Chronic Myelogenous Leukemia in Chronic Phase, Philadelphia Chromosome Positive
Conditions
Keywords
Chronic phase, Chronic myelogenous leukemia, CML, Philadelphia chromosome positive, Ph+, Nilotinib, CML-CP, Suboptimal molecular response
Brief summary
To evaluate the major molecular response (MMR) rate at 12 months of nilotinib treatment on study in patients with Philadelphia Chromosome Positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP) who have a suboptimal molecular response to imatinib at 18 months or later.
Interventions
DRUGNilotinib
400 mg BID
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. ECOG 0, 1, or 2. 3. Have been diagnosed with Ph+ CML-CP and receiving imatinib therapy. 4. Patients with suboptimal molecular response to imatinib treatment continued for at least 18 months (first line therapy) Suboptimal molecular response defined as all of the following conditions: 1. Patients who have achieved CCyR (0% Ph+ chromosomes). 2. Patients who don't achieve MMR (MMR defined as BCR-ABL/ABL ratio of ≤ 0.1% on the International Scale as detected by RQ-PCR). The treatment with imatinib defined as: Dose of 300 mg or higher daily must be maintained for a minimum of 3 months prior to study entry. 5. Patients who meet the following laboratory tests criteria: 1. total bilirubin \< 1.5 x ULN, 2. SGOT and SGPT \< 2.5 x ULN, 3. creatinine \< 1.5 x ULN, 4. Serum amylase and lipase ≤ 1.5 x ULN, 5. Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related. 6. Serum potassium, phosphorus, magnesium and calcium ≥ LLN or correctable with supplements prior to the first dose of study drug. 6. Written informed consent prior to any study related screening procedures being performed.
Exclusion criteria
1. Prior accelerated phase or blast crisis CML. 2. Previously documented T315I mutations. 3. Presence of chromosomal abnormalities other than Ph+. 4. Previous treatment with any other tyrosine kinase inhibitor except imatinib. 5. Impaired cardiac function including any one of the following: 1. Complete left bundle branch block 2. Congenital long QT syndrome or family history of long QT syndrome 3. History of or presence of significant ventricular or atrial tachyarrhythmias 4. Clinically significant resting brachycardia (\<50 bpm) 5. QTcF \> 450 msec on screening ECG 6. Use of a ventricular-paced pacemaker 7. Myocardial infarction during the last 12 months 8. Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, unstable angina). 6. Treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St John's Wort), and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. See Section 6.4.3 for complete list of these medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MMR Rate at 12 Mos. of Nilotinib Treatment on Study in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Who Have a Suboptimal Molecular Response to Imatinib at 18 Months or Later. | 12 months after treatment | MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MMR Rate at 24 Months of Nilotinib Treatment on Study in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) | 24 months after treatment | MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value |
| Time to First MMR of Nilotinib in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) . | month 24 | MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value |
| Duration of MMR of Nilotinib in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) . | month 24 | MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nilotinib Nilotinib 400 mg BID | 45 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative Problems | 1 |
| Overall Study | Adverse Event | 3 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Nilotinib |
|---|---|
| Age, Continuous | 49.5 years STANDARD_DEVIATION 14.89 |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 45 / 45 |
| serious Total, serious adverse events | 7 / 45 |
Outcome results
Primary
MMR Rate at 12 Mos. of Nilotinib Treatment on Study in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Who Have a Suboptimal Molecular Response to Imatinib at 18 Months or Later.
MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value
Time frame: 12 months after treatment
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib | MMR Rate at 12 Mos. of Nilotinib Treatment on Study in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Who Have a Suboptimal Molecular Response to Imatinib at 18 Months or Later. | 51.1 % participants achieving MMR |
Secondary
Duration of MMR of Nilotinib in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) .
MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value
Time frame: month 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib | Duration of MMR of Nilotinib in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) . | 51.1 % participants w/ durable MMR at 24 mos |
Secondary
MMR Rate at 24 Months of Nilotinib Treatment on Study in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)
MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value
Time frame: 24 months after treatment
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib | MMR Rate at 24 Months of Nilotinib Treatment on Study in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) | 66.7 % participants achieving MMR |
Secondary
Time to First MMR of Nilotinib in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) .
MMR is defined as BCR-ABL ratio (%) on IS ≤ 0.1% (corresponds to ≥ 3 log reduction of BCR-ABL transcripts from standardized baseline value
Time frame: month 24
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nilotinib | Time to First MMR of Nilotinib in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) . | 5.19 months | Standard Deviation 5.494 |