Chronic Myelogenous Leukemia in Chronic Phase
Conditions
Keywords
CML, Chronic Myelogenous Leukemia, Leukemia, CML-CP, Nilotinib
Brief summary
This is a single-arm, open-label, multi-center study of complete molecular response (CMR) in adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP). The study is designed to evaluate early and deep molecular responses up to 4 years on nilotinib treatment. The primary end point is Rate of confirmed CMR in newly diagnosed Philadelphia chromosome positive CML-CP patients.
Interventions
DRUGNilotinib
Nilotinib was supplied as 150 mg and 200 mg hard gelatin capsules.
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
Patients with Ph+ CML-CP within 3 months of diagnosis. Male or female patients' ≥ 18 years of age. Patients must have adequate end organ function.
Exclusion criteria
Previously documented T315I mutation. Other CML treatment is an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Confirmed Complete Molecular Response (CMR) | 4 years | CMR was defined as at least 4.5 log reduction of breakpoint cluster region gene/Abelson proto-oncogene (Bcr-Abl) transcipts from the standardized baseline on the international scale (equivalent to Bcr-Abl \<=0.0032% IS) with a minimum of 25,614 ABL control copies. CMR was to be confirmed by a second polymerase chain reaction (PCR) sample drawn 3 months later where the results should be less than or equal to 0.0032% with a minimum of 25,614 Abelson proto-oncogene (ABL) control copies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to CMR, CCyR and MMR | 4 years | Time to CMR, CCyR, and MMR was defined as the time from the date of enrollment to the date of first documented CMR, CCyR and MMR, respectively. |
| Duration of CMR, CCyR and MMR | 4 years | Duration of CMR, CCyR and MMR were defined as the time from the first date of achievement of the response to the date of first documented loss of the response. |
| Number of Participants With Progression to Accelerated Phase/Blastic Crisis (AP/BC) | 4 years | Progression to AP/BC is defined as loss of CCyR, MMR, and CMR and was summarized by frequencies and percentages. |
| Number of Participants With Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR) | 4 years | CCyR was defined as 0% Philadelphia chromosome-positive (Ph+) metaphases in the bone marrow. MMR was defined as a 3 log reduction of Bcr-Abl transcripts from the standardized baseline on the international scale (equivalent to Bcr-Abl ≤ 0.1% IS). Bcr-Abl transcripts assessed by peripheral blood quatitative real time polymerase chain reaction (RQ-PCR) were used for the determination of all molecular responses. |
| Number of Participants With Loss of CCyR, MMR and CMR | 4 years | Rate of loss of CMR was defined as an increase in the Bcr-Abl transcripts to greater than 0.0032% IS. Rate of loss of CCyR was defined as an increase in the Ph+ bone marrow cells to greater than 0%. Rate of loss of MMR was defined as an increase in the Bcr-Abl transcripts to greater than 0.1% IS. |
| Number of Participants With CMR Who Were Dosed to 400 mg b.i.d. | 4 years | CMR was defined as at least 4.5 log reduction of breakpoint cluster region gene/Abelson proto-oncogene (Bcr-Abl) transcipts from the standardized baseline on the international scale (equivalent to Bcr-Abl \<=0.0032% IS) with a minimum of 25,614 ABL control copies. CMR was to be confirmed by a second polymerase chain reaction (PCR) sample drawn 3 months later where the results should be less than or equal to 0.0032% with a minimum of 25,614 Abelson proto-oncogene (ABL) control copies. |
| Event-free Survival, Progression-free Survival and Overall Survival | 4 years | Event-free survival was defined as the time from the date of enrollment to the date of first occurrence of any of the following: loss of Complete Hematological Response (CHR), loss of CCyR, loss of Partial Cytogenetic Response (PCyR), progression to the accelerated phase or blast crisis, and death from any cause. Progression-free survival was defined as the time from the date of enrollment to the date of first occurrence of any of the following: progression to the accelerated phase or blast crisis, death, and loss of CMR. Overall survival was defined as the time from the date of enrollment until death due to any cause. |
| Time to Progression of AP/BC | 4 years | Time to progression of AP/BC was defined as the time from the date of the first dose of study drug to the date of first documented progression of AP/BC. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nilotinib Participants received 300 mg twice daily (b.i.d.). Dose increases to 400 b.i.d. were permitted, per Investigator's discretion. | 128 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative problems | 2 |
| Overall Study | Adverse Event | 17 |
| Overall Study | Death | 3 |
| Overall Study | Lack of Efficacy | 5 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Protocol deviation | 3 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Nilotinib |
|---|---|
| Age, Continuous | 55.6 Years STANDARD_DEVIATION 14.99 |
| Sex: Female, Male Female | 64 Participants |
| Sex: Female, Male Male | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 122 / 128 |
| serious Total, serious adverse events | 27 / 128 |
Outcome results
Primary
Number of Participants With Confirmed Complete Molecular Response (CMR)
CMR was defined as at least 4.5 log reduction of breakpoint cluster region gene/Abelson proto-oncogene (Bcr-Abl) transcipts from the standardized baseline on the international scale (equivalent to Bcr-Abl \<=0.0032% IS) with a minimum of 25,614 ABL control copies. CMR was to be confirmed by a second polymerase chain reaction (PCR) sample drawn 3 months later where the results should be less than or equal to 0.0032% with a minimum of 25,614 Abelson proto-oncogene (ABL) control copies.
Time frame: 4 years
Population: Full Analysis Set (FAS): The FAS included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib | Number of Participants With Confirmed Complete Molecular Response (CMR) | 34 Participants |
Secondary
Duration of CMR, CCyR and MMR
Duration of CMR, CCyR and MMR were defined as the time from the first date of achievement of the response to the date of first documented loss of the response.
Time frame: 4 years
Population: Of the 128 participants analyzed, 34 participants achieved CMR within 18 months of treatment, 93 participants achieved CCyR and did not experience loss of CCyR during the study, and 94 participants achieved MMR with up to 24 months of treatment (most achieved MMR within 12 months of treatment).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nilotinib | Duration of CMR, CCyR and MMR | CMR (n=34) | 7.97 Months | Standard Deviation 3.705 |
| Nilotinib | Duration of CMR, CCyR and MMR | CCyR (n=93) | NA Months | — |
| Nilotinib | Duration of CMR, CCyR and MMR | MMR (n=94) | 4.86 Months | Standard Deviation 5.003 |
Secondary
Event-free Survival, Progression-free Survival and Overall Survival
Event-free survival was defined as the time from the date of enrollment to the date of first occurrence of any of the following: loss of Complete Hematological Response (CHR), loss of CCyR, loss of Partial Cytogenetic Response (PCyR), progression to the accelerated phase or blast crisis, and death from any cause. Progression-free survival was defined as the time from the date of enrollment to the date of first occurrence of any of the following: progression to the accelerated phase or blast crisis, death, and loss of CMR. Overall survival was defined as the time from the date of enrollment until death due to any cause.
Time frame: 4 years
Population: Full Analysis Set (FAS): The FAS included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nilotinib | Event-free Survival, Progression-free Survival and Overall Survival | Event-free | NA Months |
| Nilotinib | Event-free Survival, Progression-free Survival and Overall Survival | Progression-free | NA Months |
| Nilotinib | Event-free Survival, Progression-free Survival and Overall Survival | Overall | NA Months |
Secondary
Number of Participants With CMR Who Were Dosed to 400 mg b.i.d.
CMR was defined as at least 4.5 log reduction of breakpoint cluster region gene/Abelson proto-oncogene (Bcr-Abl) transcipts from the standardized baseline on the international scale (equivalent to Bcr-Abl \<=0.0032% IS) with a minimum of 25,614 ABL control copies. CMR was to be confirmed by a second polymerase chain reaction (PCR) sample drawn 3 months later where the results should be less than or equal to 0.0032% with a minimum of 25,614 Abelson proto-oncogene (ABL) control copies.
Time frame: 4 years
Population: Of the 128 participants analyzed, 3 participants received an escalated dose of 400 mg b.i.d.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib | Number of Participants With CMR Who Were Dosed to 400 mg b.i.d. | 0 Participants |
Secondary
Number of Participants With Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR)
CCyR was defined as 0% Philadelphia chromosome-positive (Ph+) metaphases in the bone marrow. MMR was defined as a 3 log reduction of Bcr-Abl transcripts from the standardized baseline on the international scale (equivalent to Bcr-Abl ≤ 0.1% IS). Bcr-Abl transcripts assessed by peripheral blood quatitative real time polymerase chain reaction (RQ-PCR) were used for the determination of all molecular responses.
Time frame: 4 years
Population: Full Analysis Set (FAS): The FAS included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nilotinib | Number of Participants With Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR) | MMR | 94 Participants |
| Nilotinib | Number of Participants With Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR) | CCyR | 93 Participants |
Secondary
Number of Participants With Loss of CCyR, MMR and CMR
Rate of loss of CMR was defined as an increase in the Bcr-Abl transcripts to greater than 0.0032% IS. Rate of loss of CCyR was defined as an increase in the Ph+ bone marrow cells to greater than 0%. Rate of loss of MMR was defined as an increase in the Bcr-Abl transcripts to greater than 0.1% IS.
Time frame: 4 years
Population: Numbers are based on the total number of participants who achieved and experienced loss of CMR (34 participants), CCyr (93 participants) and MMR (94 participants), respectively.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nilotinib | Number of Participants With Loss of CCyR, MMR and CMR | CMR (n=34) | 6 Participants |
| Nilotinib | Number of Participants With Loss of CCyR, MMR and CMR | CCyR (n=93) | 0 Participants |
| Nilotinib | Number of Participants With Loss of CCyR, MMR and CMR | MMR (n=94) | 13 Participants |
Secondary
Number of Participants With Progression to Accelerated Phase/Blastic Crisis (AP/BC)
Progression to AP/BC is defined as loss of CCyR, MMR, and CMR and was summarized by frequencies and percentages.
Time frame: 4 years
Population: Full Analysis Set (FAS): The FAS included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib | Number of Participants With Progression to Accelerated Phase/Blastic Crisis (AP/BC) | 1 Participants |
Secondary
Time to CMR, CCyR and MMR
Time to CMR, CCyR, and MMR was defined as the time from the date of enrollment to the date of first documented CMR, CCyR and MMR, respectively.
Time frame: 4 years
Population: Of the 128 participants analyzed, 34 participants achieved CMR within 18 months of treatment, 93 participants achieved CCyR and did not experience loss of CCyR during the study, and 94 participants achieved MMR with up to 24 months of treatment (most achieved MMR within 12 months of treatment).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nilotinib | Time to CMR, CCyR and MMR | CMR (n=34) | NA Months |
| Nilotinib | Time to CMR, CCyR and MMR | CCyR (n=93) | 5.5 Months |
| Nilotinib | Time to CMR, CCyR and MMR | MMR (n=94) | 5.7 Months |
Secondary
Time to Progression of AP/BC
Time to progression of AP/BC was defined as the time from the date of the first dose of study drug to the date of first documented progression of AP/BC.
Time frame: 4 years
Population: Of the 128 participants analyzed, 1 participant experienced progression to AP/BC.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Time to Progression of AP/BC | NA Months |