Chronic Myelogenous Leukemia
Conditions
Keywords
Chronic, Myelogenous, Leukemia, CML, Chronic Phase, Suboptimal Response
Brief summary
There is no available data on the clinical benefit of dose escalation for patients with suboptimal response to imatinib, and patients may still improve their response with continuation of therapy at the standard dose as shown in the IRIS trial after 5 years of follow-up. However, there is no data yet regarding the potential benefit of using nilotinib in the group of patients with suboptimal response. In this study, the efficacy of nilotinib 400mg BID will be compared to imatinib 600mg QD.
Detailed description
The comparative efficacy between imatinib dose escalation (600 mg QD) and nilotinib (400 mg BID), in terms of CCyR after 6 months, for patients with CML in chronic phase with suboptimal response to imatinib standard dose will be determined.
Interventions
DRUGnilotinib
Supplied as 200 mg tablets
DRUGimatinib
Supplied as 100 mg and 400 mg tablets
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female ≥ 18 years old; 2. ECOG of 0, 1, or 2; 3. Ph+ CML in CP defined as: * \<15% blasts in peripheral blood or bone marrow; * \<30% blasts + promyelocytes in peripheral blood or bone marrow; * \<20% basophils in the peripheral blood; •≥100x109/L (≥ 100,000/mm3) platelets; * no evidence of extramedullary leukemia involvement, with the exception of hepatosplenomegaly; 4. SoR to 400 mg imatinib, defined as (min of 20 metaphases): * No cytogenetic response at ≥ 3 to \<6 months (\> 95% Ph+ metaphases);or * No PCyR at ≥ 6 to \<12 months (36 to 95% Ph+ metaphases on bone marrow); or * No CCyR at ≥ 12 to \<18 months (1 to 35% Ph+ metaphases on bone marrow); Confirmation of SoR by FISH is allowed if BMK is done outside the screening window up to 4 wks. 5. 400mg/daily imatinib (no higher doses) for at least 3months but no longer than 18 months; 6. Previous use of IFN, taken prior to imatinib treatment, is allowed at a maximum of 90 days unless reason for switch from IFN to imatinib was intolerance. 7. Parameters must be present: * Creatinine \<2.0 X ULN * Total bilirubin \<1.5 X ULN (\< 3.0 X ULN if related to disease); * SGOT and SGPT \< 2.5 X ULN; * Serum lipase ≤1.5 X ULN; * Alkaline phosphatase ≤2.5 X ULN * Serum potassium, phosphorus, magnesium and calcium ≥ LLN or corrected to WNL with supplements prior to first dose of study drug; 8. Written informed consent prior to any study procedures being performed.
Exclusion criteria
1. Prior accelerated phase including clonal evolution or blast crisis CML; 2. Prior therapy with imatinib in combination with any other CML drug other than Hydroxyurea and/or Anagrelide; 4.Imatinib therapy started more than 12 months after the date of the original diagnosis; 5.Unable to tolerate imatinib at 400mg; 6.Previous treatment with any other tyrosine kinase inhibitor except Glivec and/or CML therapy other than IFN, hydroxyurea, and /or anagrelide; 7.Myelotoxicity ≥ Grade 2 present at the time of randomization, 8.Previously documented T315I mutations; 9.Impaired cardiac function including one of these: * Long QT syndrome or family history of long QT syndrome * Clinically significant resting brachycardia (\<50 bpm) * QTcF \>450 msec on screening ECG (using the QTcF formula). If QTc \>450 and electrolytes are not with normal ranges, electrolytes should be corrected and then the patient rescreened for QTc to certify QTc \<450 msec; * Myocardial infarction ≤ 12 months prior to the first dose of study drug; * Other clinically significant heart disease (e.g., CHF, uncontrolled hypertension, unstable angina, significant ventricular or atrial tachyarrhythmias) 10. Impairment of GI function or disease that may significantly alter the absorption of study drug; 11. Treated with strong CYP3A4 inhibitors that cannot be either discontinued or switched to a different medication prior to starting study drug; 12.Currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug; 13.History of previous acute pancreatitis within one year of study entry or medical history of chronic pancreatitis; 14.Known cytopathologically confirmed CNS 15.Women who are pregnant, breast feeding or of a childbearing potential without a negative urine pregnancy test at screening. Female patients of childbearing potential unwilling to use effective contraceptive precautions throughout the trial and for 3 months post trial end. Post-menopausal women must be ammenorrheic for at least 12 months to be considered of non-childbearing potential; 16. History of another primary malignancy that is currently clinically significant or currently requires active intervention; 17.Any other clinically significant medical or surgical condition which, according to investigators' discretion, should preclude participation; 18.Use of investigational agent within 28 days prior to enrollment; 19.Patients unwilling or unable to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Cytogenetic Response (CCyR) | 6 months | CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With CCyr | 12 and 24 months | CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow. |
| Time to CCyR | 24 months | Time to CCyR was defined as time from date of randomization to date of first documented CCyR. |
| Duration of CCyR | 24 months | Duration of CCyR was defined as time from the date of ransomization to the date of first loss of CCyR or death, whichever came first. |
| Percentage of Participants With Major Molecular Response (MMR) | 12 and 24 months | MMR was defined as having a fusion gene of the Bcr and Abl genes of (BCR-ACL) less than or equal to 0.1% on the International Scale (IS). |
| Event-Free Survival (EFS) | 24 months | EFS was defined as the time from the date of randomization to the date of the first occurrence of any of the following: loss of Complete Hematological Response (CHR), loss of Partial Cytogenetic Response (PCyR), loss of CCyR, death on treatment or progression to AP/BC. |
| Overall Survival (OS) | 24 months | OS was defined as time from date of randomization to the date of the death. |
| Progression-Free Survival (PFS) | 24 months | PFS was defined as the time from the date of randomization to the date of documented disease progression to accelerated phase or blast crisis (AP/BC), or death due to any cause. |
Countries
Argentina, Brazil, China, Colombia, Germany, Guatemala, India, Mexico, Panama, Poland, Russia, Venezuela
Participant flow
Recruitment details
Participants were randomized in 1:1 ratio to imatinib 600 mg QD or nilotinib 400 mg BID for a 2 year study period.
Pre-assignment details
Cross-over from one arm to the other was allowed for intolerant patients anytime during treatment, patients who failed to achieve CCyR after 6 months of treatment, loss of response, loss of CHR, loss of best achieved cytogenetic response any time during treatment, or other reason approved by the Study Management Committee.
Participants by arm
| Arm | Count |
|---|---|
| Nilotinib Participants received 400 mg nilotinib twice daily (BID). | 96 |
| Imatinib Participants receievd 600 mg imatinib once daily (QD). | 95 |
| Total | 191 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 1 | 0 |
| Overall Study | Adverse Event | 8 | 2 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Disease progression | 7 | 3 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Protocol deviation | 2 | 6 |
| Overall Study | Treatment duration completed | 66 | 76 |
| Overall Study | Withdrawal by Subject | 9 | 5 |
Baseline characteristics
| Characteristic | Nilotinib | Imatinib | Total |
|---|---|---|---|
| Age, Continuous | 44.6 Years STANDARD_DEVIATION 14.47 | 44.2 Years STANDARD_DEVIATION 15.02 | 44.4 Years STANDARD_DEVIATION 14.75 |
| Sex: Female, Male Female | 42 Participants | 37 Participants | 79 Participants |
| Sex: Female, Male Male | 54 Participants | 58 Participants | 112 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 80 / 96 | 61 / 93 | 44 / 56 | 11 / 13 |
| serious Total, serious adverse events | 11 / 96 | 9 / 93 | 4 / 56 | 1 / 13 |
Outcome results
Primary
Percentage of Participants With Complete Cytogenetic Response (CCyR)
CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow.
Time frame: 6 months
Population: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nilotinib | Percentage of Participants With Complete Cytogenetic Response (CCyR) | 50.0 Percentage of participants |
| Imatinib | Percentage of Participants With Complete Cytogenetic Response (CCyR) | 42.1 Percentage of participants |
p-value: 0.3106Fisher Exact
Secondary
Duration of CCyR
Duration of CCyR was defined as time from the date of ransomization to the date of first loss of CCyR or death, whichever came first.
Time frame: 24 months
Population: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Duration of CCyR | NA Months |
| Imatinib | Duration of CCyR | 17.2 Months |
Secondary
Event-Free Survival (EFS)
EFS was defined as the time from the date of randomization to the date of the first occurrence of any of the following: loss of Complete Hematological Response (CHR), loss of Partial Cytogenetic Response (PCyR), loss of CCyR, death on treatment or progression to AP/BC.
Time frame: 24 months
Population: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Event-Free Survival (EFS) | NA Months |
| Imatinib | Event-Free Survival (EFS) | 24.3 Months |
Secondary
Overall Survival (OS)
OS was defined as time from date of randomization to the date of the death.
Time frame: 24 months
Population: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Overall Survival (OS) | NA Months |
| Imatinib | Overall Survival (OS) | 25.7 Months |
Secondary
Percentage of Participants With CCyr
CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow.
Time frame: 12 and 24 months
Population: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nilotinib | Percentage of Participants With CCyr | 12 months | 53.1 Percentage of participants |
| Nilotinib | Percentage of Participants With CCyr | 24 months | 51.0 Percentage of participants |
| Imatinib | Percentage of Participants With CCyr | 12 months | 55.8 Percentage of participants |
| Imatinib | Percentage of Participants With CCyr | 24 months | 61.1 Percentage of participants |
Secondary
Percentage of Participants With Major Molecular Response (MMR)
MMR was defined as having a fusion gene of the Bcr and Abl genes of (BCR-ACL) less than or equal to 0.1% on the International Scale (IS).
Time frame: 12 and 24 months
Population: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nilotinib | Percentage of Participants With Major Molecular Response (MMR) | 12 months | 36.5 Percentage of participants |
| Nilotinib | Percentage of Participants With Major Molecular Response (MMR) | 24 months | 37.5 Percentage of participants |
| Imatinib | Percentage of Participants With Major Molecular Response (MMR) | 12 months | 25.3 Percentage of participants |
| Imatinib | Percentage of Participants With Major Molecular Response (MMR) | 24 months | 35.8 Percentage of participants |
Secondary
Progression-Free Survival (PFS)
PFS was defined as the time from the date of randomization to the date of documented disease progression to accelerated phase or blast crisis (AP/BC), or death due to any cause.
Time frame: 24 months
Population: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Progression-Free Survival (PFS) | NA Months |
| Imatinib | Progression-Free Survival (PFS) | NA Months |
Secondary
Time to CCyR
Time to CCyR was defined as time from date of randomization to date of first documented CCyR.
Time frame: 24 months
Population: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nilotinib | Time to CCyR | 5.55 Months |
| Imatinib | Time to CCyR | 5.85 Months |