Clinical trial NCT00124748: Efficacy of 400 Mg Versus 800 Mg Imatinib in Chronic Myeloid Leukemia in Chronic Phase Patients - TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity)
Official 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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Leukemia, Myeloid, Chronic Phase
Keywords: CML
Philadelphia positive
Bcr-abl
imatinib mesylate
Chronic myeloid leukemia (CML) in chronic phase
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2005-07-28
Enrollment: 476
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months
timeFrame: 12 months
Secondary outcomes:
measure: Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months
timeFrame: 24, 36 and 42 months
measure: Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months
timeFrame: 12, 24, 36, 42 months
measure: Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months
timeFrame: 12, 24, 36, and 42 months
measure: 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
timeFrame: 12 , 24, 36 and 42 months
measure: Time to First Major Molecular Response
timeFrame: 42 months overall
measure: Time to First Complete Cytogenetic Response
timeFrame: 60 months overall
measure: Time to First Complete Hematological Response (CHR)]
timeFrame: 60 months overall
measure: Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms
timeFrame: 60 months over all
measure: Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms
timeFrame: 60 months over all and follow up period
measure: Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms
timeFrame: 60 months over all and follow up period
measure: Estimated Rate of Overall Survival (OS) in Two Treatment Arms
timeFrame: 60 months over all and follow up period
measure: Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss
timeFrame: From First major molecular response to first confirmed loss or censoring
measure: Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR)
timeFrame: From first complete cytogenetic response to first confirmed loss or censoring
measure: Mean Actual Dose Intensity Per Day
timeFrame: start of treatment to Month 36
measure: Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12
timeFrame: Month 12
measure: Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR)
timeFrame: 42 months
measure: Time to First Complete Molecular Response (CMR)]
timeFrame: 48 months overall
measure: Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes
timeFrame: 12 months
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama
state: Alabama
city: Berkeley
country: United States
facility: Alta Bates Comprehsenive Cancer Center
state: California
city: Berkeley
country: United States
facility: University of Miami
state: California
city: Campbell
country: United States
facility: South Bay Oncology Hematology Partners
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Center
state: Colorado
city: Melbourne
country: United States
facility: Osler Medical Inc.
state: Florida
city: Miami
country: United States
facility: Advanced Medical Specialists
state: Florida
city: Orange Park
country: United States
facility: Integrated Community Oncology Network
state: Florida
city: Pensacola
country: United States
facility: Hematology-Oncology Associates, P.A.
state: Florida
city: West Palm Beach
country: United States
facility: Palm Beach Cancer Institute
state: Florida
city: West Palm Beach
country: United States
facility: Palm Beach Cancer Institute
state: Florida
city: Honolulu
country: United States
facility: Cancer Research Center of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Beech Grove
country: United States
facility: Indiana Blood and Marrow Institutw
state: Indiana
city: Beech Grove
country: United States
facility: Indiana Blood and Marrow Transplant
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinic
state: Iowa
city: Lexington
country: United States
facility: University of Kentucky - C201 Clinic
state: Kentucky
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Louisville
country: United States
facility: Lousville Oncology, Clinical Research Program M-25
state: Kentucky
city: Metairie
country: United States
facility: Jayne S. Gurtler, MD, Laura A. Brinz, MD & Angelo Russo, MD
state: Louisiana
city: New Orleans
country: United States
facility: Hematology and Oncology Specialists
state: Louisiana
city: Shreveport
country: United States
facility: LSU Health Science Center
state: Louisiana
city: Shreveport
country: United States
facility: LSU Health Scine Center
state: Louisiana
city: Baltimore
country: United States
facility: St. Agnes Hospital
state: Maryland
city: Lansing
country: United States
facility: Great Lakes Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: U of Minnesota
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Hackensack
country: United States
facility: Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Farmington
country: United States
facility: San Juan Oncology Associates
state: New Mexico
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greenville
country: United States
facility: Cancer Center of the Carolinas
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals of Cleveland, Case Comprehensive Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Kaiser Permanente Northwest Region Oncology/Hemacology
state: Oregon
city: Portland
country: United States
facility: Kaiser Permanente Northwest Region
state: Oregon
city: Pittsburgh
country: United States
facility: Western Pennsylvania Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburg, Hillman Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: MUSC Hollings Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: Cancer Center of the Carolinas
state: South Carolina
city: Greenville
country: United States
facility: Cancer Centers of the Carolinas
state: South Carolina
city: Germantown
country: United States
facility: The Jones Clinic
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Harold C. Simmons Comprehensive Cancer Center
state: Texas
city: Houston
country: United States
facility: University of Texas / MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virgina Cancer Center, UVA Division of Hematology & Oncology
state: Virginia
city: Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: La Plata
country: Argentina
facility: Novartis Investigative Site
city: St. Leonards
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Waratah
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Herston
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Woolloongabba
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: East Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Fitzroy
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Frankston
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Prahran
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: South Brisbane
country: Australia
facility: Novartis Investigative Site
city: Campinas
country: Brazil
facility: Novartis Investigative Site
city: Calgary
country: Canada
facility: Novartis Investigative Site
city: Montreal
country: Canada
facility: Novartis Investigative Site
city: Ottawa
country: Canada
facility: Novartis Investigative Site
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
city: Firenze
country: Italy
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Orbassano
country: Italy
facility: Novartis Investigative Site
city: Roma
country: Italy
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.