Chronic Phase Chronic Myeloid Leukemia
Conditions
Brief summary
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.
Interventions
DRUGImatinib
DRUGDasatinib
Sponsors
ICON Clinical Research
PPD Development, LP
Molecular MD
MultiPharma
Q2 Solutions
Donald E. Morisky
MD Anderson Symptom Inventory (MDASI-CML)
OBiS, Inc
Steering Committee
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving Major Molecular Response (MMR) After 12 Months of CML Treatment | 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. | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Major Molecular Response (MMR) | From randomization to study completion. Approximately 115 months | 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. |
| Time to Molecular Response (MR)^4.5 | From randomization to study completion. Approximately 115 months | 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. |
| Progression Free Survival (PFS) | From randomization to study completion. Approximately 115 months | 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 |
| Overall Survival (OS) | From randomization to study completion. Approximately 115 months | 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. |
Countries
Argentina, Austria, Belgium, Brazil, Canada, China, Czechia, France, Hungary, Italy, Poland, South Korea, Spain, Thailand, United States
Participant flow
Pre-assignment details
260 participants treated
Participants by arm
| Arm | Count |
|---|---|
| Arm 2: Dasatinib (100 mg) Dasatinib 100 mg tablet by mouth QD up to 60 months | 174 |
| Arm 1: Imatinib (≥400 mg) Imatinib ≥400 mg tablets by mouth once daily (QD) or twice daily (BID) up to 60 months. | 86 |
| Total | 260 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Admin reason by sponsor | 7 | 3 |
| Overall Study | AE unrelated to study drug | 0 | 1 |
| Overall Study | Death | 3 | 3 |
| Overall Study | Disease progression | 2 | 7 |
| Overall Study | Imatinib treatment failure | 2 | 0 |
| Overall Study | lost to follow up | 1 | 6 |
| Overall Study | maximum clinical benefit | 1 | 2 |
| Overall Study | Other Reasons | 61 | 115 |
| Overall Study | participant no longer meets study criteria | 1 | 1 |
| Overall Study | participant request to discontinue study treatment | 1 | 3 |
| Overall Study | participant withdrew consent | 0 | 9 |
| Overall Study | Poor/non compliance | 1 | 1 |
| Overall Study | Pregnancy | 0 | 3 |
| Overall Study | Study drug toxicity | 6 | 20 |
Baseline characteristics
| Characteristic | Arm 1: Imatinib (≥400 mg) | Total | Arm 2: Dasatinib (100 mg) |
|---|---|---|---|
| Age, Continuous | 39.5 years | 37.0 years | 35.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 86 Participants | 260 Participants | 174 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 63 Participants | 190 Participants | 127 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 12 Participants | 7 Participants |
| Race (NIH/OMB) White | 15 Participants | 51 Participants | 36 Participants |
| Sex: Female, Male Female | 16 Participants | 57 Participants | 41 Participants |
| Sex: Female, Male Male | 70 Participants | 203 Participants | 133 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 86 | 11 / 174 | 4 / 46 |
| other Total, other adverse events | 68 / 86 | 159 / 171 | 42 / 46 |
| serious Total, serious adverse events | 11 / 86 | 48 / 171 | 8 / 46 |
Outcome results
Primary
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).
Time frame: 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.
Population: All Randomized Participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1: Imatinib (≥400 mg) | Percentage of Patients Achieving Major Molecular Response (MMR) After 12 Months of CML Treatment | 12.8 Percentage of Patients |
| Arm 2: Dasatinib (100 mg) | Percentage of Patients Achieving Major Molecular Response (MMR) After 12 Months of CML Treatment | 28.7 Percentage of Patients |
p-value: 0.005Cochran-Mantel-Haenszel
Secondary
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.
Time frame: From randomization to study completion. Approximately 115 months
Population: All Randomized Participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Imatinib (≥400 mg) | Median Time to Major Molecular Response (MMR) | 19.7 Months |
| Arm 2: Dasatinib (100 mg) | Median Time to Major Molecular Response (MMR) | 13.9 Months |
Secondary
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.
Time frame: From randomization to study completion. Approximately 115 months
Population: All randomized participants who died
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Imatinib (≥400 mg) | Overall Survival (OS) | NA Months |
| Arm 2: Dasatinib (100 mg) | Overall Survival (OS) | NA Months |
Secondary
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
Time frame: From randomization to study completion. Approximately 115 months
Population: All randomized participants with a progression event
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Imatinib (≥400 mg) | Progression Free Survival (PFS) | NA Months |
| Arm 2: Dasatinib (100 mg) | Progression Free Survival (PFS) | NA Months |
Secondary
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.
Time frame: From randomization to study completion. Approximately 115 months
Population: All Randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Imatinib (≥400 mg) | Time to Molecular Response (MR)^4.5 | 67.7 Months |
| Arm 2: Dasatinib (100 mg) | Time to Molecular Response (MR)^4.5 | 74.5 Months |