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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT00124748
Registration number
NCT00124748
Ethics application status
Date submitted
27/07/2005
Date registered
28/07/2005
Date last updated
3/02/2012
Titles & IDs
Public title
Efficacy of 400 Mg Versus 800 Mg Imatinib in Chronic Myeloid Leukemia in Chronic Phase Patients - TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity)
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Scientific title
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.
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Secondary ID [1]
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CSTI571K2301
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Universal Trial Number (UTN)
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Trial acronym
TOPS
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Leukemia, Myeloid, Chronic Phase
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Imatinib mesylate
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.
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.
Treatment: Drugs: Imatinib mesylate
Imatinib is packaged in bottles as 100mg and 400mg tablets
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months
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Assessment method [1]
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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).
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Timepoint [1]
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12 months
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Secondary outcome [1]
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Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months
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Assessment method [1]
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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).
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Timepoint [1]
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24, 36 and 42 months
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Secondary outcome [2]
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Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months
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Assessment method [2]
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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.
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Timepoint [2]
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12, 24, 36, 42 months
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Secondary outcome [3]
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Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months
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Assessment method [3]
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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.
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Timepoint [3]
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12, 24, 36, and 42 months
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Secondary outcome [4]
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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
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Assessment method [4]
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"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).
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Timepoint [4]
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12 , 24, 36 and 42 months
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Secondary outcome [5]
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Time to First Major Molecular Response
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Assessment method [5]
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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
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Timepoint [5]
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42 months overall
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Secondary outcome [6]
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Time to First Complete Cytogenetic Response
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Assessment method [6]
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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.
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Timepoint [6]
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60 months overall
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Secondary outcome [7]
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Time to First Complete Hematological Response (CHR)]
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Assessment method [7]
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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.
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Timepoint [7]
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60 months overall
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Secondary outcome [8]
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Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms
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Assessment method [8]
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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).
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Timepoint [8]
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60 months over all
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Secondary outcome [9]
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Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms
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Assessment method [9]
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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).
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Timepoint [9]
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60 months over all and follow up period
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Secondary outcome [10]
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Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms
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Assessment method [10]
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(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).
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Timepoint [10]
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60 months over all and follow up period
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Secondary outcome [11]
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Estimated Rate of Overall Survival (OS) in Two Treatment Arms
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Assessment method [11]
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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).
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Timepoint [11]
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60 months over all and follow up period
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Secondary outcome [12]
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Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss
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Assessment method [12]
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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).
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Timepoint [12]
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From First major molecular response to first confirmed loss or censoring
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Secondary outcome [13]
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Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR)
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Assessment method [13]
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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).
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Timepoint [13]
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From first complete cytogenetic response to first confirmed loss or censoring
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Secondary outcome [14]
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Mean Actual Dose Intensity Per Day
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Assessment method [14]
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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)
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Timepoint [14]
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start of treatment to Month 36
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Secondary outcome [15]
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Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12
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Assessment method [15]
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Imatinib PK trough plasma concentration (Cmin) was defined as any pre-dose Imatinib plasma concentration
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Timepoint [15]
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Month 12
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Secondary outcome [16]
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Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR)
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Assessment method [16]
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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.
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Timepoint [16]
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42 months
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Secondary outcome [17]
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Time to First Complete Molecular Response (CMR)]
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Assessment method [17]
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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.
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Timepoint [17]
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48 months overall
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Secondary outcome [18]
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Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes
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Assessment method [18]
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Timepoint [18]
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12 months
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Eligibility
Key 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
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Minimum age
18
Years
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Maximum age
75
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Terminated
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
1/06/2005
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
1/11/2010
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Sample size
Target
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Accrual to date
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Final
476
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
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Recruitment hospital [1]
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Novartis Investigative Site - St. Leonards
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Recruitment hospital [2]
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Novartis Investigative Site - Waratah
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Recruitment hospital [3]
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Novartis Investigative Site - Westmead
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Recruitment hospital [4]
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Novartis Investigative Site - Herston
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Recruitment hospital [5]
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Novartis Investigative Site - Woolloongabba
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Recruitment hospital [6]
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Novartis Investigative Site - Adelaide
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Recruitment hospital [7]
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Novartis Investigative Site - East Melbourne
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Recruitment hospital [8]
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Novartis Investigative Site - Fitzroy
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Recruitment hospital [9]
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Novartis Investigative Site - Frankston
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Recruitment hospital [10]
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Novartis Investigative Site - Parkville
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Recruitment hospital [11]
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Novartis Investigative Site - Prahran
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Recruitment hospital [12]
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Novartis Investigative Site - South Brisbane
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Recruitment postcode(s) [1]
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- St. Leonards
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Recruitment postcode(s) [2]
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- Waratah
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Recruitment postcode(s) [3]
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- Westmead
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Recruitment postcode(s) [4]
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- Herston
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Recruitment postcode(s) [5]
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- Woolloongabba
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Recruitment postcode(s) [6]
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- Adelaide
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Recruitment postcode(s) [7]
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- East Melbourne
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Recruitment postcode(s) [8]
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- Fitzroy
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Recruitment postcode(s) [9]
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- Frankston
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Recruitment postcode(s) [10]
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- Parkville
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Recruitment postcode(s) [11]
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- Prahran
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Recruitment postcode(s) [12]
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- South Brisbane
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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Alabama
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United States of America
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State/province [2]
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California
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United States of America
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State/province [3]
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Colorado
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United States of America
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State/province [4]
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Florida
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United States of America
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State/province [5]
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Hawaii
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0
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United States of America
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State/province [6]
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Illinois
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United States of America
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Indiana
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United States of America
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Iowa
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United States of America
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State/province [9]
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Kentucky
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United States of America
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State/province [10]
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Louisiana
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United States of America
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State/province [11]
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Maryland
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United States of America
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Michigan
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Minnesota
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United States of America
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New Jersey
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United States of America
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State/province [15]
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New Mexico
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United States of America
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New York
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United States of America
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North Carolina
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Ohio
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United States of America
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Oregon
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Pennsylvania
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South Carolina
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Tennessee
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Texas
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Virginia
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Argentina
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State/province [25]
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Buenos Aires
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Argentina
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State/province [26]
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La Plata
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Brazil
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State/province [27]
0
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Campinas
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0
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Canada
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Calgary
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0
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Canada
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Montreal
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0
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Canada
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Ottawa
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Canada
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Quebec
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Italy
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State/province [32]
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Bologna
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Italy
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State/province [33]
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Firenze
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0
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Italy
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Milano
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Italy
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Napoli
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Italy
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State/province [36]
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Orbassano
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Italy
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State/province [37]
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Roma
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Novartis Pharmaceuticals
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT00124748
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Novartis Pharmaceuticals
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Address
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Novartis Pharmaceuticals
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT00124748
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