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

Phase 3TerminatedNCT00124748

Novartis Pharmaceuticals476 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

476

Conditions

Leukemia, Myeloid, Chronic Phase

Interventions

Imatinib mesylateDRUG

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

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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.

Locations (75)

Outcomes

Primary Outcomes

Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months

Time frame: 12 months

Secondary Outcomes

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

Time frame: 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.

Time frame: 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.

Time frame: 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

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

University of South Alabama

Mobile, Alabama, United States

Alta Bates Comprehsenive Cancer Center

Berkeley, California, United States

University of Miami

Berkeley, California, United States

South Bay Oncology Hematology Partners

Campbell, California, United States

UCLA Medical Center

Los Angeles, California, United States

Rocky Mountain Cancer Center

Denver, Colorado, United States

Osler Medical Inc.

Melbourne, Florida, United States

Advanced Medical Specialists

Miami, Florida, United States

Integrated Community Oncology Network

Orange Park, Florida, United States

Hematology-Oncology Associates, P.A.

Pensacola, Florida, United States

...and 65 more locations

"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).

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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)

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 48 months overall

Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes

Time frame: 12 months