Leukemia, Myeloid, Chronic Phase Clinical Trial
— TOPSOfficial 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.
| Verified date | January 2012 |
| Source | Novartis |
| Contact | n/a |
| Is FDA regulated | No |
| Health authority | United States: Food and Drug Administration |
| Study type | Interventional |
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.
| Status | Terminated |
| Enrollment | 476 |
| Est. completion date | November 2010 |
| Est. primary completion date | November 2010 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years to 75 Years |
| Eligibility |
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. |
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| Argentina | Novartis Investigative Site | Buenos Aires | |
| Argentina | Novartis Investigative Site | La Plata | |
| Australia | Novartis Investigative Site | Adelaide | South Australia |
| Australia | Novartis Investigative Site | East Melbourne | Victoria |
| Australia | Novartis Investigative Site | Fitzroy | Victoria |
| Australia | Novartis Investigative Site | Frankston | Victoria |
| Australia | Novartis Investigative Site | Herston | Queensland |
| Australia | Novartis Investigative Site | Parkville | Victoria |
| Australia | Novartis Investigative Site | Prahran | Victoria |
| Australia | Novartis Investigative Site | South Brisbane | |
| Australia | Novartis Investigative Site | 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 | Woolloongabba | Queensland |
| Brazil | Novartis Investigative Site | Campinas | |
| Canada | Novartis Investigative Site | Calgary | |
| Canada | Novartis Investigative Site | Montreal | |
| Canada | Novartis Investigative Site | Ottawa | |
| Canada | Novartis Investigative Site | Quebec | |
| Italy | Novartis Investigative Site | 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 | |
| United States | St. Agnes Hospital | Baltimore | Maryland |
| United States | Indiana Blood and Marrow Institutw | Beech Grove | Indiana |
| United States | Indiana Blood and Marrow Transplant | Beech Grove | Indiana |
| United States | Alta Bates Comprehsenive Cancer Center | Berkeley | California |
| United States | University of Miami | Berkeley | California |
| United States | Roswell Park Cancer Institute | Buffalo | New York |
| United States | South Bay Oncology Hematology Partners | Campbell | California |
| United States | MUSC Hollings Cancer Center | Charleston | South Carolina |
| United States | University of Virgina Cancer Center, UVA Division of Hematology & Oncology | Charlottesville | Virginia |
| United States | Rush University Medical Center | Chicago | Illinois |
| United States | Cleveland Clinic Foundation | Cleveland | Ohio |
| United States | University Hospitals of Cleveland, Case Comprehensive Cancer Center | Cleveland | Ohio |
| United States | UT Southwestern Harold C. Simmons Comprehensive Cancer Center | Dallas | Texas |
| United States | Rocky Mountain Cancer Center | Denver | Colorado |
| United States | Duke University Medical Center | Durham | North Carolina |
| United States | San Juan Oncology Associates | Farmington | New Mexico |
| United States | The Jones Clinic | Germantown | Tennessee |
| United States | Cancer Center of the Carolinas | Greenville | South Carolina |
| United States | Cancer Center of the Carolinas | Greenville | North Carolina |
| United States | Cancer Centers of the Carolinas | Greenville | South Carolina |
| United States | Cancer Center at Hackensack University Medical Center | Hackensack | New Jersey |
| United States | Hackensack University Medical Center | Hackensack | New Jersey |
| United States | Cancer Research Center of Hawaii | Honolulu | Hawaii |
| United States | MD Anderson Cancer Center | Houston | Texas |
| United States | University of Texas / MD Anderson Cancer Center | Houston | Texas |
| United States | University of Iowa Hospitals & Clinic | Iowa City | Iowa |
| United States | Great Lakes Cancer Institute | Lansing | Michigan |
| United States | University of Kentucky | Lexington | Kentucky |
| United States | University of Kentucky - C201 Clinic | Lexington | Kentucky |
| United States | UCLA Medical Center | Los Angeles | California |
| United States | Lousville Oncology, Clinical Research Program M-25 | Louisville | Kentucky |
| United States | Osler Medical Inc. | Melbourne | Florida |
| United States | Jayne S. Gurtler, MD, Laura A. Brinz, MD & Angelo Russo, MD | Metairie | Louisiana |
| United States | Advanced Medical Specialists | Miami | Florida |
| United States | U of Minnesota | Minneapolis | Minnesota |
| United States | University of Minnesota | Minneapolis | Minnesota |
| United States | University of South Alabama | Mobile | Alabama |
| United States | Sarah Cannon Research Institute | Nashville | Tennessee |
| United States | Hematology and Oncology Specialists | New Orleans | Louisiana |
| United States | Integrated Community Oncology Network | Orange Park | Florida |
| United States | Hematology-Oncology Associates, P.A. | Pensacola | Florida |
| United States | University of Pittsburg, Hillman Cancer Center | Pittsburgh | Pennsylvania |
| United States | Western Pennsylvania Hospital | Pittsburgh | Pennsylvania |
| United States | Kaiser Permanente Northwest Region | Portland | Oregon |
| United States | Kaiser Permanente Northwest Region Oncology/Hemacology | Portland | Oregon |
| United States | LSU Health Science Center | Shreveport | Louisiana |
| United States | LSU Health Scine Center | Shreveport | Louisiana |
| United States | Palm Beach Cancer Institute | West Palm Beach | Florida |
| United States | Palm Beach Cancer Institute | West Palm Beach | Florida |
| United States | Wake Forest University Health Sciences | Winston-Salem | North Carolina |
| Lead Sponsor | Collaborator |
|---|---|
| Novartis Pharmaceuticals |
United States, Argentina, Australia, Brazil, Canada, Italy,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | 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 | No |
| Secondary | Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes | 12 months | No |