bosutinib)

Interventions

  • DrugSKI-606 (Bosutinib)

    Formulation: 100 mg Capsule for Part 1, 100 mg tablet for Part1 and Part 2. SKI-606 (Bosutinib) will be taken by mouth with water and food as continuous once-daily dosing.

06

What researchers measure

Primary outcomes

  1. Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1

    DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity.

    Time frame: Baseline up to Day 28 (Part 1 )

  2. Maximum Tolerated Dose (MTD) - Part 1

    MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT.

    Time frame: Baseline up to Day 28 (Part 1 )

  3. Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line Cohort - Part 2

    Cytogenetic response (CyR) is based on the prevalence of Philadelphia chromosome positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells.

    Time frame: Week 24

Secondary outcomes

  1. Maximum Observed Plasma Concentration (Cmax) - Part 1

    Time frame: Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15

  2. Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1

    Time frame: Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15

  3. Plasma Decay Half-Life (t1/2) - Part 1

    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

    Time frame: Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1

  4. Area Under the Concentration-Time Curve (AUC) - Part 1

    Area under the plasma concentration time-curve from zero to infinity. AUC on Day 15 was assessed as the steady state AUC.

    Time frame: Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15

  5. Apparent Oral Clearance (CL/F) - Part 1

    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F on Day 15 was assessed as the steady state CL/F.

    Time frame: Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15

  6. Apparent Volume of Distribution (Vz/F) - Part 1

    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

    Time frame: Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1

  7. Accumulation Ratio (R) - Part 1

    R=accumulation ratio (AUCss on Day 15/AUC\[0-24\] on Day 1)

    Time frame: Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15

  8. Percentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 2

    Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells. The responder for maintained MCyR included 'participants without baseline response who had a response at a specified time' and 'participants with baseline response who had a post-baseline response either maintained or improved at a specified time'.

    Time frame: Week 24

  9. Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1

    Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells.

    Time frame: Week 24

  10. Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Third-line Cohort - Part 2

    Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells.

    Time frame: Week 24

  11. Time to Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2

    Time to MCyR was the interval from the date of first dose of study medication until the first date of achieving a given response. Time to response in weeks = (event date minus first dose date plus 1)/7, where the event date is the non-missing date of the first attained response or last cytogenetic assessment date of a participants.

    Time frame: 204 weeks in the second-line participants and 48 weeks in the third-line participants

  12. Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2

    Duration of MCyR was defined as the interval from the date of the earliest demonstration of a response, until the earliest date of loss of that response. Duration of response in weeks = (date of confirmed loss of first attained response minus date of first attained response)/7 days.

    Time frame: 204 weeks in the second-line participants and 48 weeks in the third-line participants

  13. Percentage of Participants With Complete Hematologic Response (CHR) up to Week 192 in Advance Phase Second-line Cohort - Part 2

    CHR response was considered to be achieved if participants met all of the following criteria: White Blood Cells =\< institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes \<5% in blood, absolute neutrophil count \>=1.0\*10\^9 per liter (/L), platelets \>=100 but \<450\*10\^9/L, \<20% basophils in blood and no extramedulary involvement (including hepato- or splenomegaly), =\<5% BM blasts.

    Time frame: Baseline up to Week 192

  14. Time to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2

    The time to CHR was measured from the date of first dosing to the first date of response. Time to response in weeks = (event date - first dose date plus 1)/7, where the event date is the non-missing date of the first attained response or last assessment date of a participant.

    Time frame: Baseline up to Week 192

  15. Duration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2

    The duration of CHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of first attained response - date of first attained response)/7.

    Time frame: Baseline up to Week 192

  16. Percentage of Participants With Overall Hematologic Response (OHR) Up to Week 192 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2

    OHR included CHR, no evidence of leukemia (NEL), minor hematologic response (MiHR) or return to chronic phase (RCP), participants had to meet at least 1 of this criterion. Criteria for RCP: disappearance of features defining AP/BP, but still in CP and persistence of clonal evolution. Criteria for MiHR: \<15% blasts in blood and bone marrow, \<30% blasts+promyelocytes in blood and bone marrow, \<20% basophils in blood, no extramedullary disease other than liver/spleen. Criteria for CHR and NEL: \<20% basophils in blood, no extramedullary involvement including liver/spleen, no peripheral blasts or promyelocytes, myelocytes + metamyelocytes \<5% in blood, \<5% (NEL) and \<=5% (CHR) marrow blasts, 0.5\*10\^9 \<= Absolute neutrophil count (ANC) \<1.0\*10\^9/L (NEL) and ANC\>=1.0\*10\^9/L (CHR), 20\*10\^9 \<=platelets\<100 \*10\^9/L (NEL) and platelets\>=100 but \<450x10\^9/L (CHR), white blood cells \<=institutional upper limit of the normal range.

    Time frame: Baseline up to Week 192

  17. Time to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2

    The time to OHR was measured from the date of first dosing to the first date of response. Time to response in weeks = (event date - first dose date plus 1)/7, where the event date is the non-missing date of the first attained response or last assessment date of a participant.

    Time frame: Baseline up to Week 192

  18. Duration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2

    The duration of OHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of first attained response - date of first attained response)/7.

    Time frame: Baseline up to Week 192

  19. Time to Treatment Failure (TTF) Rate - Part 2

    TTF was the interval from the date of first dose of bosutinib until the earlier date of progression or death (any cause), withdrawal from treatment owing to an AE, subject refusal, or loss to follow-up (censored at the last contact date), or further anti-tumor therapy before documented progression (whichever occurred first). TTF rate indicates the probability of no treatment failure. Percent of participants with no treatment failure were estimated.

    Time frame: Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants

  20. Progression-free Survival (PFS) Rate - Part 2

    PFS was based on Kaplan-Meier estimates. PFS was defined as time in weeks from start of study treatment to treatment discontinuation due to disease progression as assessed by the investigator. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease \[PD\]), or from death case report forms (CRFs). Percent of participants with PFS were estimated.

    Time frame: Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants

  21. Overall Survival (OS) Rate - Part 2

    OS was based on Kaplan-Meier method. Survival was defined as the time period from the date of first dose of bosutinib to the date of death, censored at the participant's last contact date. Percent of participants with OS were estimated.

    Time frame: Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants

07

Results

Posted Jun 4, 2014

Participant flow

Participant flow — Overall Study
MilestoneBosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )Bosutinib Primary Second-line 500 mg (Part 2 )Bosutinib Advanced Second-line 500 mg (Part 2 )Bosutinib Exploratory Third-line 500 mg (Part 2 )
Started77328711
Completed66326210
Not completed110251
Withdrew: Death000250
Withdrew: Other100000
Withdrew: Withdrawal by subject010000
Withdrew: Physician decision000001

Outcome measures

PrimaryNumber of Participants With Dose-Limiting Toxicity (DLT) - Part 1

DLT was defined as any of the following events occurring during the first 28 days of study medication and considered at least possibly-related to study medication: any grade 3 or 4 clinically-relevant non-hematologic toxicity.

Time frame:
Baseline up to Day 28 (Part 1 )
Reported as:
Number · Participants
Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1
ParticipantsBosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )
Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1110
PrimaryMaximum Tolerated Dose (MTD) - Part 1

MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT.

Time frame:
Baseline up to Day 28 (Part 1 )
Reported as:
Number · mg
Maximum Tolerated Dose (MTD) - Part 1
mgAll Treated Participants (Part 1 )
Maximum Tolerated Dose (MTD) - Part 1NA
SecondaryMaximum Observed Plasma Concentration (Cmax) - Part 1
Time frame:
Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15
Reported as:
Mean · nanogram per milliliter (ng/mL)
Maximum Observed Plasma Concentration (Cmax) - Part 1
nanogram per milliliter (ng/mL)Bosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )
Day 1 (n = 7, 7, 3)131 ± 29.7128 ± 23.1155 ± 44.4
Day 15 (n = 5, 4, 2)129 ± 24.4226 ± 49.5214 ± NA
SecondaryTime to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1
Time frame:
Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15
Reported as:
Median · hour
Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1
hourBosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )
Day 1 (n = 7, 7, 3)4.00 (3.97 to 7.90)3.95 (3.00 to 5.98)3.98 (3.97 to 4.03)
Day 15 (n = 5, 4, 2)4.03 (3.92 to 8.00)3.95 (3.93 to 7.98)4.00 (3.98 to 4.02)
SecondaryPlasma Decay Half-Life (t1/2) - Part 1

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

Time frame:
Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1
Reported as:
Mean · hour
Plasma Decay Half-Life (t1/2) - Part 1
hourBosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )
Plasma Decay Half-Life (t1/2) - Part 116.82 ± 2.3716.90 ± 2.4717.27 ± 3.64
SecondaryArea Under the Concentration-Time Curve (AUC) - Part 1

Area under the plasma concentration time-curve from zero to infinity. AUC on Day 15 was assessed as the steady state AUC.

Time frame:
Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15
Reported as:
Mean · nanogram*hour per milliliter (ng•hr/mL)
Area Under the Concentration-Time Curve (AUC) - Part 1
nanogram*hour per milliliter (ng•hr/mL)Bosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )
Day 1 (n = 7, 7, 3)2474 ± 482.72720 ± 560.42760 ± 625.9
Day 15 (n = 5, 4, 2)2235 ± 220.13690 ± 962.13371 ± NA
SecondaryApparent Oral Clearance (CL/F) - Part 1

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. CL/F on Day 15 was assessed as the steady state CL/F.

Time frame:
Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15
Reported as:
Mean · L/hr
Apparent Oral Clearance (CL/F) - Part 1
L/hrBosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )
Day 1 (n = 7, 7, 3)167 ± 34.6190 ± 37.8224 ± 45.7
Day 15 (n = 5, 4, 2)180 ± 17.4144 ± 41.8179 ± NA
SecondaryApparent Volume of Distribution (Vz/F) - Part 1

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

Time frame:
Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1
Reported as:
Mean · liter
Apparent Volume of Distribution (Vz/F) - Part 1
literBosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )
Apparent Volume of Distribution (Vz/F) - Part 14035 ± 879.84570 ± 713.85707 ± 2187
SecondaryAccumulation Ratio (R) - Part 1

R=accumulation ratio (AUCss on Day 15/AUC\[0-24\] on Day 1)

Time frame:
Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1, and before and 1, 2, 3, 4, 6, 8, and 24 hours after administration on Day 15
Reported as:
Mean · ratio
Accumulation Ratio (R) - Part 1
ratioBosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )
Accumulation Ratio (R) - Part 11.67 ± 0.3692.16 ± 0.5562.46 ± NA
PrimaryPercentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line Cohort - Part 2

Cytogenetic response (CyR) is based on the prevalence of Philadelphia chromosome positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells.

Time frame:
Week 24
Reported as:
Number · percentage of participants
Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line Cohort - Part 2
percentage of participantsBosutinib Primary Second-line 500 mg (Part 2 )
Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line Cohort - Part 235.7 (18.6 to 55.9)
SecondaryPercentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 2

Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells. The responder for maintained MCyR included 'participants without baseline response who had a response at a specified time' and 'participants with baseline response who had a post-baseline response either maintained or improved at a specified time'.

Time frame:
Week 24
Reported as:
Number · percentage of participants
Percentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 2
percentage of participantsBosutinib Primary Second-line 500 mg (Part 2 )Bosutinib Advanced Second-line 500 mg (Part 2 )Bosutinib Exploratory Third-line 500 mg (Part 2 )
Percentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 264.3 (44.1 to 81.4)14.3 (0.4 to 57.9)63.6 (30.8 to 89.1)
SecondaryPercentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1

Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells.

Time frame:
Week 24
Reported as:
Number · percentage of participants
Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1
percentage of participantsBosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )
Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 142.9 (9.9 to 81.6)57.1 (18.4 to 90.1)33.3 (0.8 to 90.6)
SecondaryPercentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Third-line Cohort - Part 2

Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells and PCyR was achieved when 1 to 35% Ph+ cells.

Time frame:
Week 24
Reported as:
Number · percentage of participants
Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Third-line Cohort - Part 2
percentage of participantsBosutinib Exploratory Third-line 500 mg (Part 2 )
Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Third-line Cohort - Part 218.2 (2.3 to 51.8)
SecondaryTime to Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2

Time to MCyR was the interval from the date of first dose of study medication until the first date of achieving a given response. Time to response in weeks = (event date minus first dose date plus 1)/7, where the event date is the non-missing date of the first attained response or last cytogenetic assessment date of a participants.

Time frame:
204 weeks in the second-line participants and 48 weeks in the third-line participants
Reported as:
Median · weeks
Time to Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2
weeksBosutinib Primary Second-line 500 mg (Part 2 )Bosutinib Exploratory Third-line 500 mg (Part 2 )
Time to Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 212.3 (12.0 to 24.1)18.1 (12.1 to 24.1)
SecondaryDuration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2

Duration of MCyR was defined as the interval from the date of the earliest demonstration of a response, until the earliest date of loss of that response. Duration of response in weeks = (date of confirmed loss of first attained response minus date of first attained response)/7 days.

Time frame:
204 weeks in the second-line participants and 48 weeks in the third-line participants
Reported as:
Median · weeks
Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2
weeksBosutinib Primary Second-line 500 mg (Part 2 )Bosutinib Exploratory Third-line 500 mg (Part 2 )
Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2NA (NA to NA)NA (NA to NA)
SecondaryPercentage of Participants With Complete Hematologic Response (CHR) up to Week 192 in Advance Phase Second-line Cohort - Part 2

CHR response was considered to be achieved if participants met all of the following criteria: White Blood Cells =\< institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes \<5% in blood, absolute neutrophil count \>=1.0\*10\^9 per liter (/L), platelets \>=100 but \<450\*10\^9/L, \<20% basophils in blood and no extramedulary involvement (including hepato- or splenomegaly), =\<5% BM blasts.

Time frame:
Baseline up to Week 192
Reported as:
Number · percentage of participants
Percentage of Participants With Complete Hematologic Response (CHR) up to Week 192 in Advance Phase Second-line Cohort - Part 2
percentage of participantsBosutinib Advanced Second-line 500 mg (Part 2 )
Percentage of Participants With Complete Hematologic Response (CHR) up to Week 192 in Advance Phase Second-line Cohort - Part 214.3 (0.4 to 57.9)
SecondaryTime to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2

The time to CHR was measured from the date of first dosing to the first date of response. Time to response in weeks = (event date - first dose date plus 1)/7, where the event date is the non-missing date of the first attained response or last assessment date of a participant.

Time frame:
Baseline up to Week 192
Reported as:
Median · weeks
Time to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2
weeksBosutinib Advanced Second-line 500 mg (Part 2 )
Time to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 284.0 (NA to NA)
SecondaryDuration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2

The duration of CHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of first attained response - date of first attained response)/7.

Time frame:
Baseline up to Week 192
Reported as:
Median · weeks
Duration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2
weeksBosutinib Advanced Second-line 500 mg (Part 2 )
Duration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 295.3 (NA to NA)
SecondaryPercentage of Participants With Overall Hematologic Response (OHR) Up to Week 192 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2

OHR included CHR, no evidence of leukemia (NEL), minor hematologic response (MiHR) or return to chronic phase (RCP), participants had to meet at least 1 of this criterion. Criteria for RCP: disappearance of features defining AP/BP, but still in CP and persistence of clonal evolution. Criteria for MiHR: \<15% blasts in blood and bone marrow, \<30% blasts+promyelocytes in blood and bone marrow, \<20% basophils in blood, no extramedullary disease other than liver/spleen. Criteria for CHR and NEL: \<20% basophils in blood, no extramedullary involvement including liver/spleen, no peripheral blasts or promyelocytes, myelocytes + metamyelocytes \<5% in blood, \<5% (NEL) and \<=5% (CHR) marrow blasts, 0.5\*10\^9 \<= Absolute neutrophil count (ANC) \<1.0\*10\^9/L (NEL) and ANC\>=1.0\*10\^9/L (CHR), 20\*10\^9 \<=platelets\<100 \*10\^9/L (NEL) and platelets\>=100 but \<450x10\^9/L (CHR), white blood cells \<=institutional upper limit of the normal range.

Time frame:
Baseline up to Week 192
Reported as:
Number · percentage of participants
Percentage of Participants With Overall Hematologic Response (OHR) Up to Week 192 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2
percentage of participantsBosutinib Exploratory Third-line 500 mg - AP/BP (Part 2 )
Percentage of Participants With Overall Hematologic Response (OHR) Up to Week 192 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2100
SecondaryTime to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2

The time to OHR was measured from the date of first dosing to the first date of response. Time to response in weeks = (event date - first dose date plus 1)/7, where the event date is the non-missing date of the first attained response or last assessment date of a participant.

Time frame:
Baseline up to Week 192
Reported as:
Median · weeks
Time to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2
weeksBosutinib Exploratory Third-line 500 mg - AP/BP (Part 2 )
Time to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 212.4 (NA to NA)
SecondaryDuration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2

The duration of OHR was defined as the interval from the first date of response until the first date of confirmed loss of response. Duration of response in weeks =(date of confirmed loss of first attained response - date of first attained response)/7.

Time frame:
Baseline up to Week 192
Reported as:
Median · weeks
Duration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2
weeksBosutinib Exploratory Third-line 500 mg - AP/BP (Part 2 )
Duration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 236.1 (NA to NA)
SecondaryTime to Treatment Failure (TTF) Rate - Part 2

TTF was the interval from the date of first dose of bosutinib until the earlier date of progression or death (any cause), withdrawal from treatment owing to an AE, subject refusal, or loss to follow-up (censored at the last contact date), or further anti-tumor therapy before documented progression (whichever occurred first). TTF rate indicates the probability of no treatment failure. Percent of participants with no treatment failure were estimated.

Time frame:
Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants
Reported as:
Number · percentage of participants
Time to Treatment Failure (TTF) Rate - Part 2
percentage of participantsBosutinib Primary Second-line 500 mg (Part 2 )Bosutinib Advanced Second-line 500 mg (Part 2 )Bosutinib Exploratory Third-line 500 mg (Part 2 )
Week 4867.9 (50.6 to 85.2)14.3 (0.0 to 40.2)81.8 (59.0 to 100)
Week 9660.7 (42.6 to 78.8)14.3 (0.0 to 40.2)72.7 (46.4 to 99.0)
Week 14457.1 (38.8 to 75.5)14.3 (0.0 to 40.2)63.6 (35.2 to 92.1)
Week 19253.6 (35.1 to 72.0)NA (NA to NA)NA (NA to NA)
Week 24053.6 (35.1 to 72.0)NA (NA to NA)NA (NA to NA)
Week 28845.9 (24.9 to 67.0)NA (NA to NA)NA (NA to NA)
Week 336NA (NA to NA)NA (NA to NA)NA (NA to NA)
SecondaryProgression-free Survival (PFS) Rate - Part 2

PFS was based on Kaplan-Meier estimates. PFS was defined as time in weeks from start of study treatment to treatment discontinuation due to disease progression as assessed by the investigator. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease \[PD\]), or from death case report forms (CRFs). Percent of participants with PFS were estimated.

Time frame:
Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants
Reported as:
Number · percentage of participants
Progression-free Survival (PFS) Rate - Part 2
percentage of participantsBosutinib Primary Second-line 500 mg (Part 2 )Bosutinib Advanced Second-line 500 mg (Part 2 )Bosutinib Exploratory Third-line 500 mg (Part 2 )
Week 48100 (100 to 100)21.4 (0.0 to 56.3)100 (100 to 100)
Week 9694.4 (83.9 to 100)21.4 (0.0 to 56.3)88.9 (68.4 to 100)
Week 14494.4 (83.9 to 100)21.4 (0.0 to 56.3)88.9 (68.4 to 100)
Week 19294.4 (83.9 to 100)NA (NA to NA)NA (NA to NA)
Week 24094.4 (83.9 to 100)NA (NA to NA)NA (NA to NA)
Week 28894.4 (83.9 to 100)NA (NA to NA)NA (NA to NA)
Week 336NA (NA to NA)NA (NA to NA)NA (NA to NA)
SecondaryOverall Survival (OS) Rate - Part 2

OS was based on Kaplan-Meier method. Survival was defined as the time period from the date of first dose of bosutinib to the date of death, censored at the participant's last contact date. Percent of participants with OS were estimated.

Time frame:
Date of first dose of study drug up to Week 336 in primary second line participants; up to Week 192 in advanced second line and exploratory third line participants
Reported as:
Number · percentage of participants
Overall Survival (OS) Rate - Part 2
percentage of participantsBosutinib Primary Second-line 500 mg (Part 2 )Bosutinib Advanced Second-line 500 mg (Part 2 )Bosutinib Exploratory Third-line 500 mg (Part 2 )
Week 4896.4 (89.6 to 100)42.9 (6.2 to 79.5)100 (100 to 100)
Week 9696.4 (89.6 to 100)42.9 (6.2 to 79.5)100 (100 to 100)
Week 14496.4 (89.6 to 100)28.6 (0.0 to 62.0)100 (100 to 100)
Week 19296.4 (89.6 to 100)NA (NA to NA)NA (NA to NA)
Week 24096.4 (89.6 to 100)NA (NA to NA)NA (NA to NA)
Week 28882.7 (57.0 to 100)NA (NA to NA)NA (NA to NA)
Week 336NA (NA to NA)NA (NA to NA)NA (NA to NA)

Adverse events

Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Total Second-line—19/52 (36.5%)52/52 (100%)
Exploratory Third-line—2/11 (18.2%)11/11 (100%)
Total Population—21/63 (33.3%)63/63 (100%)
Most frequent serious events
Showing 10 of 31
Most frequent serious events
EventTotal Second-lineExploratory Third-lineTotal Population
Acute myocardial infarctionCardiac disorders0/521/111/63
CataractEye disorders1/521/112/63
GastroenteritisInfections and infestations1/521/112/63
Pleural effusionRespiratory, thoracic and mediastinal disorders2/520/112/63
ThrombocytopeniaBlood and lymphatic system disorders1/520/111/63
Macular fibrosisEye disorders1/520/111/63
DiarrhoeaGastrointestinal disorders1/520/111/63
VomitingGastrointestinal disorders1/520/111/63
FatigueGeneral disorders1/520/111/63
Hepatic function abnormalHepatobiliary disorders1/520/111/63
Most frequent other events
Showing 10 of 115
Most frequent other events
EventTotal Second-lineExploratory Third-lineTotal Population
DiarrhoeaGastrointestinal disorders50/5210/1160/63
RashSkin and subcutaneous tissue disorders31/525/1136/63
NasopharyngitisInfections and infestations30/526/1136/63
LymphopeniaBlood and lymphatic system disorders19/525/1124/63
NauseaGastrointestinal disorders19/525/1124/63
VomitingGastrointestinal disorders22/521/1123/63
Alanine aminotransferase increasedInvestigations20/524/1124/63
Aspartate aminotransferase increasedInvestigations15/524/1119/63
Lipase increasedInvestigations11/524/1115/63
ThrombocytopeniaBlood and lymphatic system disorders16/522/1118/63

Baseline characteristics

Age, Customized
Age, Customized(Participants)Bosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )Bosutinib Primary Second-line 500 mg (Part 2 )Bosutinib Advanced Second-line 500 mg (Part 2 )Bosutinib Exploratory Third-line 500 mg (Part 2 )Total
< 65 years742203945
>= 65 years03184218
Sex: Female, Male
Sex: Female, Male(Participants)Bosutinib Second-line 400 mg (Part 1 )Bosutinib Second-line 500 mg (Part 1 )Bosutinib Second-line 600 mg (Part 1 )Bosutinib Primary Second-line 500 mg (Part 2 )Bosutinib Advanced Second-line 500 mg (Part 2 )Bosutinib Exploratory Third-line 500 mg (Part 2 )Total
Female322121424
Male451166739
08

Study locations

23 sites
  • Tohoku University Hospital
    Sendai-city, Miyagi 980-8574, Japan
  • National Cancer Center Hospital
    Chuo-ku, Tokyo 104-0045, Japan
  • Toyohashi Municipal Hospital
    Aichi, 441-8570, Japan
  • Japanese Red Cross Nagoya First Hospital
    Aichi, 453-8511, Japan
  • Aichi Cancer Center
    Aichi, 464-8681, Japan
  • Akita University Hospital
    Akita, 010-8543, Japan
  • Chiba University Hospital
    Chiba, 260-8677, Japan
  • National Hospital Organization Kyushu Cancer Center
    Fukuoka, 811-1395, Japan
  • Harasanshin Hospital
    Fukuoka, 812-0033, Japan
  • Kobe City Medical Center General Hospital
    Hyogo, 650-0047, Japan
  • Hospital of Hyogo College of Medicine
    Hyogo, 663-8501, Japan
  • Kanazawa University Hospital
    Ishikawa, 920-8641, Japan
  • Tokai University Hospital
    Kanagawa, 259-1193, Japan
  • Kumamoto University Hospital
    Kumamoto, 860-8556, Japan
  • University Hospital,Kyoto Prefectural University of Medicine
    Kyoto, 602-8566, Japan
  • Okayama University Hospital
    Okayama, 700-8558, Japan
  • Osaka University Hospital
    Osaka, 565-0871, Japan
  • Kinki University School of Medicine
    Osaka, 589-8511, Japan
  • Saga University Hospital
    Saga, 846-8501, Japan
  • Hamamatsu Medical Univ. HP Faculty of Medicine
    Shizuoka, 431-3192, Japan
  • Tokyo Metropolitan Cancer&Infectious disease Ctr Komagome Hp
    Tokyo, 113-8677, Japan
  • Japanese Red Cross Medical Center
    Tokyo, 150-8935, Japan
  • Jikei University Hospital Daisan
    Tokyo, 201-8601, Japan
09

References and documents

Publications

  • Takahashi N, Cortes JE, Sakaida E, Ishizawa K, Ono T, Doki N, Matsumura I, Garcia-Gutierrez V, Rosti G, Ono C, Ohkura M, Tanetsugu Y, Viqueira A, Brummendorf TH. Safety profile of bosutinib in Japanese versus non-Japanese patients with chronic myeloid leukemia: a pooled analysis. Int J Hematol. 2022 Jun;115(6):838-851. doi: 10.1007/s12185-022-03314-y. Epub 2022 Mar 2. PubMed 35235189 ↗
  • Takahashi N, Nakaseko C, Kobayashi Y, Miyamura K, Ono C, Koide Y, Fujii Y, Ohnishi K. Long-term treatment with bosutinib in a phase 1/2 study in Japanese chronic myeloid leukemia patients resistant/intolerant to prior tyrosine kinase inhibitor treatment. Int J Hematol. 2017 Sep;106(3):398-410. doi: 10.1007/s12185-017-2239-8. Epub 2017 Apr 13. PubMed 28409328 ↗
  • Nakaseko C, Takahashi N, Ishizawa K, Kobayashi Y, Ohashi K, Nakagawa Y, Yamamoto K, Miyamura K, Taniwaki M, Okada M, Kawaguchi T, Shibata A, Fujii Y, Ono C, Ohnishi K. A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia. Int J Hematol. 2015 Feb;101(2):154-64. doi: 10.1007/s12185-014-1722-8. Epub 2014 Dec 25. PubMed 25540064 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jun 28, 2016, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00811070
Lead sponsor
Pfizer
Responsible party
Sponsor
First posted
Dec 18, 2008
Start date
Dec 2007
Primary completion
Mar 2013
Completion
Jun 2015
Results posted
Jun 4, 2014
Last update
Jun 28, 2016

Study contacts

Pfizer CT.gov Call Center
study director · Pfizer

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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