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

• ClinicalTrials.gov Identifier: NCT00811070
• Recruitment Status: Completed
• First Posted: December 18, 2008
• Results First Posted: June 4, 2014
• Last Update Posted: June 28, 2016
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Chronic Myelogenous Leukemia	Drug: SKI-606 (Bosutinib)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 63 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Study Of SKI-606 Administered As A Single Agent In Japanese Subjects With Philadelphia Chromosome Positive Leukemias
• Study Start Date: December 2007
• Actual Primary Completion Date: March 2013
• Actual Study Completion Date: June 2015

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.
3. 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.

Secondary Outcome Measures :

1. 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 ]
2. 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 ]
3. 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.
4. 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.
5. 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.
6. 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.
7. 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)
8. 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'.

9. 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.
10. 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.
11. 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.

12. 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 ]
    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.
13. Percentage of Participants With Complete Hematologic Response (CHR) up to Week 192 in Advance Phase Second-line Cohort - Part 2 [ Time Frame: Baseline up to Week 192 ]
    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.
14. Time to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2 [ Time Frame: Baseline up to Week 192 ]
    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.
15. Duration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2 [ Time Frame: Baseline up to Week 192 ]
    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.
16. Percentage of Participants With Overall Hematologic Response (OHR) Up to Week 192 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 [ Time Frame: Baseline up to Week 192 ]
    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.
17. Time to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 [ Time Frame: Baseline up to Week 192 ]
    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.
18. Duration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2 [ Time Frame: Baseline up to Week 192 ]
    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.
19. Time to Treatment Failure (TTF) Rate - Part 2 [ Time Frame: 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 ]
    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.
20. Progression-free Survival (PFS) Rate - Part 2 [ Time Frame: 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 ]
    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.
21. Overall Survival (OS) Rate - Part 2 [ Time Frame: 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 ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 20 Years to 74 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

Locations

Japan

Tohoku University Hospital

Sendai-city, Miyagi, Japan, 980-8574

National Cancer Center Hospital

Chuo-ku, Tokyo, Japan, 104-0045

Toyohashi Municipal Hospital

Aichi, Japan, 441-8570

Japanese Red Cross Nagoya First Hospital

Aichi, Japan, 453-8511

Aichi Cancer Center

Aichi, Japan, 464-8681

Akita University Hospital

Akita, Japan, 010-8543

Chiba University Hospital

Chiba, Japan, 260-8677

National Hospital Organization Kyushu Cancer Center

Fukuoka, Japan, 811-1395

Harasanshin Hospital

Fukuoka, Japan, 812-0033

Kobe City Medical Center General Hospital

Hyogo, Japan, 650-0047

Hospital of Hyogo College of Medicine

Hyogo, Japan, 663-8501

Kanazawa University Hospital

Ishikawa, Japan, 920-8641

Tokai University Hospital

Kanagawa, Japan, 259-1193

Kumamoto University Hospital

Kumamoto, Japan, 860-8556

University Hospital,Kyoto Prefectural University of Medicine

Kyoto, Japan, 602-8566

Okayama University Hospital

Okayama, Japan, 700-8558

Osaka University Hospital

Osaka, Japan, 565-0871

Kinki University School of Medicine

Osaka, Japan, 589-8511

Saga University Hospital

Saga, Japan, 846-8501

Hamamatsu Medical Univ. HP Faculty of Medicine

Shizuoka, Japan, 431-3192

Tokyo Metropolitan Cancer&Infectious disease Ctr Komagome Hp

Tokyo, Japan, 113-8677

Japanese Red Cross Medical Center

Tokyo, Japan, 150-8935

Jikei University Hospital Daisan

Tokyo, Japan, 201-8601

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Takahashi N, Cortes JE, Sakaida E, Ishizawa K, Ono T, Doki N, Matsumura I, Garcia-Gutierrez V, Rosti G, Ono C, Ohkura M, Tanetsugu Y, Viqueira A, Brummendorf TH. Safety profile of bosutinib in Japanese versus non-Japanese patients with chronic myeloid leukemia: a pooled analysis. Int J Hematol. 2022 Jun;115(6):838-851. doi: 10.1007/s12185-022-03314-y. Epub 2022 Mar 2.

Takahashi N, Nakaseko C, Kobayashi Y, Miyamura K, Ono C, Koide Y, Fujii Y, Ohnishi K. Long-term treatment with bosutinib in a phase 1/2 study in Japanese chronic myeloid leukemia patients resistant/intolerant to prior tyrosine kinase inhibitor treatment. Int J Hematol. 2017 Sep;106(3):398-410. doi: 10.1007/s12185-017-2239-8. Epub 2017 Apr 13.

Nakaseko C, Takahashi N, Ishizawa K, Kobayashi Y, Ohashi K, Nakagawa Y, Yamamoto K, Miyamura K, Taniwaki M, Okada M, Kawaguchi T, Shibata A, Fujii Y, Ono C, Ohnishi K. A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia. Int J Hematol. 2015 Feb;101(2):154-64. doi: 10.1007/s12185-014-1722-8. Epub 2014 Dec 25.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00811070
• Other Study ID Numbers: 3160A4-2203; B1871007 ( Other Identifier: Alias Study Number )
• First Posted: December 18, 2008
• Results First Posted: June 4, 2014
• Last Update Posted: June 28, 2016
• Last Verified: May 2016

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; Hematologic Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Translocation, Genetic; Chromosome Aberrations; Bosutinib; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action