Philadelphia Chromosome positive leukemias occur as a result of a reciprocal translocation between chromosomes 9 and 22. Its most common phenotype is Chronic Myelogenous Leukemia (CML), which has three disease phases (chronic, accelerated and blast) of increasing leukemic blast count and clinical severity. Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ ALL) resembles blast phase CML in clinical severity. MedDRA version: 14.1 Level: LLT Classification code 10034877 Term: Phil
Conditions
Interventions
Product Name: Bosutinib
Product Code: PF-05208763
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Bosutinib
Current Sponsor code: PF-05208763
Other descriptive name: SKI-606 monohydrate
C
Sponsors
Wyeth Pharmaceuticals Inc., a wholly owned subsidary of Pfizer Inc., 500 Arcola Road, Collegeville, PA 19426, USA
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed and dated institutional review board (IRB) or independent ethics committee (IEC)-approved informed consent form before any protocol-specific screening procedures. 2. Cytogenetic or PCR based diagnosis of any phase of Ph+ CML or Ph+ ALL whose disease is resistant to full-dose imatinib ( 1000/mm^3 (>1000x10^9/L) b. Platelets >/= 100,000/mm^3 (>100 x 10^9/L), absent any platelet transfusions during the preceding 14 days 10. Adequate hepatic, and renal function a. AST/ALT /= 18 years 12. Willingness of male and female subjects, who are not surgically sterile or postmenopausal, to use 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 13. Documented normal INR if not on oral anticoagulant therapy (OAT), or if no OAT consistent target INR=65 years) yes F.1.3.1 Number of subjects for this age range 128
Exclusion criteria
Exclusion criteria: 1. Subjects with Philadelphia chromosome and bcr-abl negative CML. 2. Subjects previously intolerant of imatinib - Part 1 (dose escalation only) 3. Overt leptomeningeal leukemia. Subjects must be free of CNS involvement for a minimum of 2 months. Subjects with CNS symptoms must have a diagnostic lumbar puncture prior to study enrolment. 4. Subjects with extramedullary disease only 5. In part 1, no prior exposure to Src, Abl, or Src/Abl kinase inhibitors is allowed. 6. Ongoing requirement for warfarin or other OAT (Part 1 only) 7. Ongoing requirement for hydroxyurea or anagrelide (Part 1 only) 8. Graft Versus Host Disease (GVHD) a. part 1 - no previous GVHD allowed b. Part 2 - no treated or untreated GVHD within 60 days of study start 9. Major surgery within 14 days or radiotherapy within 7 before the first dose of SKI-606 (recovery from any previous surgery should be complete before day 1) 10. Ongoing clinical requirement for administration of a strong inhibitor of CYP-3A4 (See attachment 3) - Part 1 only 11. A history of a clinically-significant ventricular arrhythmia, congenital or acquired prolonged QT interval, a baseline QTcF > 0.47 sec (average of triplicate readings) or unexplained syncope, uncontrolled or symptomatic congestive heart failure (CHF) within 3 months, or myocardial infarction (MI) within 6 months. 12. Concomitant use of or need for medications known to prolong the QT interval (see attachment 4) 13. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval 14. Recent (within 30 days of study entry) or ongoing clinically significant gastrointestinal disorder (e.g., malabsorption, short bowel syndrome, bleeding or Grade >1 diarrhea, nausea or emesis lasting more than 2 days, despite adequate medical therapy) 15. Pregnant or breastfeeding women 16. Evidence of serious active infection, or significant medical or psychiatric illness 17. Known seropositivity to HIV, or current acute or chronic Hepatitis B or Hepatitis C (antigen positive), cirrhosis, hypokalemia (anygrade), or clinically significant abnormal laboratory finding that would, in the investigator's judgment, make the subject imappropriae for this study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1 (Dose-escalation part): Part 1 of study is Completed - Define the maximum tolerated dose, less than or equal to 1000 mg/day, in subjects with CML in chronic phase resistant or refractory to imatinib - Evaluate the overall PK parameters in this population. Part 2 (Efficacy components): - Determine the rate of attaining major cytogenetic response in subjects entering with imatinib-resistant chronic phase CML, who have no prior Src, Abl, or Src-Abl kinase inhibitor exposure other than imatinib - Determine the population PK parameters of this population;Secondary Objective: Part 2- Estimate: - Time to and duration of major cytogenetic response in subjects entering with imatinib-resistant chronic phase CML who have no prior Src, Abl, or Src/Abl kinase inhibitor exposure other than imatinib - MCyR rate in CP CML subjects intolerant of imatinib, who have no prior Src, Abl, or Src/Abl kinase inhibitor exposure other than imatinib - Time to and duration of major cytogenetic response in CP CML subjects intolerant of imatinib who have no prior Src, Abl, or Src/Abl kinase inhibitor exposure other than imatinib - Time to and duration of CHR in the imatinib-resistant and imatinib-intolerant groups - MCyR rate in CP CML subjects who have failed imatinib and are resistant to dasatinib (1); who have failed imatinib and are intolerant to dasatinib (2) - CHR rate in advanced leukemia subjects - Assess safety of SKI-606 during prolonged oral exposure in a leukemic population - Explore overall survival and progression free survival rates at 1 and 2 yrs;Primary end point(s): SAFETY -Incidence and severity of dose-limiting toxicities (DLTs) at each dose level -Incidence, severity and duration of adverse events at each dose level and for all subjects combined EFFICACY Primary endpoint:- MCyR rate in chronic phase patients, who have no prior Src, Abl, or Src-Abl inhibitor exposure other than imatinib, who have completed at least 24 weeks of treatment, or obta | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): SAFETY - Changes in laboratory test results, inlcuding electrocardiogram (ECG), and chest x-ray. - Concomitant medications used for management of AEs - Changes in ECOG performance score or physical examination EFFICACY - Disease-phase-appropriate hematologic and cytogenetic endpoint assessments (MCyR for chronic phase and CHr or OHR for advance leukemia patients) - Overall survival (OS) and progression free survival (PFS) rates at 1 and 2 years;Timepoint(s) of evaluation of this end point: ongoing during the study based on cumulative data and MCyR rates at 24 weeks and OHR rate in imatinib-resistant accelerated phase and blast phase CML subjects at 48 weeks. For details see protocol. | — |
Countries
Argentina, Australia, Austria, Brazil, Canada, Chile, China, Colombia, Finland, Germany, Hong Kong, Hungary, India, Italy, Korea, Republic of, Mexico, Netherlands, Norway, Peru, Russian Federation, Singapore, South Africa, Spain, Sweden, Taiwan, United Kingdom, United States
Contacts
Public ContactClinical Trials.gov Call Center
Pfizer Inc
Outcome results
None listed