Clinical trial NCT00811070: Study Evaluating SKI-606 (Bosutinib) In Japanese Subjects With Philadelphia Chromosome Positive Leukemias
Official title: A Phase 1/2 Study Of SKI-606 Administered As A Single Agent In Japanese Subjects With Philadelphia Chromosome Positive Leukemias
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myelogenous Leukemia
Keywords: CML. Chronic myelocytic leukemia. Philadelphia Chromosome. Japanese. SKI-606. Bosutinib. Imatinib resistant. Imatinib intolerant
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2008-12-18
Enrollment: 63
Sex: ALL
Minimum age (years): 20
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicity (DLT) - Part 1
timeFrame: Baseline up to Day 28 (Part 1 )
measure: Maximum Tolerated Dose (MTD) - Part 1
timeFrame: Baseline up to Day 28 (Part 1 )
measure: Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line Cohort - Part 2
timeFrame: Week 24
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) - Part 1
timeFrame: 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
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1
timeFrame: 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
measure: Plasma Decay Half-Life (t1/2) - Part 1
timeFrame: Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1
measure: Area Under the Concentration-Time Curve (AUC) - Part 1
timeFrame: 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
measure: Apparent Oral Clearance (CL/F) - Part 1
timeFrame: 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
measure: Apparent Volume of Distribution (Vz/F) - Part 1
timeFrame: Before and 1, 2, 3, 4, 6, 8, 24 and 48 hours after administration on Day 1
measure: Accumulation Ratio (R) - Part 1
timeFrame: 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
measure: Percentage of Participants With Maintained Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Second-line and Third-line Cohort - Part 2
timeFrame: Week 24
measure: Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 - Part 1
timeFrame: Week 24
measure: Percentage of Participants With Major Cytogenetic Response (MCyR) at Week 24 in Chronic Phase Third-line Cohort - Part 2
timeFrame: Week 24
measure: Time to Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2
timeFrame: 204 weeks in the second-line participants and 48 weeks in the third-line participants
measure: Duration of Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Third-line Cohort - Part 2
timeFrame: 204 weeks in the second-line participants and 48 weeks in the third-line participants
measure: Percentage of Participants With Complete Hematologic Response (CHR) up to Week 192 in Advance Phase Second-line Cohort - Part 2
timeFrame: Baseline up to Week 192
measure: Time to Achieve Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2
timeFrame: Baseline up to Week 192
measure: Duration of Complete Hematologic Response (CHR) in Advanced Phase Second-line Cohort - Part 2
timeFrame: Baseline up to Week 192
measure: Percentage of Participants With Overall Hematologic Response (OHR) Up to Week 192 in Accelerated Phase/Blast Phase Third-line Cohort - Part 2
timeFrame: Baseline up to Week 192
measure: Time to Achieve Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2
timeFrame: Baseline up to Week 192
measure: Duration of Overall Hematologic Response (OHR) in Accelerated Phase/Blast Phase Third-line Cohort - Part 2
timeFrame: Baseline up to Week 192
measure: Time to Treatment Failure (TTF) Rate - Part 2
timeFrame: 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
measure: Progression-free Survival (PFS) Rate - Part 2
timeFrame: 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
measure: Overall Survival (OS) Rate - Part 2
timeFrame: 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
Other outcomes:
Locations:
city: Sendai-city
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Aichi
country: Japan
facility: Toyohashi Municipal Hospital
city: Aichi
country: Japan
facility: Japanese Red Cross Nagoya First Hospital
city: Aichi
country: Japan
facility: Aichi Cancer Center
city: Akita
country: Japan
facility: Akita University Hospital
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Fukuoka
country: Japan
facility: National Hospital Organization Kyushu Cancer Center
city: Fukuoka
country: Japan
facility: Harasanshin Hospital
city: Hyogo
country: Japan
facility: Kobe City Medical Center General Hospital
city: Hyogo
country: Japan
facility: Hospital of Hyogo College of Medicine
city: Ishikawa
country: Japan
facility: Kanazawa University Hospital
city: Kanagawa
country: Japan
facility: Tokai University Hospital
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Kyoto
country: Japan
facility: University Hospital,Kyoto Prefectural University of Medicine
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Osaka
country: Japan
facility: Kinki University School of Medicine
city: Saga
country: Japan
facility: Saga University Hospital
city: Shizuoka
country: Japan
facility: Hamamatsu Medical Univ. HP Faculty of Medicine
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Cancer&Infectious disease Ctr Komagome Hp
city: Tokyo
country: Japan
facility: Japanese Red Cross Medical Center
city: Tokyo
country: Japan
facility: Jikei University Hospital Daisan
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.