CLINICAL PHARMACOLOGY
Mechanism Of Action
Imatinib mesylate is a protein-tyrosine kinase inhibitor
that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine
kinase created by the Philadelphia chromosome abnormality in CML. Imatinib
inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as
well as fresh leukemic cells from Philadelphia chromosome positive chronic
myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral
blood and bone marrow samples from CML patients.
In vivo, imatinib inhibits tumor growth of BCR-ABL
transfected murine myeloid cells as well as BCR-ABL positive leukemia lines
derived from CML patients in blast crisis.
Imatinib is also an inhibitor of the receptor tyrosine
kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF),
c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib
inhibits proliferation and induces apoptosis in GIST cells, which express an
activating c-kit mutation.
Pharmacokinetics
The pharmacokinetics of Gleevec have been evaluated in
studies in healthy subjects and in population pharmacokinetic studies in over
900 patients. The pharmacokinetics of Gleevec are similar in CML and GIST
patients.
Absorption And Distribution
Imatinib is well absorbed after oral administration with
Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability is 98%.
Mean imatinib AUC increases proportionally with increasing doses ranging from
25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of
imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at steady
state when Gleevec is dosed once-daily. At clinically relevant concentrations
of imatinib, binding to plasma proteins in in vitro experiments is
approximately 95%, mostly to albumin and α1-acid glycoprotein.
Elimination
Metabolism
CYP3A4 is the major enzyme responsible for metabolism of
imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and
CYP2C19, play a minor role in its metabolism. The main circulating active
metabolite in humans is the N-demethylated piperazine derivative, formed
predominantly by CYP3A4. It shows in vitro potency similar to the parent
imatinib. The plasma AUC for this metabolite is about 15% of the AUC for
imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is
similar to that of the parent compound. Human liver microsome studies
demonstrated that Gleevec is a potent competitive inhibitor of CYP2C9, CYP2D6,
and CYP3A4/5 with Ki values of 27, 7.5, and 8 μM, respectively.
Excretion
Imatinib elimination is predominately in the feces,
mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled
dose of imatinib, approximately 81% of the dose was eliminated within 7 days,
in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted
for 25% of the dose (5% urine, 20% feces), the remainder being metabolites.
Following oral administration in healthy volunteers, the
elimination half-lives of imatinib and its major active metabolite, the
N-demethyl derivative (CGP74588), are approximately 18 and 40 hours,
respectively.
Typically, clearance of imatinib in a 50-year-old patient
weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient
weighing 100 kg the clearance will increase to 14 L/h. The inter-patient
variability of 40% in clearance does not warrant initial dose adjustment based
on body weight and/or age but indicates the need for close monitoring for
treatment-related toxicity.
Specific Populations
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics
of both imatinib and its major metabolite, CGP74588, was assessed in 84
patients with cancer and varying degrees of hepatic impairment [see Use In Specific
Populations] at imatinib doses ranging from 100 mg to 800 mg. Exposure to
both imatinib and CGP74588 was comparable between each of the mildly and
moderately hepatically-impaired groups and the normal group. Patients with
severe hepatic impairment tend to have higher exposure to both imatinib and its
metabolite than patients with normal hepatic function. At steady state, the
mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%,
respectively, in patients with severe hepatic impairment compared to patients
with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588
increased by about 56% and 55%, respectively, in patients with severe hepatic
impairment compared to patients with normal hepatic function. Dose reductions
are necessary for patients with severe hepatic impairment [see DOSAGE AND
ADMINISTRATION].
Renal Impairment
The effect of renal impairment on the pharmacokinetics of
imatinib was assessed in 59 cancer patients with varying degrees of renal
impairment [see Use In Specific Populations] at single and steady state
imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib
(dose normalized AUC) in patients with mild and moderate renal impairment
increased 1.5- to 2-fold compared to patients with normal renal function. The
AUCs did not increase for doses greater than 600 mg in patients with mild renal
impairment. The AUCs did not increase for doses greater than 400 mg in patients
with moderate renal impairment. Two patients with severe renal impairment were
dosed with 100 mg/day and their exposures were similar to those seen in
patients with normal renal function receiving 400 mg/day. Dose reductions are
necessary for patients with moderate and severe renal impairment [see DOSAGE
AND ADMINISTRATION].
Pediatric Use
As in adult patients, imatinib was rapidly absorbed after
oral administration in pediatric patients, with a Cmax of 2-4 hours. Apparent
oral clearance was similar to adult values (11.0 L/hr/m² in children vs. 10.0
L/hr/m² in adults), as was the half-life (14.8 hours in children vs. 17.1 hours
in adults). Dosing in children at both 260 mg/m² and 340 mg/m² achieved an AUC
similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs. Day 1
at 260 mg/m² and 340 mg/m² dose levels revealed a 1.5- and 2.2-fold drug
accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC
did not increase proportionally with increasing dose.
Based on pooled population pharmacokinetic analysis in
pediatric patients with hematological disorders (CML, Ph+ ALL, or other
hematological disorders treated with imatinib), clearance of imatinib increases
with increasing body surface area (BSA). After correcting for the BSA effect,
other demographics such as age, body weight and body mass index did not have clinically
significant effects on the exposure of imatinib. The analysis confirmed that
exposure of imatinib in pediatric patients receiving 260 mg/m² once-daily (not
exceeding 400 mg once-daily) or 340 mg/m² once-daily (not exceeding 600 mg
once-daily) were similar to those in adult patients who received imatinib 400
mg or 600 mg once-daily.
Drug Interactions
Agents Inducing CYP3A Metabolism
Pretreatment of healthy volunteers with multiple doses of
rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose
clearance by 3.8-fold, which significantly (p less than 0.05) decreased mean Cmax
and AUC.
Similar findings were observed in patients receiving 400
to 1200 mg/day Gleevec concomitantly with enzyme-inducing anti-epileptic drugs
(EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin,
phenobarbital, and primidone). The mean dose normalized AUC for imatinib in the
patients receiving EIAED's decreased by 73% compared to patients not receiving
EIAED.
Concomitant administration of Gleevec and St. John's Wort
led to a 30% reduction in the AUC of imatinib.
Consider alternative therapeutic agents with less enzyme
induction potential in patients when rifampin or other CYP3A4 inducers are
indicated. Gleevec doses up to 1200 mg/day (600 mg twice daily) have been given
to patients receiving concomitant strong CYP3A4 inducers [see DOSAGE AND
ADMINISTRATION].
Agents Inhibiting CYP3A Metabolism
There was a significant increase in exposure to imatinib
(mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects
when Gleevec was coadministered with a single dose of ketoconazole (a CYP3A4
inhibitor). Caution is recommended when administering Gleevec with strong
CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin,
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin, and voriconazole). Grapefruit juice may also increase plasma
concentrations of imatinib and should be avoided.
Interactions With Drugs Metabolized By CYP3A4
Gleevec increases the mean Cmax and AUC of simvastatin
(CYP3A4 substrate) 2- and 3.5-fold, respectively, suggesting an inhibition of
the CYP3A4 by Gleevec. Particular caution is recommended when administering
Gleevec with CYP3A4 substrates that have a narrow therapeutic window (e.g.,
alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide,
quinidine, sirolimus or tacrolimus).
Gleevec will increase plasma concentration of other
CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine
calcium channel blockers, certain HMG-CoA reductase inhibitors, etc.).
Because warfarin is metabolized by CYP2C9 and CYP3A4,
patients who require anticoagulation should receive low-molecular weight or
standard heparin instead of warfarin.
Interactions With Drugs Metabolized By CYP2D6
Gleevec increased the mean Cmax and AUC of metoprolol by
approximately 23% suggesting that Gleevec has a weak inhibitory effect on
CYP2D6-mediated metabolism. No dose adjustment is necessary, however, caution
is recommended when administering Gleevec with CYP2D6 substrates that have a
narrow therapeutic window.
Interactions With Acetaminophen
In vitro, Gleevec inhibits the acetaminophen
O-glucuronidate pathway (Ki 58.5 μM). Coadministration of Gleevec (400
mg/day for 8 days) with acetaminophen (1000 mg single dose on day 8) in
patients with CML did not result in any changes in the pharmacokinetics of
acetaminophen. Gleevec pharmacokinetics were not altered in the presence of
single-dose acetaminophen. There is no pharmacokinetic or safety data on the
concomitant use of Gleevec at doses greater than 400 mg/day or the chronic use
of concomitant acetaminophen and Gleevec.
Animal Toxicology And/Or Pharmacology
Toxicities From Long-Term Use
It is important to consider potential toxicities
suggested by animal studies, specifically, liver, kidney, and cardiac
toxicity and immunosuppression. Severe liver toxicity was observed in dogs
treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile
duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in
monkeys treated for 2 weeks, with focal mineralization and dilation of the
renal tubules and tubular nephrosis. Increased BUN and creatinine were observed
in several of these animals. An increased rate of opportunistic infections was
observed with chronic imatinib treatment in laboratory animal studies. In a 39
week monkey study, treatment with imatinib resulted in worsening of normally
suppressed malarial infections in these animals. Lymphopenia was observed in
animals (as in humans). Additional long-term toxicities were identified in a
2-year rat study. Histopathological examination of the treated rats that died
on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy
(females) and preputial gland papilloma as principal causes of death or reasons
for sacrifice. Non-neoplastic lesions seen in this 2-year study which were not
identified in earlier preclinical studies were the cardiovascular system,
pancreas, endocrine organs and teeth. The most important changes included cardiac
hypertrophy and dilatation, leading to signs of cardiac insufficiency in some
animals.
Clinical Studies
Chronic Myeloid Leukemia
Chronic Phase, Newly Diagnosed
An open-label, multicenter, international randomized
Phase 3 study (Gleevec versus IFN+Ara-C) has been conducted in patients with
newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia
(CML) in chronic phase. This study compared treatment with either single-agent
Gleevec or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C).
Patients were allowed to cross over to the alternative treatment arm if they
failed to show a complete hematologic response (CHR) at 6 months, a major
cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR. Patients
with increasing WBC or severe intolerance to treatment were also allowed to
cross over to the alternative treatment arm with the permission of the study
monitoring committee (SMC). In the Gleevec arm, patients were treated initially
with 400 mg daily. Dose escalations were allowed from 400 mg daily to 600 mg
daily, then from 600 mg daily to 800 mg daily. In the IFN arm, patients were
treated with a target dose of IFN of 5 MIU/m²/day subcutaneously in combination
with subcutaneous Ara-C 20 mg/m²/day for 10 days/month.
A total of 1,106 patients were randomized from 177
centers in 16 countries, 553 to each arm. Baseline characteristics were well
balanced between the two arms. Median age was 51 years (range 18 to 70 years),
with 21.9% of patients greater than or equal to 60 years of age. There were 59%
males and 41% females; 89.9% Caucasian and 4.7% black patients. At the cut-off
for this analysis (7 years after last patient had been recruited), the median
duration of first-line treatment was 82 and 8 months in the Gleevec and IFN
arm, respectively. The median duration of second-line treatment with Gleevec
was 64 months. Sixty percent of patients randomized to Gleevec are still
receiving first-line treatment. In these patients, the average dose of Gleevec
was 403 mg ± 57 mg. Overall, in patients receiving first line Gleevec, the
average daily dose delivered was 406 mg ± 76 mg. Due to discontinuations and
cross-overs, only 2% of patients randomized to IFN were still on first-line
treatment. In the IFN arm, withdrawal of consent (14%) was the most frequent
reason for discontinuation of first-line therapy, and the most frequent reason
for cross over to the Gleevec arm was severe intolerance to treatment (26%) and
progression (14%).
The primary efficacy endpoint of the study was
progression-free survival (PFS). Progression was defined as any of the
following events: progression to accelerated phase or blast crisis (AP/BC),
death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing
WBC despite appropriate therapeutic management. The protocol specified that the
progression analysis would compare the intent to treat (ITT) population:
patients randomized to receive Gleevec were compared with patients randomized
to receive IFN. Patients that crossed over prior to progression were not
censored at the time of cross-over, and events that occurred in these patients
following cross-over were attributed to the original randomized treatment. The
estimated rate of progression-free survival at 84 months in the ITT population
was 81.2 % [95% CI: 78, 85] in the Gleevec arm and 60.6 % [56, 65] in the IFN
arm (p less than 0.0001, log-rank test), (Figure 1). With 7 years follow up
there were 93 (16.8%) progression events in the Gleevec arm: 37(6.7%) progression
to AP/BC, 31 (5.6%) loss of MCyR, 15 (2.7%) loss of CHR or increase in WBC and
10 (1.8%) CML unrelated deaths. In contrast, there were 165 (29.8%) events in
the IFN+Ara-C arm of which 130 occurred during first-line treatment with
IFN-Ara-C. The estimated rate of patients free of progression to accelerated
phase (AP) or blast crisis (BC) at 84 months was 92.5%[90, 95] in the Gleevec
arm compared to the 85.1%, [82, 89] (p less than or equal to 0.001) in the IFN
arm, (Figure 2). The annual rates of any progression events have decreased with
time on therapy. The probability of remaining progression free at 60 months was
95% for patients who were in complete cytogenetic response (CCyR) with
molecular response (greater than or equal to 3 log reduction in BCR-ABL
transcripts as measured by quantitative reverse transcriptase polymerase chain
reaction) at 12 months, compared to 89% for patients in complete cytogenetic
response but without a major molecular response and 70% in patients who were
not in complete cytogenetic response at this time point (p less than 0.001).
Figure 1: Progression Free Survival (ITT Principle)
Figure 2: Time to Progression to AP or BC (ITT
Principle)
 |
A total of 71 (12.8%) and 85 (15.4%) patients died in the
Gleevec and IFN+Ara-C group, respectively. At 84 months the estimated overall
survival is 86.4% (83, 90) vs. 83.3% (80, 87) in the randomized Gleevec and the
IFN+Ara-C group, respectively (p=0.073 log-rank test). The hazard ratio is
0.750 with 95% CI 0.547-1.028. This time-to-event endpoint may be affected by
the high crossover rate from IFN+Ara-C to Gleevec. Major cytogenetic response,
hematologic response, evaluation of minimal residual disease (molecular response),
time to accelerated phase or blast crisis and survival were main secondary
endpoints. Response data are shown in Table 18. Complete hematologic response,
major cytogenetic response and complete cytogenetic response were also
statistically significantly higher in the Gleevec arm compared to the IFN +
Ara-C arm (no cross-over data considered for evaluation of responses). Median
time to CCyR in the 454 responders was 6 months (range 2 to 64 months, 25th to
75th percentiles=3 to 11 months) with 10% of responses seen only after 22
months of therapy.
Table 18: Response in Newly Diagnosed CML Study
(84-Month Data)
(Best Response Rate) |
n=553 |
n=553 |
Hematologic Response1 |
CHR Rate n (%) |
534 (96.6%)* |
313 (56.6%)* |
[95% CI] |
[94.7%, 97.9%] |
[52.4%, 60.8%] |
Cytogenetic Response2 |
Major Cytogenetic Response n (%) |
472 (85.4 %)* |
93 (16.8%)* |
[95% CI] |
[82.1%, 88.2%] |
[13.8%, 20.2%] |
Unconfirmed3 |
88.6%* |
23.3%* |
Complete Cytogenetic Response n (%) |
413 (74.7%)* |
36 (6.5%)* |
[95% CI] |
[70.8, 78.3] |
[4.6, 8.9] |
Unconfirmed3 |
82.5%* |
11.6%* |
*p less than 0.001, Fischer’s exact test
1Hematologic response criteria (all responses to be confirmed after
greater than or equal to 4 weeks): WBC less than 10 x 109/L, platelet less than
450 x 109/L, myelocyte + metamyelocyte less than 5% in blood, no blasts and
promyelocytes in blood, no extramedullary involvement.
2Cytogenetic response criteria (confirmed after greater than or
equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1%–35%). A major
response (0%–35%) combines both complete and partial responses.
3Unconfirmed cytogenetic response is based on a single bone marrow
cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic
responses might have had a lesser cytogenetic response on a subsequent bone
marrow evaluation. |
Molecular response was defined as follows: in the
peripheral blood, after 12 months of therapy, reduction of greater than or
equal to 3 logarithms in the amount of BCR-ABL transcripts (measured by
real-time quantitative reverse transcriptase PCR assay) over a standardized
baseline. Molecular response was only evaluated in a subset of patients who had
a complete cytogenetic response by 12 months or later (N=333). The molecular
response rate in patients who had a complete cytogenetic response in the
Gleevec arm was 59% at 12 months and 72% at 24 months.
Physical, functional, and treatment-specific biologic
response modifier scales from the FACT-BRM (Functional Assessment of Cancer
Therapy - Biologic Response Modifier) instrument were used to assess
patient-reported general effects of interferon toxicity in 1,067 patients with
CML in chronic phase. After one month of therapy to 6 months of therapy, there
was a 13% to 21% decrease in median index from baseline in patients treated
with IFN, consistent with increased symptoms of IFN toxicity. There was no
apparent change from baseline in median index for patients treated with
Gleevec.
An open-label, multicenter, randomized trial (Gleevec
versus nilotinib) was conducted to determine the efficacy of Gleevec versus
nilotinib in adult patients with cytogenetically confirmed, newly diagnosed Ph+
CML-CP. Patients were within 6 months of diagnosis and were previously
untreated for CML-CP, except for hydroxyurea and/or anagrelide. Efficacy was
based on a total of 846 patients: 283 patients in the Gleevec 400 mg once daily
group, 282 patients in the nilotinib 300 mg twice daily group, 281 patients in
the nilotinib 400 mg twice daily group.
Median age was 46 years in the Gleevec group and 47 years
in both nilotinib groups, with 12%, 13%, and 10% of patients greater than or
equal to 65 years of age in Gleevec 400 mg once-daily, nilotinib 300 mg twice
daily and nilotinib 400 mg twice daily treatment groups, respectively. There
were slightly more male than female patients in all groups (56%, 56%, and 62%
in Gleevec 400 mg once-daily, nilotinib 300 mg twice-daily and nilotinib 400 mg
twice-daily treatment groups, respectively). More than 60% of all patients were
Caucasian, and 25% were Asian.
The primary data analysis was performed when all 846
patients completed 12 months of treatment or discontinued earlier. Subsequent
analyses were done when patients completed 24, 36, 48 and 60 months of
treatment or discontinued earlier. The median time on treatment was
approximately 61 months in all three treatment groups.
The primary efficacy endpoint was major molecular
response (MMR) at 12 months after the start of study medication. MMR was
defined as less than or equal to 0.1% BCR-ABL/ABL % by international scale
measured by RQ-PCR, which corresponds to a greater than or equal to3 log
reduction of BCR-ABL transcript from standardized baseline. Efficacy endpoints
are summarized in Table 19.
Twelve patients in the Gleevec arm progressed to either
accelerated phase or blast crises (7 patients within first 6 months, 2 patients
within 6 to 12 months, 2 patients within 12 to 18 months and 1 patient within
18 to 24 months) while two patients on the nilotinib arm progressed to either
accelerated phase or blast crisis (both within the first 6 months of
treatment).
Table 19: Efficacy (MMR and CCyR) of Gleevec Compared
to Nilotinib in Newly Diagnosed Ph+ CML-CP
|
Gleevec 400 mg once daily
N=283 |
nilotinib 300 mg twice daily
N=282 |
MMR at 12 months (95% CI) |
22% (17.6, 27.6) |
44% (38.4, 50.3) |
P-Valuea |
< 0.0001 |
CCyRb by 12 months (95% CI) |
65% (59.2, 70.6) |
80% (75.0, 84.6) |
MMR at 24 months (95% CI) |
38% (31.8, 43.4) |
62% (55.8, 67.4) |
CCyRb by 24 months (95% CI) |
77% (71.7, 81.8) |
87% (82.4, 90.6) |
aCMH test stratified by Sokal risk group
bCCyR: 0% Ph+ metaphases. Cytogenetic responses were based on the
percentage of Ph-positive metaphases among greater than or equal to20 metaphase
cells in each bone marrow sample. |
By the 60 months, MMR was achieved by 60% of patients on
Gleevec and 77% of patients on nilotinib.
Median overall survival was not reached in either arm. At
the time of the 60-month final analysis, the estimated survival rate was 91.7%
for patients on Gleevec and 93.7% for patients on nilotinib.
Late Chronic Phase CML And Advanced Stage CML
Three international, open-label, single-arm Phase 2
studies were conducted to determine the safety and efficacy of Gleevec in
patients with Ph+ CML: 1) in the chronic phase after failure of IFN therapy, 2)
in accelerated phase disease, or 3) in myeloid blast crisis. About 45% of
patients were women and 6% were black. In clinical studies, 38% to 40% of
patients were greater than or equal to 60 years of age and 10% to 12% of
patients were greater than or equal to 70 years of age.
Chronic Phase, Prior Interferon-Alpha Treatment
532 patients were treated at a starting dose of 400 mg;
dose escalation to 600 mg was allowed. The patients were distributed in three
main categories according to their response to prior interferon: failure to
achieve (within 6 months), or loss of a complete hematologic response (29%),
failure to achieve (within 1 year) or loss of a major cytogenetic response
(35%), or intolerance to interferon (36%). Patients had received a median of 14
months of prior IFN therapy at doses greater than or equal to 25 x 106 IU/week
and were all in late chronic phase, with a median time from diagnosis of 32
months. Effectiveness was evaluated on the basis of the rate of hematologic
response and by bone marrow exams to assess the rate of major cytogenetic
response (up to 35% Ph+ metaphases) or complete cytogenetic response (0% Ph+
metaphases). Median duration of treatment was 29 months with 81% of patients
treated for greater than or equal to 24 months (maximum = 31.5 months). Efficacy
results are reported in Table 20. Confirmed major cytogenetic response rates
were higher in patients with IFN intolerance (66%) and cytogenetic failure
(64%), than in patients with hematologic failure (47%). Hematologic response
was achieved in 98% of patients with cytogenetic failure, 94% of patients with
hematologic failure, and 92% of IFN-intolerant patients.
Accelerated Phase
235 patients with accelerated phase disease were
enrolled. These patients met one or more of the following criteria: greater
than or equal to 15% - less than 30% blasts in PB or BM; greater than or equal
to 30% blasts + promyelocytes in PB or BM; greater than or equal to 20%
basophils in PB; and less than 100 x 109/L platelets. The first 77 patients
were started at 400 mg, with the remaining 158 patients starting at 600 mg.
Effectiveness was evaluated primarily on the basis of the
rate of hematologic response, reported as either complete hematologic response,
no evidence of leukemia (i.e., clearance of blasts from the marrow and the
blood, but without a full peripheral blood recovery as for complete responses),
or return to chronic phase CML. Cytogenetic responses were also evaluated.
Median duration of treatment was 18 months with 45% of patients treated for
greater than or equal to 24 months (maximum=35 months). Efficacy results are
reported in Table 20. Response rates in accelerated phase CML were higher for
the 600 mg dose group than for the 400 mg group: hematologic response (75% vs.
64%), confirmed and unconfirmed major cytogenetic response (31% vs. 19%).
Myeloid Blast Crisis
260 patients with myeloid blast crisis were enrolled.
These patients had greater than or equal to 30% blasts in PB or BM and/or
extramedullary involvement other than spleen or liver; 95 (37%) had received
prior chemotherapy for treatment of either accelerated phase or blast crisis
(“pretreated patients”) whereas 165 (63%) had not (“untreated patients”). The
first 37 patients were started at 400 mg; the remaining 223 patients were
started at 600 mg.
Effectiveness was evaluated primarily on the basis of
rate of hematologic response, reported as either complete hematologic response,
no evidence of leukemia, or return to chronic phase CML using the same criteria
as for the study in accelerated phase. Cytogenetic responses were also
assessed. Median duration of treatment was 4 months with 21% of patients
treated for greater than or equal to 12 months and 10% for greater than or
equal to 24 months (maximum=35 months). Efficacy results are reported in Table
20. The hematologic response rate was higher in untreated patients than in
treated patients (36% vs. 22%, respectively) and in the group receiving an
initial dose of 600 mg rather than 400 mg (33% vs. 16%). The confirmed and
unconfirmed major cytogenetic response rate was also higher for the 600 mg dose
group than for the 400 mg dose group (17% vs. 8%).
Table 20: Response in CML Studies
|
Chronic Phase IFN Failure
(n=532) 400 mg |
Accelerated Phase
(n=235) 600 mg n=158 400 mg n=77 % of patients [CI 95%] |
Myeloid ]last Crisis
(n=260) 600 mg n=223 400 mg n=37 |
Hematologic Response1 |
95%
[92.3-96.3] |
71%
[64.8-76.8] |
31%
[25.2-36.8] |
Complete Hematologic Response (CHR) |
95% |
38% |
7% |
No Evidence of Leukemia (NEL) |
Not applicable |
13% |
5% |
Return to Chronic Phase (RTC) |
Not applicable |
20% |
18% |
Major Cytogenetic Response2 |
60%
[55.3-63.8] |
21%
[16.2-27.1] |
7%
[4.5-11.2] |
(Unconfirmed3) |
(65%) |
(27%) |
(15%) |
Complete4 (Unconfirmed3) |
39% (47%) |
16% (20%) |
2% (7%) |
1Hematologic response criteria (all responses
to be confirmed after greater than or equal to 4 weeks):
CHR:Chronic phase study [WBC less than 10 x 109/L, platelet less than 450 x 109/L,
myelocytes + metamyelocytes less than 5% in blood, no blasts and promyelocytes
in blood, basophils less than 20%, no extramedullary involvement] and in the
accelerated and blast crisis studies [ANC greater than or equal to 1.5 x 109/L,
platelets greater than or equal to 100 x 109/L, no blood blasts, BM blasts less
than 5% and no extramedullary disease]
NEL: Same criteria as for CHR but ANC greater than or equal to 1 x 109/L and
platelets greater than or equal to 20 x 109/L (accelerated and blast crisis
studies)
RTC: less than 15% blasts BM and PB, less than 30% blasts + promyelocytes in BM
and PB, less than 20% basophils in PB, no extramedullary disease other than
spleen and liver (accelerated and blast crisis studies).
BM=bone marrow, PB=peripheral blood
2Cytogenetic response criteria (confirmed after greater than or
equal to 4 weeks): complete (0% Ph+ metaphases) or partial (1%–35%). A major
response (0%–35%) combines both complete and partial responses.
3Unconfirmed cytogenetic response is based on a single bone marrow
cytogenetic evaluation, therefore unconfirmed complete or partial cytogenetic
responses might have had a lesser cytogenetic response on a subsequent bone
marrow evaluation.
4Complete cytogenetic response confirmed by a second bone marrow
cytogenetic evaluation performed at least 1 month after the initial bone marrow
study. |
The median time to hematologic response was 1 month. In
late chronic phase CML, with a median time from diagnosis of 32 months, an
estimated 87.8% of patients who achieved MCyR maintained their response 2 years
after achieving their initial response. After 2 years of treatment, an
estimated 85.4% of patients were free of progression to AP or BC, and estimated
overall survival was 90.8% [88.3, 93.2]. In accelerated phase, median duration
of hematologic response was 28.8 months for patients with an initial dose of
600 mg (16.5 months for 400 mg). An estimated 63.8% of patients who achieved
MCyR were still in response 2 years after achieving initial response. The
median survival was 20.9 [13.1, 34.4] months for the 400 mg group and was not
yet reached for the 600 mg group (p=0.0097). An estimated 46.2% [34.7, 57.7] vs.
65.8% [58.4, 73.3] of patients were still alive after 2 years of treatment in
the 400 mg vs. 600 mg dose groups, respectively. In blast crisis, the estimated
median duration of hematologic response is 10 months. An estimated 27.2% [16.8,
37.7] of hematologic responders maintained their response 2 years after
achieving their initial response. Median survival was 6.9 [5.8, 8.6] months,
and an estimated 18.3% [13.4, 23.3] of all patients with blast crisis were
alive 2 years after start of study.
Efficacy results were similar in men and women and in
patients younger and older than age 65. Responses were seen in black patients,
but there were too few black patients to allow a quantitative comparison.
Pediatric CML
A total of 51 pediatric patients with newly diagnosed and
untreated CML in chronic phase were enrolled in an open-label, multicenter,
single-arm Phase 2 trial. Patients were treated with Gleevec 340 mg/m²/day,
with no interruptions in the absence of dose limiting toxicity. Complete
hematologic response (CHR) was observed in 78% of patients after 8 weeks of
therapy. The complete cytogenetic response rate (CCyR) was 65%, comparable to
the results observed in adults. Additionally, partial cytogenetic response
(PCyR) was observed in 16%. The majority of patients who achieved a CCyR developed
the CCyR between months 3 and 10 with a median time to response based on the
Kaplan-Meier estimate of 6.74 months. Patients were allowed to be removed from
protocol therapy to undergo alternative therapy including hematopoietic stem
cell transplantation. Thirty-one children received stem cell transplantation.
Of the 31 children, 5 were transplanted after disease progression on study and
1 withdrew from study during first week treatment and received transplant
approximately 4 months after withdrawal. Twenty-five children withdrew from
protocol therapy to undergo stem cell transplant after receiving a median of 9
twenty-eight day courses (range 4 to 24). Of the 25 patients 13 (52%) had CCyR
and 5 (20%) had PCyR at the end of protocol therapy.
One open-label, single-arm study enrolled 14 pediatric
patients with Ph+ chronic phase CML recurrent after stem cell transplant or
resistant to interferon-alpha therapy. These patients had not previously
received Gleevec and ranged in age from 3 to 20 years old; 3 were 3 to 11 years
old, 9 were 12 to 18 years old, and 2 were greater than 18 years old. Patients
were treated at doses of 260 mg/m²/day (n=3), 340 mg/m²/day (n=4), 440 mg/m²/day
(n=5) and 570 mg/m²/day (n=2). In the 13 patients for whom cytogenetic data are
available, 4 achieved a major cytogenetic response, 7 achieved a complete
cytogenetic response, and 2 had a minimal cytogenetic response.
In a second study, 2 of 3 patients with Ph+ chronic phase
CML resistant to interferon-alpha therapy achieved a complete cytogenetic
response at doses of 242 and 257 mg/m²/day.
Acute Lymphoblastic Leukemia
A total of 48 Philadelphia chromosome positive acute
lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were
studied, 43 of whom received the recommended Gleevec dose of 600 mg/day. In
addition 2 patients with relapsed/refractory Ph+ ALL received Gleevec 600
mg/day in a Phase 1 study.
Confirmed and unconfirmed hematologic and cytogenetic
response rates for the 43 relapsed/refractory Ph+ALL Phase 2 study patients and
for the 2 Phase 1 patients are shown in Table 21. The median duration of
hematologic response was 3.4 months and the median duration of MCyR was 2.3
months.
Table 21: Effect of Gleevec on Relapsed/Refractory Ph+
ALL
|
Phase 2 Study
(N=43) n(%) |
Phase 1 Study
(N=2) n(%) |
CHR |
8 (19) |
2(100) |
NEL |
5 (12) |
|
RTC/PHR |
11 (26) |
|
MCyR |
15 (35) |
|
CCyR |
9 (21) |
|
PCyR |
6 (14) |
|
Pediatric ALL
Pediatric and young adult patients with very high risk
ALL, defined as those with an expected 5-year event-free survival (EFS) less
than 45%, were enrolled after induction therapy on a multicenter,
non-randomized cooperative group pilot protocol.
The safety and effectiveness of Gleevec (340 mg/m²/day)
in combination with intensive chemotherapy was evaluated in a subgroup of
patients with Ph+ ALL. The protocol included intensive chemotherapy and
hematopoietic stem cell transplant after 2 courses of chemotherapy for patients
with an appropriate HLA-matched family donor. There were 92 eligible patients
with Ph+ ALL enrolled. The median age was 9.5 years (1 to 21 years: 2.2%
between 1 and less than 2 years, 56.5% between 2 and less than 12 years, 34.8%
between 12 and less than 18 years, and 6.5% between 18 and 21 years).
Sixty-four percent were male, 75% were white, 9% were Asian/Pacific Islander,
and 5% were black. In 5 successive cohorts of patients, Gleevec exposure was systematically
increased by earlier introduction and prolonged duration. Cohort 1 received the
lowest intensity and cohort 5 received the highest intensity of Gleevec
exposure.
There were 50 patients with Ph+ ALL assigned to cohort 5
all of whom received Gleevec plus chemotherapy; 30 were treated exclusively
with chemotherapy and Gleevec and 20 received chemotherapy plus Gleevec and
then underwent hematopoietic stem cell transplant, followed by further Gleevec
treatment. Patients in cohort 5 treated with chemotherapy received continuous
daily exposure to Gleevec beginning in the first course of post induction
chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy.
During maintenance cycles 5 through 12 Gleevec was administered 28 days out of
the 56 day cycle. Patients who underwent hematopoietic stem cell transplant
received 42 days of Gleevec prior to HSCT, and 28 weeks (196 days) of Gleevec
after the immediate post transplant period. The estimated 4-year EFS of
patients in cohort 5 was 70% (95% CI: 54, 81). The median follow-up time for
EFS at data cutoff in cohort 5 was 40.5 months.
Myelodysplastic/Myeloproliferative Diseases
An open-label, multicenter, Phase 2 clinical trial was
conducted testing Gleevec in diverse populations of patients suffering from
life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine
kinases. This study included 7 patients with MDS/MPD. These patients were
treated with Gleevec 400 mg daily. The ages of the enrolled patients ranged from
20 to 86 years. A further 24 patients with MDS/MPD aged 2 to 79 years were
reported in 12 published case reports and a clinical study. These patients also
received Gleevec at a dose of 400 mg daily with the exception of three patients
who received lower doses. Of the total population of 31 patients treated for
MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a
major cytogenetic response (including 10 with a complete cytogenetic response).
Sixteen patients had a translocation, involving chromosome 5q33 or 4q12,
resulting in a PDGFR gene re-arrangement. All of these patients responded
hematologically (13 completely). Cytogenetic response was evaluated in 12 out
of 14 patients, all of whom responded (10 patients completely). Only 1 (7%) out
of the 14 patients without a translocation associated with PDGFR gene
re-arrangement achieved a complete hematological response and none achieved a
major cytogenetic response. A further patient with a PDGFR gene re-arrangement
in molecular relapse after bone marrow transplant responded molecularly. Median
duration of therapy was 12.9 months (0.8 to 26.7) in the 7 patients treated
within the Phase 2 study and ranged between 1 week and more than 18 months in
responding patients in the published literature. Results are provided in Table
22. Response durations of Phase 2 study patients ranged from 141+ days to 457+
days.
Table 22: Response in MDS/MPD
|
Number of patients N |
Complete Hematologic Response
n (%) |
Major Cytogenetic Response
n (%) |
Overall Population |
31 |
14 (45) |
12 (39) |
Chromosome 5 Translocation |
14 |
11 (79) |
11 (79) |
Chromosome 4 Translocation |
2 |
2(100) |
1 (50) |
Others / no Translocation |
14 |
1 (7) |
0 |
Molecular Relapse |
1 |
NE1 |
NE1 |
1 NE: Not Evaluable |
Aggressive Systemic Mastocytosis
One open-label, multicenter, Phase 2 study was conducted
testing Gleevec in diverse populations of patients with life-threatening
diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study
included 5 patients with ASM treated with 100 mg to 400 mg of Gleevec daily.
These 5 patients ranged from 49 to 74 years of age. In addition to these 5
patients, 10 published case reports and case series describe the use of Gleevec
in 23 additional patients with ASM aged 26 to 85 years who also received 100 mg
to 400 mg of Gleevec daily.
Cytogenetic abnormalities were evaluated in 20 of the 28
ASM patients treated with Gleevec from the published reports and in the Phase 2
study. Seven of these 20 patients had the FIP1L1-PDGFRα fusion kinase (or
CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly
males and had eosinophilia associated with their systemic mast cell disease.
Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and
one K509I) and four patients had a D816V c-Kit mutation (not considered
sensitive to Gleevec), one with concomitant CML.
Of the 28 patients treated for ASM, 8 (29%) achieved a
complete hematologic response and 9 (32%) a partial hematologic response (61%
overall response rate). Median duration of Gleevec therapy for the 5 ASM
patients in the Phase 2 study was 13 months (range 1.4 to 22.3 months) and
between 1 month and more than 30 months in the responding patients described in
the published medical literature. A summary of the response rates to Gleevec in
ASM is provided in Table 23. Response durations of literature patients ranged
from 1+ to 30+ months.
Table 23: Response in ASM
Cytogenetic Abnormality |
Number of Patients
N |
Complete Hematologic Response
N (%) |
Partial Hematologic Response
N (%) |
FIP1L1-PDGFRα Fusion Kinase (or CHIC2 Deletion) |
7 |
7(100) |
0 |
Juxtamembrane Mutation |
2 |
0 |
2(100) |
Unknown or No Cytogenetic Abnormality Detected |
15 |
0 |
7 (44) |
D816V Mutation |
4 |
1* (25) |
0 |
Total |
28 |
8 (29) |
9 (32) |
*Patient had concomitant CML and ASM |
Gleevec has not been shown to be effective in patients
with less aggressive forms of systemic mastocytosis (SM). Gleevec is therefore
not recommended for use in patients with cutaneous mastocytosis, indolent
systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM
with an associated clonal hematological non-mast cell lineage disease, mast
cell leukemia, mast cell sarcoma or extracutaneous mastocytoma. Patients that
harbor the D816V mutation of c-Kit are not sensitive to Gleevec and should not
receive Gleevec.
Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia
One open-label, multicenter, Phase 2 study was conducted
testing Gleevec in diverse populations of patients with life-threatening
diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study
included 14 patients with Hypereosinophilic Syndrome/Chronic Eosinophilic
Leukemia (HES/CEL). HES patients were treated with 100 mg to 1000 mg of Gleevec
daily. The ages of these patients ranged from 16 to 64 years. A further 162
patients with HES/CEL aged 11 to 78 years were reported in 35 published case
reports and case series. These patients received Gleevec at doses of 75 mg to
800 mg daily. Hematologic response rates are summarized in Table 24. Response
durations for literature patients ranged from 6+ weeks to 44 months.
Table 24: Response in HES/CEL
Cytogenetic Abnormality |
Number of Patients |
Complete Hematological Response N (%) |
Partial Hematological Response N (%) |
Positive FIP1L1-PDGFRa Fusion Kinase |
61 |
61(100) |
0 |
Negative FIP1L1-PDGFRa Fusion Kinase |
56 |
12 (21) |
9 (16) |
Unknown Cytogenetic Abnormality |
59 |
34 (58) |
7 (12) |
Total |
176 |
107 (61) |
23 (13) |
Dermatofibrosarcoma Protuberans
Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous
soft tissue sarcoma. It is characterized by a translocation of chromosomes 17
and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the
PDGF B gene.
An open-label, multicenter, Phase 2 study was conducted
testing Gleevec in a diverse population of patients with life-threatening
diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study
included 12 patients with DFSP who were treated with Gleevec 800 mg daily (age
range 23 to 75 years). DFSP was metastatic, locally recurrent following initial
surgical resection and not considered amenable to further surgery at the time
of study entry. A further 6 DFSP patients treated with Gleevec are reported in
5 published case reports, their ages ranging from 18 months to 49 years. The
total population treated for DFSP therefore comprises 18 patients, 8 of them
with metastatic disease. The adult patients reported in the published literature
were treated with either 400 mg (4 cases) or 800 mg (1 case) Gleevec daily. A
single pediatric patient received 400 mg/m²/daily, subsequently increased to
520 mg/m²/daily. Ten patients had the PDGF B gene rearrangement, 5 had no
available cytogenetics and 3 had complex cytogenetic abnormalities. Responses
to treatment are described in Table 25.
Table 25: Response in DFSP
|
Number of Patients
(n=18) |
% |
Complete Response |
7 |
39 |
Partial Response * |
8 |
44 |
Total Responders |
15 |
83 |
*5 patients made disease free by surgery |
Twelve of these 18 patients either achieved a complete
response (7 patients) or were made disease free by surgery after a partial
response (5 patients, including one child) for a total complete response rate
of 67%. A further 3 patients achieved a partial response, for an overall
response rate of 83%. Of the 8 patients with metastatic disease, five responded
(62%), three of them completely (37%). For the 10 study patients with the PDGF
B gene rearrangement, there were 4 complete and 6 partial responses. The median
duration of response in the Phase 2 study was 6.2 months, with a maximum
duration of 24.3 months, while in the published literature it ranged between 4
weeks and more than 20 months.
Gastrointestinal Stromal Tumors
Unresectable And/Or Malignant Metastatic GIST
Two open-label, randomized, multinational Phase 3 studies
were conducted in patients with unresectable or metastatic malignant
gastrointestinal stromal tumors (GIST). The two study designs were similar
allowing a predefined combined analysis of safety and efficacy. A total of 1640
patients were enrolled into the two studies and randomized 1:1 to receive
either 400 mg or 800 mg orally daily continuously until disease progression or
unacceptable toxicity. Patients in the 400 mg daily treatment group who
experienced disease progression were permitted to crossover to receive
treatment with 800 mg daily. The studies were designed to compare response
rates, progression-free survival and overall survival between the dose groups.
Median age at patient entry was 60 years. Males comprised 58% of the patients
enrolled. All patients had a pathologic diagnosis of CD117 positive
unresectable and/or metastatic malignant GIST.
The primary objective of the two studies was to evaluate
either progression-free survival (PFS) with a secondary objective of overall
survival (OS) in one study or overall survival with a secondary objective of
PFS in the other study. A planned analysis of both OS and PFS from the combined
datasets from these two studies was conducted. Results from this combined
analysis are shown in Table 26.
Table 26: Overall Survival, Progression-Free Survival
and Tumor Response Rates in the Phase 3 GIST Trials
|
Gleevec 400 mg
N=818 |
Gleevec 800 mg
N=822 |
Progression-Free Survival (months) |
Median |
18.9 |
23.2 |
95% CI |
17.4-21.2 |
20.8-24.9 |
Overall Survival (months) |
49.0 |
48.7 |
95% CI |
45.3-60.0 |
45.3-51.6 |
Best Overall Tumor Response |
Complete Response (CR) |
43 (5.3%) |
41 (5.0%) |
Partial Response (PR) |
377 (46.1%) |
402 (48.9%) |
Median follow up for the combined studies was 37.5
months. There were no observed differences in overall survival between the
treatment groups (p=0.98). Patients who crossed over following disease
progression from the 400 mg/day treatment group to the 800 mg/day treatment
group (n=347) had a 3.4 month median and a 7.7 month mean exposure to Gleevec
following crossover.
One open-label, multinational Phase 2 study was conducted
in patients with Kit (CD117) positive unresectable or metastatic malignant
GIST. In this study, 147 patients were enrolled and randomized to receive
either 400 mg or 600 mg orally every day for up to 36 months. The primary
outcome of the study was objective response rate. Tumors were required to be
measurable at entry in at least one site of disease, and response
characterization was based on Southwestern Oncology Group (SWOG) criteria.
There were no differences in response rates between the 2 dose groups. The
response rate was 68.5% for the 400 mg group and 67.6% for the 600 mg group.
The median time to response was 12 weeks (range was 3 to 98 weeks) and the
estimated median duration of response is 118 weeks (95% CI: 86, not reached).
Adjuvant Treatment Of GIST
In the adjuvant setting, Gleevec was investigated in a
multicenter, double-blind, placebo-controlled, randomized trial involving 713
patients (Study 1). Patients were randomized one to one to Gleevec at 400
mg/day or matching placebo for 12 months. The ages of these patients ranged
from 18 to 91 years. Patients were included who had a histologic diagnosis of
primary GIST, expressing KIT protein by immunochemistry and a tumor size
greater than or equal to 3 cm in maximum dimension with complete gross
resection of primary GIST within 14 to 70 days prior to registration.
Recurrence-free survival (RFS) was defined as the time
from date of randomization to the date of recurrence or death from any cause.
In a planned interim analysis, the median follow up was 15 months in patients
without a RFS event; there were 30 RFS events in the 12-month Gleevec arm
compared to 70 RFS events in the placebo arm with a hazard ratio of 0.398 (95%
CI: 0.259, 0.610), p less than 0.0001. After the interim analysis of RFS, 79 of
the 354 patients initially randomized to the placebo arm were eligible to cross
over to the 12-month Gleevec arm. Seventy-two of these 79 patients subsequently
crossed over to Gleevec therapy. In an updated analysis, the median follow-up
for patients without a RFS event was 50 months. There were 74 (21%) RFS events
in the 12-month Gleevec arm compared to 98 (28%) events in the placebo arm with
a hazard ratio of 0.718 (95% CI: 0.531-0.971) (Figure 3). The median follow-up
for OS in patients still living was 61 months. There were 26 (7%) and 33 (9%)
deaths in the 12-month Gleevec and placebo arms, respectively with a hazard
ratio of 0.816 (95% CI: 0.488-1.365).
Figure 3: Study 1 Recurrence-Free Survival (ITT
Population)
A second randomized, multicenter, open-label, Phase 3
trial in the adjuvant setting (Study 2) compared 12 months of Gleevec treatment
to 36 months of Gleevec treatment at 400 mg/day in adult patients with KIT
(CD117) positive GIST after surgical resection with one of the following: tumor
diameter greater than 5 cm and mitotic count greater than 5/50 high power
fields (HPF), or tumor diameter greater than 10 cm and any mitotic count, or
tumor of any size with mitotic count greater than 10/50 HPF, or tumors ruptured
into the peritoneal cavity. There were a total of 397 patients randomized in
the trial with 199 patients on the 12-month treatment arm and 198 patients on
the 36-month treatment arm. The median age was 61 years (range 22 to 84 years).
RFS was defined as the time from date of randomization to
the date of recurrence or death from any cause. The median follow-up for
patients without a RFS event was 42 months. There were 84 (42%) RFS events in the
12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm.
Thirty-six months of Gleevec treatment significantly prolonged RFS compared to
12 months of Gleevec treatment with a hazard ratio of 0.46 (95% CI: 0.32,
0.65), p less than 0.0001 (Figure 4).
The median follow-up for overall survival (OS) in
patients still living was 48 months. There were 25 (13%) deaths in the 12-month
treatment arm and 12 (6%) deaths in the 36-month treatment arm. Thirty-six
months of Gleevec treatment significantly prolonged OS compared to 12 months of
Gleevec treatment with a hazard ratio of 0.45 (95% CI: 0.22, 0.89), p=0.0187
(Figure 5).
Figure 4: Study 2 Recurrence-Free Survival (ITT
Population)
Figure 5: Study 2 Overall Survival (ITT Population)
REFERENCES
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