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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00811070
First received: December 17, 2008
Last updated: July 8, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Chronic Myelogenous Leukemia
Drug: SKI-606 (Bosutinib)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study Of SKI-606 (Bosutinib) Administered As A Single Agent In Japanese Subjects With Philadelphia Chromosome Positive Leukemias

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1 [ Time Frame: Baseline up to Day 28 (Part 1 ) ] [ Designated as safety issue: Yes ]
    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 ) ] [ Designated as safety issue: Yes ]
    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) up to Week 24 in Chronic Phase Second-line Cohort - Part 2 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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: 24 weeks ] [ Designated as safety issue: No ]

    "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) up to Week 24 - Part 1 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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) up to Week 24 in Chronic Phase Third-line Cohort - Part 2 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    "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 second-line participants and 48 weeks in the third-line participants ] [ Designated as safety issue: No ]

    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.

    "


  • Percentage of Participants With Complete Hematologic Response (CHR) up to Week 24 in Advance Phase Second-line Cohort - Part 2 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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.

  • Time to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2 [ Time Frame: 179 weeks ] [ Designated as safety issue: No ]
    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.

  • Duration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2 [ Time Frame: 179 weeks ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Overall Hematologic Response (OHR) Up to Week 24 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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.

  • Time to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    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.

  • Duration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    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.

  • Time to Treatment Failure (TTF) Rate - Part 2 [ Time Frame: 204 weeks in the second-line participants and 48 weeks in the third-line participants ] [ Designated as safety issue: No ]
    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 at Week 48 and Week 96 were estimated.

  • Progression-free Survival (PFS) Rate - Part 2 [ Time Frame: 204 weeks in the second-line participants and 48 weeks in the third-line participants ] [ Designated as safety issue: No ]
    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 at Week 48 and Week 96 were estimated.

  • Overall Survival (OS) Rate - Part 2 [ Time Frame: 204 weeks in the second-line participants and 48 weeks in the third-line participants ] [ Designated as safety issue: No ]
    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 at Week 48 and Week 96 were estimated.


Enrollment: 63
Study Start Date: December 2007
Estimated Study Completion Date: May 2015
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: SKI-606 (Bosutinib)

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.


  Eligibility

Ages Eligible for Study:   20 Years to 74 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00811070

Locations
Japan
Pfizer Investigational Site
Sendai-city, Miyagi, Japan
Pfizer Investigational Site
Chuo-ku, Tokyo, Japan
Pfizer Investigational Site
Aichi, Japan
Pfizer Investigational Site
Akita, Japan
Pfizer Investigational Site
Chiba, Japan
Pfizer Investigational Site
Fukuoka, Japan
Pfizer Investigational Site
Hyogo, Japan
Pfizer Investigational Site
Ishikawa, Japan
Pfizer Investigational Site
Kanagawa, Japan
Pfizer Investigational Site
Kumamoto, Japan
Pfizer Investigational Site
Kyoto, Japan
Pfizer Investigational Site
Okayama, Japan
Pfizer Investigational Site
Osaka, Japan
Pfizer Investigational Site
Saga, Japan
Pfizer Investigational Site
Shizuoka, Japan
Pfizer Investigational Site
Tokyo, Japan
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided

Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00811070     History of Changes
Other Study ID Numbers: 3160A4-2203, B1871007
Study First Received: December 17, 2008
Results First Received: March 3, 2014
Last Updated: July 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
CML. Chronic myelocytic leukemia. Philadelphia Chromosome. Japanese. SKI-606. Bosutinib. Imatinib resistant. Imatinib intolerant

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes

ClinicalTrials.gov processed this record on July 23, 2014