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

28. června 2017 aktualizováno: 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.

Přehled studie

Postavení

Dokončeno

Podmínky

Intervence / Léčba

Typ studie

Intervenční

Zápis (Aktuální)

571

Fáze

  • Fáze 2

Kontakty a umístění

Tato část poskytuje kontaktní údaje pro ty, kteří studii provádějí, a informace o tom, kde se tato studie provádí.

Studijní místa

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

Kritéria účasti

Výzkumníci hledají lidi, kteří odpovídají určitému popisu, kterému se říká kritéria způsobilosti. Některé příklady těchto kritérií jsou celkový zdravotní stav osoby nebo předchozí léčba.

Kritéria způsobilosti

Věk způsobilý ke studiu

18 let a starší (Dospělý, Starší dospělý)

Přijímá zdravé dobrovolníky

Ne

Pohlaví způsobilá ke studiu

Všechno

Popis

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)

Studijní plán

Tato část poskytuje podrobnosti o studijním plánu, včetně toho, jak je studie navržena a co studie měří.

Jak je studie koncipována?

Detaily designu

  • Primární účel: Léčba
  • Přidělení: N/A
  • Intervenční model: Přiřazení jedné skupiny
  • Maskování: Žádné (otevřený štítek)

Zbraně a zásahy

Skupina účastníků / Arm
Intervence / Léčba
Experimentální: SKI-606
Lék: Bosutinib

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

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

Ostatní jména:
  • SKI-606

Co je měření studie?

Primární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Number of Participants With Dose Limiting Toxicity (DLT)
Časové okno: 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)
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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)
Časové okno: 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
Časové okno: 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

Sekundární výstupní opatření

Měření výsledku
Popis opatření
Časové okno
Percentage of Participants With Major Cytogenetic Response (MCyR) - Part 1
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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)
Časové okno: 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)
Časové okno: 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
Časové okno: 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
Časové okno: 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
Časové okno: 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)
Časové okno: 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)
Časové okno: 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
Časové okno: 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
Časové okno: 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

Spolupracovníci a vyšetřovatelé

Zde najdete lidi a organizace zapojené do této studie.

Sponzor

Pfizer

Publikace a užitečné odkazy

Osoba odpovědná za zadávání informací o studiu tyto publikace poskytuje dobrovolně. Mohou se týkat čehokoli, co souvisí se studiem.

Obecné publikace

Užitečné odkazy

Termíny studijních záznamů

Tato data sledují průběh záznamů studie a předkládání souhrnných výsledků na ClinicalTrials.gov. Záznamy ze studií a hlášené výsledky jsou před zveřejněním na veřejné webové stránce přezkoumány Národní lékařskou knihovnou (NLM), aby se ujistily, že splňují specifické standardy kontroly kvality.

Hlavní termíny studia

Začátek studia (Aktuální)

18. ledna 2006

Primární dokončení (Aktuální)

25. září 2009

Dokončení studie (Aktuální)

6. srpna 2015

Termíny zápisu do studia

První předloženo

2. prosince 2005

První předloženo, které splnilo kritéria kontroly kvality

2. prosince 2005

První zveřejněno (Odhad)

5. prosince 2005

Aktualizace studijních záznamů

Poslední zveřejněná aktualizace (Aktuální)

27. července 2017

Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality

28. června 2017

Naposledy ověřeno

1. června 2017

Více informací

Termíny související s touto studií

Klíčová slova

Další relevantní podmínky MeSH

Další identifikační čísla studie

  • 3160A4-200
  • B1871006, 3160A4-200-WW
  • 2005-004230-40 (Číslo EudraCT)
  • B1871006 (Jiný identifikátor: Alias Study Number)

Tyto informace byly beze změn načteny přímo z webu clinicaltrials.gov. Máte-li jakékoli požadavky na změnu, odstranění nebo aktualizaci podrobností studie, kontaktujte prosím register@clinicaltrials.gov. Jakmile bude změna implementována na clinicaltrials.gov, bude automaticky aktualizována i na našem webu .

Klinické studie na Chronická myeloidní leukémie

Klinické studie na Bosutinib

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Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

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Podmínky

Vzácné nemoci

Drogové intervence

Doplňky stravy

Sponzor / Spolupracovníci

Místa

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