CLINICAL PHARMACOLOGY
Mechanism Of Action
Enzymes convert capecitabine to 5-fluorouracil (5-FU) in
vivo. Both normal and tumor cells metabolize 5-FU to 5-fluoro-2'-deoxyuridine
monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These
metabolites cause cell injury by two different mechanisms. First, FdUMP and the
folate cofactor,
N5-10 -methylenetetrahydrofolate, bind to
thymidylate synthase (TS) to form a covalently bound ternary complex. This
binding inhibits the formation of thymidylate from 2'-deoxyuridylate.
Thymidylate is the necessary precursor of thymidine triphosphate, which is
essential for the synthesis of DNA, so that a deficiency of this compound can
inhibit cell division. Second, nuclear transcriptional enzymes can mistakenly
incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of
RNA. This metabolic error can interfere with RNA processing and protein
synthesis.
Pharmacokinetics
Absorption
Following oral administration of 1255 mg/m BID to cancer
patients, capecitabine reached peak blood levels in about 1.5 hours (T ) with
peak 5-FU levels occurring slightly later, at 2 hours. Food reduced both the
rate and extent of absorption of capecitabine with mean C and AUC decreased by
60% and 35%, respectively. The C and AUC of 5-FU were also reduced by food by
43% and 21%, respectively. Food delayed T of both parent and 5-FU by 1.5 hours [see
WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION, and Drug-Food
Interaction].
The pharmacokinetics of capecitabine and its metabolites
have been evaluated in about 200 cancer patients over a dosage range of 500 to
3500 mg/m /day. Over this range, the pharmacokinetics of capecitabine and its
metabolite, 5'-DFCR were dose proportional and did not change over time. The increases
in the AUCs of 5'-DFUR and 5-FU, however, were greater than proportional to the
increase in dose and the AUC of 5-FU was 34% higher on day 14 than on day 1.
The interpatient variability in the Cmax and AUC of 5-FU was greater than 85%.
Distribution
Plasma protein binding of capecitabine and its
metabolites is less than 60% and is not concentrationdependent. Capecitabine
was primarily bound to human albumin (approximately 35%). Capecitabine has a low
potential for pharmacokinetic interactions related to plasma protein binding.
Bioactivation And Metabolism
Capecitabine is extensively metabolized enzymatically to
5-FU. In the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound
to 5'-deoxy-5-fluorocytidine (5'-DFCR). Cytidine deaminase, an enzyme found in
most tissues, including tumors, subsequently converts 5'-DFCR to 5'-DFUR. The enzyme,
thymidine phosphorylase (dThdPase), then hydrolyzes 5'-DFUR to the active drug
5-FU. Many tissues throughout the body express thymidine phosphorylase. Some
human carcinomas express this enzyme in higher concentrations than surrounding
normal tissues. Following oral administration of capecitabine 7 days before
surgery in patients with colorectal cancer, the median ratio of 5-FU concentration
in colorectal tumors to adjacent tissues was 2.9 (range from 0.9 to 8.0). These
ratios have not been evaluated in breast cancer patients or compared to 5-FU
infusion.
Metabolic Pathway of capecitabine to 5-FU
The enzyme dihydropyrimidine dehydrogenase hydrogenates
5-FU, the product of capecitabine metabolism, to the much less toxic
5-fluoro-5, 6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the
pyrimidine ring to yield 5-fluoro-ureido-propionic acid (FUPA). Finally,
μ-ureidopropionase cleaves FUPA to α-fluoro-μ-alanine (FBAL)
which is cleared in the urine.
In vitro enzymatic studies with human liver microsomes
indicated that capecitabine and its metabolites (5'-DFUR, 5'-DFCR, 5-FU, and
FBAL) did not inhibit the metabolism of test substrates by cytochrome P450
isoenzymes 1A2, 2A6, 3A4, 2C19, 2D6, and 2E1.
Excretion
Capecitabine and its metabolites are predominantly
excreted in urine; 95.5% of administered capecitabine dose is recovered in
urine. Fecal excretion is minimal (2.6%). The major metabolite excreted in
urine is FBAL which represents 57% of the administered dose. About 3% of the administered
dose is excreted in urine as unchanged drug. The elimination half-life of both
parent capecitabine and 5-FU was about 0.75 hour.
Effect Of Age, Gender, And Race On The Pharmacokinetics Of
Capecitabine
A population analysis of pooled data from the two large
controlled studies in patients with metastatic colorectal cancer (n=505) who
were administered capecitabine at 1250 mg/m² twice a day indicated that gender
(202 females and 303 males) and race (455 white/Caucasian patients, 22 black
patients, and 28 patients of other race) have no influence on the
pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Age has no significant influence on
the pharmacokinetics of 5'-DFUR and 5-FU over the range of 27 to 86 years. A
20% increase in age results in a 15% increase in AUC of FBAL [see WARNINGS
AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].
Following oral administration of 825 mg/m² capecitabine
twice daily for 14 days, Japanese patients (n=18) had about 36% lower Cmax and
24% lower AUC for capecitabine than the Caucasian patients (n=22). Japanese
patients had also about 25% lower Cmax and 34% lower AUC for FBAL than the Caucasian
patients. The clinical significance of these differences is unknown. No
significant differences occurred in the exposure to other metabolites (5'-DFCR,
5'-DFUR, and 5-FU).
Effect Of Hepatic Insufficiency
Capecitabine has been evaluated in 13 patients with mild
to moderate hepatic dysfunction due to liver metastases defined by a composite
score including bilirubin, AST/ALT and alkaline phosphatase following a single
1255 mg/m² dose of capecitabine. Both AUC0-∞ and Cmax of capecitabine increased
by 60% in patients with hepatic dysfunction compared to patients with normal
hepatic function (n=14). The AUC0-∞ and Cmax of 5-FU were not affected.
In patients with mild to moderate hepatic dysfunction due to liver metastases,
caution should be exercised when capecitabine is administered. Â The effect of
severe hepatic dysfunction on capecitabine is not known [see WARNINGS AND
PRECAUTIONS and Use in Special Populations].
Effect Of Renal Insufficiency
Following oral administration of 1250 mg/m² capecitabine
twice a day to cancer patients with varying degrees of renal impairment,
patients with moderate (creatinine clearance = 30 to 50 mL/min) and severe (creatinine
clearance < 30 mL/min) renal impairment showed 85% and 258% higher systemic
exposure to FBAL on day 1 compared to normal renal function patients
(creatinine clearance > 80 mL/min). Systemic exposure to 5'-DFUR was 42% and
71% greater in moderately and severely renal impaired patients, respectively,
than in normal patients. Systemic exposure to capecitabine was about 25%
greater in both moderately and severely renal impaired patients [see DOSAGE
AND ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS,
and Use in Special Populations].
Effect Of Capecitabine On The Pharmacokinetics Of Warfarin
In four patients with cancer, chronic administration of
capecitabine (1250 mg/m² bid) with a single 20 mg dose of warfarin increased
the mean AUC of S-warfarin by 57% and decreased its clearance by 37%. Baseline
corrected AUC of INR in these 4 patients increased by 2.8-fold, and the maximum
observed mean INR value was increased by 91% [see BOXED WARNING and DRUG
INTERACTIONS].
Effect Of Antacids On The Pharmacokinetics Of Capecitabine
When Maalox® (20 mL), an aluminum hydroxide- and
magnesium hydroxide-containing antacid, was administered immediately after
capecitabine (1250 mg/m², n=12 cancer patients), AUC and Cmax increased by 16%
and 35%, respectively, for capecitabine and by 18% and 22%, respectively, for
5'-Â DFCR. No effect was observed on the other three major metabolites
(5'-DFUR, 5-FU, FBAL) of capecitabine.
Effect Of Capecitabine On The Pharmacokinetics Of Docetaxel
And Vice Versa
A Phase 1 study evaluated the effect of capecitabine on
the pharmacokinetics of docetaxel (Taxotere®) and the effect of docetaxel on
the pharmacokinetics of capecitabine was conducted in 26 patients with solid
tumors. Capecitabine was found to have no effect on the pharmacokinetics of
docetaxel (Cmax and AUC) and docetaxel has no effect on the pharmacokinetics of
capecitabine and the 5-FU precursor 5'-DFUR.
Clinical Studies
Adjuvant Colon Cancer
A multicenter randomized, controlled phase 3 clinical
trial in patients with Dukes' C colon cancer (XACT) provided data concerning
the use of capecitabine for the adjuvant treatment of patients with colon cancer.
The primary objective of the study was to compare disease-free survival (DFS)
in patients receiving capecitabine to those receiving IV 5-FU/LV alone. In this
trial, 1987 patients were randomized either to treatment with capecitabine 1250
mg/m² orally twice daily for 2 weeks followed by a 1-week rest period, given as
3-week cycles for a total of 8 cycles (24 weeks) or IV bolus 5-FU 425 mg/m² and
20 mg/m² IV leucovorin on days 1 to 5, given as 4-week cycles for a total of 6
cycles (24 weeks). Patients in the study were required to be between 18 and 75
years of age with histologically-confirmed Dukes' stage C colon cancer with at
least one positive lymph node and to have undergone (within 8 weeks prior to
randomization) complete resection of the primary tumor without macroscopic or
microscopic evidence of remaining tumor. Patients were also required to have no
prior cytotoxic chemotherapy or immunotherapy (except steroids), and have an
ECOG performance status of 0 or 1 (KPS ≥ 70%), ANC ≥ 1.5x109/L,
platelets ≥ 100x109/L, serum creatinine ≤ 1.5 ULN, total
bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits
at time of randomization.
The baseline demographics for capecitabine and 5-FU/LV
patients are shown in Table 10. The baseline characteristics were well-balanced
between arms.
Table 10 : Baseline Demographics
|
Capecitabine
(n=1004) |
5-FU/LV
(n=983) |
Age (median, years) |
62 |
63 |
Range |
(25 to 80) |
(22 to 82) |
Gender |
Male (n, %) |
542 (54) |
532(54) |
Female (n, %) |
461 (46) |
451 (46) |
ECOG PS |
0 (n, %) |
849 (85) |
830 (85) |
1 (n, %) |
152 (15) |
147 (15) |
Staging - Primary Tumor |
PT1 (n, %) |
12 (1) |
6 (0.6) |
PT2 (n, %) |
90 (9) |
92 (9) |
PT3 (n, %) |
763 (76) |
746 (76) |
PT4 (n, %) |
138 (14) |
139(14) |
Other (n, %) |
1 (0.1) |
0 (0) |
Staging - Lymph Node |
pN1 (n, %) |
695 (69) |
694 (71) |
pN2 (n, %) |
305 (30) |
288 (29) |
Other (n, %) |
4 (0.4) |
1 (0.1) |
All patients with normal renal function or mild renal
impairment began treatment at the full starting dose of 1250 mg/m² orally twice
daily. The starting dose was reduced in patients with moderate renal impairment
(calculated creatinine clearance 30 to 50 mL/min) at baseline [see DOSAGE
AND ADMINISTRATION]. Subsequently, for all patients, doses were adjusted
when needed according to toxicity. Dose management for capecitabine included
dose reductions, cycle delays and treatment interruptions (see Table 11).
Table 11 : Summary of Dose Modifications in X-ACT
Study
|
Capecitabine
N = 995 |
5-FU/LV
N = 974 |
Median relative dose intensity (%) |
93 |
92 |
Patients completing full course of treatment (%) |
83 |
87 |
Patients with treatment interruption (%) |
15 |
5 |
Patients with cycle delay (%) |
46 |
29 |
Patients with dose reduction (%) |
42 |
44 |
Patients with treatment interruption, cycle delay, or dose reduction (%) |
57 |
52 |
The median follow-up at the time of the analysis was 83
months (6.9 years). The hazard ratio for DFS for capecitabine compared to
5-FU/LV was 0.88 (95% C.I. 0.77 to 1.01) (see Table 12 and Figure 1). Because
the upper 2-sided 95% confidence limit of hazard ratio was less than 1.20,
capecitabine was non-inferior to 5-FU/LV. The choice of the non-inferiority
margin of 1.20 corresponds to the retention of approximately 75% of the 5-FU/LV
effect on DFS. The hazard ratio for capecitabine compared to 5-FU/LV with
respect to overall survival was 0.86 (95% C.I. 0.74 to 1.01). The 5-year
overall survival rates were 71.4% for capecitabine and 68.4% for 5-FU/LV (see
Figure 2).
Table 12 : Efficacy of Capecitabine vs 5-FU/LV in
Adjuvant Treatment of Colon Cancer*
All Randomized Population |
Capecitabine (n=1004) |
5-FU/LV (n=983) |
Median follow-up (months) |
83 |
83 |
5-year Disease-free Survival Rates (%) † |
59.1 |
54.6 |
Hazard Ratio (Capecitabine/5-FU/LV) (95% C.I. for Hazard Ratio) |
0.88 (0.77 to 1.01) |
p-value ‡ |
p = 0.068 |
*Approximately 93.4 % had 5-year DFS information
†Based on Kaplan-Meier estimates
‡Test of superiority of Capecitabine vs 5-FU/LV (Wald chi-square test) |
Figure 1 : Kaplan-Meier Estimates of Disease-Free
Survival (All Randomized Population)*
*Capecitabine has been demonstrated to be non-inferior to
5-FU/LV.
Figure 2 : Kaplan-Meier Estimates of Overall Survival
(All Randomized Population)
Metastatic Colorectal Cancer
General
The recommended dose of capecitabine was determined in an
open-label, randomized clinical study, exploring the efficacy and safety of
continuous therapy with capecitabine (1331 mg/m²/day in two divided doses,
n=39), intermittent therapy with capecitabine (2510 mg/m²/day in two divided
doses, n=34), and intermittent therapy with capecitabine in combination with
oral leucovorin (LV) (capecitabine 1657 mg/m²/day in two divided doses, n=35;
leucovorin 60 mg/day) in patients with advanced and/or metastatic colorectal
carcinoma in the first-line metastatic setting. There was no apparent advantage
in response rate to adding leucovorin to capecitabine; however, toxicity was
increased. Capecitabine, 1250 mg/m² twice daily for 14 days followed by a
1-week rest, was selected for further clinical development based on the overall
safety and efficacy profile of the three schedules studied.
Monotherapy
Data from two open-label, multicenter, randomized,
controlled clinical trials involving 1207 patients support the use of
capecitabine in the first-line treatment of patients with metastatic colorectal
carcinoma. The two clinical studies were identical in design and were conducted
in 120 centers in different countries. Study 1 was conducted in the US, Canada,
Mexico, and Brazil; Study 2 was conducted in Europe, Israel, Australia, New
Zealand, and Taiwan. Altogether, in both trials, 603 patients were randomized
to treatment with capecitabine at a dose of 1250 mg/m² twice daily for 2 weeks followed
by a 1-week rest period and given as 3-week cycles; 604 patients were
randomized to treatment with 5-FU and leucovorin (20 mg/m² leucovorin IV
followed by 425 mg/m² IV bolus 5-FU, on days 1 to 5, every 28 days).
In both trials, overall survival, time to progression and
response rate (complete plus partial responses) were assessed. Responses were
defined by the World Health Organization criteria and submitted to a blinded
independent review committee (IRC). Differences in assessments between the
investigator and IRC were reconciled by the sponsor, blinded to treatment arm,
according to a specified algorithm. Survival was assessed based on a
non-inferiority analysis.
The baseline demographics for capecitabine and 5-FU/LV
patients are shown in Table 13.
Table 13 : Baseline Demographics of Controlled
Colorectal Trials
|
Study 1 |
Study 2 |
Capecitabine
(n=302) |
5-FU/LV
(n=303) |
Capecitabine
(n=301) |
5-FU/LV
(n=301) |
Age (median, years) Range |
64 (23 to 86) |
63 (24 to 87) |
64 (29 to 84) |
64 (36 to 86) |
Gender |
Male (%) |
181 (60) |
197 (65) |
172 (57) |
173 (57) |
Female (%) |
121 (40) |
106 (35) |
129 (43) |
128 (43) |
Karnofsky PS (median) Range |
90 (70 to 100) |
90 (70 to 100) |
90 (70 to 100) |
90 (70 to 100) |
Colon (%) |
222(74) |
232 (77) |
199 (66) |
196 (65) |
Rectum (%) |
79 (26) |
70 (23) |
101 (34) |
105 (35) |
Prior radiation therapy (%) |
52 (17) |
62 (21) |
42(14) |
42 (14) |
Prior adjuvant 5-FU (%) |
84 (28) |
110 (36) |
56 (19) |
41 (14) |
The efficacy endpoints for the two phase 3 trials are
shown in Table 14 and Table 15.
Table 14 : Efficacy of Capecitabine vs 5-FU/LV in
Colorectal Cancer (Study 1)
|
Capecitabine
(n=302) |
5-FU/LV
(n=303) |
Overall Response Rate (%, 95% C.I.) |
21 (16 to 26) |
11 (8 to 15) |
( p-value) |
0.0014 |
Time to Progression (Median, days, 95% C.I.) |
128 (120 to 136) |
131 (105 to 153) |
Hazard Ratio (capecitabine/5-FU/LV) |
0.99 |
95% C.I. for Hazard Ratio |
(0.84 to 1.17) |
Survival (Median, days, 95% C.I.) |
380 (321 to 434) |
407 (366 to 446) |
Hazard Ratio (capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio |
1.00 (0.84 to 1.18) |
Table 15 : Efficacy of Capecitabine vs 5-FU/LV in
Colorectal Cancer (Study 2)
|
Capecitabine (n=301) |
5-FU/LV (n=301) |
Overall Response Rate (%, 95% C.I.) |
21 (16-26) |
14 (10-18) |
( p-value) |
0.027 |
Time to Progression (Median, days, 95% C.I.) |
137 (128-165) |
131 (105 to 153) |
Hazard Ratio (Capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio |
0.97 (0.82-1.14) |
Survival (Median, days, 95% C.I.) |
404 (367-452) |
369 (338-430) |
Hazard Ratio (Capecitabine/5-FU/LV) 95% C.I. for Hazard Ratio |
0.92 (0.78-1.09) |
Figure 3: Kaplan-Meier Curve for Overall Survival of
Pooled Data (Studies 1 and 2)
 |
Capecitabine was superior to 5-FU/LV for objective
response rate in Study 1 and Study 2. The similarity of capecitabine and
5-FU/LV in these studies was assessed by examining the potential difference
between the two treatments. In order to assure that capecitabine has a
clinically meaningful survival effect, statistical analyses were performed to
determine the percent of the survival effect of 5-FU/LV that was retained by
capecitabine. The estimate of the survival effect of 5-FU/LV was derived from a
meta-analysis of ten randomized studies from the published literature comparing
5-FU to regimens of 5-FU/LV that were similar to the control arms used in these
Studies 1 and 2. The method for comparing the treatments was to examine the
worst case (95% confidence upper bound) for the difference between 5-FU/LV and
capecitabine, and to show that loss of more than 50% of the 5-FU/LV survival
effect was ruled out. It was demonstrated that the percent of the survival
effect of 5-FU/LV maintained was at least 61% for Study 2 and 10% for Study 1.
The pooled result is consistent with a retention of at least 50% of the effect
of 5-FU/LV. It should be noted that these values for preserved effect are based
on the upper bound of the 5-FU/LV vs capecitabine difference. These results do
not exclude the possibility of true equivalence of capecitabine to 5-FU/LV (see
Table 14, Table 15, and Figure 3).
Breast Cancer
Capecitabine has been evaluated in clinical trials in
combination with docetaxel (Taxotere®) and as monotherapy.
In Combination With Docetaxel
The dose of capecitabine used in the phase 3 clinical
trial in combination with docetaxel was based on the results of a phase 1
study, where a range of doses of docetaxel administered in 3-week cycles in combination
with an intermittent regimen of capecitabine (14 days of treatment, followed by
a 7-day rest period) were evaluated. The combination dose regimen was selected
based on the tolerability profile of the 75 mg/m² administered in 3-week cycles
of docetaxel in combination with 1250 mg/m² twice daily for 14 days of
capecitabine administered in 3-week cycles. The approved dose of 100 mg/m² of docetaxel
administered in 3-week cycles was the control arm of the phase 3 study.
Capecitabine in combination with docetaxel was assessed
in an open-label, multicenter, randomized trial in 75 centers in Europe, North
America, South America, Asia, and Australia. A total of 511 patients with metastatic
breast cancer resistant to, or recurring during or after an anthracycline-containing
therapy, or relapsing during or recurring within 2 years of completing an
anthracycline-containing adjuvant therapy were enrolled. Two hundred and
fifty-five (255) patients were randomized to receive capecitabine 1250 mg/m²
twice daily for 14 days followed by 1 week without treatment and docetaxel 75
mg/m² as a 1- hour intravenous infusion administered in 3-week cycles. In the
monotherapy arm, 256 patients received docetaxel 100 mg/m² as a 1-hour
intravenous infusion administered in 3-week cycles. Patient demographics are
provided in Table 16.
Table 16 : Baseline Demographics and Clinical
Characteristics Capecitabine and Docetaxel Combination vs Docetaxel in Breast
Cancer Trial
|
Capecitabine + Docetaxel
(n=255) |
Docetaxel
(n=256) |
Age (median, years) |
52 |
51 |
Karnofsky PS (median) |
90 |
90 |
Site of Disease |
Lymph nodes |
121 (47%) |
125 (49%) |
Liver |
116 (45%) |
122 (48%) |
Bone |
107 (42%) |
119 (46%) |
Lung |
95 (37%) |
99 (39%) |
Skin |
73 (29%) |
73 (29%) |
Prior Chemotherapy |
Anthracycline * |
255 (100%) |
256 (100%) |
5-FU |
196 (77%) |
189 (74%) |
Paclitaxel |
25 (10%) |
22 (9%) |
Resistance to an Anthracycline |
No resistance |
19 (7%) |
19 (7%) |
Progression on anthracycline therapy |
65 (26%) |
73 (29%) |
Stable disease after 4 cycles of anthracycline therapy |
41 (16%) |
40 (16%) |
Relapsed within 2 years of completion of anthracycline-adjuvant therapy |
78 (31%) |
74 (29%) |
Experienced a brief response to anthracycline therapy, with subsequent progression while on therapy or within 12 months after last dose |
51 (20%) |
50 (20%) |
No. of Prior Chemotherapy Regimens for Treatment of Metastatic Disease |
0 |
89 (35%) |
80 (31%) |
1 |
123 (48%) |
135 (53%) |
2 |
43 (17%) |
39 (15%) |
3 |
0 (0%) |
2 (1%) |
*Includes 10 patients in combination and 18 patients in
monotherapy arms treated with an Anthracenedione |
Capecitabine in combination with docetaxel resulted in
statistically significant improvement in time to disease progression, overall
survival and objective response rate compared to monotherapy with docetaxel as
shown in Table 17, Figure 4, and Figure 5.
Table 17 : Efficacy of Capecitabine and Docetaxel
Combination vs Docetaxel Monotherapy
Efficacy Parameter |
Combination Therapy |
Monotherapy |
p-value |
Hazard Ratio |
Time to Disease Progression Median Days 95% C.I. |
186 (165 to 198) |
128 (105 to 136) |
0.0001 |
0.643 |
Overall Survival Median Days 95% C.I. |
442 (375 to 497) |
352 (298 to 387) |
0.0126 |
0.775 |
Response Rate * |
32% |
22% |
0.009 |
NA† |
*The response rate reported represents a reconciliation
of the investigator and IRC assessments performed by the sponsor according to a
predefined algorithm.
†NA = Not Applicable |
Figure 4 : Kaplan-Meier Estimates for Time to Disease
Progression Capecitabine and Docetaxel vs Docetaxel
Figure 5 : Kaplan-Meier Estimates of Survival
Capecitabine and Docetaxel vs Docetaxel
Monotherapy
The antitumor activity of capecitabine as a monotherapy
was evaluated in an open-label single-arm trial conducted in 24 centers in the
US and Canada. A total of 162 patients with stage IV breast cancer were enrolled.
The primary endpoint was tumor response rate in patients with measurable
disease, with response defined as a ≥ 50% decrease in sum of the products
of the perpendicular diameters of bidimensionally measurable disease for at
least 1 month. Capecitabine was administered at a dose of 1255 mg/m² twice
daily for 2 weeks followed by a 1-week rest period and given as 3-week cycles.
The baseline demographics and clinical characteristics for all patients (n=162)
and those with measurabledisease (n=135) are shown in Table 18. Resistance was
defined as progressive disease while on treatment, with or without an initial
response, or relapse within 6 months of completing treatment with an anthracycline-containing
adjuvant chemotherapy regimen.
Table 18 : Baseline Demographics and Clinical
Characteristics Single-Arm Breast Cancer Trial
|
Patients With Measurable Disease
(n=135) |
All Patients
(n=162) |
Age (median, years) |
55 |
56 |
Karnofsky PS |
90 |
90 |
No. Disease Sites |
1 to 2 |
43 (32%) |
60 (37%) |
3 to 4 |
63 (46%) |
69 (43%) |
> 5 |
29 (22%) |
34 (21%) |
Dominant Site of Disease |
Visceral * |
101 (75%) |
110 (68%) |
Soft Tissue |
30 (22%) |
35 (22%) |
Bone |
4 (3%) |
17 (10%) |
Prior Chemotherapy |
Paclitaxel |
135 (100%) |
162 (100%) |
Anthracycline † |
122 (90%) |
147 (91%) |
5-FU |
110 (81%) |
133 (82%) |
Resistance to Paclitaxel |
103 (76%) |
124 (77%) |
Resistance to an Anthracycline † |
55 (41%) |
67 (41%) |
Resistance to both Paclitaxel and an Anthracycline † |
43 (32%) |
51 (31%) |
*Lung, pleura, liver, peritoneum
†Includes 2 patients treated with an anthracenedione |
Antitumor responses for patients with disease resistant
to both paclitaxel and an anthracycline are shown in Table 19.
Table 19 : Response Rates in Doubly-Resistant Patients
Single-Arm Breast Cancer Trial
|
Resistance to Both Paclitaxel and an Anthracycline
(n=43) |
CR |
0 |
PR * |
11 |
CR + PR * |
11 |
Response Rate * |
25.6% |
(95% C.I.) |
(13.5, 41.2) |
Duration of Response, * Median in days† |
154 |
(Range) |
(63 to 233) |
*Includes 2 patients treated with an anthracenedione
†From date of first response |
For the subgroup of 43 patients who were doubly
resistant, the median time to progression was 102 days and the median survival
was 255 days. The objective response rate in this population was supported by a
response rate of 18.5% (1 CR, 24 PRs) in the overall population of 135 patients
with measurable disease, who were less resistant to chemotherapy (see Table
18). The median time to progression was 90 days and the median survival was 306
days.