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

Study Overview
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Brief Summary
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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.

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

Conditions
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Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: SKI-606 (Bosutinib)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: SKI-606 (Bosutinib)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to Day 28 (Part 1 ) | 
| 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. | Baseline up to Day 28 (Part 1 ) | 
| 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. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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. | Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1 | 
| Accumulation Ratio (R) - Part 1 | R=accumulation ratio (AUCss on Day 15/AUC[0-24] on Day 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 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'. | Week 24 | 
| 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. | Week 24 | 
| 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. | Week 24 | 
| 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. | 204 weeks in the second-line participants and 48 weeks in the third-line participants | 
| 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. | 204 weeks in the second-line participants and 48 weeks in the third-line participants | 
| 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. | Baseline up to Week 192 | 
| 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. | Baseline up to Week 192 | 
| 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. | Baseline up to Week 192 | 
| 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. | Baseline up to Week 192 | 
| 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. | Baseline up to Week 192 | 
| 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. | Baseline up to Week 192 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML. Chronic myelocytic leukemia. Philadelphia Chromosome. Japanese. SKI-606. Bosutinib. Imatinib resistant. Imatinib intolerant