Chronic Myelogenous Leukemia
Conditions
Keywords
CML, Leukemia, Tasigna, nilotinib, AMN107, CML-CP, Chronic Phase
Brief summary
The purpose of this exploratory study will be to examine changes in chronic low grade chronic adverse events, measured by Common Terminology Criteria for Adverse Events (CTCAE) grading, when patients are switched from imatinib to nilotinib therapy.
Interventions
DRUGNilotinib
Participants received two 150 \[a total of 300 mg at each dosing\] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules \[a total of 400 mg at each dosing\] for patients enrolled prior to Protocol Amendment 1).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female patients ≥ 18 years of age 2. Eastern Cooperative Oncology Group (ECOG) 0, 1, or 2 3. Diagnosis of CML-CP associated with Bcr-Abl quantifiable by RQ-PCR (IS) 4. Patients must be an imatinib responder and achieved the following efficacy milestones as appropriate for the length of time on imatinib therapy as per protocol 5. CML-CP patients initiated on any dose of imatinib 6. Ability to provide written informed consent prior to any study related screening procedures being done
Exclusion criteria
1. Loss of CHR or cytogenetic response 2. Prior accelerated phase or blast phase CML 3. Previously documented T315I mutation 4. Presence of chromosomal abnormalities (trisomy 8) and/or clonal evolution other than Ph+. 5. Previous treatment with any other tyrosine kinase inhibitor except for imatinib. 6. Treatment with other investigational agents within 30 days of Day 1. 7. History of non-compliance to medical regimens or inability to grant consent. 8. Women who are pregnant, breast feeding, or of childbearing potential without a negative serum test at baseline. Male or female patients of childbearing potential unwilling to use contraceptive precautions throughout the trial and 3 months following discontinuation of study drug. Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Women of childbearing potential must have a negative serum pregnancy test prior to the first dose of nilotinib. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Improvement in Imatinib Related Chronic Low Grade Non Hematologic Adverse Event (AE) After Switch to Treatment With Nilotinib at End of Cycle 3 | End of Cycles 1, 2, and 3 | A patient was considered improved if 50% or more of the chronic imatinib-related chronic low grade nonhematologic AEs showed improvement (a decrease in CTCAE \[Common Terminology Criteria for Adverse Events\] grade or complete resolution). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Major Molecular Response (MMR) in Participants With MMR Absent at Baseline | Cycles 1,2,3,6,9,12 | For time to MMR, an event is defined as achievement of MMR documented by RQ-PCR. Patients with MMR at the Screening RQ-PCR assay are counted as having time to MMR equal to 0. |
| Percentage of Participants Achieving Complete Cytogenetic Response (CCyR) After Switching to Nilotinib for Participants Not Reporting CCyR at Baseline | Cycles 1, 2, 6, 9, and 12 | Time to complete cytogenetic response is defined as time from baseline to first time of CCyR as documented by bone marrow cytogenetics. Cytogenetic response was assessed as applicable by bone marrow cytogenetics 6, 12, and 18 months after starting imatinib therapy. Assess CCyR by bone marrow cytogenics |
| Percentage of Participants Achieving Major Molecular Response (MMR) After the Switch in the Therapy for Participants Not Reporting MMR at Baseline | Cycles 1,2,3,6,9,12 | Major Molecular Response (MMR) value at Molecular MD is designated a percentage, which is equivalent to a 3-log reduction from a standardized baseline value from the International Randomized Interferon versus STI571 (IRIS) study or 0.1% per International Scale (IS). Time to MMR is defined as time from baseline to first time of MMR as documented by RQ-PCR |
| Duration of Major Molecular Response | 18 months of follow up from the first documented response | Duration of Major Molecular Response is defined as the time from first MMR to first loss of MMR as documented by RQ-PCR. The duration of MMR begins on the day of enrollment for patients reporting MMR at baseline. |
| Duration of Complete Cytogenetic Response | 18 months of follow up from the first documented response | Duration of Complete Cytogenetic Response is defined as the time from first CCyR to first loss of CCyR as documented by bone marrow cytogenetics, or by FISH assay, whichever is earlier. The duration of CCyR begins on the day of enrollment for patients reporting CCyR at baseline. |
| Time to Complete Cytogenetic Response in Participants Not Reporting at Baseline | Cycle 12 | For time to CCyR, an event is defined as achievement of CCyR documented by bone marrow cytogenetics. |
| Time to Optimal Imatinib-related Adverse Event Improvement | 18 months of follow up from the date of the first dose of study drug to the time to maximum decrease in CTCAE grade of these events | Time to optimal improvement is defined as the time when the sum of the total CTCAE toxicity grades for a patient's chronic low-grade imatinib-related adverse events reaches its minimum value. |
| Log Change in BCR-Abl Transcript Level From Baseline After the Switch Therapy | Cycles 1,2,3,6,9, and 12 | Levels of BCR-ABL transcripts were determined by quantitative RQ-PCR testing of peripheral blood and analyzed at a central testing laboratory. Log reduction in BCR-ABL transcripts levels from the standardized baseline value will be calculated for each sample from the reported percent ratio of BCR-ABL transcripts versus control gene transcripts converted to a reference standard. |
Countries
Canada, United States
Participant flow
Recruitment details
The study was conducted at 15 centers in US and 4 centers in Canada from 10-December-2009 (first patient first visit) to 27-December-2012 (last patient last visit).
Pre-assignment details
A total of 68 patients were screened out of which 52 enrolled and 40 completed the full duration of treatment.
Participants by arm
| Arm | Count |
|---|---|
| Nilotinib Participants received two 150 \[a total of 300 mg at each dosing\] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules \[a total of 400 mg at each dosing\] for patients enrolled prior to Protocol Amendment 1). | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 8 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Patient withdrew consent | 3 |
Baseline characteristics
| Characteristic | Nilotinib |
|---|---|
| Age, Continuous | 51.7 years STANDARD_DEVIATION 10.76 |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 52 |
| other Total, other adverse events | 49 / 52 |
| serious Total, serious adverse events | 9 / 52 |
Outcome results
Primary
Percentage of Participants With Improvement in Imatinib Related Chronic Low Grade Non Hematologic Adverse Event (AE) After Switch to Treatment With Nilotinib at End of Cycle 3
A patient was considered improved if 50% or more of the chronic imatinib-related chronic low grade nonhematologic AEs showed improvement (a decrease in CTCAE \[Common Terminology Criteria for Adverse Events\] grade or complete resolution).
Time frame: End of Cycles 1, 2, and 3
Population: Full Analysis Set (FAS): All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nilotinib | Percentage of Participants With Improvement in Imatinib Related Chronic Low Grade Non Hematologic Adverse Event (AE) After Switch to Treatment With Nilotinib at End of Cycle 3 | End of Cycle 1 | 37 Participants |
| Nilotinib | Percentage of Participants With Improvement in Imatinib Related Chronic Low Grade Non Hematologic Adverse Event (AE) After Switch to Treatment With Nilotinib at End of Cycle 3 | End of Cycle 2 | 43 Participants |
| Nilotinib | Percentage of Participants With Improvement in Imatinib Related Chronic Low Grade Non Hematologic Adverse Event (AE) After Switch to Treatment With Nilotinib at End of Cycle 3 | End of Cycle 3 | 44 Participants |
Secondary
Duration of Complete Cytogenetic Response
Duration of Complete Cytogenetic Response is defined as the time from first CCyR to first loss of CCyR as documented by bone marrow cytogenetics, or by FISH assay, whichever is earlier. The duration of CCyR begins on the day of enrollment for patients reporting CCyR at baseline.
Time frame: 18 months of follow up from the first documented response
Population: FAS: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nilotinib | Duration of Complete Cytogenetic Response | Participants with CCyR at baseline | 319.7 days | Standard Deviation 143.03 |
| Nilotinib | Duration of Complete Cytogenetic Response | Participants achieving CCyR on study | 266.3 days | Standard Deviation 86.73 |
Secondary
Duration of Major Molecular Response
Duration of Major Molecular Response is defined as the time from first MMR to first loss of MMR as documented by RQ-PCR. The duration of MMR begins on the day of enrollment for patients reporting MMR at baseline.
Time frame: 18 months of follow up from the first documented response
Population: FAS : All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nilotinib | Duration of Major Molecular Response | Participants with MMR at baseline | 277.6 days | Standard Deviation 166.88 |
| Nilotinib | Duration of Major Molecular Response | Participants achieving MMR on study | 208.3 days | Standard Deviation 123.61 |
Secondary
Log Change in BCR-Abl Transcript Level From Baseline After the Switch Therapy
Levels of BCR-ABL transcripts were determined by quantitative RQ-PCR testing of peripheral blood and analyzed at a central testing laboratory. Log reduction in BCR-ABL transcripts levels from the standardized baseline value will be calculated for each sample from the reported percent ratio of BCR-ABL transcripts versus control gene transcripts converted to a reference standard.
Time frame: Cycles 1,2,3,6,9, and 12
Population: FAS: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nilotinib | Log Change in BCR-Abl Transcript Level From Baseline After the Switch Therapy | Cycle 1 | -0.177 log change from Baseline | Standard Deviation 0.3665 |
| Nilotinib | Log Change in BCR-Abl Transcript Level From Baseline After the Switch Therapy | Cycle 2 | -0.407 log change from Baseline | Standard Deviation 0.5748 |
| Nilotinib | Log Change in BCR-Abl Transcript Level From Baseline After the Switch Therapy | Cycle 3 | -0.540 log change from Baseline | Standard Deviation 0.696 |
| Nilotinib | Log Change in BCR-Abl Transcript Level From Baseline After the Switch Therapy | Cycle 6 | -0.718 log change from Baseline | Standard Deviation 0.9313 |
| Nilotinib | Log Change in BCR-Abl Transcript Level From Baseline After the Switch Therapy | Cycle 9 | -0.844 log change from Baseline | Standard Deviation 0.913 |
| Nilotinib | Log Change in BCR-Abl Transcript Level From Baseline After the Switch Therapy | Cycle 12 | -0.902 log change from Baseline | Standard Deviation 0.9913 |
Secondary
Percentage of Participants Achieving Complete Cytogenetic Response (CCyR) After Switching to Nilotinib for Participants Not Reporting CCyR at Baseline
Time to complete cytogenetic response is defined as time from baseline to first time of CCyR as documented by bone marrow cytogenetics. Cytogenetic response was assessed as applicable by bone marrow cytogenetics 6, 12, and 18 months after starting imatinib therapy. Assess CCyR by bone marrow cytogenics
Time frame: Cycles 1, 2, 6, 9, and 12
Population: FAS : All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nilotinib | Percentage of Participants Achieving Complete Cytogenetic Response (CCyR) After Switching to Nilotinib for Participants Not Reporting CCyR at Baseline | Cycle 1 | 2 Participants |
| Nilotinib | Percentage of Participants Achieving Complete Cytogenetic Response (CCyR) After Switching to Nilotinib for Participants Not Reporting CCyR at Baseline | Cycle 2 | 3 Participants |
| Nilotinib | Percentage of Participants Achieving Complete Cytogenetic Response (CCyR) After Switching to Nilotinib for Participants Not Reporting CCyR at Baseline | Cycle 3 | 0 Participants |
| Nilotinib | Percentage of Participants Achieving Complete Cytogenetic Response (CCyR) After Switching to Nilotinib for Participants Not Reporting CCyR at Baseline | Cycle 6 | 2 Participants |
| Nilotinib | Percentage of Participants Achieving Complete Cytogenetic Response (CCyR) After Switching to Nilotinib for Participants Not Reporting CCyR at Baseline | Cycle 9 | 0 Participants |
| Nilotinib | Percentage of Participants Achieving Complete Cytogenetic Response (CCyR) After Switching to Nilotinib for Participants Not Reporting CCyR at Baseline | Cycle 12 | 0 Participants |
Secondary
Percentage of Participants Achieving Major Molecular Response (MMR) After the Switch in the Therapy for Participants Not Reporting MMR at Baseline
Major Molecular Response (MMR) value at Molecular MD is designated a percentage, which is equivalent to a 3-log reduction from a standardized baseline value from the International Randomized Interferon versus STI571 (IRIS) study or 0.1% per International Scale (IS). Time to MMR is defined as time from baseline to first time of MMR as documented by RQ-PCR
Time frame: Cycles 1,2,3,6,9,12
Population: FAS : All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nilotinib | Percentage of Participants Achieving Major Molecular Response (MMR) After the Switch in the Therapy for Participants Not Reporting MMR at Baseline | Cycle 1 | 2 Participants |
| Nilotinib | Percentage of Participants Achieving Major Molecular Response (MMR) After the Switch in the Therapy for Participants Not Reporting MMR at Baseline | Cycle 2 | 6 Participants |
| Nilotinib | Percentage of Participants Achieving Major Molecular Response (MMR) After the Switch in the Therapy for Participants Not Reporting MMR at Baseline | Cycle 3 | 3 Participants |
| Nilotinib | Percentage of Participants Achieving Major Molecular Response (MMR) After the Switch in the Therapy for Participants Not Reporting MMR at Baseline | Cycle 6 | 2 Participants |
| Nilotinib | Percentage of Participants Achieving Major Molecular Response (MMR) After the Switch in the Therapy for Participants Not Reporting MMR at Baseline | Cycle 9 | 2 Participants |
| Nilotinib | Percentage of Participants Achieving Major Molecular Response (MMR) After the Switch in the Therapy for Participants Not Reporting MMR at Baseline | Cycle 12 | 0 Participants |
Secondary
Time to Complete Cytogenetic Response in Participants Not Reporting at Baseline
For time to CCyR, an event is defined as achievement of CCyR documented by bone marrow cytogenetics.
Time frame: Cycle 12
Population: FAS: All participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Time to Complete Cytogenetic Response in Participants Not Reporting at Baseline | 1.9 months |
Secondary
Time to Major Molecular Response (MMR) in Participants With MMR Absent at Baseline
For time to MMR, an event is defined as achievement of MMR documented by RQ-PCR. Patients with MMR at the Screening RQ-PCR assay are counted as having time to MMR equal to 0.
Time frame: Cycles 1,2,3,6,9,12
Population: FAS : All participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Time to Major Molecular Response (MMR) in Participants With MMR Absent at Baseline | 2.8 months |
Secondary
Time to Optimal Imatinib-related Adverse Event Improvement
Time to optimal improvement is defined as the time when the sum of the total CTCAE toxicity grades for a patient's chronic low-grade imatinib-related adverse events reaches its minimum value.
Time frame: 18 months of follow up from the date of the first dose of study drug to the time to maximum decrease in CTCAE grade of these events
Population: FAS: All participants who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Time to Optimal Imatinib-related Adverse Event Improvement | 1.9 months |