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A Multicenter Phase 3, Open-Label Study of Bosutinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia

Primary Purpose

Leukemia, Myelogenous, Chronic, Breakpoint Cluster Region-Abelson Proto-oncogene (BCR-ABL) Positive

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Bosutinib

Imatinib

About this trial

This is an interventional treatment trial for Leukemia, Myelogenous, Chronic, Breakpoint Cluster Region-Abelson Proto-oncogene (BCR-ABL) Positive focused on measuring Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Bosutinib, Leukemia, Myeloid, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Philadelphia Chromosome, Neoplasms by Histologic Type, Bone Marrow Diseases, Hematologic Diseases, Translocation, Genetic, Pathologic Processes, Imatinib, Therapeutic Uses, Pharmacologic Actions, Molecular Mechanisms of Pharmacological Action

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Molecular diagnosis of CP CML of ≤ 6 months (from initial diagnosis).
Adequate hepatic, renal and pancreatic function.
Age ≥ 18 years.

Exclusion Criteria:

Any prior medical treatment for CML, including tyrosine kinase inhibitors (TKIs), with the exception of hydroxyurea and/or anagrelide treatment, which are permitted for up to 6 months prior to study entry (signature of ICF) if suitably approved for use in the subject's region.
Any past or current Central Nervous System (CNS) involvement, including leptomeningeal leukemia.
Extramedullary disease only.
Major surgery or radiotherapy within 14 days of randomization.
History of clinically significant or uncontrolled cardiac disease.
Known seropositivity to human immunodeficiency virus (HIV), current acute or chronic hepatitis B (hepatitis B surface-antigen positive), hepatitis C, cirrhosis or evidence of decompensated liver disease. Patients with resolved Hepatitis B can be included.
Recent or ongoing clinically significant GI disorder, e.g. Crohn's Disease, Ulcerative Colitis, or prior total or partial gastrectomy.
History of another malignancy within 5 years with the exception of basal cell carcinoma or cervical carcinoma in situ or stage 1 or 2 cancer that is considered adequately treated and currently in complete remission for at least l2 months.
Current, or recent (within 30 days, or 5 half-lives of investigational product) participation in other clinical trials of investigational agents and/or containing interventional procedures deemed contrary to the objectives and conduct of this trial.

Sites / Locations

Pacific Cancer Medical Center, Inc.
Emory University Hospital
The Emory Clinic
Winship Cancer Institute, Emory University
Kaiser Permanente Hawaii
Saint Alphonsus Regional Medical Center, Cancer Care Center
Saint Alphonsus Regional Medical Center
Saint Alphonsus Caldwell Cancer Care Center
Saint Alphonsus Medical Center Nampa
University of Illinois Cancer Center
John H. Stroger, Jr. Hospital of Cook County
Indiana Blood and Marrow Transplantation
PHARMACY Department Franciscan St. Francis Health ATTN:Jill Leslie, Pharm D
Cancer Center of Acadiana at Lafayette General Medical Center
Lafayette General Medical Center
LSU Health Sciences Center-Shreveport
University Health Shreveport
Rcca Md Llc
University of Massachusetts Memorial Medical Center, ONC/Research Pharmacy
University of Massachusetts Memorial Medical Center
St. Joseph Mercy Hospital - Inpatient Pharmacy
St. Joseph Mercy Hospital
St. Joseph Mercy-Brighton
St. Joseph Mercy-Canton
Chelsea Community Hospital
St. John Hospital&Medical Center
St. John Hospital&Medical Center-Van Elslander Cancer Center
Van Elslander Cancer Center, Pharmacy
Minnesota Oncology Hematology, PA
Park Nicollet Frauenshuh Cancer center
Lakeview Hospital
North Mississippi Medical Center Hematology and Oncology Clinic
Nebraska Methodist Hospital
Hackensack University Medical Center
John Theurer Cancer Center at Hackensack University Medical Center
San Juan Oncology Associates
NYU Winthrop Hospital - Oncology / Hematology department
NYU Winthrop Hospital - Pharmacy Department
Beth Israel Medical Center
University of Rochester Investigational Drug Pharmacy
University of Rochester
FirstHealth Moore Regional Hospital
FirstHealth Outpatient Cancer Center
University of Cincinnati Medical Center
UC Health Physicians Office South,
MUSC University Hospital
MUSC University of South Carolina, Investigational Drug Services
MUSC-Hollings Cancer Center
GHS Cancer Institute
GHS Cancer Institute
GHS Cancer Institute
GHS Cancer Institute
GHS Cancer Institute
GHS Cancer Institute
The University of Texas, MD Anderson Cancer Center
Utah Cancer Specialists
Utah Cancer Specialists
Huntsman Cancer Hospital
Huntsman Cancer Institute
Virginia Mason Medical Center
Seattle Cancer Care Alliance
HSHS St. Vincent Hospital Regional Cancer Center at HSHS St. Vincent Hospital
HSHS St. Vincent Hospital
HSHS St. Vincent Hospital Regional Cancer Center at HSHS St. Mary's Hospital Medical Center
Froedtert Hospital and the Medical College of Wisconsin
St George Hospital - Hematology Department
Eastern Clinical Research Unit, Level 2
UZ Ghent (University Hospital Ghent)
Department of Haematology at UZ Leuven (7 th Floor)
Hematology Department of CHU de Liège
Hematology Department CHR Verviers
Horizon Health Network - The Moncton Hospital
Juravinski Cancer Centre
Lakeridge Health
Princess Margaret Cancer Centre
Hopital Maisonneuve-Rosemont
Saskatoon Cancer Centre
CHU de Québec - Université Laval
Fakultní Nemocnice Brno
Fakultní Nemocnice Hradec Králové
Fakultní nemocnice Olomouc
Všeobecná fakultní Nemocnice v Praze
Aalborg University Hospital
Aarhus University Hospital
Roskilde Hospital
Helsinki University Central Hospital
Oncologie Centre de Radiotherapie
Institut Bergonié
private Practice of Pr Philippe Rousselot
private Practice of Dr. Viviane Dubruille
Hôpital L'Archet 1-CHU Nice
Institut de Cancérologie du Gard - Hématologie Clinique
Pr Mauricette Michallet Centre Hospitalier Lyon Sud
INSERM CIC 1402 - CHU Poitiers
Institut Universitaire du Cancer de Toulouse - Oncopole
Universitätsklinikum Bonn
Uniklinikum Aachen
Charité, CVK, Med. Klinik m.S Hämatologie und Onkologie
Universitätsklinikum Freiburg, Klinik für Innere Medizin I
Universitätsklinikum Hamburg-Eppendorf, Onkologisches Zentrum
Universitätsklinikum Jena, Klinik für Innere Medizin II
Schwerpunktpraxis für Hämatologie und Onkologie
Semmelweis Egyetem I. Belgyógyászat
Debreceni Egyetem Klinikai Központ, Belgyógyászati Inézet Hematológiai Tanszék
Petz Aladár Megyei OktatóKórház, II. Belgyógyászati Osztály és Haematológiai Részleg
Somogy Megyei Kaposi Mór Oktató Kórház
Szegedi Tudományegyetem, AOK, Szent-Györgyi Albert Klinikai Központ, II. sz.
Jász-Nagykun-Szolnok Megyei Hetényi, Géza Kórház-Rendelőintézet
Hematology Department, Rambam Medical Centre
Hematology Div. Davidoff Cancer Center, Rabin Medical Center
Azienda Ospedaliero-Universitaria "Policlinico - Vittorio Emanuele" - P.O. G. Rodolico
USC Ematologia, A. O. Papa Giovanni XXIII
Policlinico S. Orsola - Malpighi,
A.O. Brozu - P.O. Armando Businco
Azienda Ospedaliero Universitaria Careggi
IRCCS - AOU San Martino_IST, Ematologia 1
Istituto Scientifico San Raffaele
Unità di Ricerca Clinica, U.O. Ematologia Adulti
A.O.U. Policlinico Università degli Studi di Napoli "Federico II"
Dipartimento di ematologia
ASL Roma 2 - Ospedale Sant'Eugenio
Hallym University Sacred Heart Hospital
Dong A University Hospital
Keimyung University Dongsan Hospital
Chonbuk National University Hospital
Kangbuk Samsung Hospital
Seoul St. Mary's Hospital of the Catholic University of Korea
Hospital Angeles del Pedregal (S.A. de C.V.)
Monterrey International Research Center
VU University Medical Center
Klinische Farrnacologie en Apotheek
Haukeland University Hospital Department of Hematology
St. Olavs Hospital
Klinika Hematologii i Transplantologii Uniwersyteckie Centrum Kliniczne
SPZOZ ZSM w Chorzowie Oddzial Hematologiczny
Samodzielny Publiczny Szpital Kliniczny im. A Mielęckiego, ŚUM w Katowicach
Szpital Uniwersytecki w Krakowie, Oddział Kliniczny Hematologii
SPSK, Klinika Hematoonkologii i Transplantacji Szpiku w Lublinie
Universytet Medyczny im. Piastów Śląskich we Wrocławiu Katedra i
Wojewódzki Szpital Specjalistyczny im M. Kopernika, Klinika Hematologii Uniwersytetu Medycznego
National University Hospital, Main Building
Singapore General Hospital
Tan Tock Seng Hospital
Univerzitná Nemocnica Bratislava-Nemocnica sv. Cyrila a Metoda
The Medical Oncology Centre of Rosebank
Department of Medical Oncology, University of Pretoria and Steve Biko
Groenkloof Life hospital.
Department of Haematology
Hospital (Universitari(o)) Germans Trias i Pujol
Hospital Universitario La Princesa
Hospital Vall d'Hebron
Hospital Clínic
Hospital Universitario Gregorio Marañón
Hospital Ramón y Cajal
Hospital Clinico San Carlos
Hospital Universitario de Salamanca
Hospital Virgen de la Salud
Hospital Clínico Universitario de Valencia
Linköping University Hospital
Skåne University Hospital
Karolinska University Hospital Solna
Norrlands University Hospital
Akademiska Hospital
China Medical University Hospital
Chi-Mei Medical Center
Mackay Memorial Hospital
Kaohsiung Medical University Chung-Ho Memorial Hospital
Division of Hematology, Department of Internal Medicine, Maharaj Nakorn Chiang Mai Hospital
King Chulalongkorn Memorial Hospital
Phramongkutklao Hospital
Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital
MI "Cherkasy Regional Oncological Dispensary " of Cherkasy Regional Council
Regional Clinical Hospital in Ivano-Frankivsk, Hematology Department
Khmelnytskyi Regional Hospital, Hematology Department
State Institution "National research center for radiation medicine of NAMS of Ukraine",
State Institution "National research center for radiation medicine of NAMS of Ukraine"
transplantation department of hemotology and transplantology division within Clinical Radiology
Chair of internal medicine #2.
Kyiv City Clinical Hospital #9, Hematology department #1,
State Institution "Institute of Blood Pathology and Transfusion Medicine NAMS of Ukraine"
Catherine Lewis Centre, Hammersmith Hospital
Linda McCartney Centre
Department of Clinical Haematology
Cancer & Haematology Centre, Churchill Hospital
Department of Haematology The Royal Hallamshire Hospital
Heartlands Hospital
St James's Institute of Oncology
Department of Haematology
The Hope Clinical Trials Facility

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Bosutinib

Imatinib

Arm Description

Bosutinib, 400 mg, oral administration once a day

Imatinib, 400 mg, oral administration once a day

Outcomes

Primary Outcome Measures

Percentage of Participants With Major Molecular Response (MMR) at Month 12

MMR was defined as a ratio of breakpoint cluster region to abelson (BCR-ABL/ABL) less than or equal to (<=) 0.1 percent (%) on the international scale (IS) (greater than or equal to [>=] 3 log reduction from standardized baseline in ratio of BCR-ABL to ABL transcripts [>=3000 ABL required]) by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR). The percentage of participants with MMR at Month 12 are reported.

Secondary Outcome Measures

Percentage of Participants With Major Molecular Response (MMR) Up to Month 18

MMR was defined as a ratio of BCR-ABL/ABL <=0.1% on the international scale (>=3 log reduction from standardized baseline in ratio of BCR-ABL to ABL transcripts [>=3000 ABL required]) by quantitative RT-qPCR. The percentage of participants with MMR for up to Month 18 are reported.

Kaplan-Meier Estimate of Probability of Retaining Major Molecular Response (MMR) at Month 48

The Kaplan-Meier curve was generated based on the first date of MMR until the date of the confirmed loss of MMR or censoring, objectively documented, for responders only. Confirmed loss of MMR was BCR-ABL/ABL IS ratio >0.1% in association with a >=5-fold increase in BCR-ABL/ABL IS ratio from the lowest value achieved up to that time-point confirmed by a second assessment at least 28 days later. Treatment discontinuation due to suboptimal response/treatment failure, progressive disease (PD) or death due to PD within 28 days of last dose were considered confirmed loss of MMR. PD was defined as disease progression to accelerated phase (AP) or blast phase (BP) CML.

Percentage of Participants With Complete Cytogenetic Response (CCyR) Up to Month 12

Complete Cytogenetic Response (CCyR) was based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow (BM) aspirate. CCyR was achieved when there was 0% Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analyzed, or MMR if no BM was available. The percentage of participants with CCyR for up to Month 12 are reported.

Kaplan-Meier Estimate of Probability of Retaining Complete Cytogenetic Response (CCyR) at Month 48

The Kaplan-Meier curve was generated based on the first date of CCyR until the date of the confirmed loss of CCyR or censoring, objectively documented, for responders only. Confirmed loss of CCyR was the presence of at least one Ph+ metaphase confirmed by a second assessment at least 28 days later. Treatment discontinuation due to suboptimal response/treatment failure, PD or death due to PD within 28 days of last dose were considered confirmed loss of CCyR. PD was defined as disease progression to AP or BP CML.

Cumulative Incidence of Event Free Survival (EFS) Events

EFS was defined as time from randomization to death due to any cause, transformation to AP or BP at any time, confirmed loss of complete hematologic response (CHR), confirmed loss of CCyR or censoring. Loss of CHR was defined as a hematologic assessment of non-CHR (chronic phase, AP, or BP) confirmed by 2 assessments at least 4 weeks apart. Loss of CHR was defined as appearance of any of the following: WBC count that rises to >20.0*10^9/L, platelet count rises to >=600*10^9/L, appearance of palpable spleen or other extramedullary involvement proven by biopsy, appearance of 5% myelocytes in peripheral blood, appearance of blasts or promyelocytes in peripheral blood. Loss of CCyR was defined as at least 1 Ph+ metaphase from analysis of <100 metaphases confirmed by follow up cytogenetic analysis after 1 month. Cumulative incidence of EFS was defined as percentage of participants with EFS event at Month 60 and was adjusted for competing risk of treatment discontinuation without event.

Overall Survival (OS) Rate

OS was defined as the time (in months) from randomization to the occurrence of death due to any cause or censoring. Kaplan-meier analysis was used for determination of OS. Percentage of participants who were alive were estimated in this outcome measure.

Full Information

NCT ID

NCT02130557

First Posted

May 1, 2014

Last Updated

April 16, 2021

Sponsor

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT02130557

Brief Title

A Multicenter Phase 3, Open-Label Study of Bosutinib Versus Imatinib in Adult Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia

Official Title

A MULTICENTER PHASE 3 RANDOMIZED, OPEN-LABEL STUDY OF BOSUTINIB VERSUS IMATINIB IN ADULT PATIENTS WITH NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOGENOUS LEUKEMIA

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

July 15, 2014 (Actual)

Primary Completion Date

August 11, 2016 (Actual)

Study Completion Date

April 17, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pfizer

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Phase 3, 2-arm, randomized, open label trial. Patients will be randomized to receive bosutinib or imatinib for the duration of the study.

Detailed Description

The study will be open for enrollment until the planned number of approximately 500 Philadelphia Chromosome Positive (Ph+) patients have been randomized (approximately 250 Ph+ patients in each treatment arm; a total of approximately 530 Ph+ and Ph- patients). All patients will be treated and/or followed for approximately 5 years (240 weeks) after randomization until the study has closed. Patients who discontinue study therapy early due to disease progression or intolerance to study medication will continue to be followed yearly for survival for up to approximately 5 years (240 weeks) after randomization.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leukemia, Myelogenous, Chronic, Breakpoint Cluster Region-Abelson Proto-oncogene (BCR-ABL) Positive

Keywords

Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Bosutinib, Leukemia, Myeloid, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Philadelphia Chromosome, Neoplasms by Histologic Type, Bone Marrow Diseases, Hematologic Diseases, Translocation, Genetic, Pathologic Processes, Imatinib, Therapeutic Uses, Pharmacologic Actions, Molecular Mechanisms of Pharmacological Action

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Masking Description

NOTE: Value was Open Label in old format; This study has an open-label design. Although most efficacy studies have a double blind design, this is not feasible in this trial, due to the complexity of the dose reduction and dose escalation schemes with tablets of various sizes, dosage strengths, as well as the number of tablets that would be required daily. However, the opportunity for bias is mitigated by the use of objective outcome measures (MMR, CCyR, CHR). The Investigators will be instructed to ensure that laboratory/pathology personnel are blinded to treatment information. For these reasons, an open-label, randomized study is appropriate.

Allocation

Randomized

Enrollment

536 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bosutinib

Arm Type

Experimental

Arm Description

Bosutinib, 400 mg, oral administration once a day

Arm Title

Imatinib

Arm Type

Active Comparator

Arm Description

Imatinib, 400 mg, oral administration once a day

Intervention Type

Drug

Intervention Name(s)

Bosutinib

Intervention Description

Bosutinib (Bosulif®) is an orally bioavailable, potent, multi-targeted, dual Src-Abl tyrosine kinase inhibitor (TKI) that has been approved for the treatment of adult patients with Philadelphia positive (Ph+) chronic phase (CP), accelerated phase (AP) and blast phase (BP) chronic myelogenous leukemia (CML) previously treated with other TKI inhibitor therapy.[1] This study will investigate the use of bosutinib as first-line treatment for patients with Ph+ CP CML.

Intervention Type

Drug

Intervention Name(s)

Imatinib

Intervention Description

Imatinib mesylate (referred to in this protocol as imatinib) is an inhibitor of the BCR-ABL kinase and been the standard first-line therapy for patients with chronic-phase CML. Imatinib was granted approval by the European Commission in November 2001 and by the FDA in December 2002 for the treatment of newly diagnosed patients with CP Ph+ CML based on results from the IRIS trial. Imatinib is considered the standard of care for both first-line and later line settings, and consequently is an appropriate active comparator.

Primary Outcome Measure Information:

Title

Percentage of Participants With Major Molecular Response (MMR) at Month 12

Description

Time Frame

Month 12

Secondary Outcome Measure Information:

Title

Percentage of Participants With Major Molecular Response (MMR) Up to Month 18

Description

Time Frame

Up to Month 18

Title

Kaplan-Meier Estimate of Probability of Retaining Major Molecular Response (MMR) at Month 48

Description

Time Frame

Month 48

Title

Percentage of Participants With Complete Cytogenetic Response (CCyR) Up to Month 12

Description

Time Frame

Up to Month 12

Title

Kaplan-Meier Estimate of Probability of Retaining Complete Cytogenetic Response (CCyR) at Month 48

Description

Time Frame

Month 48

Title

Cumulative Incidence of Event Free Survival (EFS) Events

Description

Time Frame

Up to Month 60

Title

Overall Survival (OS) Rate

Description

Time Frame

Up to Month 60

Other Pre-specified Outcome Measures:

Title

Summary of Trough Plasma Concentration by Complete Cytogenetic Response (CCyR) of Bosutinib

Description

CCyR was based on the prevalence of Ph+ metaphases among cells in metaphase on a BM aspirate. CCyR was achieved when there was 0% Ph+ metaphases among cells in a BM sample when at least 20 metaphases from a BM sample were analyzed, or MMR if no BM was available. Trough plasma concentration of participants who had CCyR are presented in this outcome measure.

Time Frame

Pre-dose on Days 28, 56 and 84

Title

Summary of Trough Plasma Concentration by Major Molecular Response (MMR) of Bosutinib

Description

MMR was defined as a ratio of BCR-ABL/ABL <=0.1% on the international scale (>=3 log reduction from standardized baseline in ratio of BCR-ABL to ABL transcripts) by quantitative RT-qPCR. Trough plasma concentration of participants who had MMR are presented in this outcome measure.

Time Frame

Pre-dose on Days 28, 56 and 84

Title

Summary of Trough Plasma Concentration by Presence of Grade 1 or Higher Adverse Events (AEs) of Bosutinib

Description

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening or disabling; urgent intervention indicated; Grade 5= death. Trough plasma concentration of participants who had grade 1 or higher AE are presented in this outcome measure. Data of plasma concentration is reported separately for each preferred term of AE.

Time Frame

Pre-dose on Days 28, 56 and 84

Title

Summary of Trough Plasma Concentration by Presence of Grade 3 or Higher Adverse Events (AEs) of Bosutinib

Description

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on NCI CTCAE version 4.0. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening or disabling; urgent intervention indicated; Grade 5= death. Trough plasma concentration of participants who had grade 3 or higher AE are presented in this outcome measure. Data of plasma concentration is reported separately for each preferred term of AE.

Time Frame

Pre-dose on Days 28, 56 and 84

Title

Number of Participants With Vital Signs Abnormalities

Description

Criteria for vital signs abnormalities: systolic blood pressure <80 millimeter of mercury (mmHg), >210 mmHg; diastolic blood pressure <40 mmHg, >130 mmHg; heart rate <40 beats per minute (bpm), >150 bpm; temperature <32 degree celsius, >40 degree celsius; weight >=10% increase from baseline, >=10% decrease from baseline. The number of participants with any vital sign abnormalities during On-treatment period are reported. On-Treatment was defined as values collected after the date of the first dose of test article until the last date of test article +28 days.

Time Frame