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

NCT00124748 | Terminated Phase 3 Results

• 1 other identifier: CSTI571K2301
• Study Type: interventional
• Target: 476
• Locations: 6 countries
• Sites: 75

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.

Conditions

Leukemia, Myeloid, Chronic Phase

Keywords

CML; Philadelphia positive; Bcr-abl; imatinib mesylate; Chronic myeloid leukemia (CML) in chronic phase

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (18)

• Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months

  24, 36 and 42 months

• Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months

  12, 24, 36, 42 months

• Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months

  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

  12 , 24, 36 and 42 months

• Time to First Major Molecular Response

  42 months overall

Study Arms (2)

Imatinib 400 mg

EXPERIMENTAL

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 800 mg

EXPERIMENTAL

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

Interventions

Imatinib mesylate DRUG

Imatinib is packaged in bottles as 100mg and 400mg tablets

Also known as: STI571, Gleevec, Glivec

Imatinib 400 mg; imatinib 800 mg

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (75)

University of South Alabama

Mobile, Alabama, 36693, United States

Location

Alta Bates Comprehsenive Cancer Center

Berkeley, California, 94704, United States

Location

University of Miami

Berkeley, California, 94704, United States

Location

South Bay Oncology Hematology Partners

Campbell, California, 95008, United States

Location

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Rocky Mountain Cancer Center

Denver, Colorado, 80218, United States

Location

Osler Medical Inc.

Melbourne, Florida, 32901, United States

Location

Advanced Medical Specialists

Miami, Florida, 33176, United States

Location

Integrated Community Oncology Network

Orange Park, Florida, 32073, United States

Location

Hematology-Oncology Associates, P.A.

Pensacola, Florida, 32501, United States

Location

Palm Beach Cancer Institute

West Palm Beach, Florida, 233401, United States

Location

Palm Beach Cancer Institute

West Palm Beach, Florida, 33401, United States

Location

Cancer Research Center of Hawaii

Honolulu, Hawaii, 96813, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Indiana Blood and Marrow Institutw

Beech Grove, Indiana, 46107, United States

Location

Indiana Blood and Marrow Transplant

Beech Grove, Indiana, 46107, United States

Location

University of Iowa Hospitals & Clinic

Iowa City, Iowa, 52242, United States

Location

University of Kentucky - C201 Clinic

Lexington, Kentucky, 40536, United States

Location

University of Kentucky

Lexington, Kentucky, 40536, United States

Location

Lousville Oncology, Clinical Research Program M-25

Louisville, Kentucky, 40202, United States

Location

Jayne S. Gurtler, MD, Laura A. Brinz, MD & Angelo Russo, MD

Metairie, Louisiana, 70006, United States

Location

Hematology and Oncology Specialists

New Orleans, Louisiana, 70115, United States

Location

LSU Health Science Center

Shreveport, Louisiana, 71103, United States

Location

LSU Health Scine Center

Shreveport, Louisiana, 71130, United States

Location

St. Agnes Hospital

Baltimore, Maryland, 21229, United States

Location

Great Lakes Cancer Institute

Lansing, Michigan, 48910, United States

Location

U of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

San Juan Oncology Associates

Farmington, New Mexico, 87401, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Cancer Center of the Carolinas

Greenville, North Carolina, 29615, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

University Hospitals of Cleveland, Case Comprehensive Cancer Center

Cleveland, Ohio, 44106, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Kaiser Permanente Northwest Region Oncology/Hemacology

Portland, Oregon, 97227, United States

Location

Kaiser Permanente Northwest Region

Portland, Oregon, 97227, United States

Location

Western Pennsylvania Hospital

Pittsburgh, Pennsylvania, 15224, United States

Location

University of Pittsburg, Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MUSC Hollings Cancer Center

Charleston, South Carolina, 29425, United States

Location

Cancer Center of the Carolinas

Greenville, South Carolina, 29615, United States

Location

Cancer Centers of the Carolinas

Greenville, South Carolina, 29615, United States

Location

The Jones Clinic

Germantown, Tennessee, 38138, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

UT Southwestern Harold C. Simmons Comprehensive Cancer Center

Dallas, Texas, 75390, United States

Location

University of Texas / MD Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Virgina Cancer Center, UVA Division of Hematology & Oncology

Charlottesville, Virginia, 22908, United States

Location

Novartis Investigative Site

Buenos Aires, Argentina

Location

Novartis Investigative Site

La Plata, Argentina

Location

Novartis Investigative Site

St Leonards, New South Wales, Australia

Location

Novartis Investigative Site

Waratah, New South Wales, Australia

Location

Novartis Investigative Site

Westmead, New South Wales, Australia

Location

Novartis Investigative Site

Herston, Queensland, Australia

Location

Novartis Investigative Site

Woolloongabba, Queensland, Australia

Location

Novartis Investigative Site

Adelaide, South Australia, Australia

Location

Novartis Investigative Site

East Melbourne, Victoria, Australia

Location

Novartis Investigative Site

Fitzroy, Victoria, Australia

Location

Novartis Investigative Site

Frankston, Victoria, Australia

Location

Novartis Investigative Site

Parkville, Victoria, Australia

Location

Novartis Investigative Site

Prahran, Victoria, Australia

Location

Novartis Investigative Site

South Brisbane, Australia

Location

Novartis Investigative Site

Campinas, Brazil

Location

Novartis Investigative Site

Calgary, Canada

Location

Novartis Investigative Site

Montreal, Canada

Location

Novartis Investigative Site

Ottawa, Canada

Location

Novartis Investigative Site

Québec, Canada

Location

Novartis Investigative Site

Bologna, Italy

Location

Novartis Investigative Site

Florence, Italy

Location

Novartis Investigative Site

Milan, Italy

Location

Novartis Investigative Site

Napoli, Italy

Location

Novartis Investigative Site

Orbassano, Italy

Location

Novartis Investigative Site

Roma, Italy

Location

Related Publications (3)

• 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.

  PMID: 24859364 DERIVED

• 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.

  PMID: 23515925 DERIVED

• 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.

  PMID: 22315495 DERIVED

Related Links

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

MeSH Terms

Conditions

Leukemia, Myeloid, Chronic-Phase; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Interventions

Imatinib Mesylate

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2005
• First Posted: July 28, 2005
• Study Start: June 1, 2005
• Primary Completion: November 1, 2010
• Study Completion: November 1, 2010
• Last Updated: February 3, 2012
• Results First Posted: February 3, 2012

Record last verified: 2012-01

Locations

IT (6); US (50); CA (4); AU (12); AR (2); BR (1)