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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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

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.

Detailed Summary:
Sponsor: Pfizer

Current Primary Outcome:

  • Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.


Original Primary Outcome:

  • Part 1:Safety confirmation of establishment of Maximum tolerated dose and evaluate the overall Pharmacokinetics parameters in this population. [ Time Frame: 2 years ]
  • Part 2: Determine the rate of attaining Major Cytogenetic Response. [ Time Frame: 2 years ]


Current Secondary Outcome:

  • 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 ]
  • 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 ]
  • Plasma Decay Half-Life (t1/2) - Part 1 [ Time Frame: 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 [ 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 ]
    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 [ 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 ]
    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 [ Time Frame: 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 [ 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 ]
    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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.

  • Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2 [ Time Frame: 204 weeks in the

    Original Secondary Outcome:

    • Part 1:Determine the rate of Major Cytogenetic Response. [ Time Frame: 2 years ]
    • Part 2: Estimate the time to and duration of Major Cytogenetic Response, Estimate the time to and duration of Complete Hematologic Response, Overall survival and progression free survival rates. [ Time Frame: 2 years ]


    Information By: Pfizer

    Dates:
    Date Received: December 17, 2008
    Date Started: December 2007
    Date Completion:
    Last Updated: May 19, 2016
    Last Verified: May 2016