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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Leukemia, Myeloid, Chronic Phase

Intervention / Treatment
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* Drug: Imatinib mesylate


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imatinib 400 mg<br>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<br>* Imatinib is packaged in bottles as 100mg and 400mg tablets<br>* Other names: Glivec;|
| Experimental: imatinib 800 mg<br>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<br>* Imatinib is packaged in bottles as 100mg and 400mg tablets<br>* Other names: Glivec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML, Philadelphia positive, Bcr-abl, imatinib mesylate, Chronic myeloid leukemia (CML) in chronic phase