Study Evaluating SKI-606 (Bosutinib) 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.

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.