Efficacy of 400 Mg Versus 800 Mg Imatinib in Chronic Myeloid Leukemia in Chronic Phase Patients - TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) (TOPS)

A Randomized Open-label Study of 400 mg Versus 800 mg of Imatinib Mesylate in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Using Molecular Endpoints.

This study investigated the safety and efficacy of 400mg Versus 800mg imatinib in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) using molecular endpoints.

Study Overview

• Status: Terminated
• Conditions: Leukemia, Myeloid, Chronic Phase
• Intervention / Treatment: Drug: Imatinib mesylate

• Study Type: Interventional
• Enrollment (Actual): 476
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Novartis Investigative Site
  • La Plata, Argentina
    • Novartis Investigative Site
• Australia
  • South Brisbane, Australia
    • Novartis Investigative Site
  • New South Wales
    • St. Leonards, New South Wales, Australia
      • Novartis Investigative Site
    • Waratah, New South Wales, Australia
      • Novartis Investigative Site
    • Westmead, New South Wales, Australia
      • Novartis Investigative Site
  • Queensland
    • Herston, Queensland, Australia
      • Novartis Investigative Site
    • Woolloongabba, Queensland, Australia
      • Novartis Investigative Site
  • South Australia
    • Adelaide, South Australia, Australia
      • Novartis Investigative Site
  • Victoria
    • East Melbourne, Victoria, Australia
      • Novartis Investigative Site
    • Fitzroy, Victoria, Australia
      • Novartis Investigative Site
    • Frankston, Victoria, Australia
      • Novartis Investigative Site
    • Parkville, Victoria, Australia
      • Novartis Investigative Site
    • Prahran, Victoria, Australia
      • Novartis Investigative Site
• Brazil
  • Campinas, Brazil
    • Novartis Investigative Site
• Canada
  • Calgary, Canada
    • Novartis Investigative Site
  • Montreal, Canada
    • Novartis Investigative Site
  • Ottawa, Canada
    • Novartis Investigative Site
  • Quebec, Canada
    • Novartis Investigative Site
• Italy
  • Bologna, Italy
    • Novartis Investigative Site
  • Firenze, Italy
    • Novartis Investigative Site
  • Milano, Italy
    • Novartis Investigative Site
  • Napoli, Italy
    • Novartis Investigative Site
  • Orbassano, Italy
    • Novartis Investigative Site
  • Roma, Italy
    • Novartis Investigative Site
• United States
  • Alabama
    • Mobile, Alabama, United States, 36693
      • University of South Alabama
  • California
    • Berkeley, California, United States, 94704
      • Alta Bates Comprehsenive Cancer Center
    • Berkeley, California, United States, 94704
      • University of Miami
    • Campbell, California, United States, 95008
      • South Bay Oncology Hematology Partners
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Center
  • Florida
    • Melbourne, Florida, United States, 32901
      • Osler Medical Inc.
    • Miami, Florida, United States, 33176
      • Advanced Medical Specialists
    • Orange Park, Florida, United States, 32073
      • Integrated Community Oncology Network
    • Pensacola, Florida, United States, 32501
      • Hematology-Oncology Associates, P.A.
    • West Palm Beach, Florida, United States, 33401
      • Palm Beach Cancer Institute
    • West Palm Beach, Florida, United States, 233401
      • Palm Beach Cancer Institute
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Cancer Research Center of Hawaii
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • Indiana Blood and Marrow Transplant
    • Beech Grove, Indiana, United States, 46107
      • Indiana Blood and Marrow Institutw
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinic
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky - C201 Clinic
    • Louisville, Kentucky, United States, 40202
      • Lousville Oncology, Clinical Research Program M-25
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • Jayne S. Gurtler, MD, Laura A. Brinz, MD & Angelo Russo, MD
    • New Orleans, Louisiana, United States, 70115
      • Hematology and Oncology Specialists
    • Shreveport, Louisiana, United States, 71103
      • LSU Health Science Center
    • Shreveport, Louisiana, United States, 71130
      • LSU Health Scine Center
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • St. Agnes Hospital
  • Michigan
    • Lansing, Michigan, United States, 48910
      • Great Lakes Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • U of Minnesota
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • Hackensack, New Jersey, United States, 07601
      • Cancer Center at Hackensack University Medical Center
  • New Mexico
    • Farmington, New Mexico, United States, 87401
      • San Juan Oncology Associates
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Greenville, North Carolina, United States, 29615
      • Cancer Center Of The Carolinas
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • University Hospitals of Cleveland, Case Comprehensive Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97227
      • Kaiser Permanente Northwest Region
    • Portland, Oregon, United States, 97227
      • Kaiser Permanente Northwest Region Oncology/Hemacology
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Western Pennsylvania Hospital
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburg, Hillman Cancer Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • MUSC Hollings Cancer Center
    • Greenville, South Carolina, United States, 29615
      • Cancer Centers of the Carolinas
    • Greenville, South Carolina, United States, 29615
      • Cancer Center Of The Carolinas
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • The Jones Clinic
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Harold C. Simmons Comprehensive Cancer Center
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
    • Houston, Texas, United States, 77030-4009
      • University of Texas / MD Anderson Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virgina Cancer Center, UVA Division of Hematology & Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients within 6 months of diagnosis (date of initial diagnosis is the date of first cytogenetic analysis)
• Diagnosis of chronic myelogenous leukemia (CML) in chronic phase with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations and presence of Breakpoint cluster region gene-abelson proto-oncogene (Bcr-Abl)
• Documented chronic phase CML

• Adequate end organ function as defined by:

  • total bilirubin < 1.5 x Upper Limit of Normal (ULN)
  • Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) < 2.5 x ULN
  • creatinine < 1.5 x ULN

Exclusion Criteria:

• Patients in late chronic phase, accelerated phase, or blastic phase are excluded
• Patients who have received other investigational agents
• Patients who received Gleevec/Glivec for any duration prior to study entry, with the exception of those patients successfully completing [CSTI571A2107 (NCT00428909)] study immediately prior to the participation in this study
• Patient received any treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide
• Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention
• Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) male or female of childbearing potential unwilling to use barrier contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential).
• Patient with a severe or uncontrolled medical condition (i.e., uncontrolled diabetes,chronic renal disease)
• Patient previously received radiotherapy to ≥ 25% of the bone marrow
• Patient had major surgery within 4 weeks prior to study entry, or who have not recovered from prior major surgery
• Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status Score ≥ 3
• Patients with International normalized ratio (INR) or partial thromboplastin time (PTT) > 1.5 x ULN, with the exception of patients on treatment with oral anticoagulants
• Patients with known positivity for human immunodeficiency virus (HIV); baseline testing for HIV is not required
• Patients with identified sibling donors where allogeneic bone marrow transplant is elected as first line treatment

Other protocol-defined inclusion/exclusion criteria applied.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Imatinib 400 mg; Oral dose of 400mg Imatinib once daily. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol.	Drug: Imatinib mesylate; Imatinib is packaged in bottles as 100mg and 400mg tablets; Other Names: Gleevec; Glivec; STI571
Experimental: imatinib 800 mg; Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol.	Drug: Imatinib mesylate; Imatinib is packaged in bottles as 100mg and 400mg tablets; Other Names: Gleevec; Glivec; STI571

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months	MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally).	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months	MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally).	24, 36 and 42 months
Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months	Cytogenetic response (CyR)is the percentage of Philadelphia chromosome positive metaphases (among at least 20 metaphase cells in bone marrow (BM)) with Complete Cytogenetic Response (CCyR) being 0 percent.	12, 24, 36, 42 months
Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months	Complete Hematologic Response (CHR) is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) < 5% in PB and No evidence of extramedullary involvement.	12, 24, 36, and 42 months
Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts	"Undetectable levels" or Complete molecular response is defined as Bcr-Abl ratio (%) on international scale (IS) <= 0.0032% (≥ 4.5 log reduction of BCR-Abl transcripts from a standardized baseline).	12 , 24, 36 and 42 months
Time to First Major Molecular Response	MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region [Bcr] gene and Abelson proto-oncogene [Abl] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction [RT-PCR] (performed centrally). Time to MMR (months) = (date of first MMR or censoring - date of randomization + 1) / 30.4375. Time to first MMR was evaluated using the Kaplan-Meier method	42 months overall
Time to First Complete Cytogenetic Response	Cytogenetic response (CyR) is the percentage of Philadelphia positive metaphases (among at least 20 metaphase cells in Bone Marrow) with Complete Cytogenetic Response (CCyR) being 0 percent. Time to CCyR (months) = (date of first CCyR or censoring - date of randomization + 1) / 30.4375. Time to first CCyR was evaluated using the Kaplan-Meier method.	60 months overall
Time to First Complete Hematological Response (CHR)]	Complete Hematological Response (CHR) is defined is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) < 5% in PB and No evidence of extramedullary involvement. Time to CHR (months) = (date of first CHR or censoring - date of randomization + 1) / 30.4375. Time to first CHR was evaluated using the Kaplan-Meier method.	60 months overall
Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms	EFS on treatment was defined as time between randomization and either (1) death due to any cause during study treatment, (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment, (3) loss of complete hematological response (CHR), or (4) loss of major cytogenic response (MCyR) while on treatment. Estimated rate of EFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).	60 months over all
Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms	PFS on study which was defined as time between randomization and either (1) death due to any cause on treatment of during follow-up after discontinuation of treatment or (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment during follow-up after discontinuation of study treatment. Estimated rate of PFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).	60 months over all and follow up period
Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms	(Accelerated Phase/Blast Crisis) AP/BC was defined as time between randomization and either (1) (Chronic Myeloid Leukemia) CML-related death (if death was primary reason for discontinuation) or (2) progression to AP or BC (during treatment). Estimated rate of AC/BC was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).	60 months over all and follow up period
Estimated Rate of Overall Survival (OS) in Two Treatment Arms	OS was defined as time between randomization and death due to any cause during study treatment or during follow-up after discontinuation of treatment. Estimated rate of OS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).	60 months over all and follow up period
Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss	Duration of MMR (months) = (date of first confirmed loss or censoring - date of MMR + 1 ) / 30.4375. Estimated rate of duration of first MMR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).	From First major molecular response to first confirmed loss or censoring
Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR)	Duration of CCyR was defined as the time between date of CCyR and the earliest of either (1) loss of CCyR OR (2) (Chronic Myeloid Leukemia) CML-related death or progression to (Accelerated Phase/Blast Crisis) AP/BC during study treatment. Estimated rate of duration of first CCyR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).	From first complete cytogenetic response to first confirmed loss or censoring
Mean Actual Dose Intensity Per Day	The mean actual dose intensity per day from start of treatment up to last dose or discontinuation was evaluated up to Month 36. Actual dose intensity (mg/day) = total dose/time on treatment (periods of zero dose are included)	start of treatment to Month 36
Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12	Imatinib PK trough plasma concentration (Cmin) was defined as any pre-dose Imatinib plasma concentration	Month 12
Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR)	A Landmark Kaplan-Meier analysis was performed for PFS at 42 months by MMR status at 6, 12, and 18 months to investigate their prognostic value.	42 months
Time to First Complete Molecular Response (CMR)]	Complete Molecular Response is defined as a Bcr-Abl (a fusion of gene of Bcr and ABl genes) ratio ≤0.0032% on the International Scale Bcr = breakpoint cluster gene Abl = abelson proto-oncogene.	48 months overall
Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes		12 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Branford S, Yeung DT, Parker WT, Roberts ND, Purins L, Braley JA, Altamura HK, Yeoman AL, Georgievski J, Jamison BA, Phillis S, Donaldson Z, Leong M, Fletcher L, Seymour JF, Grigg AP, Ross DM, Hughes TP. Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood. 2014 Jul 24;124(4):511-8. doi: 10.1182/blood-2014-03-566323. Epub 2014 May 23.
• Branford S, Yeung DT, Ross DM, Prime JA, Field CR, Altamura HK, Yeoman AL, Georgievski J, Jamison BA, Phillis S, Sullivan B, Briggs NE, Hertzberg M, Seymour JF, Reynolds J, Hughes TP. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood. 2013 May 9;121(19):3818-24. doi: 10.1182/blood-2012-10-462291. Epub 2013 Mar 20.
• Guilhot F, Hughes TP, Cortes J, Druker BJ, Baccarani M, Gathmann I, Hayes M, Granvil C, Wang Y. Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial. Haematologica. 2012 May;97(5):731-8. doi: 10.3324/haematol.2011.045666. Epub 2012 Feb 7.

Helpful Links

• Visit NovartisClinicalTrials.com: Pre-qualify for a trial, and view a list of trials and participating study centers.

Study record dates

Study Major Dates

• Study Start: June 1, 2005
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): November 1, 2010

Study Registration Dates

• First Submitted: July 27, 2005
• First Submitted That Met QC Criteria: July 27, 2005
• First Posted (Estimate): July 28, 2005

Study Record Updates

• Last Update Posted (Estimate): February 3, 2012
• Last Update Submitted That Met QC Criteria: January 5, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: imatinib mesylate; CML; Philadelphia positive; Bcr-abl; Chronic myeloid leukemia (CML) in chronic phase
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: CSTI571K2301