Clinical trial NCT00261846: Study Evaluating SKI-606 (Bosutinib) In Philadelphia Chromosome Positive Leukemias
Official title: A Phase 1/2 Study Of Bosutinib (Ski-606) In Philadelphia Chromosome Positive Leukemias
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia
Keywords: Leukemia
tyrosine kinase inhibitor
philadelphia chromosome
Myeloid
Philadelphia Positive
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2005-12-05
Enrollment: 571
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* Ph+ CML or Ph+ ALL who are primarily refractory to full-dose imatinib (600 mg), have disease progression/relapse while on full-dose imatinib, or are intolerant of any dose of imatinib.
* At least 3 months post stem cell transplantation
* Able to take daily oral capsules/tablets reliably

Exclusion Criteria:

* Subjects with Philadelphia chromosome, and bcr-abl negative CML
* Overt leptomeningeal leukemia
* Subjects without evidence of leukemia in bone marrow (extramedullary disease only)

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicity (DLT)
timeFrame: Part 1 Baseline up to Day 28
measure: Maximum Tolerated Dose (MTD)
timeFrame: Part 1 Baseline up to Day 28
measure: Maximum Observed Plasma Concentration (Cmax) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
measure: Plasma Decay Half-Life (t1/2) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
measure: Area Under the Concentration-Time Curve (AUC) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
measure: Apparent Oral Clearance (CL/F) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
measure: Apparent Volume of Distribution (Vz/F) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
measure: Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
measure: Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
measure: Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
measure: Area Under the Concentration-Time Curve at Steady State (AUCss) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
measure: Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
measure: Accumulation Ratio (R)
timeFrame: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15
measure: Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2
timeFrame: Week 24
Secondary outcomes:
measure: Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1
timeFrame: Weeks 12, 24, 36, 48 and the end of active treatment phase of Part 1 (Week 52)
measure: Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1
timeFrame: Baseline, Weeks 4, 8, 12, 24, 36, 48 and the end of the active treatment phase of Part 1 (Week 52)
measure: Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1
timeFrame: 0 (pre-dose) on Day 1 (Baseline)
measure: Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1
timeFrame: 6 hours post-dose on Day 1, 0 (pre-dose), 6 hours post-dose on Day 8, 15
measure: Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2
timeFrame: Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L) or Year 5 (CP2L)
measure: Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2
timeFrame: From first MCyR to loss of MCyR or censoring, assessed every 12 weeks up to 2 years and then every 24 weeks thereafter up to Year 5
measure: Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2
timeFrame: Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 5
measure: Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) - Part 2
timeFrame: From date of first confirmed CHR to loss of CHR or censoring, assessed at Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)
measure: Duration of Complete Hematologic Response (CHR) - Part 2
timeFrame: From date of first confirmed CHR to loss of CHR or censoring, assessed at Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)
measure: Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2
timeFrame: Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)
measure: Cumulative Incidence of Progression/Death - Part 2
timeFrame: Years 1, 2, 3, 4, and 5 (CP2L only)
measure: Progression Free Survival (PFS) - Part 2
timeFrame: Years 1, 2, 3, 4, and 5 (CP2L only)
measure: Kaplan-Meier Estimate of Overall Survival (OS) - Part 2
timeFrame: Years 1, 2, 3, 4, and 5 (CP2L only)
measure: Overall Survival (OS) - Part 2
timeFrame: Years 1, 2, 3, 4, and 5 (CP2L only)
measure: Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2
timeFrame: Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 4 (CP3L and ADV) or Year 5 (CP2L)
measure: Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Population - Part 2
timeFrame: Day 1 and 7 of Week 1, Day 7 of Week 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 1 year
measure: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
timeFrame: Baseline up to follow up visit (30 days after last dose of study treatment)
measure: Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)
timeFrame: Baseline up to follow-up visit (30 days after last dose of study treatment)
measure: Percentage of Participants With Change From Baseline in Laboratory Tests Results
timeFrame: Week 1, 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter
measure: Percentage of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings
timeFrame: Baseline, 0 (pre-dose), 2, 4, 6 hours on Day 1, 0 (pre-dose), 2, 4, 6, 20-23 hours on Day 21, and end of treatment visit
measure: Number of Participants With Change From Baseline in Findings of Chest X-ray
timeFrame: Baseline, Week 8, and end of treatment
measure: Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs)
timeFrame: Baseline and Weeks 1, 2, 3, 4, 8, 12, then every 12 weeks thereafter until end of treatment, for a mean duration of 28 months
measure: Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)
timeFrame: Baseline, Week 1, 2, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter
measure: Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs
timeFrame: Screening, Baseline, and end of treatment
measure: Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs and Number of Participants With PCI Values
timeFrame: Post-therapy
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Denver
country: United States
facility: HealthONE Presbyterian
state: Colorado
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Washington, D.C.
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Atlanta
country: United States
facility: Emory Clinic
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Atlanta
country: United States
facility: Winship Cancer Institute
state: Georgia
city: Niles
country: United States
facility: Oncology Specialists, S.C.
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Blood and Marrow Transplantation
state: Indiana
city: Shreveport
country: United States
facility: LSU Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: University Of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: University Of Maryland
state: Maryland
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Hawthorne
country: United States
facility: Hudson Valley Hematology and Oncology Associates
state: New York
city: Hawthorne
country: United States
facility: Westchester Oncology Hematology Group, P.C.
state: New York
city: Hawthorne
country: United States
facility: Westchester Oncology Hematology, Group, P.C.
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester Cancer Center Pharmacy
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center Strong Memorial Hospital - James P. Wilmot Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester-James P. Wilmot Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Valhalla
country: United States
facility: Westchester Medical Center
state: New York
city: Hershey
country: United States
facility: Penn State Milton S Hershey Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: The University of Texas
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: La Plata
country: Argentina
facility: Hospital Italiano de la Plata
state: Provincia de Buenos Aires
city: Buenos Aires
country: Argentina
facility: Hospital Britanico
city: Buenos Aires
country: Argentina
facility: Academia Nacional de Medicina-Instituto de Investigaciones Hematologicas
city: Buenos Aires
country: Argentina
facility: Instituto Medico Especializado Alexander Fleming
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Clinica del Sol
city: Corrientes
country: Argentina
facility: Centro Medico S.A.
city: Corrientes
country: Argentina
facility: Hospital Jose Ramon Vidal
city: Pcia de Buenos Aires
country: Argentina
facility: Hospital universitario austral
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Adelaide
country: Australia
facility: Institute of Medical and Veterinary Science
city: Melbourne
country: Australia
facility: Department of Clinical Haematology and Bone Marrow Transplantation
city: Queensland
country: Australia
facility: Royal Brisbane and Women's Hospital
city: Queensland
country: Australia
facility: Haematology and Oncology Clinics of Australia
city: Wels
country: Austria
facility: Klinikum Kreuzschwestern Wels
city: Jardim Paulista
country: Brazil
facility: Hospital Brigadeiro da Secretaria de Estado da Saude de Sao Paulo
state: Sao Paulo/sp - Brazil
city: Santo Andre
country: Brazil
facility: Centro de Estudos da Disciplina dr Hematologia da Faculdade de Medicine do ABC
state: Sp - Brazil
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
state: Sp Brazil
city: Curitiba, PR
country: Brazil
facility: Hospital de Clinicas - Universidade Federal do Parana
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Kelowna
country: Canada
facility: BC Cancer Agency - Cancer Centre for the Southern Interior
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Toronto
country: Canada
facility: University Health Network Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Sir Mortimer B. Davis, Jewish General Hospital
state: Quebec
city: Temuco
country: Chile
facility: Instituto Clinico Oncologico del Sur
city: Zhejiang
country: China
facility: The First Hospital affiliated to the Medical School of Zhejiang University
state: P.r China
city: Beijing
country: China
facility: Peking Union Medical College Hospital of Chinese Academy of Medical Sciences
state: P.r. China
city: Beijing
country: China
facility: The Department of Hematology, The Chinese PLA General Hospital
state: P.r. China
city: Tianjin
country: China
facility: The Hematology Hospital of Chinese Academy of Medical Sciences
state: P.r. China
city: Shanghai
country: China
facility: The Department of Hematology, Ruijin Hospital Affiliated to School of Medicine of Shanghai Jiaotong
city: Medellin
country: Colombia
facility: Hospital Pablo Tobon Uribe
state: Antioquia
city: Bogota
country: Colombia
facility: Fundacion Santa Fe de Bogota
state: Cundinamarca
city: Helsinki
country: Finland
facility: Biomedicum Helsinki
city: Mainz
country: Germany
facility: Universitaet Mainz
state: RP
city: Dresden
country: Germany
facility: University Hospital Carl Gustav Carus
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg - Eppendorf
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf
city: Magdeburg
country: Germany
facility: Universitaetsklinikum Magdeburg A. oe. R.
city: Mainz
country: Germany
facility: III Medizinische Klinik und Poliklinik
city: Mainz
country: Germany
facility: Klinikum der Johann Gutenberg Universitaet Mainz
city: Mainz
country: Germany
facility: Universitaet Mainz Iii. Medizinische Klinik Abteilung Fuer Haematologie
city: Mainz
country: Germany
facility: Universitaetsklinikum Mainz
city: Mannheim
country: Germany
facility: III. Medizinische Klinik
city: Chai Wan
country: Hong Kong
facility: Pamela Youde Nethersole Eastern Hosp.
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Budapest
country: Hungary
facility: Fovarosi Onkormanyzat Egyesitett Szent Istvan es Szent Laszlo
city: Vellore
country: India
facility: Christian Medical College
state: Tamil Nadu
city: Bologna
country: Italy
facility: University of Bologna
state: Province of Bologna
city: Orbassano
country: Italy
facility: Azienda Ospedaliero - Universitaria San Luigi Gonzaga
state: Torino
city: Bologna
country: Italy
facility: AOU-S.Orsola-Malpighi - Universita degli Studi di Bologna
city: Monza
country: Italy
facility: Azienda Ospedaliera San Gerardo
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary Hospital
city: Seoul
country: Korea, Republic of
facility: Dept. of Hematology
city: Nuevo Leon
country: Mexico
facility: Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
city: Toluca Estado de Mexico
country: Mexico
facility: Centro Oncologico Estatal ISSEMYM
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Groningen
country: Netherlands
facility: UMCG - Pharmacy
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: The Netherlands
country: Netherlands
facility: VUMC
city: Trondheim
country: Norway
facility: Avd. for blodsykdommer
state: Norge
city: Lima
country: Peru
facility: Hospital Nacional Edgardo Rebagliati Martins
city: Ekaterinburg
country: Russian Federation
facility: State Healthcare Institution, Sverdlovsk Regional Clinical Hospital
city: Kirov
country: Russian Federation
facility: Kirov Research Institute of Hematology and Blood transfusion of Roszdrav Hematology clinic
city: Moscow
country: Russian Federation
facility: Hematological Research Centre of RAMS
city: Moscow
country: Russian Federation
facility: Moscow regional Clinical Research Institute named after M.F Vladimirsky
city: Rostov-on Don
country: Russian Federation
facility: Rostov State Medical University of Roszdrav
city: Saint Petersburg
country: Russian Federation
facility: Saint Petersburg State Medical University Hematology Department
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Bloemfontein
country: South Africa
facility: University of the Free State
city: Cape Town
country: South Africa
facility: University of Cape Town
city: Parktown
country: South Africa
facility: Johannesburg Hospital
city: Soweto
country: South Africa
facility: Clinical Haematology Unit
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona (Hospital Clinic i Provincial)
state: Catalonia
city: Barcelona
country: Spain
facility: Hospital Universitari Clinic de Barcelona
state: Catalonia
city: Madrid
country: Spain
facility: Hospital Universitario La Princesa
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia (CHUV)
city: Uppsala
country: Sweden
facility: Akademiska University Hospital
city: Taipei 100
country: Taiwan
facility: National Taiwan University Hospital - Section of Hematology-Oncology
city: Newcastle Upon Tyne
country: United Kingdom
facility: Northern Centre for Cancer Care - The Newcastle Upon Tyne Hospitals - NHS Foundation Trust
state: North East England
city: University upon Tyne
country: United Kingdom
facility: School of Clinical and Laboratory Sciences
state: North East England
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: Newcastle Upon Tyne, North East England
country: United Kingdom
facility: Clinical Research Facility
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.
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citation: Whiteley J, Reisman A, Shapiro M, Cortes J, Cella D. Health-related quality of life during bosutinib (SKI-606) therapy in patients with advanced chronic myeloid leukemia after imatinib failure. Curr Med Res Opin. 2016 Aug;32(8):1325-34. doi: 10.1185/03007995.2016.1174108. Epub 2016 May 5.
citation: Hsyu PH, Mould DR, Abbas R, Amantea M. Population pharmacokinetic and pharmacodynamic analysis of bosutinib. Drug Metab Pharmacokinet. 2014;29(6):441-8. doi: 10.2133/dmpk.DMPK-13-RG-126. Epub 2014 Jun 10.
citation: Gambacorti-Passerini C, Brummendorf TH, Kim DW, Turkina AG, Masszi T, Assouline S, Durrant S, Kantarjian HM, Khoury HJ, Zaritskey A, Shen ZX, Jin J, Vellenga E, Pasquini R, Mathews V, Cervantes F, Besson N, Turnbull K, Leip E, Kelly V, Cortes JE. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol. 2014 Jul;89(7):732-42. doi: 10.1002/ajh.23728. Epub 2014 Apr 28.
citation: Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brummendorf TH, Porkka K, Martinelli G, Durrant S, Leip E, Kelly V, Turnbull K, Besson N, Gambacorti-Passerini C. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014 Feb 27;123(9):1309-18. doi: 10.1182/blood-2013-07-513937. Epub 2013 Dec 17.
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