`
`1
`2
`3
`4
`5
`
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`
`21
`22
`23
`24
`25
`26
`27
`
`
`
`XELODA®
`(capecitabine)
`TABLETS
`
`Rx only
`
`WARNING
`XELODA Warfarin Interaction: Patients receiving concomitant capecitabine and oral
`coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR
`or prothrombin time) monitored frequently in order to adjust the anticoagulant dose
`accordingly. A clinically
`important XELODA-Warfarin drug
`interaction was
`demonstrated in a clinical pharmacology trial (see CLINICAL PHARMACOLOGY
`and PRECAUTIONS). Altered coagulation parameters and/or bleeding, including death,
`have been reported in patients taking XELODA concomitantly with coumarin-derivative
`anticoagulants such as warfarin and phenprocoumon. Postmarketing reports have shown
`clinically significant increases in prothrombin time (PT) and INR in patients who were
`stabilized on anticoagulants at the time XELODA was introduced. These events occurred
`within several days and up to several months after initiating XELODA therapy and, in a
`few cases, within 1 month after stopping XELODA. These events occurred in patients
`with and without liver metastases. Age greater than 60 and a diagnosis of cancer
`independently predispose patients to an increased risk of coagulopathy.
`
`DESCRIPTION
`XELODA (capecitabine) is a fluoropyrimidine carbamate with antineoplastic activity. It
`is an orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which
`is converted to 5-fluorouracil.
`The chemical name for capecitabine is 5’-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-
`cytidine and has a molecular weight of 359.35. Capecitabine has the following structural
`formula:
`
`O
`
`N
`
`NH
`
`O
`
`H3C
`
`O
`
`N
`
`O
`
`F
`
`28
`29
`30
`31
`32
`
`
`HO
`OH
`Capecitabine is a white to off-white crystalline powder with an aqueous solubility of
`26 mg/mL at 20ºC.
`XELODA is supplied as biconvex, oblong film-coated tablets for oral administration.
`Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored
`
`1
`
`IMMUNOGEN 2217, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`tablet contains 500 mg capecitabine. The inactive ingredients in XELODA include:
`anhydrous
`lactose,
`croscarmellose
`sodium,
`hydroxypropyl methylcellulose,
`microcrystalline cellulose, magnesium stearate and purified water. The peach or light
`peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and
`synthetic yellow and red iron oxides.
`
`CLINICAL PHARMACOLOGY
`XELODA is relatively non-cytotoxic in vitro. This drug is enzymatically converted to
`5-fluorouracil (5-FU) in vivo.
`
`Bioactivation
`Capecitabine is readily absorbed from the gastrointestinal tract. 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’-deoxy-5-fluorouridine (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.
`
`Metabolic Pathway of capecitabine to 5-FU
`
`NH2
`NH-CO-O
`F
`
`N
`
`F
`
`N
`
`O
`
`N
`
`O
`
`O
`
`N
`O
`
`H 3 C
`
`H3C
`Carboxylesterase
`HO
`OH
`
`Capecitabine
`
`HO
`OH
`5’-DFCR
`
`
`Cyd deaminase
`
`
`F
`
`O
`
`NH
`
`HN
`O
`
`5-FU
`
`
`
`dThdPase
`
`
`O
`
`N
`
`HN
`O
`
`O
`
`F
`
`H 3 C
`
`HO
`OH
`5’-DFUR
`
`Mechanism of Action
`to 5-fluoro-2’-deoxyuridine
`Both normal and
`tumor cells metabolize 5-FU
`monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites
`cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor,
`
`2
`
`33
`34
`35
`36
`37
`
`38
`39
`40
`
`41
`42
`43
`44
`45
`46
`47
`48
`49
`
`50
`
`51
`
`52
`53
`54
`55
`
`IMMUNOGEN 2217, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`56
`57
`58
`59
`60
`61
`62
`
`63
`64
`65
`66
`67
`
`68
`69
`70
`71
`72
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`
`83
`84
`85
`86
`87
`88
`89
`90
`91
`92
`93
`94
`95
`96
`
`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 in Colorectal Tumors and Adjacent Healthy Tissue
`Following oral administration of XELODA 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.
`
`Human Pharmacokinetics
`The pharmacokinetics of XELODA and its metabolites have been evaluated in about 200
`cancer patients over a dosage range of 500 to 3500 mg/m2/day. Over this range, the
`pharmacokinetics of XELODA 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 elimination half-life of both parent capecitabine and
`5-FU was about ¾ of an hour. The inter-patient variability in the Cmax and AUC of 5-FU
`was greater than 85%.
`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).
`
`Absorption, Distribution, Metabolism and Excretion
`Capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU levels
`occurring slightly later, at 2 hours. Food reduced both the rate and extent of absorption of
`capecitabine with mean Cmax and AUC0-∞ decreased by 60% and 35%, respectively. The
`Cmax and AUC0-∞ of 5-FU were also reduced by food by 43% and 21%, respectively.
`Food delayed Tmax of both parent and 5-FU by 1.5 hours (see PRECAUTIONS and
`DOSAGE AND ADMINISTRATION).
`Plasma protein binding of capecitabine and its metabolites is less than 60% and is not
`concentration-dependent. Capecitabine was primarily bound
`to human albumin
`(approximately 35%).
`to 5-FU. The enzyme
`Capecitabine
`is extensively metabolized enzymatically
`dihydropyrimidine dehydrogenase hydrogenates 5-FU, the product of capecitabine
`toxic 5-fluoro-5, 6-dihydro-fluorouracil (FUH2).
`metabolism,
`to
`the much
`less
`Dihydropyrimidinase cleaves the pyrimidine ring to yield 5-fluoro-ureido-propionic acid
`
`3
`
`IMMUNOGEN 2217, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`97
`98
`99
`100
`101
`102
`103
`104
`105
`106
`107
`108
`
`109
`110
`111
`112
`113
`114
`115
`116
`117
`
`118
`119
`120
`121
`122
`123
`124
`125
`126
`127
`
`128
`129
`130
`131
`132
`133
`134
`135
`136
`
`(FUPA). Finally, β-ureido-propionase cleaves FUPA to α-fluoro-β-alanine (FBAL)
`which is cleared in the urine.
`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.
`A clinical phase 1 study evaluating the effect of XELODA on the pharmacokinetics of
`docetaxel (Taxotere®) and the effect of docetaxel on the pharmacokinetics of XELODA
`was conducted in 26 patients with solid tumors. XELODA 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.
`
`Special Populations
`A population analysis of pooled data from the two large controlled studies in patients
`with metastatic colorectal cancer (n=505) who were administered XELODA 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 DOSAGE AND ADMINISTRATION).
`
`Hepatic Insufficiency
`XELODA 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 XELODA. 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 XELODA is administered. The effect of severe hepatic
`dysfunction on XELODA is not known (see PRECAUTIONS and DOSAGE AND
`ADMINISTRATION).
`
`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
`
`4
`
`IMMUNOGEN 2217, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`137
`138
`
`139
`140
`141
`142
`143
`144
`145
`
`146
`147
`148
`149
`150
`
`151
`152
`153
`154
`155
`156
`157
`158
`
`159
`160
`161
`162
`163
`164
`165
`166
`167
`168
`169
`170
`171
`
`172
`173
`174
`
`CONTRAINDICATIONS,
`ADMINISTRATION).
`
`WARNINGS,
`
`and
`
`DOSAGE
`
`AND
`
`Drug-Drug Interactions
`Anticoagulants
`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 PRECAUTIONS: Drug-Drug Interactions).
`
`Drugs Metabolized by Cytochrome P450 Enzymes
`In vitro enzymatic studies with human liver microsomes indicated that capecitabine and
`its metabolites (5’-DFUR, 5’-DFCR, 5-FU, and FBAL) had no inhibitory effects on
`substrates of cytochrome P450 for the major isoenzymes such as 1A2, 2A6, 3A4, 2C9,
`2C19, 2D6, and 2E1.
`
`Antacid
`When Maalox® (20 mL), an aluminum hydroxide- and magnesium hydroxide-containing
`antacid, was administered immediately after XELODA (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’-DFCR. No effect was observed on the other three
`major metabolites (5’-DFUR, 5-FU, FBAL) of XELODA.
`XELODA has a low potential for pharmacokinetic interactions related to plasma protein
`binding.
`
`CLINICAL STUDIES
`General
`The recommended dose of XELODA 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 XELODA; however, toxicity was increased.
`XELODA, 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.
`
`Adjuvant Colon Cancer
`A multicenter randomized, controlled phase 3 clinical trial in patients with Dukes’ C
`colon cancer provided data concerning the use of XELODA for the adjuvant treatment of
`
`5
`
`IMMUNOGEN 2217, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`175
`176
`177
`178
`179
`180
`181
`182
`183
`184
`185
`186
`187
`188
`189
`190
`191
`
`192
`
`193
`194
`195
`196
`197
`
`
`
`patients with colon cancer. The primary objective of the study was to compare disease-
`free survival (DFS) in patients receiving XELODA to those receiving IV 5-FU/LV alone.
`In this trial, 1987 patients were randomized either to treatment with XELODA
`2
`1250 mg/m orally twice daily for 2 weeks followed by a 1-week rest period, given as 3-
`2
`2
`week cycles for a total of 8 cycles (24 weeks)or IV bolus 5-FU 425 mg/m and 20 mg/m
`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%),
`9
`9
`serum
`total
`ANC ≥ 1.5x10 /L,
`platelets ≥ 100 x 10 /L,
`creatinine ≤ 1.5 ULN,
`bilirubin ≤ 1.5 ULN, AST/ALT ≤ 2.5 ULN and CEA within normal limits at time of
`randomization.
`The baseline demographics for XELODA and 5-FU/LV patients are shown in Table 1.
`The baseline characteristics were well-balanced between arms.
`
`Table 1
`
`
`
`Age (median, years)
`Range
`Gender
`Male (n, %)
`Female (n, %)
`ECOG PS
`0 (n, %)
`1 (n, %)
`Staging – Primary Tumor
`PT1 (n, %)
`PT2 (n, %)
`PT3 (n, %)
`PT4 (n, %)
`Other (n, %)
`Staging – Lymph Node
`pN1 (n, %)
`pN2 (n, %)
`Other (n, %)
`
`Baseline Demographics
`XELODA
`(n=1004)
`62
`(25-80)
`
`542 (54)
`461 (46)
`
`849 (85)
`152 (15)
`
`12 (1)
`90 (9)
`763 (76)
`138 (14)
`1 (0.1)
`
`695 (69)
`305 (30)
`4 (0.4)
`
`5-FU/LV
`(n=983)
`63
`(22-82)
`
`532 (54)
`451 (46)
`
`830 (85)
`147 (15)
`
`6 (0.6)
`92 (9)
`746 (76)
`139 (14)
`0 (0)
`
`694 (71)
`288 (29)
`1 (0.1)
`
`6
`
`
`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
`
`IMMUNOGEN 2217, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`198
`199
`200
`
`201
`
`202
`203
`204
`205
`206
`207
`208
`209
`210
`
`211
`212
`
`213
`214
`215
`216
`
`patients, doses were adjusted when needed according to toxicity. Dose management for
`XELODA included dose reductions, cycle delays and treatment interruptions (see
`Table 2).
`
`
`
`Table 2
`
`
`Summary of Dose Modifications in X-ACT Study
`XELODA
`5-FU/LV
`N = 995
`N = 974
`93
`92
`83
`87
`15
`5
`46
`29
`42
`44
`57
`52
`
`Median relative dose intensity (%)
`Patients completing full course of treatment (%)
`Patients with treatment interruption (%)
`Patients with cycle delay (%)
`Patients with dose reduction (%)
`Patients with treatment interruption, cycle delay,
`or dose reduction (%)
`
`The median follow-up at the time of the analysis was 53 months. The hazard ratio for
`DFS for XELODA compared to 5-FU/LV was 0.87 (95% C.I. 0.76 – 1.00). Because the
`upper 2-sided 95% confidence limit of hazard ratio was less than 1.20, XELODA 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.
`Survival data were not mature at the time of the analysis with a median follow-up of 53
`months. The comparison of overall survival did not reach statistical significance for the
`test of difference (HR 0.88, 95% C.I. 0.74 – 1.05; p = 0.169).
`
`Table 3
`
`Efficacy of XELODA vs 5-FU/LV in Adjuvant Treatment of
`Colon Cancera
`All Randomized Population
`
`
`0.87
`(0.76 – 1.00)
`p = 0.055
`
`7
`
`XELODA
`(n=1004)
`53
`
`66.0
`
`5-FU/LV
`(n=983)
`53
`
`62.9
`
`Median follow-up (months)
`3-year Disease-free Survival
`Rates
`
`Hazard Ratio
`(XELODA/5-FU/LV)
`(95% C.I. for Hazard Ratio),
`p-valueb
`aApproximately 85% had 3-year DFS information
`bLog-rank test for differences of XELODA vs 5-FU/LV
`
`
`
`IMMUNOGEN 2217, pg. 7
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`217
`218
`219
`
`Figure 1
`
`
`
`Estimated
`Probability
`
`Kaplan-Meier Estimates of Disease-Free Survival (All
`a
`Randomized Population)
`
`
`
`n at risk
`
`5-FU + LEUCOVORIN
` CAPECITABINE
`
` 983
`1004
`
`898
`929
`
` 795
` 835
`
`710
`747
`
`621
`687
`
`573
`638
`
` 460
` 492
`
`341
`367
`
`223 117
`226 114
`
` 50
` 57
`
`2
`1
`
`Months Since Randomization
`0
`1
`
`aXELODA has been demonstrated to be non-inferior to 5-FU/LV.
`
`
`
`Metastatic Colorectal Cancer
`Data from two open-label, multicenter, randomized, controlled clinical trials involving
`1207 patients support the use of XELODA 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 XELODA 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 XELODA and 5-FU/LV patients are shown in Table 4.
`
`220
`221
`
`222
`223
`224
`225
`226
`227
`228
`229
`230
`231
`232
`233
`234
`235
`236
`237
`238
`239
`
`8
`
`IMMUNOGEN 2217, pg. 8
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`240
`
`Table 4
`
`
`
`
`Baseline Demographics of Controlled Colorectal Trials
`Study 1
`Study 2
`XELODA
`5-FU/LV
`XELODA
`(n=302)
`(n=303)
`(n=301)
`64
`63
`64
`(23-86)
`(24-87)
`(29-84)
`
`
`
`172 (57)
`197 (65)
`181 (60)
`129 (43)
`106 (35)
`121 (40)
`90
`90
`90
`(70-100)
`(70-100)
`(70-100)
`222 (74)
`232 (77)
`199 (66)
`79 (26)
`70 (23)
`101 (34)
`52 (17)
`62 (21)
`42 (14)
`84 (28)
`110 (36)
`56 (19)
`
`5-FU/LV
`(n=301)
`64
`(36-86)
`
`173 (57)
`128 (43)
`90
`(70-100)
`196 (65)
`105 (35)
`42 (14)
`41(14)
`
`Age (median, years)
`Range
`Gender
`Male (%)
`Female (%)
`Karnofsky PS (median)
`Range
`Colon (%)
`Rectum (%)
`Prior radiation therapy (%)
`Prior adjuvant 5-FU (%)
`
`
`The efficacy endpoints for the two phase 3 trials are shown in Table 5 and Table 6.
`
`241
`242
`
`243
`244
`
`245
`
`Efficacy of XELODA vs 5-FU/LV in Colorectal Cancer
`(Study 1)
`
`Table 5
`
`
`
`Overall Response Rate
`(%, 95% C.I.)
`(p-value)
`Time to Progression
`(Median, days, 95% C.I.)
`Hazard Ratio (XELODA/5-FU/LV)
`95% C.I. for Hazard Ratio
`Survival
`(Median, days, 95% C.I.)
`Hazard Ratio (XELODA/5-FU/LV)
`95% C.I. for Hazard Ratio
`
`
`XELODA
`(n=302)
`
`21 (16-26)
`0.0014
`
`5-FU/LV
`(n=303)
`
`11 (8-15)
`
`
`131 (105-153)
`
`
`128 (120-136)
`0.99
`(0.84-1.17)
`
`
`380 (321-434)
`1.00
`0.84-1.18
`
`
`407 (366-446)
`
`
`
`9
`
`IMMUNOGEN 2217, pg. 9
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Table 6
`
`246
`247
`
`Efficacy of XELODA vs 5-FU/LV in Colorectal Cancer
`(Study 2)
`
`
`
`XELODA
`(n=301)
`
`21 (16-26)
`0.027
`
`5-FU/LV
`(n=301)
`
`14 (10-18)
`
`
`131 (102-156)
`
`
`137 (128-165)
`0.97
`0.82-1.14
`
`
`404 (367-452)
`0.92
`0.78-1.09
`
`
`369 (338-430)
`
`
`
`Overall Response Rate
`(%, 95% C.I.)
`(p-value)
`Time to Progression
`(Median, days, 95% C.I.)
`Hazard Ratio (XELODA/5-FU/LV)
`95% C.I. for Hazard Ratio
`Survival
`(Median, days, 95% C.I.)
`Hazard Ratio (XELODA/5-FU/LV)
`95% C.I. for Hazard Ratio
`
`
`248
`
`249
`250
`
`Figure 2
`
`Kaplan-Meier Curve for Overall Survival of Pooled Data
`(Studies 1 and 2)
`
`251
`252
`253
`254
`255
`256
`257
`
`
`XELODA was superior to 5-FU/LV for objective response rate in Study 1 and Study 2.
`The similarity of XELODA and 5-FU/LV in these studies was assessed by examining the
`potential difference between the two treatments. In order to assure that XELODA 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 XELODA. The estimate of
`the survival effect of 5-FU/LV was derived from a meta-analysis of ten randomized
`
`10
`
`IMMUNOGEN 2217, pg. 10
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`258
`259
`260
`261
`262
`263
`264
`265
`266
`267
`
`268
`269
`270
`
`271
`272
`273
`274
`275
`276
`277
`278
`279
`280
`281
`282
`283
`284
`285
`286
`287
`288
`289
`
`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 XELODA, 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 XELODA difference. These results do not exclude the possibility of true
`equivalence of XELODA to 5-FU/LV (see Table 5, Table 6, and Figure 2).
`
`Breast Cancer
`XELODA has been evaluated in clinical trials in combination with docetaxel
`(Taxotere®) and as monotherapy.
`
`Breast Cancer Combination Therapy
`The dose of XELODA 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 XELODA
`(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
`XELODA 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.
`XELODA 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 XELODA
`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 7.
`
`11
`
`IMMUNOGEN 2217, pg. 11
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Baseline Demographics and Clinical Characteristics
`XELODA and Docetaxel Combination vs Docetaxel in Breast
`Cancer Trial
`
`
`
`Table 7
`
`290
`291
`292
`
`
`
`Age (median, years)
`
`Karnofsky PS (median)
`
`Site of Disease
`Lymph nodes
`Liver
`Bone
`Lung
`Skin
`
`Prior Chemotherapy
`Anthracycline1
`5-FU
`Paclitaxel
`
`Resistance to an Anthracycline
`No resistance
`Progression on anthracycline therapy
`
`Stable disease after 4 cycles of anthracycline
`therapy
`
`Relapsed within 2 years of completion of
`anthracycline-adjuvant therapy
`
`Experienced a brief response to anthracycline
`therapy, with subsequent progression while
`on therapy or within 12 months after last dose
`
`XELODA + Docetaxel
`(n=255)
`
`Docetaxel
`(n=256)
`
`52
`
`90
`
`51
`
`90
`
`121 (47%)
`116 (45%)
`107 (42%)
`95 (37%)
`73 (29%)
`
`255 (100%)
`196 (77%)
`25 (10%)
`
`125 (49%)
`122 (48%)
`119 (46%)
`99 (39%)
`73 (29%)
`
`256 (100%)
`189 (74%)
`22 (9%)
`
`19 (7%)
`65 (26%)
`
`19 (7%)
`73 (29%)
`
`41 (16%)
`
`40 (16%)
`
`78 (31%)
`
`74 (29%)
`
`51 (20%)
`
`50 (20%)
`
`No. of Prior Chemotherapy Regimens for
`Treatment of Metastatic Disease
`0
`80 (31%)
`89 (35%)
`1
`135 (53%)
`123 (48%)
`39 (15%)
`43 (17%)
`2
`3
`2 (1%)
`0 (0%)
`1Includes 10 patients in combination and 18 patients in monotherapy arms treated with an anthracenedione
`
`XELODA 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 8, Figure 3, and Figure 4.
`
`293
`294
`295
`296
`297
`
`12
`
`IMMUNOGEN 2217, pg. 12
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`298
`299
`
`300
`301
`302
`303
`
`304
`305
`
`306
`
`Table 8
`
`
`
`Efficacy of XELODA and Docetaxel Combination vs
`Docetaxel Monotherapy
`Efficacy Parameter Combination
`Monotherapy
`Therapy
`
`p-value
`
`Hazard
`Ratio
`
`Time to Disease
`Progression
`
`Median Days
`
`
`
`
`186
`
`
`
`
`
`
`
`
`
`
`128
`
`0.0001
`
`0.643
`
`95% C.I.
`
`(165-198)
`
`(105-136)
`
`Overall Survival
`
`Median Days
`
`
`
`442
`
`
`
`352
`
`
`
`
`
`0.0126
`
`0.775
`
`95% C.I.
`
`(375-497)
`
`(298-387)
`
`NA2
`Response Rate1
`0.009
`22%
`32%
`1 The response rate reported represents a reconciliation of the investigator and IRC assessments performed
`by the sponsor according to a predefined algorithm.
`2 NA = Not Applicable
`
`
`Figure 3
`
`Kaplan-Meier Estimates for Time to Disease Progression
`XELODA and Docetaxel vs Docetaxel
`
`
`
`13
`
`IMMUNOGEN 2217, pg. 13
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`Figure 4
`
`307
`308
`
`Kaplan-Meier Estimates of Survival
`XELODA and Docetaxel vs Docetaxel
`
`
`
`309
`
`310
`311
`312
`313
`314
`315
`316
`317
`318
`319
`320
`321
`322
`
`
`
`Breast Cancer Monotherapy
`The antitumor activity of XELODA 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. XELODA 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
`measurable disease (n=135) are shown in Table 9. 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.
`
`14
`
`IMMUNOGEN 2217, pg. 14
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`
`All Patients
`(n=162)
`56
`90
`
`60 (37%)
`69 (43%)
`34 (21%)
`
`110 (68%)
`35 (22%)
`17 (10%)
`
`162 (100%)
`147 (91%)
`133 (82%)
`
`124 (77%)
`67 (41%)
`
`51 (31%)
`
`Baseline Demographics and Clinical Characteristics
`Single Arm Breast Cancer Trial
`Patients With
`Measurable Disease
`(n=135)
`55
`90
`
`Age (median, years)
`Karnofsky PS
`No. Disease Sites
`1-2
`3-4
`>5
`Dominant Site of Disease
`Visceral1
`Soft Tissue
`Bone
`Prior Chemotherapy
`Paclitaxel
`Anthracycline2
`5-FU
`
`Resistance to Paclitaxel
`Resistance to an Anthracycline2
`Resistance to both Paclitaxel
`and an Anthracycline2
`1Lung, pleura, liver, peritoneum
`2Includes 2 patients treated with an anthracenedione
`
`Antitumor responses for patients with disease resistant to both paclitaxel and an
`anthracycline are shown in Table 10.
`
`
`43 (32%)
`63 (46%)
`29 (22%)
`
`101 (75%)
`30 (22%)
`4 (3%)
`
`135 (100%)
`122 (90%)
`110 (81%)
`
`103 (76%)
`55 (41%)
`
`43 (32%)
`
`Table 9
`
`323
`324
`
`
`
`325
`326
`327
`328
`329
`
`330
`331
`
`332
`333
`
`Table 10
`
`Response Rates in Doubly-Resistant Patients
`Single-Arm Breast Cancer Trial
`Resistance to Both Paclitaxel and
`
`an Anthracycline
`(n=43)
`0
`11
`11
`25.6%
`(13.5, 41.2)
`
`154
`(63 - 233)
`
`CR
`PR1
`CR + PR1
`Response Rate1
`(95% C.I.)
`Duration of Response,1
`Median in days2
`(Range)
`1Includes 2 patients treated with an anthracenedione
`2From date of first response
`
`15
`
`IMMUNOGEN 2217, pg. 15
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`
`
`334
`335
`336
`337
`338
`339
`340
`
`341
`342
`343
`344
`345
`346
`347
`348
`349
`350
`351
`352
`353
`354
`355
`356
`357
`358
`
`359
`360
`361
`362
`363
`364
`365
`366
`367
`368
`369
`370
`
`371
`372
`373
`
`
`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 9). The median time to progression was 90 days and the
`median survival was 306 days.
`
`INDICATIONS AND USAGE
`Colorectal Cancer
`• XELODA is indicated as a single agent for adjuvant treatment in patients with
`Dukes’ C colon cancer who have undergone complete resection of the primary
`tumor when treatment with fluoropyrimidine therapy alone is preferred.
`XELODA was non-inferior to 5-fluorouracil and leucovorin (5-FU/LV) for
`disease-free survival (DFS). Although neither XELODA nor combination
`chemotherapy prolongs overall survival (OS), combination chemotherapy has
`been demonstrated to improve disease-free survival compared to 5-FU/LV.
`Physicians should consider these results when prescribing single-agent XELODA
`in the adjuvant treatment of Dukes’ C colon cancer.
`• XELODA is indicated as first-line treatment of patients with metastatic colorectal
`carcinoma when treatment with fluoropyrimidine therapy alone is preferred.
`Combination chemotherapy has shown a survival benefit compared to 5-FU/LV
`alone. A survival benefit over 5-FU/LV has not been demonstrated with
`XELODA monotherapy. Use of XELODA instead of 5-FU/LV in combinations
`has not been adequately studied to assure safety or preservation of the survival
`advantage.
`
`Breast Cancer
`• XELODA in combination with docetaxel is indicated for the treatment of patients
`with metastatic breast cancer after failure of prior anthracycline-containing
`chemotherapy.
`• XELODA monotherapy is also indicated for the treatment of patients with
`metastatic breast cancer resistant to both paclitaxel and an anthracycline-
`containing chemotherapy regimen or resistant to paclitaxel and for whom further
`anthracycline therapy is not indicated, eg, patients who have received cumulative
`doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents. Resistance is
`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 ad