Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/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)
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.
Secondary ID [1] 0 0
CSTI571K2301
Universal Trial Number (UTN)
Trial acronym
TOPS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Leukemia, Myeloid, Chronic Phase 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
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
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months
Timepoint [1] 0 0
12 months
Secondary outcome [1] 0 0
Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months
Timepoint [1] 0 0
24, 36 and 42 months
Secondary outcome [2] 0 0
Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months
Timepoint [2] 0 0
12, 24, 36, 42 months
Secondary outcome [3] 0 0
Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months
Timepoint [3] 0 0
12, 24, 36, and 42 months
Secondary outcome [4] 0 0
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
Timepoint [4] 0 0
12 , 24, 36 and 42 months
Secondary outcome [5] 0 0
Time to First Major Molecular Response
Timepoint [5] 0 0
42 months overall
Secondary outcome [6] 0 0
Time to First Complete Cytogenetic Response
Timepoint [6] 0 0
60 months overall
Secondary outcome [7] 0 0
Time to First Complete Hematological Response (CHR)]
Timepoint [7] 0 0
60 months overall
Secondary outcome [8] 0 0
Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms
Timepoint [8] 0 0
60 months over all
Secondary outcome [9] 0 0
Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms
Timepoint [9] 0 0
60 months over all and follow up period
Secondary outcome [10] 0 0
Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms
Timepoint [10] 0 0
60 months over all and follow up period
Secondary outcome [11] 0 0
Estimated Rate of Overall Survival (OS) in Two Treatment Arms
Timepoint [11] 0 0
60 months over all and follow up period
Secondary outcome [12] 0 0
Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss
Timepoint [12] 0 0
From First major molecular response to first confirmed loss or censoring
Secondary outcome [13] 0 0
Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR)
Timepoint [13] 0 0
From first complete cytogenetic response to first confirmed loss or censoring
Secondary outcome [14] 0 0
Mean Actual Dose Intensity Per Day
Timepoint [14] 0 0
start of treatment to Month 36
Secondary outcome [15] 0 0
Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12
Timepoint [15] 0 0
Month 12
Secondary outcome [16] 0 0
Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR)
Timepoint [16] 0 0
42 months
Secondary outcome [17] 0 0
Time to First Complete Molecular Response (CMR)]
Timepoint [17] 0 0
48 months overall
Secondary outcome [18] 0 0
Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes
Timepoint [18] 0 0
12 months

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
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/06/2005
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/11/2010
Sample size
Target
Accrual to date
Final
476
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - St. Leonards
Recruitment hospital [2] 0 0
Novartis Investigative Site - Waratah
Recruitment hospital [3] 0 0
Novartis Investigative Site - Westmead
Recruitment hospital [4] 0 0
Novartis Investigative Site - Herston
Recruitment hospital [5] 0 0
Novartis Investigative Site - Woolloongabba
Recruitment hospital [6] 0 0
Novartis Investigative Site - Adelaide
Recruitment hospital [7] 0 0
Novartis Investigative Site - East Melbourne
Recruitment hospital [8] 0 0
Novartis Investigative Site - Fitzroy
Recruitment hospital [9] 0 0
Novartis Investigative Site - Frankston
Recruitment hospital [10] 0 0
Novartis Investigative Site - Parkville
Recruitment hospital [11] 0 0
Novartis Investigative Site - Prahran
Recruitment hospital [12] 0 0
Novartis Investigative Site - South Brisbane
Recruitment postcode(s) [1] 0 0
- St. Leonards
Recruitment postcode(s) [2] 0 0
- Waratah
Recruitment postcode(s) [3] 0 0
- Westmead
Recruitment postcode(s) [4] 0 0
- Herston
Recruitment postcode(s) [5] 0 0
- Woolloongabba
Recruitment postcode(s) [6] 0 0
- Adelaide
Recruitment postcode(s) [7] 0 0
- East Melbourne
Recruitment postcode(s) [8] 0 0
- Fitzroy
Recruitment postcode(s) [9] 0 0
- Frankston
Recruitment postcode(s) [10] 0 0
- Parkville
Recruitment postcode(s) [11] 0 0
- Prahran
Recruitment postcode(s) [12] 0 0
- South Brisbane
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Hawaii
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Indiana
Country [8] 0 0
United States of America
State/province [8] 0 0
Iowa
Country [9] 0 0
United States of America
State/province [9] 0 0
Kentucky
Country [10] 0 0
United States of America
State/province [10] 0 0
Louisiana
Country [11] 0 0
United States of America
State/province [11] 0 0
Maryland
Country [12] 0 0
United States of America
State/province [12] 0 0
Michigan
Country [13] 0 0
United States of America
State/province [13] 0 0
Minnesota
Country [14] 0 0
United States of America
State/province [14] 0 0
New Jersey
Country [15] 0 0
United States of America
State/province [15] 0 0
New Mexico
Country [16] 0 0
United States of America
State/province [16] 0 0
New York
Country [17] 0 0
United States of America
State/province [17] 0 0
North Carolina
Country [18] 0 0
United States of America
State/province [18] 0 0
Ohio
Country [19] 0 0
United States of America
State/province [19] 0 0
Oregon
Country [20] 0 0
United States of America
State/province [20] 0 0
Pennsylvania
Country [21] 0 0
United States of America
State/province [21] 0 0
South Carolina
Country [22] 0 0
United States of America
State/province [22] 0 0
Tennessee
Country [23] 0 0
United States of America
State/province [23] 0 0
Texas
Country [24] 0 0
United States of America
State/province [24] 0 0
Virginia
Country [25] 0 0
Argentina
State/province [25] 0 0
Buenos Aires
Country [26] 0 0
Argentina
State/province [26] 0 0
La Plata
Country [27] 0 0
Brazil
State/province [27] 0 0
Campinas
Country [28] 0 0
Canada
State/province [28] 0 0
Calgary
Country [29] 0 0
Canada
State/province [29] 0 0
Montreal
Country [30] 0 0
Canada
State/province [30] 0 0
Ottawa
Country [31] 0 0
Canada
State/province [31] 0 0
Quebec
Country [32] 0 0
Italy
State/province [32] 0 0
Bologna
Country [33] 0 0
Italy
State/province [33] 0 0
Firenze
Country [34] 0 0
Italy
State/province [34] 0 0
Milano
Country [35] 0 0
Italy
State/province [35] 0 0
Napoli
Country [36] 0 0
Italy
State/province [36] 0 0
Orbassano
Country [37] 0 0
Italy
State/province [37] 0 0
Roma

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

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.
Trial website
https://clinicaltrials.gov/study/NCT00124748
Trial related presentations / 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.
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT00124748