A Study of Dasatinib vs. High-Dose Imatinib (600 mg) in Patients With Chronic Phase Chronic Myeloid Leukemia (CML) Who Failed to Achieve Complete Cytogenetic Response After 3-18 Months of Imatinib Therapy

Study Overview
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Brief Summary
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The purpose of this clinical research study is to compare the rate of complete cytogenetic response of dasatinib to imatinib therapy at 6 months after randomization in chronic phase CML patients. The safety of this treatment will also be studied.

Official Title
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An Open-Label Randomized Phase III Study of Dasatinib vs. High-Dose (600 mg) Imatinib Mesylate in the Treatment of Subjects With Chronic Phase Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Who Are Imatinib Failures or Who Have Had a Suboptimal Response After 3-18 Months of Therapy With 400 mg Imatinib

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Dasatinib
* Drug: Imatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women ≥18 years diagnosed with Chronic Phase Philadelphia chromosome positive (CP Ph+) CML who have failed to achieve CCyR after 3-18 months of therapy with imatinib 400 mg Treatment initiation with imatinib 400 mg within 6 months of initial CML diagnosis Able to tolerate chronic administration of imatinib at the highest dose (400-600 mg) the subject has received in the past Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 Adequate hepatic and renal function Exclusion Criteria: Eligible and willing to undergo immediate autologous/allogeneic stem cell transplant Previous diagnosis of accelerated/blast crisis CML Subjects with clonal evolution in Ph+ cells observed in ≥2 metaphases Previous documentation of T315I mutation Uncontrolled or significant cardiovascular disease Serious uncontrolled medical disorder/active infection History of significant bleeding disorder unrelated to CML Intolerance to imatinib ≥400 mg Concurrent malignancies other than CML

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: A<br>50-180 mg once daily (QD) | Drug: Dasatinib<br>* Tablets, Oral, Once daily, 5-7 years<br>* Other names: Sprycel®;|
| Active Comparator: B<br>200-800 mg QD | Drug: Imatinib<br>* Tablets, Oral, Once daily, 5-7 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Cytogenetic Response (CCyR) Rate at Month 6 | Cytogenetic Response (CyR) is based on the prevalence of Philadelphia chromosome positive (Ph+) metaphases among cells in metaphase on a bone marrow sample. The criteria for CCyR is 0% Ph+ metaphases among cells in a bone marrow sample. | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Molecular Response (MMR) Rates | MMR is defined as a 3-log reduction in BCR-ABL gene transcripts from a standardized baseline. Reductions in BCR-ABL transcripts on logarithmic scale are calculated based on the absolute values expressed as percent of ratio of BCR-ABL gene transcripts to the control gene. In this study,ABL was used as the control gene. | Month 3, Month 6, Month 12, Month 24 and Month 36 | 
| CCyR Rates | CyR is based on the prevalence of Ph+ metaphases among cells in metaphase on a bone marrow sample. The criteria for CCyR is 0% Ph+ metaphases among cells in a bone marrow sample. | Month 3, Month 12, Month 24 and Month 36 | 
| Estimate Time to MMR and CCyR | Time to MMR is defined as the time from first treatment dose until measurement criteria are first met for MMR. Time to MMR is computed only for subjects who achieved a MMR. Time to CCyR is defined as the time from first treatment dose until measurement criteria are first met for CCyR. Time to CCyR is computed only for subjects who achieved a CCyR. | throughout the study | 
| Progression Free Survival (PFS) | PFS=time from randomization until progression or death. Participants who died without progression=progression on date of death. Participants who neither progressed nor died were censored on date of last hematologic assessment. Participants who did not receive study treatment and neither progressed nor died were censored on date of randomization. | at 36 months | 
| Adverse Events (AEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to AEs | An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a patient or clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event. | From 2 weeks prior to randomization through Month 36. At least every 4 weeks until all study-related toxicities resolve to baseline, stabilize, or are deemed irreversible. | 
| Duration of CCyR and MMR | Duration of CCyR computed for subjects with CCyR as best response; measured from time the criteria are first met for CCyR until date of progression or death. Duration of MMR computed for subjects with MMR as best response; measured from time the criteria are first met for MMR until date the MMR was first lost, disease progression or death. | Throughout the study | 
| Best MMR Rates | MMR is defined as a 3-log reduction in BCR-ABL gene transcripts from a standardized baseline. Reductions in BCR-ABL transcripts on logarithmic scale are calculated based on the absolute values expressed as % of ratio of BCR-ABL gene transcripts to the control gene. In this study, ABL was used as the control gene. | throughout study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia (chronic myeloid leukemia - chronic phase)