Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Philadelphia Chromosome

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Translocation, Genetic

Chromosome Aberrations

Chronic Graft Versus Host Disease

Myeloid Leukemia

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Bosutinib

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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.

SKI-606 (Bosutinib)

Pfizer CT.gov Call Center

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.

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

A Phase 1/2 Study Of SKI-606 Administered As A Single Agent In Japanese Subjects With Philadelphia Chromosome Positive Leukemias

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.

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

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.

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

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

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.

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.

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

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'.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Pfizer

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.

All participants who received bosutinib orally once daily in second-line chronic myelogenous leukemia (CML), who were imatinib resistant/refractory/intolerant.

Total Second-line

All participants who received bosutinib 500 mg orally once daily in third-line chronic myelogenous leukemia (CML), participants were with imatinib resistant/refractory/intolerant followed by dasatinib or nilotinib resistant/refractory/intolerant.

Exploratory Third-line

Total participants who were second-line or third-line chronic myelogenous leukemia (CML).

Total Population

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.

Bosutinib Second-line 400 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.

Bosutinib Second-line 500 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.

Bosutinib Second-line 600 mg (Part 1 )

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.

Bosutinib Primary 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.

Bosutinib Advanced Second-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.

Bosutinib Exploratory Third-line 500 mg (Part 2 )

Total

< 65 years

>= 65 years

Age, Customized

Sex: Female, Male

Pfizer ClinicalTrials.gov Call Center

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.

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

All participants who received single oral dose of bosutinib 400 mg, 500 mg or 600 mg on Day 1 and then bosutinib 400 mg, 500 mg or 600 mg orally once daily continuously from Day 3 up to Week 4.

All Treated Participants (Part 1 )

Maximum Tolerated Dose (MTD) - Part 1

Day 1 (n = 7, 7, 3)

Day 15 (n = 5, 4, 2)

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.

Maximum Observed Plasma Concentration (Cmax) - Part 1

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

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.

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

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

Apparent Oral Clearance (CL/F) - Part 1

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

Accumulation Ratio (R) - Part 1

All treated population was defined as all participants who received at least 1 dose of bosutinib.

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

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 Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1

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

Subset of participants who had the response among all treated population

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

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

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

Subset of participants who had the response among all treated population.

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

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

Bosutinib 500 mg was administered orally once-daily in participants with accelerated or blast phase (AP/BP) third-line imatinib resistant/intolerant followed by dasatinib or nilotinib resistant/intolerant chronic myelogenous leukemia (CML). Intra-subject dose escalation up to 600 mg was allowed for lack of efficacy.

Bosutinib Exploratory Third-line 500 mg - AP/BP (Part 2 )

Subset of the third-line cohort who was in accelerated or blast phase

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

Subset of participants who had the response among all treated population and who was in accelerated or blast phase in the third-line cohort

Spots Global Cancer Trial Database for Study Evaluating SKI-606 (Bosutinib) In Japanese Subjects With Philadelphia Chromosome Positive Leukemias

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