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

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

Official Title: A Phase 1/2 Study Of Bosutinib (SKI-606) In Philadelphia Chromosome Positive Leukemias

Brief Summary: This is an open-label, continuous daily dosing, two-part safety and efficacy study of SKI-606 (bosutinib) in Philadelphia chromosome positive leukemias (Ph+). Part 1 is a dose-escalation study in chronic phase Chronic Myelogenous Leukemia (CML) subjects to establish the maximum tolerated dose (MTD) in this subject population. Part 2 has begun after the completion of Part 1 and after a dose has been established for the compound in chronic phase subjects. Part 2 is a study of the the efficacy of 500mg daily oral SKI-606 (bosutinib) in patients with all phases of Ph+ CML and Ph+ Acute Lymphocytic Leukemia (ALL). The protocol will test the hypotheses that oral daily dosing of bosutinib at 500 mg will attain (1) Major Cytogenetic Response (MCyR) in chronic phase CML patients and (2) Overall Hematological Response (OHR) in advanced leukemia patients. Each phase of the disease will be evaluated as a separate cohort.

Detailed Summary:
Sponsor: Pfizer

Current Primary Outcome:

  • Number of Participants With Dose Limiting Toxicity (DLT) [ Time Frame: Part 1 Baseline up to Day 28 ]
    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, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).
  • Maximum Tolerated Dose (MTD) [ Time Frame: Part 1 Baseline up to Day 28 ]
    MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT. 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, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).
  • Maximum Observed Plasma Concentration (Cmax) - Part 1 [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1 ]
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1 [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1 ]
  • Plasma Decay Half-Life (t1/2) - Part 1 [ Time Frame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1 ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
  • Area Under the Curve From Time Zero to Last Quantifiab

    Original Primary Outcome:

    Current Secondary Outcome:

    • Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1 [ Time Frame: Baseline, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5 ]
      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.
    • Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1 [ Time Frame: Baseline, Week 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5 ]
      bcr-Abl is a protein resulting from the transcription of the Philadelphia chromosome following 9:22 chromosomal translocation, and phosphorylation inhibition of which correlates with inhibition of tumor cell growth.
    • Phosphorylated Cancer-Testis 10 (CT10) Regulator of Kinase Like (p-CrkL) Protein Level in Blood at Baseline - Part 1 [ Time Frame: 0 (pre-dose) on Day 1 (Baseline) ]
      CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells by using fluorescent activated cell sorter (FACS) flow cytometry. Amount of CrkL protein phosphorylated (in moles) per 100 blood cells was reported.
    • Percent Change From Baseline in Phosphorylated Cancer-testis 10 (CT10) Regulator of Kinase Like (p-CrkL) Protein Level in Blood at Day 1, 8 and 15 - Part 1 [ Time Frame: 6 hours post-dose on Day 1, 0 (pre-dose), 6 hours post-dose on Day 8, 15 ]
      CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells by using FACS flow cytometry. Percent change in p-CrkL protein at different time points give measure of phosphorylation inhibition from baseline.
    • Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line Imatinib Intolerant CML and Chronic Phase Third-line CML Population - Part 2 [ Time Frame: Week 24 for second line, Baseline through Week 24 for third line ]
      Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells in metaphase from Bone Marrow (BM) sample. 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 in metaphase in BM and PCyR was achieved when 1 to 35% Ph+ cells in metaphase in BM.
    • Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML and Chronic Phase Third-line CML - Part 2 [ Time Frame: Baseline, Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5 ]
      Cytogenetic response (CyR) is based on the prevalence of Philadelphia positive (Ph+) cells in metaphase from Bone Marrow (BM) sample. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CCyR was achieved when there was 0% Ph+ cells in metaphase in BM and PCyR was achieved when 1 to 35% Ph+ cells in metaphase in BM.
    • Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML and Chronic Phase Third-line CML - Part 2 [ Time Frame: Baseline, Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5 ]

      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. 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 in metaphase in BM and PCyR was achieved when 1 to 35% Ph+ cells in metaphase in BM.

    • Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML and Chronic Phase Third-line CML - Part 2 [ Time Frame: Baseline, Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks up to Year 5 ]

      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 - 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. Major cytogenetic response was categorized as either complete cytogenetic response (CCyR) or partial cytogenet

      Original Secondary Outcome:

      Information By: Pfizer

      Dates:
      Date Received: December 2, 2005
      Date Started: March 2006
      Date Completion:
      Last Updated: October 27, 2015
      Last Verified: October 2015