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

28. juni 2017 opdateret af: Pfizer

A Phase 1/2 Study Of Bosutinib (Ski-606) In Philadelphia Chromosome Positive Leukemias

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.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

571

Fase

  • Fase 2

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Argentina
      • Buenos Aires, Argentina, 1280
        • Hospital Británico
      • Buenos Aires, Argentina, 1426
        • Instituto Médico Especializado Alexander Fleming
      • Buenos Aires, Argentina, 1425
        • Academia Nacional de Medicina-Instituto de Investigaciones Hematologicas
      • Ciudad Autonoma de Buenos Aires, Argentina, C1425DQI
        • Clinica del Sol
      • Corrientes, Argentina, 3400
        • Centro Medico S.A.
      • Corrientes, Argentina, 3400
        • Hospital Jose Ramon Vidal
      • Pcia de Buenos Aires, Argentina, B1629ODT
        • Hospital Universitario Austral
    • Provincia de Buenos Aires
      • La Plata, Provincia de Buenos Aires, Argentina, 1900
        • Hospital Italiano de La Plata
  • Australien
      • Adelaide, Australien, SA 5000
        • Institute of Medical and Veterinary Science
      • Melbourne, Australien, 3181
        • Department of Clinical Haematology and Bone Marrow Transplantation
      • Queensland, Australien, 4029
        • Royal Brisbane and Women'S Hospital
      • Queensland, Australien, 4101
        • Haematology and Oncology Clinics of Australia
    • South Australia
      • Adelaide, South Australia, Australien, 5000
        • Royal Adelaide Hospital
  • Brasilien
      • Curitiba, PR, Brasilien, CEP: 80060-900
        • Hospital de Clinicas - Universidade Federal do Parana
    • Sao Paulo/sp - Brazil
      • Jardim Paulista, Sao Paulo/sp - Brazil, Brasilien, CEP: 01401-901
        • Hospital Brigadeiro da Secretaria de Estado da Saude de Sao Paulo
    • Sp - Brazil
      • Santo Andre, Sp - Brazil, Brasilien, CEP 09060-650
        • Centro de Estudos da Disciplina dr Hematologia da Faculdade de Medicine do ABC
    • Sp Brazil
      • Sao Paulo, Sp Brazil, Brasilien, 05403-000
        • Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo
  • Canada
    • Alberta
      • Edmonton, Alberta, Canada, T6G1Z2
        • Cross Cancer Institute
    • British Columbia
      • Kelowna, British Columbia, Canada, V1Y 5L3
        • BC Cancer Agency - Cancer Centre for the Southern Interior
    • Manitoba
      • Winnipeg, Manitoba, Canada, R3E 0V9
        • CancerCare Manitoba
    • Ontario
      • Toronto, Ontario, Canada, M5G 2M9
        • University Health Network Princess Margaret Hospital
    • Quebec
      • Montreal, Quebec, Canada, H3T 1E2
        • Sir Mortimer B. Davis, Jewish General Hospital
  • Chile
      • Temuco, Chile
        • Instituto Clinico Oncologico del Sur
  • Colombia
    • Antioquia
      • Medellin, Antioquia, Colombia, 4459000
        • Hospital Pablo Tobon Uribe
    • Cundinamarca
      • Bogota, Cundinamarca, Colombia
        • Fundacion Santa Fe de Bogota
  • Den Russiske Føderation
      • Ekaterinburg, Den Russiske Føderation, 620102
        • State Healthcare Institution, Sverdlovsk Regional Clinical Hospital
      • Kirov, Den Russiske Føderation, 610027
        • Kirov Research Institute of Hematology and Blood transfusion of Roszdrav Hematology clinic
      • Moscow, Den Russiske Føderation, 125167
        • Hematological Research Centre of RAMS
      • Moscow, Den Russiske Føderation, 129110
        • Moscow regional Clinical Research Institute named after M.F Vladimirsky
      • Rostov-on Don, Den Russiske Føderation, 344022
        • Rostov State Medical University of Roszdrav
      • Saint Petersburg, Den Russiske Føderation, 197022
        • Saint Petersburg State Medical University Hematology Department
  • Det Forenede Kongerige
      • London, Det Forenede Kongerige, W12 0HS
        • Hammersmith Hospital
      • Newcastle Upon Tyne, North East England, Det Forenede Kongerige, NE1 4LP
        • Clinical Research Facility
    • North East England
      • Newcastle Upon Tyne, North East England, Det Forenede Kongerige, NE7 7DN
        • Northern Centre for Cancer Care - The Newcastle Upon Tyne Hospitals - NHS Foundation Trust
      • University upon Tyne, North East England, Det Forenede Kongerige, NE1 7RU
        • School of Clinical and Laboratory Sciences
  • Finland
      • Helsinki, Finland, FIN-00029 HUS
        • Biomedicum Helsinki
  • Forenede Stater
    • California
      • Duarte, California, Forenede Stater, 91010
        • City of Hope National Medical Center
    • Colorado
      • Denver, Colorado, Forenede Stater, 80218
        • Rocky Mountain Cancer Centers
      • Denver, Colorado, Forenede Stater, 80218
        • HealthONE Presbyterian
    • District of Columbia
      • Washington, D.C., District of Columbia, Forenede Stater, 20007
        • Georgetown University Hospital
    • Georgia
      • Atlanta, Georgia, Forenede Stater, 30322
        • Emory University Hospital
      • Atlanta, Georgia, Forenede Stater, 30322
        • Emory Clinic
      • Atlanta, Georgia, Forenede Stater, 30322
        • Winship Cancer Institute
    • Illinois
      • Niles, Illinois, Forenede Stater, 60714
        • Oncology Specialists, S.C.
    • Indiana
      • Indianapolis, Indiana, Forenede Stater, 46237
        • Indiana Blood and Marrow Transplantation
    • Louisiana
      • Shreveport, Louisiana, Forenede Stater, 71103
        • LSU Health Sciences Center
    • Maryland
      • Baltimore, Maryland, Forenede Stater, 21201
        • University of Maryland
      • Baltimore, Maryland, Forenede Stater, 21201
        • University of Maryland Medical Center
    • New York
      • Buffalo, New York, Forenede Stater, 14263
        • Roswell Park Cancer Institute
      • Hawthorne, New York, Forenede Stater, 10532
        • Hudson Valley Hematology and Oncology Associates
      • Hawthorne, New York, Forenede Stater, 10532
        • Westchester Oncology Hematology Group, P.C.
      • Hawthorne, New York, Forenede Stater, 10532
        • Westchester Oncology Hematology, Group, P.C.
      • New York, New York, Forenede Stater, 10021
        • New York Presbyterian Hospital
      • New York, New York, Forenede Stater, 10065
        • New York Presbyterian Hospital
      • Rochester, New York, Forenede Stater, 14642
        • University of Rochester
      • Rochester, New York, Forenede Stater, 14642
        • University of Rochester Medical Center
      • Rochester, New York, Forenede Stater, 14642
        • University of Rochester Cancer Center Pharmacy
      • Rochester, New York, Forenede Stater, 14642
        • University of Rochester-James P. Wilmot Cancer Center
      • Rochester, New York, Forenede Stater, 14642
        • University of Rochester Medical Center Strong Memorial Hospital - James P. Wilmot Cancer Center
      • Valhalla, New York, Forenede Stater, 10595
        • Westchester Medical Center
    • Pennsylvania
      • Hershey, Pennsylvania, Forenede Stater, 17033-0850
        • Penn State Milton S Hershey Medical Center
    • Texas
      • Houston, Texas, Forenede Stater, 77030
        • The University of Texas MD Anderson Cancer Center
      • Houston, Texas, Forenede Stater, 77030
        • The University Of Texas
      • Houston, Texas, Forenede Stater, 77030-4009
        • MD Anderson Cancer Center
    • Virginia
      • Richmond, Virginia, Forenede Stater, 23298-0157
        • Virginia Commonwealth University
  • Holland
      • Amsterdam, Holland, 1081 HV
        • VU University Medical Center
      • Groningen, Holland, 9700 RB
        • University Medical Center Groningen
      • Groningen, Holland, 9713 GZ
        • Universitair Medisch Centrum Groningen
      • Groningen, Holland, 9713 AP
        • UMCG - Pharmacy
      • The Netherlands, Holland
        • VUMC
  • Hong Kong
      • Chai Wan, Hong Kong
        • Pamela Youde Nethersole Eastern Hosp.
      • Hong Kong, Hong Kong
        • Queen Mary Hospital
  • Indien
    • Tamil Nadu
      • Vellore, Tamil Nadu, Indien, 632 004
        • Christian medical college
  • Italien
      • Bologna, Italien, 40138
        • AOU-S.Orsola-Malpighi - Universita degli Studi di Bologna
      • Monza, Italien, 20900
        • Azienda Ospedaliera San Gerardo
    • Province of Bologna
      • Bologna, Province of Bologna, Italien, 40138
        • University of Bologna
    • Torino
      • Orbassano, Torino, Italien, 10043
        • Azienda Ospedaliero - Universitaria San Luigi Gonzaga
  • Kina
      • Shanghai, Kina, 200025
        • The Department of Hematology, Ruijin Hospital Affiliated to School of Medicine of Shanghai Jiaotong
    • P.r China
      • Zhejiang, P.r China, Kina, 310003
        • The First Hospital affiliated to the Medical School of Zhejiang University
    • P.r. China
      • Beijing, P.r. China, Kina, 100730
        • Peking Union Medical College Hospital of Chinese Academy of Medical Sciences
      • Beijing, P.r. China, Kina, 100853
        • The Department of Hematology, The Chinese PLA General Hospital
      • Tianjin, P.r. China, Kina, 300020
        • The Hematology Hospital of Chinese Academy of Medical Sciences
  • Korea, Republikken
      • Seoul, Korea, Republikken, 137-701
        • The Catholic University of Korea, Seoul St. Mary Hospital
      • Seoul, Korea, Republikken, 138736
        • Dept. of Hematology
  • Mexico
      • Nuevo Leon, Mexico, 64460
        • Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
      • Toluca Estado de Mexico, Mexico, CP50180
        • Centro Oncologico Estatal ISSEMYM
  • Norge
    • Norge
      • Trondheim, Norge, Norge, 7006
        • Avd. for blodsykdommer
  • Peru
      • Lima, Peru, 11
        • Hospital Nacional Edgardo Rebagliati Martins
  • Singapore
      • Singapore, Singapore, 169608
        • Singapore General Hospital
  • Spanien
      • Madrid, Spanien, 28006
        • Hospital Universitario La Princesa
      • Valencia, Spanien, 46010
        • Hospital Clinico Universitario de Valencia (CHUV)
    • Catalonia
      • Barcelona, Catalonia, Spanien, 08036
        • Hospital Clinic de Barcelona (Hospital Clinic i Provincial)
      • Barcelona, Catalonia, Spanien, 08036
        • Hospital Universitari Clínic de Barcelona
  • Sverige
      • Uppsala, Sverige, 75185
        • Akademiska University Hospital
  • Sydafrika
      • Bloemfontein, Sydafrika, 9301
        • University of The Free State
      • Cape Town, Sydafrika, 7925
        • University of Cape Town
      • Parktown, Sydafrika, 2193
        • Johannesburg Hospital
      • Soweto, Sydafrika, 2013
        • Clinical Haematology Unit
  • Taiwan
      • Taipei 100, Taiwan, 10018
        • National Taiwan University Hospital - Section of Hematology-Oncology
  • Tyskland
      • Dresden, Tyskland, 01307
        • University Hospital Carl Gustav Carus
      • Hamburg, Tyskland, 20246
        • Universitaetsklinikum Hamburg-Eppendorf
      • Hamburg, Tyskland, 20246
        • Universitaetsklinikum Hamburg - Eppendorf
      • Magdeburg, Tyskland, 39120
        • Universitaetsklinikum Magdeburg A. oe. R.
      • Mainz, Tyskland
        • Universitaetsklinikum Mainz
      • Mainz, Tyskland, 55101
        • III Medizinische Klinik und Poliklinik
      • Mainz, Tyskland, 55131
        • Klinikum der Johann Gutenberg Universitaet Mainz
      • Mainz, Tyskland, D-55101
        • Universitaet Mainz Iii. Medizinische Klinik Abteilung Fuer Haematologie
      • Mannheim, Tyskland, 68169
        • III. Medizinische Klinik
    • RP
      • Mainz, RP, Tyskland, 55101
        • Universitaet Mainz
  • Ungarn
      • Budapest, Ungarn, 1096
        • Fovarosi Onkormanyzat Egyesitett Szent Istvan es Szent Laszlo
  • Østrig
      • Wels, Østrig, 4600
        • Klinikum Kreuzschwestern Wels

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år og ældre (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

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)

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: N/A
  • Interventionel model: Enkelt gruppeopgave
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: SKI-606
Medicin: Bosutinib

Part 1, starting dose 400 mg oral, daily dosing in the dose-escalation component.

Part 2, 500 mg oral, continuous, daily dosing.

Andre navne:
  • SKI-606

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Number of Participants With Dose Limiting Toxicity (DLT)
Tidsramme: Part 1 Baseline up to Day 28
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, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).
Part 1 Baseline up to Day 28
Maximum Tolerated Dose (MTD)
Tidsramme: Part 1 Baseline up to Day 28

MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced DLT. 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, any clinically-significant grade 2 non-hematologic toxicity that requires 14 days to resolve (to grade 1).

NA = not estimable.
Part 1 Baseline up to Day 28
Maximum Observed Plasma Concentration (Cmax) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Time to Reach Maximum Observed Plasma Concentration (Tmax) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Plasma Decay Half-Life (t1/2) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

NA = not estimable.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC(0-48)] - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
AUC(0-48)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-48).
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Area Under the Concentration-Time Curve (AUC) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.

NA = not estimable.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Apparent Oral Clearance (CL/F) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1

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. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

NA = not estimable.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Apparent Volume of Distribution (Vz/F) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose 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.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24, 48 hours post-dose on Day 1
Maximum Observed Plasma Concentration at Steady State (Cmax,ss) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Maximum plasma concentration over 24 hours at steady state (ss), on Day 15.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Time to reach maximum observed plasma concentration over 24 hours at steady state (ss), on Day 15.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Plasma Decay Half-Life at Steady State (t1/2,ss) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half-life over 24 hours at steady state (ss), on Day 15 was calculated.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Area Under the Concentration-Time Curve at Steady State (AUCss) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. AUC over 24 hours at steady state (ss), on Day 15 was calculated.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Apparent Oral Clearance at Steady State (CL/F,ss) - Part 1
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose 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. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent oral clearence over 24 hours at steady state (ss), on Day 15 was calculated.
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 15
Accumulation Ratio (R)
Tidsramme: 0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15
R=accumulation ratio (AUCss on Day 15/AUC0-24 on Day 1)
0 (pre-dose), 1, 2, 3, 4, 6, 8, 24 hours post-dose on Day 1 and Day 15
Percentage of Participants With MCyR at Week 24 in Chronic Phase Second-line Imatinib Resistant CML Population - Part 2
Tidsramme: Week 24
CyR is based on the prevalence of Ph+ cells. Major cytogenetic response was categorized as either CCyR or partial CyR (PCyR). CCyR was achieved when there was 0 percent (%) Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or less than (<) 1% positive cells from at least 200 cells analyzed from fluorescent in situ hybridization (FISH). PCyR was achieved when 1 to 35% Ph+ cells were present.
Week 24

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1
Tidsramme: Weeks 12, 24, 36, 48 and the end of active treatment phase of Part 1 (Week 52)
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% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present.
Weeks 12, 24, 36, 48 and the end of active treatment phase of Part 1 (Week 52)
Phosphorylation Inhibition of Breakpoint Cluster Region-Abelson Kinase (Bcr-Abl) - Part 1
Tidsramme: Baseline, Weeks 4, 8, 12, 24, 36, 48 and the end of the active treatment phase of Part 1 (Week 52)
bcr-Abl is a protein resulting from the transcription of the Philadelphia chromosome following 9:22 chromosomal translocation, and phosphorylation inhibition of which correlates with inhibition of tumor cell growth.
Baseline, Weeks 4, 8, 12, 24, 36, 48 and the end of the active treatment phase of Part 1 (Week 52)
Phosphorylation Inhibition of Crk Like (CrkL) Protein at Baseline - Part 1
Tidsramme: 0 (pre-dose) on Day 1 (Baseline)
CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells, as well as in the cluster of differentiation 3 (CD3+) (T cell), CD19+ (B cell) and CD34+ (blast cell) compartments by using fluorescent activated cell sorter (FACS) flow cytometry.
0 (pre-dose) on Day 1 (Baseline)
Percent Change From Baseline in Phosphorylation Inhibition of Crk Like Protein (CrkL) at Day 1, 8 and 15 - Part 1
Tidsramme: 6 hours post-dose on Day 1, 0 (pre-dose), 6 hours post-dose on Day 8, 15

CrkL is a protein, phosphorylation of which has been shown to correlate with CML cell growth; and conversely inhibition of their phosphorylation correlates with inhibition of tumor cell growth. Phosphorylation of CrkL was monitored in whole blood cells, as well as in the CD3+ (T cell), CD19+ (B cell) and CD34+ (blast cell) compartments by using FACS flow cytometry.

NA = not estimable.
6 hours post-dose on Day 1, 0 (pre-dose), 6 hours post-dose on Day 8, 15
Percentage of Participants With Major Cytogenetic Response (MCyR) in Chronic Phase Second-line and Chronic Phase Third-line CML Population - Part 2
Tidsramme: 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)
CyR is based on the prevalence of Ph+ cells. MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present.
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)
Kaplan-Meier Estimate of Retaining an Attained/Maintained Major Cytogenetic Response (MCyR) at Year 5 in Chronic Phase Second-line CML - Part 2
Tidsramme: 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
MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. The Kaplan-Meier probability of retaining an attained/maintained MCyR at Year 5 is reported. Median durations were not reached as of the minimum follow-up. Duration of response in weeks =(date of confirmed loss of first attained response or last valid cytogenetic assessment for those censored - date of first attained response)/7.
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
Time to Achieve Major Cytogenetic Response (MCyR) in Chronic Phase Second-line CML for Responders Only - Part 2
Tidsramme: Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 5

MCyR was categorized as either CCyR or PCyR. CCyR was achieved when there was 0% Ph+ cells from at least 20 metaphases from conventional bone marrow cytogenetics or <1% positive cells from at least 200 cells analyzed from FISH. PCyR was achieved when 1 to 35% Ph+ cells were present. 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 equals (=) (event date minus (-) first dose date plus (+) 1)divided (/)7, where the event date is the non-missing date of the first attained response for responders only.
Week 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter up to Year 5
Kaplan-Meier Estimate of Maintaining Complete Hematologic Response (CHR) at Year 4 (CP3L and ADV) or Year 5 (CP2L) - Part 2
Tidsramme: 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)

Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells equal to or less than (≤) institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes <5% in blood, absolute neutrophil count greater than or equal to (≥) 1.0×10^9 per liter (/L) , platelets ≥100×10^9/L & <450×10^9/L, <20% basophils in blood & no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (ADV only & applicable to CP if BM aspirate was performed). 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 attained response or last valid hematologic assessment for those censored - date of first confirmed response)/7. The Kaplan-Meier estimate of maintaining CHR at the end of minimum follow-up is presented (CP2L: Year 5; CP3L & ADV: Year 4). NA = not estimable.

NA = not estimable.
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)
Duration of Complete Hematologic Response (CHR) - Part 2
Tidsramme: 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)

Hematologic response: if participants met all of the following criteria of CHR: White Blood Cells equal to or less than (≤) institutional upper limit of normal, no peripheral blood blasts or promyelocytes, myelocytes+metamyelocytes less than (<)5% in blood, absolute neutrophil count greater than or equal to (≥) 1.0×10^9 per liter (/L) , platelets <450×10^9/L, platelets ≥100×10^9/L, <20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (required for ADV only and applicable to CP if BM aspirate was performed). 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 attained response or last valid hematologic assessment for those censored - date of first confirmed response)/7.

NA = not estimable.
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)
Time to Achieve Complete Hematologic Response (CHR) for Responders Only - Part 2
Tidsramme: 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)
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 for responders only.
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)
Cumulative Incidence of Progression/Death - Part 2
Tidsramme: Years 1, 2, 3, 4, and 5 (CP2L only)

The cumulative incidence of on-treatment progression or death adjusting for the competing risk of treatment discontinuation without the event. Disease progression was determined by the investigator as the reason for treatment discontinuation and death was due to any cause within 30 days of last dose. Duration in months = (date of PD/death or last valid cytogenetic/hematologic assessment if censored - first dose date)/30.4. 95% confidence intervals were calculated using Gray's method.

NA = not estimable. One year = 12 months.
Years 1, 2, 3, 4, and 5 (CP2L only)
Progression Free Survival (PFS) - Part 2
Tidsramme: Years 1, 2, 3, 4, and 5 (CP2L only)

PFS was based on Kaplan-Meier method. Disease progression was determined by the investigator as the reason for treatment discontinuation and death was due to any cause within 30 days of last dose. Duration in months = (date of PD/death or last valid cytogenetic/hematologic assessment if censored - first dose date)/30.4.

NA = not estimable. One year = 12 months
Years 1, 2, 3, 4, and 5 (CP2L only)
Kaplan-Meier Estimate of Overall Survival (OS) - Part 2
Tidsramme: Years 1, 2, 3, 4, and 5 (CP2L only)

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 or date of last contact for those censored.

NA = not estimable. One year = 12 months.
Years 1, 2, 3, 4, and 5 (CP2L only)
Overall Survival (OS) - Part 2
Tidsramme: Years 1, 2, 3, 4, and 5 (CP2L only)

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 or date of last contact for those censored.

NA = not estimable. One year = 12 months.
Years 1, 2, 3, 4, and 5 (CP2L only)
Percentage of Participants With Confirmed Complete Hematologic Response (CHR) - Part 2
Tidsramme: 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)
Hematologic response: if participants met all of the following criteria of CHR: 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/L , platelets <450×10^9/L, platelets ≥100×10^9/L, <20% basophils in blood and no extramedually involvement (including hepato- or splenomegaly), ≤5% BM blasts (required for ADV only and applicable to CP if BM aspirate was performed).
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)
Percentage of Participants With Overall Hematologic Response (OHR) by Week 48 in Advanced Leukemia Population - Part 2
Tidsramme: 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
OHR included CHR, no evidence of leukemia (≤5% bone marrow blasts, no peripheral blood blasts or promyelocytes, <5% myelocytes + metamyelocytes in blood, white blood cells ≤ institutional upper limit of normal, 450x10^9/L > platelets > 20x10^9/L, absolute neutrophil count ≥0.5x10^9/L, <20% basophils in blood, no extramedullary involvement [including liver or spleen]), minor hematologic response (acute lymphoblastic leukemia [ALL] patients only, defined as <15% blasts in marrow & blood, <30% blasts + promyelocytes in marrow & blood, <20% basophils in peripheral blood & no extramedullary disease other than spleen & liver) or return to chronic phase (AP/BP participants, defined as <15% blasts in both peripheral blood &bone marrow, <30% blasts + promyelocytes in both peripheral blood & bone marrow, <20% basophils in both peripheral blood & bone marrow, no extramedullary Involvement other than liver or spleen). Participants had to meet at least 1 criterion.
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
Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
Tidsramme: Baseline up to follow up visit (30 days after last dose of study treatment)
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Baseline up to follow up visit (30 days after last dose of study treatment)
Duration of Potentially Clinically Important (PCI) Adverse Events (AEs)
Tidsramme: Baseline up to follow-up visit (30 days after last dose of study treatment)

An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. The event did not necessarily have a causal relationship with the treatment. PCI AEs included anemia, alanine aminotranferase (ALT), aspartate aminotransferase (AST), cardiac, diarrhea, edema, effusion, gastrointestinal, hemorrhage, hypersensitivity, hypertension, infection, liver, myelosuppression, nausea, neutropenia, rash, renal, thrombocytopenia, vomiting, and vascular events. Duration of AE was calculated as (stop date minus start date) plus 1 for non-missing and non-partial dates.

NA = not estimable.
Baseline up to follow-up visit (30 days after last dose of study treatment)
Percentage of Participants With Change From Baseline in Laboratory Tests Results
Tidsramme: Week 1, 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter
Laboratory assessments included urinalysis, complete blood count (CBC), prothrombin time/partial prothromboplastin time (PT/PPT), international normalized ratio (INR), blood chemistry and serum pregnancy test (β-HCG). Parameters of special interest included liver function tests and those related to myelosuppression. Potentially clinically important (PCI) laboratory values were defined as National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 (NCI CTCAE v3.0) grade 3 or higher. Maximum CTCAE grade, and only participants who shifted to Grade 3/4 on-treatment, are reported.
Week 1, 2, 3, 4, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter
Percentage of Participants With On-treatment PCI Change From Baseline in Electrocardiogram (ECG) Findings
Tidsramme: 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
Criteria for PCI changes in ECG (12-lead) were defined as: no sinus rhythm; PR interval >=220 msec and increase of >=20 msec; QRS interval >=120 msec; QT interval corrected using the Fridericia formula (QTcF) and QT interval corrected using the Bazett formula (QTcB) >500 msec or increase of >60 msec; heart rate <=45 beats per minute (bpm) or >=120 bpm or decrease/increase of >=15 bpm.
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
Number of Participants With Change From Baseline in Findings of Chest X-ray
Tidsramme: Baseline, Week 8, and end of treatment
Number of participants whose chest X-ray results changed (worsened or improved) from the Baseline.
Baseline, Week 8, and end of treatment
Number of Participants Who Received Concomitant Medications for Management of Adverse Events (AEs)
Tidsramme: 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
Number of participants taking any non-study medications which were administered from Study Day 1 to 30 days after last dose of study treatment as a management of an AE are reported.
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
Number of Participants With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)
Tidsramme: Baseline, Week 1, 2, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter
ECOG-PS measured on-therapy (time between first dose and last dose date with a 30-day lag) assessed participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction;1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work;2=ambulatory (>50% of waking hrs), capable of all self care, unable to carry out any work activities;3=capable of only limited self care, confined to bed/chair >50% of waking hrs;4=completely disabled, cannot carry on any self care, totally confined to bed/chair;5=dead.
Baseline, Week 1, 2, 8, 12, thereafter assessed every 12 weeks up to 2 years then every 24 weeks thereafter
Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs
Tidsramme: Screening, Baseline, and end of treatment
Percentage of participants with PCI physical examinations and vital signs is reported during therapy and at post therapy. Criteria for PCI change in vital signs: heart rate value of <40 beats per min and value >150 beats per min, systolic blood pressure (SBP) of <80 or >210 millimeter of mercury (mmHg), diastolic blood pressure (DBP) of <40 or >130 mmHg, temperature <32 or >40 degree centigrade, respiratory rate (Resp) of <10 or >50 breaths/min and criteria for PCI change in physical examination: >=10% increase or decrease of body weight in kilogram (kg).
Screening, Baseline, and end of treatment
Percentage of Participants With Change From Baseline in Physical Examinations and Vital Signs and Number of Participants With PCI Values
Tidsramme: Post-therapy
Percentage of participants with PCI physical examinations and vital signs is reported during therapy and at post therapy. Criteria for PCI change in vital signs: heart rate value of <40 beats per min and value >150 beats per min, SBP of <80 or >210 mmHg, DBP of <40 or >130 mmHg, temperature <32 or >40 degree centigrade, Resp of <10 or >50 breaths/min and criteria for PCI change in physical examination: >=10% increase or decrease of body weight in kg. No Ph+ ALL participants were analyzed post-therapy (N=0). Part 1 safety data were originally presented in 2011 and are included as cumulative data in the Part 2 final safety results.
Post-therapy

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Sponsor

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Publikationer og nyttige links

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Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Faktiske)

18. januar 2006

Primær færdiggørelse (Faktiske)

25. september 2009

Studieafslutning (Faktiske)

6. august 2015

Datoer for studieregistrering

Først indsendt

2. december 2005

Først indsendt, der opfyldte QC-kriterier

2. december 2005

Først opslået (Skøn)

5. december 2005

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

27. juli 2017

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

28. juni 2017

Sidst verificeret

1. juni 2017

Mere information

Begreber relateret til denne undersøgelse

Nøgleord

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • 3160A4-200
  • B1871006, 3160A4-200-WW
  • 2005-004230-40 (EudraCT nummer)
  • B1871006 (Anden identifikator: Alias Study Number)

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