Chronic Myelogenous Leukemia
Conditions
Keywords
CML. Chronic myelocytic leukemia. Philadelphia Chromosome. Japanese. SKI-606. Bosutinib. Imatinib resistant. Imatinib intolerant
Brief 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.
Interventions
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.
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 74 Years
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
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1 | Baseline up to Day 28 (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. |
| Maximum Tolerated Dose (MTD) - Part 1 | Baseline up to Day 28 (Part 1 ) | MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT. |
| Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line Cohort - Part 2 | Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Decay Half-Life (t1/2) - Part 1 | Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Area Under the Concentration-Time Curve (AUC) - Part 1 | 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 | Area under the plasma concentration time-curve from zero to infinity. AUC on Day 15 was assessed as the steady state AUC. |
| Apparent Oral Clearance (CL/F) - Part 1 | 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 | 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. |
| Apparent Volume of Distribution (Vz/F) - Part 1 | Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 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. |
| Accumulation Ratio (R) - Part 1 | 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 | R=accumulation ratio (AUCss on Day 15/AUC\[0-24\] on Day 1) |
| Percentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 2 | Week 24 | 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'. |
| Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1 | Week 24 | 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. |
| Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Third-line Cohort - Part 2 | Week 24 | 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 to Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2 | 204 weeks in the second-line participants and 48 weeks in the third-line participants | 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. |
| Maximum Observed Plasma Concentration (Cmax) - Part 1 | 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 | — |
| Percentage of Participants With Complete Hematologic Response (CHR) up to Week 192 in Advance Phase Second-line Cohort - Part 2 | Baseline up to Week 192 | 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. |
| Duration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2 | Baseline up to Week 192 | 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. |
| Percentage of Participants With Overall Hematologic Response (OHR) Up to Week 192 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 | Baseline up to Week 192 | 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 to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 | Baseline up to Week 192 | 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. |
| Duration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 | Baseline up to Week 192 | 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. |
| Overall Survival (OS) Rate - Part 2 | 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 | 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 to Treatment Failure (TTF) Rate - Part 2 | 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 | 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. |
| Progression-free Survival (PFS) Rate - Part 2 | 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 | 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. |
| Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2 | 204 weeks in the second-line participants and 48 weeks in the third-line participants | 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 to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 | 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 | — |
| Time to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2 | Baseline up to Week 192 | 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. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) Single oral dose of bosutinib 400 mg on Day 1 and then bosutinib 400 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort. | 7 |
| Bosutinib Second-line 500 mg (Part 1 ) Single oral dose of bosutinib 500 mg on Day 1 and then bosutinib 500 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy after the safety confirmation of 600 mg cohort. | 7 |
| Bosutinib Second-line 600 mg (Part 1 ) Single oral dose of bosutinib 600 mg on Day 1 and then bosutinib 600 mg orally once daily was administered continuously from Day 3 in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML) until disease progression, unacceptable toxicity, or withdrawal of consent occurred. | 3 |
| Bosutinib Primary Second-line 500 mg (Part 2 ) Bosutinib 500 mg was administered orally once-daily in participants with chronic phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML).Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy. | 28 |
| Bosutinib Advanced Second-line 500 mg (Part 2 ) Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase second-line imatinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy. | 7 |
| Bosutinib Exploratory Third-line 500 mg (Part 2 ) Bosutinib 500 mg was administered orally once-daily in participants with chronic or accelerated or blast phase third-line imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy. | 11 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 2 | 5 | 0 |
| Overall Study | Other | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|---|---|
| Age, Customized < 65 years | 7 Participants | 4 Participants | 2 Participants | 20 Participants | 3 Participants | 9 Participants | 45 Participants |
| Age, Customized >= 65 years | 0 Participants | 3 Participants | 1 Participants | 8 Participants | 4 Participants | 2 Participants | 18 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 2 Participants | 12 Participants | 1 Participants | 4 Participants | 24 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 1 Participants | 16 Participants | 6 Participants | 7 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 52 / 52 | 11 / 11 | 63 / 63 |
| serious Total, serious adverse events | 19 / 52 | 2 / 11 | 21 / 63 |
Outcome results
Primary
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 )
Population: Participants enrolled in Part 1 of the study were analyzed for DLT. Two participants (1 each in the 400 mg and 500 mg) who discontinued the treatment by Day 28 due to non-safety reasons were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Maximum Tolerated Dose (MTD) - Part 1 | NA mg |
Primary
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 )
Population: Participants enrolled in Part 1 of the study were analyzed for DLT. Two participants (1 each in the 400 mg and 500 mg) who discontinued the treatment by Day 28 due to non-safety reasons were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1 | 1 Participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1 | 1 Participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1 | 0 Participants |
Primary
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
Population: All treated population was defined as all participants who received at least 1 dose of bosutinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line Cohort - Part 2 | 35.7 percentage of participants |
Secondary
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
Population: The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Accumulation Ratio (R) - Part 1 | 1.67 ratio | Standard Deviation 0.369 |
| Bosutinib Second-line 500 mg (Part 1 ) | Accumulation Ratio (R) - Part 1 | 2.16 ratio | Standard Deviation 0.556 |
| Bosutinib Second-line 600 mg (Part 1 ) | Accumulation Ratio (R) - Part 1 | 2.46 ratio | — |
Secondary
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
Population: The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.~n= number of participants analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Apparent Oral Clearance (CL/F) - Part 1 | Day 1 (n = 7, 7, 3) | 167 L/hr | Standard Deviation 34.6 |
| Bosutinib Second-line 400 mg (Part 1 ) | Apparent Oral Clearance (CL/F) - Part 1 | Day 15 (n = 5, 4, 2) | 180 L/hr | Standard Deviation 17.4 |
| Bosutinib Second-line 500 mg (Part 1 ) | Apparent Oral Clearance (CL/F) - Part 1 | Day 1 (n = 7, 7, 3) | 190 L/hr | Standard Deviation 37.8 |
| Bosutinib Second-line 500 mg (Part 1 ) | Apparent Oral Clearance (CL/F) - Part 1 | Day 15 (n = 5, 4, 2) | 144 L/hr | Standard Deviation 41.8 |
| Bosutinib Second-line 600 mg (Part 1 ) | Apparent Oral Clearance (CL/F) - Part 1 | Day 1 (n = 7, 7, 3) | 224 L/hr | Standard Deviation 45.7 |
| Bosutinib Second-line 600 mg (Part 1 ) | Apparent Oral Clearance (CL/F) - Part 1 | Day 15 (n = 5, 4, 2) | 179 L/hr | — |
Secondary
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
Population: The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Apparent Volume of Distribution (Vz/F) - Part 1 | 4035 liter | Standard Deviation 879.8 |
| Bosutinib Second-line 500 mg (Part 1 ) | Apparent Volume of Distribution (Vz/F) - Part 1 | 4570 liter | Standard Deviation 713.8 |
| Bosutinib Second-line 600 mg (Part 1 ) | Apparent Volume of Distribution (Vz/F) - Part 1 | 5707 liter | Standard Deviation 2187 |
Secondary
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
Population: The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.~n= number of participants analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Area Under the Concentration-Time Curve (AUC) - Part 1 | Day 1 (n = 7, 7, 3) | 2474 nanogram*hour per milliliter (ng•hr/mL) | Standard Deviation 482.7 |
| Bosutinib Second-line 400 mg (Part 1 ) | Area Under the Concentration-Time Curve (AUC) - Part 1 | Day 15 (n = 5, 4, 2) | 2235 nanogram*hour per milliliter (ng•hr/mL) | Standard Deviation 220.1 |
| Bosutinib Second-line 500 mg (Part 1 ) | Area Under the Concentration-Time Curve (AUC) - Part 1 | Day 1 (n = 7, 7, 3) | 2720 nanogram*hour per milliliter (ng•hr/mL) | Standard Deviation 560.4 |
| Bosutinib Second-line 500 mg (Part 1 ) | Area Under the Concentration-Time Curve (AUC) - Part 1 | Day 15 (n = 5, 4, 2) | 3690 nanogram*hour per milliliter (ng•hr/mL) | Standard Deviation 962.1 |
| Bosutinib Second-line 600 mg (Part 1 ) | Area Under the Concentration-Time Curve (AUC) - Part 1 | Day 1 (n = 7, 7, 3) | 2760 nanogram*hour per milliliter (ng•hr/mL) | Standard Deviation 625.9 |
| Bosutinib Second-line 600 mg (Part 1 ) | Area Under the Concentration-Time Curve (AUC) - Part 1 | Day 15 (n = 5, 4, 2) | 3371 nanogram*hour per milliliter (ng•hr/mL) | — |
Secondary
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
Population: Subset of participants who had the response among all treated population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Duration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2 | 95.3 weeks |
Secondary
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
Population: Subset of participants who had the response among all treated population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2 | NA weeks |
| Bosutinib Second-line 500 mg (Part 1 ) | Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2 | NA weeks |
Secondary
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
Population: Subset of participants who had the response among all treated population and who was in accelerated or blast phase in the third-line cohort
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Duration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 | 36.1 weeks |
Secondary
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
Population: The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.~n= number of participants analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Maximum Observed Plasma Concentration (Cmax) - Part 1 | Day 15 (n = 5, 4, 2) | 129 nanogram per milliliter (ng/mL) | Standard Deviation 24.4 |
| Bosutinib Second-line 400 mg (Part 1 ) | Maximum Observed Plasma Concentration (Cmax) - Part 1 | Day 1 (n = 7, 7, 3) | 131 nanogram per milliliter (ng/mL) | Standard Deviation 29.7 |
| Bosutinib Second-line 500 mg (Part 1 ) | Maximum Observed Plasma Concentration (Cmax) - Part 1 | Day 1 (n = 7, 7, 3) | 128 nanogram per milliliter (ng/mL) | Standard Deviation 23.1 |
| Bosutinib Second-line 500 mg (Part 1 ) | Maximum Observed Plasma Concentration (Cmax) - Part 1 | Day 15 (n = 5, 4, 2) | 226 nanogram per milliliter (ng/mL) | Standard Deviation 49.5 |
| Bosutinib Second-line 600 mg (Part 1 ) | Maximum Observed Plasma Concentration (Cmax) - Part 1 | Day 1 (n = 7, 7, 3) | 155 nanogram per milliliter (ng/mL) | Standard Deviation 44.4 |
| Bosutinib Second-line 600 mg (Part 1 ) | Maximum Observed Plasma Concentration (Cmax) - Part 1 | Day 15 (n = 5, 4, 2) | 214 nanogram per milliliter (ng/mL) | — |
Secondary
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
Population: All treated population was defined as all participants who received at least 1 dose of bosutinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 96 | 96.4 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 240 | 96.4 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 192 | 96.4 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 48 | 96.4 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 336 | NA percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 288 | 82.7 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 144 | 96.4 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 192 | NA percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 48 | 42.9 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 96 | 42.9 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 144 | 28.6 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 240 | NA percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 288 | NA percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 336 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 240 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 96 | 100 percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 336 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 288 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 192 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 144 | 100 percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Overall Survival (OS) Rate - Part 2 | Week 48 | 100 percentage of participants |
Secondary
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
Population: All treated population was defined as all participants who received at least 1 dose of bosutinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Percentage of Participants With Complete Hematologic Response (CHR) up to Week 192 in Advance Phase Second-line Cohort - Part 2 | 14.3 percentage of participants |
Secondary
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
Population: All treated population was defined as all participants who received at least 1 dose of bosutinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Percentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 2 | 64.3 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Percentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 2 | 14.3 percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Percentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 2 | 63.6 percentage of participants |
Secondary
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
Population: All treated population was defined as all participants who received at least 1 dose of bosutinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Third-line Cohort - Part 2 | 18.2 percentage of participants |
Secondary
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
Population: All treated population was defined as all participants who received at least 1 dose of bosutinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1 | 42.9 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1 | 57.1 percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1 | 33.3 percentage of participants |
Secondary
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
Population: Subset of the third-line cohort who was in accelerated or blast phase
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Percentage of Participants With Overall Hematologic Response (OHR) Up to Week 192 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 | 100 percentage of participants |
Secondary
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
Population: The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Plasma Decay Half-Life (t1/2) - Part 1 | 16.82 hour | Standard Deviation 2.37 |
| Bosutinib Second-line 500 mg (Part 1 ) | Plasma Decay Half-Life (t1/2) - Part 1 | 16.90 hour | Standard Deviation 2.47 |
| Bosutinib Second-line 600 mg (Part 1 ) | Plasma Decay Half-Life (t1/2) - Part 1 | 17.27 hour | Standard Deviation 3.64 |
Secondary
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
Population: All treated population was defined as all participants who received at least 1 dose of bosutinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 288 | 94.4 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 48 | 100 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 96 | 94.4 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 144 | 94.4 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 192 | 94.4 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 240 | 94.4 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 336 | NA percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 240 | NA percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 192 | NA percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 48 | 21.4 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 144 | 21.4 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 288 | NA percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 96 | 21.4 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 336 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 96 | 88.9 percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 144 | 88.9 percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 336 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 192 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 240 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 48 | 100 percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Progression-free Survival (PFS) Rate - Part 2 | Week 288 | NA percentage of participants |
Secondary
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
Population: Subset of participants who had the response among all treated population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2 | 84.0 weeks |
Secondary
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
Population: Subset of participants who had the response among all treated population and who was in accelerated or blast phase in the third-line cohort
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 | 12.4 weeks |
Secondary
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
Population: Subset of participants who had the response among all treated population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2 | 12.3 weeks |
| Bosutinib Second-line 500 mg (Part 1 ) | Time to Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2 | 18.1 weeks |
Secondary
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
Population: The pharmacokinetic parameter population was defined as all participants who received at least 1 dose of bosutinib and had at least 1 of the pharmacokinetic parameters of interest.~n= number of participants analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 | Day 1 (n = 7, 7, 3) | 4.00 hour |
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 | Day 15 (n = 5, 4, 2) | 4.03 hour |
| Bosutinib Second-line 500 mg (Part 1 ) | Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 | Day 1 (n = 7, 7, 3) | 3.95 hour |
| Bosutinib Second-line 500 mg (Part 1 ) | Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 | Day 15 (n = 5, 4, 2) | 3.95 hour |
| Bosutinib Second-line 600 mg (Part 1 ) | Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 | Day 1 (n = 7, 7, 3) | 3.98 hour |
| Bosutinib Second-line 600 mg (Part 1 ) | Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 | Day 15 (n = 5, 4, 2) | 4.00 hour |
Secondary
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
Population: All treated population was defined as all participants who received at least 1 dose of bosutinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 96 | 60.7 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 240 | 53.6 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 192 | 53.6 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 48 | 67.9 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 336 | NA percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 288 | 45.9 percentage of participants |
| Bosutinib Second-line 400 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 144 | 57.1 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 192 | NA percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 48 | 14.3 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 96 | 14.3 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 144 | 14.3 percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 240 | NA percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 288 | NA percentage of participants |
| Bosutinib Second-line 500 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 336 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 240 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 96 | 72.7 percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 336 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 288 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 192 | NA percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 144 | 63.6 percentage of participants |
| Bosutinib Second-line 600 mg (Part 1 ) | Time to Treatment Failure (TTF) Rate - Part 2 | Week 48 | 81.8 percentage of participants |