Study of Dasatinib vs Imatinib in Patients With Chronic Myeloid Leukemia (CML) Who Did Not Have Favorable Response to Imatinib

Study Overview
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Brief Summary
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The purpose of this study is to test the hypothesis that patients with CML who have not achieved optimal response after 3 months of treatment with imatinib will have a better response by switching to dasatinib compared to staying on their original imatinib regimen.

Official Title
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An Open Label, Randomized (2:1) Phase IIb Study of Dasatinib Versus Imatinib in Patients With Chronic Phase Chronic Myeloid Leukemia Who Have Not Achieved an Optimal Response to 3 Months of Therapy With 400 mg Imatinib

Conditions
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Chronic Phase Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Imatinib
* Drug: Dasatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic Phase (CP)-CML Ph+ patients with complete hematologic response (CHR) but without one log BCR-ABL reduction (BCR-ABL level >10% IS) 3 months of imatinib 400mg treatment. (Imatinib transient dose adjustments due to Adverse Event (AEs) are allowed with a maximum of 2 weeks interruption of treatment with imatinib (cumulative) within the 3 month period before randomization). Imatinib monotherapy must have been started within 6 months of CP-CML diagnosis (Ph + /BCR-ABL detection) Currently tolerating imatinib 400mg QD. Patients with prior imatinib treatment interruption or dose reductions are required to be on treatment with 400 mg imatinib for two weeks immediately prior to randomization to ensure tolerance to imatinib Eastern Co-Operative Group (ECOG) performance status = 0 - 2 Adequate renal function defined as serum creatinine ≤3 times the institutional upper limit of normal (ULN) Adequate hepatic function defined as: total bilirubin ≤2.0 times the institutional ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the institutional ULN Exclusion Criteria: Previous diagnosis of accelerated phase or blast crisis Subjects with clonal evolution in Ph+ cells observed in ≥2 metaphases at baseline bone marrow cytogenetic test, unless the same abnormalities were present at diagnosis. Patients with no evidence of clonal evolution, including those patients whose cytogenetic testing fails or bone marrow aspiration is a dry tap at 3 months, are eligible for the study Subjects with less than CHR after 3 months of imatinib treatment or lost CHR after initial achievement Documented T315I/A, F317L, or V299L mutations (if already available - not required for screening) A serious uncontrolled medical disorder or active infection that would impair the ability of the subject to receive protocol therapy

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: Arm 1: Imatinib (≥400 mg)<br>Imatinib ≥400 mg tablets by mouth once daily (QD) or twice daily (BID) up to 60 months | Drug: Imatinib<br> <br> * Other names: Glivec;|
| Active Comparator: Arm 2: Dasatinib (100 mg)<br>Dasatinib 100 mg tablet by mouth QD up to 60 months | Drug: Dasatinib<br> <br> * Other names: Sprycel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Achieving Major Molecular Response (MMR) After 12 Months of CML Treatment | Major Molecular Response, is defined as a 3-log reduction in BCR-ABL transcripts from the standardized baseline, which represents 100% on the international scale, so a 3-log reduction is fixed at 0.1% for MMR; N/A = not applicable. 95% CI is Clopper-Pearson(Exact) two-sided 95% confidence intervals. P-value is based on Cochran-Mantel-Haenszel (CMH) test stratified by Sokal score(high, intermediate, low, and unknown) and time between 3 month molecular analysis and randomization (<=4 weeks vs >4 weeks). | At 12 months after Day 1 initiation of 1st line treatment with imatinib or imatinib at any dose, after less than optimal response to first-line imatinib. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Time to Major Molecular Response (MMR) | Median Time to Major Molecular Response (MMR) is the time between randomization date and first date that MMR (or MR4.5) criteria are satisfied. Participants who do not achieve MMR (or MR4.5) will be censored. Major Molecular Response, is defined as a 3-log reduction in BCR-ABL transcripts from the standardized baseline, which represents 100% on the international scale, so a 3-log reduction is fixed at 0.1% for MMR. | From randomization to study completion. Approximately 115 months | 
| Time to Molecular Response (MR)^4.5 | Time to Molecular Response (MR)^4.5 is the time between randomization date and first date that MMR (or MR4.5) criteria are satisfied. Participants who do not achieve MMR (or MR4.5) will be censored. MR4.5 is defined as a 4.5-log reduction in BCR-ABL transcript from the standardized baseline (0.0032% IS, either detectable disease <= 0.0032% BCR-ABL (IS) or undetectable disease in cDNA (in same volume used for BCR-ABL) with >= 32,000 ABL transcripts. | From randomization to study completion. Approximately 115 months | 
| Progression Free Survival (PFS) | PFS is the time from randomization date to progression date or death date, whichever occurs first. Participants who neither progress nor die will be censored. Progression is defined as the following, meeting the criteria for accelerated or blast crisis CML are met at any time or death from any cause during treatment. Accelerated phase of CML: The presence of ≥15%, but < 30% blasts in the blood or bone marrow At least 30% blasts plus promyelocytes in the blood or bone marrow At least 20% peripheral basophils Thrombocytopenia (fewer than 100,000 platelets/mm3) unrelated to treatment. Blast phase of CML At least 30% blasts in the blood or bone marrow Extramedullary involvement (e.g., chloromas), but not hepatosplenomegaly | From randomization to study completion. Approximately 115 months | 
| Overall Survival (OS) | OS is the time from randomization date to death date. Participants who have not died will be censored on the last date they are known to be alive. | From randomization to study completion. Approximately 115 months |