Mead Johnson
`ONCOLOGY PRODUCTS
`
`
`
`2/10/00
`
`L Only
`
`TAXOL7
`(paclitaxel)
`INJECTION
`
`WARNING
`TAXOL7 (paclitaxel) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic
`agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily
`available.
` Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension requiring treatment, angioedema, and
`generalized urticaria have occurred in 2-4% of patients receiving TAXOL in clinical trials. Fatal reactions have occurred in patients
`despite premedication. All patients should be pretreated with corticosteriods, diphenhydramine, and H2 antagonists. (See DOSAGE AND
`ADMINISTRATION section.) Patients who experience severe hypersensitivity reactions to TAXOL should not be rechallenged with the drug.
` TAXOL therapy should not be given to patients with solid tumors who have baseline neutrophil counts of less than 1500 cells/mm3 and
`should not be given to patients with AIDS-related Kaposi =s sarcoma if the baseline neutrophil count is less than 1000 cells/mm3. In order
`to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is
`recommended that frequent peripheral blood cell counts be performed on all patients receiving TAXOL.
`
`DESCRIPTION
`
`TAXOL (paclitaxel) Injection is a clear colorless to slightly yellow viscous solution. It is supplied as a
`
`nonaqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion. TAXOL
`
`is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 mg (50 mL) multidose vials. Each mL of sterile
`nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of purified Cremophor7 EL* (polyoxyethylated castor
`
`oil) and 49.7% (v/v) dehydrated alcohol, USP.
`
`Paclitaxel is a natural product with antitumor activity. TAXOL (paclitaxel) is obtained via a semi-
`
`synthetic process from Taxus baccata. The chemical name for paclitaxel is 5(cid:31),20-Epoxy-1,2(cid:31),4,7(cid:31),10(cid:31),13(cid:31)-
`hexahydroxytax-11-en-9-one 4, 10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
`
`_____________________________________
`
`*Cremophor7 EL is the registered trademark of BASF Aktiengesellschaft.
` Cremophor7 EL is further purified by a Bristol-Myers Squibb Company proprietary process before use.
`
`1
`
`AVENTIS EXHIBIT 2093
`Mylan v. Aventis, IPR2016-00712
`
`

`
`Paclitaxel has the following structural formula:
`
`(SEE CURRENTLY APPROVED PACKAGE INSERT)
`
`Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a
`molecular weight of 853.9. It is highly lipophilic, insoluble in water, and melts at around 216-217NC.
`
`CLINICAL PHARMACOLOGY
`
`Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and
`
`stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal
`
`dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular
`
`functions. In addition, paclitaxel induces abnormal arrays or Abundles@ of microtubules throughout the cell cycle
`
`and multiple asters of microtubules during mitosis.
`
`Following intravenous administration of TAXOL, paclitaxel plasma concentrations declined in a biphasic
`
`manner. The initial rapid decline represents distribution to the peripheral compartment and elimination of the
`
`drug. The later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment.
`
`Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of TAXOL at dose levels
`of 135 and 175 mg/m2 were determined in a Phase 3 randomized study in ovarian cancer patients and are
`
`summarized in the following table:
`
`TABLE 1
`SUMMARY OF PHARMACOKINETIC PARAMETERS - MEAN VALUES
`
`CLT
`(L/h/m2)
`
`21.7
` 23.8
` 17.7
` 12.2
`
`CMAX
`(ng/mL)
`
` 195
` 365
` 2170
` 3650
`
`AUC(0-4)
`(ng@h/mL)
`
` 6300
` 7993
` 7952
` 15007
`
`T-HALF
`(h)
`
` 52.7
` 15.7
` 13.1
` 20.2
`
`Dose
`(mg/m2)
`
`Infusion
`Duration (h)
`
`N
`(patients)
`
`2 4 7 5
`
`135
`175
`135
`175
`
`24
`24
` 3
` 3
`
`CMAX=Maximum plasma concentration
`AUC(0-4) = Area under the plasma concentration-time curve from time 0 to infinity
`CLT = Total body clearance
`
`It appeared that with the 24-hour infusion of TAXOL, a 30% increase in dose (135 mg/m2 versus 175
`mg/m2) increased the CMAX by 87%, whereas the AUC(0-4) remained proportional. However, with a 3-hour
`infusion, for a 30% increase in dose, the CMAX and AUC(0-4) were increased by 68% and 89%, respectively. The
`mean apparent volume of distribution at steady state, with the 24-hour infusion of TAXOL, ranged from 227 to
`688 L/m2, indicating extensive extravascular distribution and/or tissue binding of paclitaxel.
`
`The pharmacokinetics of paclitaxel were also evaluated in adult cancer patients who received single
`doses of 15-135 mg/m2 given by 1-hour infusions (n=15), 30-275 mg/m2 given by 6-hour infusions (n=36), and
`200-275 mg/m2 given by 24-hour infusions (n=54) in Phase 1 & 2 studies. Values for CLT and volume of
`
`2
`
`

`
`distribution were consistent with the findings in the Phase 3 study. The pharmacokinetics of TAXOL in patients
`
`with AIDS-related Kaposi=s sarcoma have not been studied.
`In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1
`
`to 50 (cid:31)g/mL, indicate that between 89-98% of drug is bound; the presence of cimetidine, ranitidine,
`
`dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
`After intravenous administration of 15-275 mg/m2 doses of TAXOL as 1-, 6-, or 24-hour infusions, mean
`
`values for cumulative urinary recovery of unchanged drug ranged from 1.3% to 12.6% of the dose, indicating
`extensive non-renal clearance. In five patients administered a 225 or 250 mg/m2 dose of radiolabeled TAXOL
`
`as a 3-hour infusion, a mean of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was
`
`recovered in the urine. Total recovery of radioactivity ranged from 56% to 101% of the dose. Paclitaxel
`
`represented a mean of 5% of the administered radioactivity recovered in the feces, while metabolites, primarily
`
`6(cid:31)-hydroxypaclitaxel, accounted for the balance. In vitro studies with human liver microsomes and tissue
`
`slices showed that paclitaxel was metabolized primarily to 6(cid:31)-hydroxypaclitaxel by the cytochrome P450
`isozyme CYP2C8; and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6(cid:31),3'-p-dihydroxypaclitaxel, by
`CYP3A4. In vitro, the metabolism of paclitaxel to 6(cid:31)-hydroxypaclitaxel was inhibited by a number of agents
`
`(ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and
`
`vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses.
`
`Testosterone, 17(cid:31)-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited
`the formation of 6(cid:31)-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo
`
`as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or
`
`CYP3A4. (See PRECAUTIONS: Drug Interactions section.) The effect of renal or hepatic dysfunction on the
`
`disposition of paclitaxel has not been investigated.
`
`Possible interactions of paclitaxel with concomitantly administered medications have not been formally
`
`investigated.
`
`CLINICAL STUDIES
`Ovarian Carcinoma
`First-Line Data: The safety and efficacy of TAXOL followed by cisplatin in patients with advanced ovarian cancer
`
`and no prior chemotherapy were evaluated in two Phase 3 multicenter, randomized, controlled trials. In an
`
`Intergroup study led by the European Organization for Research and Treatment of Cancer involving the
`
`Scandinavian Group NOCOVA, the National Cancer Institute of Canada, and the Scottish Group, 680 patients
`with Stage IIB-C, III, or IV disease (optimally or non-optimally debulked) received either TAXOL 175 mg/m2 infused
`over 3 hours followed by cisplatin 75 mg/m2 (Tc) or cyclophosphamide 750 mg/m2 followed by cisplatin 75 mg/m2
`
`(Cc) for a median of six courses. Although the protocol allowed further therapy, only 15% received both drugs
`
`for 9 or more courses. In a study conducted by the Gynecological Oncology Group (GOG), 410 patients with
`
`Stage III or IV disease (>1 cm residual disease after staging laparotomy or distant metastases) received either
`
`3
`
`

`
`TAXOL 135 mg/m2 infused over 24 hours followed by cisplatin 75 mg/m2 or cyclophosphamide 750 mg/m2
`followed by cisplatin 75 mg/m2 for six courses.
`
`In both studies, patients treated with TAXOL in combination with cisplatin had significantly higher
`
`response rate, longer time to progression, and longer survival time compared with standard therapy. These
`
`differences were also significant for the subset of patients in the Intergroup study with non-optimally debulked
`
`disease, although the study was not fully powered for subset analyses (Tables 2A and 2B). Kaplan-Meier
`
`survival curves for each study are shown in Figures 1 and 2.
`
`
`
`TABLE 2A
` EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA STUDIES
`Intergroup
`GOG-111
`(non-optimally debulked subset)
`T175/3a
`C750a
`c75
`c75
`(n=218)
`(n=227)
`
`T135/24a
`c75
`(n=196)
`
`$ Clinical Responseb
` ---rate (percent)
` ---p-valuec
`
`$Time to Progression
` ---median (months)
` ---p-valuec
` ---hazard ratioc
` ---95% CIc
`
`(n=153)
`58
`
`(n=153)
`43
`
`(n=113)
`62
`
`0.016
`
`0.04
`
`13.2
`
`9.9
`
`16.6
`
`13.0
`
`0.0060
`0.76
`0.62 – 0.92
`
`0.0008
`0.70
`0.56 – 0.86
`
`C750a
`c75
`(n=214)
`
`(n=127)
`48
`
`$ Survival
` ---median (months)
` ---p-valuec
` ---hazard ratioc
` ---95% CIc
`a TAXOL dose in mg/m2/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.
`b Among patients with measurable disease only.
`c Unstratified for the Intergroup Study, Stratified for Study GOG-111.
`
`29.5
`
`21.9
`
`35.5
`
`0.0057
`0.73
`0.58 – 0.91
`
`24.2
`
`0.0002
`0.64
`0.50 – 0.81
`
`TABLE 2B
` EFFICACY IN THE PHASE 3 FIRST-LINE OVARIAN CARCINOMA INTERGROUP STUDY
`
`
`
`$ Clinical Responseb
` ---rate (percent)
` ---p-valuec
`
`$Time to Progression
` ---median (months)
` ---p-valuec
` ---hazard ratioc
` ---95% CIc
`
`$ Survival
` ---median (months)
`
`T175/3a
`c75
`(n=342)
`
`(n=162)
`59
`
`C750a
`c75
`(n=338)
`
`(n=161)
`45
`
`0.014
`
`15.3
`
`11.5
`
`0.0005
`0.74
`0.63 – 0.88
`
`35.6
`
`25.9
`
`4
`
`

`
` ---p-valuec
` ---hazard ratioc
` ---95% CIc
`a TAXOL dose in mg/m2/infusion duration in hours; cyclophosphamide and cisplatin doses in mg/m2.
`b Among patients with measurable disease only.
`c Unstratified.
`
`0.0016
`0.73
`0.60 – 0.89
`
`FIGURE 1
`SURVIVAL: Cc VERSUS Tc (INTERGROUP)
`
`N
`No. events
`HR (95% CI)
`
`Tc
`Cc
`342
`338
`183
`220
`0.73 (0.60-0.89)
`
`Tc
`
`0
`4
`
`4
`
`5
`
`Number at Risk
`219
`122
`178
` 94
`
`2
`
`3
`
`YEARS
`
`Cc
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`PROPORTION SURVIVING
`
`Tc
`Cc
`
`0
`
`0
`
`292
`266
`
`1
`
`FIGURE 2
`SURVIVAL: Cc VERSUS Tc (GOG-111)
`
`5
`
`

`
`N
`No. events
`HR (95% CI)
`
`T c
`Cc
`196
`214
`114
`152
`0.64 (0.50-0.81)
`
`C c
`
`Tc
`Cc
`
`0
`
`1 6 8
`1 6 2
`
`1
`
`Number at Risk
`1 2 8
`7 3
`1 0 6
`5 2
`
`2
`
`YEARS
`
`3
`
`T c
`
`1 7
` 7
`
`4
`
`5
`
`1
`
`0 . 8
`
`0 . 6
`
`0 . 4
`
`0 . 2
`
`0
`
`PROPORTION SURVIVING
`
`6
`
`

`
`The adverse event profile for patients receiving TAXOL in combination with cisplatin in these studies
`
` was qualitatively consistent with that seen for the pooled analysis of data from 812 patients treated with single-
`
`agent TAXOL in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line ovarian
`
`carcinoma studies are described in the ADVERSE REACTIONS section in tabular (Tables 9 and 10) and
`
`narrative form.
`
`Second-Line Data: Data from five Phase 1 & 2 clinical studies (189 patients), a multicenter randomized
`
`Phase 3 study (407 patients), as well as an interim analysis of data from more than 300 patients enrolled in a
`
`treatment referral center program were used in support of the use of TAXOL in patients who have failed initial
`
`or subsequent chemotherapy for metastatic carcinoma of the ovary. Two of the Phase 2 studies (92 patients)
`utilized an initial dose of 135 to 170 mg/m2 in most patients (>90%) administered over 24 hours by continuous
`
`infusion. Response rates in these two studies were 22% (95% Cl:11 to 37%) and 30% (95% Cl: 18 to 46%)
`
`with a total of 6 complete and 18 partial responses in 92 patients. The median duration of overall response in
`
`these two studies measured from the first day of treatment was 7.2 months (range: 3.5-15.8 months) and 7.5
`
`months (range: 5.3-17.4 months), respectively. The median survival was 8.1 months (range: 0.2-36.7 months)
`
`and 15.9 months (range: 1.8-34.5 + months).
`
`The Phase 3 study had a bifactorial design and compared the efficacy and safety of TAXOL (paclitaxel),
`administered at two different doses (135 or 175 mg/m2) and schedules (3- or 24-hour infusion). The overall
`
`response rate for the 407 patients was 16.2% (95% Cl: 12.8 to 20.2%), with 6 complete and 60 partial
`
`responses. Duration of response, measured from the first day of treatment was 8.3 months (range: 3.2-21.6
`
`months). Median time to progression was 3.7 months (range 0.1+ - 25.1+ months). Median survival was 11.5
`
`months (range: 0.2-26.3 + months).
`
`7
`
`

`
`Response rates, median survival and median time to progression for the 4 arms are given in the
`
`following table.
`
`TABLE 3
`
`
`
`EFFICACY IN THE PHASE 3 SECOND-LINE OVARIAN CARCINOMA STUDY
`
`175/3
`(n=96)
`
`175/24
`(n=106)
`
`$ Response
` ---rate (percent)
` ---95% Confidence Interval
`
`14.6
`(8.5-23.6)
`
`21.7
`(14.5-31.0)
`
`$ Time to Progression
` ---median (months)
` ---95% Confidence Interval
`
`4.4
`(3.0-5.6)
`
`4.2
`(3.5-5.1)
`
`$ Survival
` ---median (months)
` ---95% Confidence Interval
`
`11.5
`(8.4-14.4)
`
`11.8
`(8.9-14.6)
`
`135/3
`(n=99)
`
`15.2
`(9.0-24.1)
`
`3.4
`(2.8-4.2)
`
`13.1
`(9.1-14.6)
`
`135/24
`(n=106)
`
`13.2
`(7.7-21.5)
`
`2.8
`(1.9-4.0)
`
`10.7
`(8.1-13.6)
`
`Analyses were performed as planned by the bifactorial study design described in the protocol, by
`comparing the two doses (135 or 175 mg/m2) irrespective of the schedule (3 or 24 hours) and the two schedules
`irrespective of dose. Patients receiving the 175 mg/m2 dose had a response rate similar to that for those
`receiving the 135 mg/m2 dose: 18% vs. 14% (p=0.28). No difference in response rate was detected when
`comparing the 3-hour with the 24-hour infusion: 15% vs. 17% (p=0.50). Patients receiving the 175 mg/m2 dose
`of TAXOL had a longer time to progression than those receiving the 135 mg/m2 dose: median 4.2 vs. 3.1 months
`
`(p=0.03). The median time to progression for patients receiving the 3-hour vs. the 24-hour infusion was 4.0
`months vs. 3.7 months, respectively. Median survival was 11.6 months in patients receiving the 175 mg/m2 dose
`of TAXOL and 11.0 months in patients receiving the 135 mg/m2 dose (p=0.92). Median survival was 11.7 months
`
`for patients receiving the 3-hour infusion of TAXOL and 11.2 months for patients receiving the 24-hour infusion
`
`(p=0.91). These statistical analyses should be viewed with caution because of the multiple comparisons made.
`
`TAXOL remained active in patients who had developed resistance to platinum-containing therapy
`
`(defined as tumor progression while on, or tumor relapse within 6 months from completion of, a platinum
`
`containing regimen) with response rates of 14% in the Phase 3 study and 31% in the Phase 1 & 2 clinical
`
`studies.
`
`The adverse event profile in this Phase 3 study was consistent with that seen for the pooled analysis
`
`of data from 812 patients treated in 10 clinical studies. These adverse events and adverse events from the
`
`Phase 3 second-line ovarian carcinoma study are described in the ADVERSE REACTIONS section in tabular
`
`(Tables 9 and 11) and narrative form.
`The results of this randomized study support the use of TAXOL at doses of 135 to 175 mg/m2,
`
`8
`
`

`
`administered by a 3-hour intravenous infusion. The same doses administered by 24-hour infusion were more
`
`toxic. However, the study had insufficient power to determine whether a particular dose and schedule produced
`
`superior efficacy.
`
`Breast Carcinoma
`Adjuvant Therapy
`
`A Phase 3 intergroup study (Cancer and Leukemia Group B [CALGB], Eastern Cooperative Oncology Group
`
`[ECOG], North Central Cancer Treatment Group [NCCTG], and Southwest Oncology Group [SWOG])
`
`randomized 3170 patients with node-positive breast carcinoma to adjuvant therapy with TAXOL or to no further
`
`chemotherapy following four courses of doxorubicin and cyclophosphamide (AC) . This multicenter trial was
`
`conducted in women with histologically positive lymph nodes following either a mastectomy or segmental
`
`mastectomy and nodal dissections. The 3 x 2 factorial study was designed to assess the efficacy and safety
`
`of three different dose levels of doxorubicin (A) and to evaluate the effect of the addition of TAXOL administered
`
`following the completion of AC therapy. After stratification for the number of positive lymph nodes (1-3, 4-9, or
`10+), patients were randomized to receive cyclophosphamide at a dose of 600 mg/m2 and doxorubicin at doses
`of either 60 mg/m2 (on day 1), 75 mg/m2 (in two divided doses on days 1 and 2), or 90 mg/m2 (in two divided
`
`doses on days 1 and 2 with prophylactic G-CSF support and ciprofloxacin) every 3 weeks for four courses and
`either TAXOL 175 mg/m2 as a 3-hour infusion every 3 weeks for four additional courses or no additional
`
`chemotherapy. Patients whose tumors were positive were to receive subsequent tamoxifen treatment (20 mg
`
`daily for 5 years); patients who received segmental mastectomies prior to study were to receive breast irradiation
`
`after recovery from treatment-related toxicities.
`
`At the time of the current analysis, median follow-up was 30.1 months. Of the 2066 patients who were
`
`hormone receptor positive, 93% received tamoxifen. The primary analyses of disease-free survival and overall
`
`survival used multivariate Cox models, which included TAXOL administration, doxorubicin dose, number of
`
`positive lymph nodes, tumor size, menopausal status, and estrogen receptor status as factors. Based on the
`
`model for disease-free survival, patients receiving AC followed by TAXOL had a 22% reduction
`
`in the risk of disease recurrence compared to patients randomized to AC alone (Hazard Ratio[HR] = 0.78, 95%
`
`CI 0.67-0.91, p=0.0022). They also had a 26% reduction in the risk of death (HR=0.74, 95% CI 0.60-0.92,
`
`p=0.0065). For disease-free survival and overall survival, p values were not adjusted for interim analyses.
`Kaplan-Meier curves are shown in Figures 3 and 4. Increasing the dose of doxorubicin higher than 60 mg/m2
`
`had no effect on either disease-free survival or overall survival.
`
`9
`
`

`
`FIGURE 3
`DISEASE-FREE SURVIVAL: AC VERSUS AC + T
`
`AC+T
`
`AC
`
`
`
`A C
`
`
`
`A C + T
`
`
`
`N
`No. events
`H R
`(95% CI)
`
`1551
`3 4 1
` 0.78
` (0.67-0.91)
`
`1570
`2 8 3
`
`Number at Risk
`
`AC+T
`
`1471
`
`AC
`
`1401
`
`1
`
`876
`
`819
`
`2
`YEARS
`
`332
`
`321
`
`3
`
`FIGURE 4
`SURVIVAL: AC VERSUS AC + T
`
`21
`
`10
`
`4
`
`10
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`PROPORTION DISEASE FREE
`
`0
`
`0
`
`

`
`1
`
`2
`YEARS
`
`3
`
`4
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`PROPORTION SURVIVING
`
`0
`
`0
`
`Subset analyses. Subsets defined by variables of known prognostic importance in adjuvant breast carcinoma
`AC
`were examined, including number of positive lymph nodes, tumor size, hormone receptor status, and
`
`AC+T
`
`N
`No. events
`HR
`(95% CI)
`
`AC
`
`1551
`192
` 0.74
` (0.60-0.92)
`
`
`
`AC+T
`1570
`150
`
` Number at Risk
`
`AC+T
`
`1534
`
`AC
`
`1496
`
`1016
`
` 962
`
`426
`
`410
`
`35
`
`25
`
`menopausal status. Such analyses must be interpreted with care, as the most secure finding is the overall
`
`study result. In general, a reduction in hazard similar to the overall reduction was seen with TAXOL for both
`
`disease-free and overall survival in all of the larger subsets with one exception; patients with receptor-positive
`
`tumors had smaller reduction in hazard (HR=0.92) for disease-free survival with TAXOL than other groups.
`
`Results of subset analyses are shown in Table 4.
`
`11
`
`

`
`1212
`
`

`
`TABLE 4
`SUBSET ANALYSES -- ADJUVANT BREAST CARCINOMA STUDY
`Disease-Free Survival
`Overall Survival
`No. of
`Hazard Ratio
`Hazard Ratio
`Recurrences
`(95% CI)
`(95% CI)
`
`No. of
`Patients
`
`No. of
`Deaths
`
`1449
`
`1310
`
` 360
`
`1096
`
`1611
`
`397
`
`1929
`
`1183
`
`2066
`
`1055
`
`221
`
`274
`
`129
`
`153
`
`358
`
`111
`
`374
`
`250
`
`293
`
`331
`
`0.72
`(0.55-0.94)
`0.78
`(0.61-0.99
`0.93
`(0.66.1.31)
`
`0.79
`(0.57-1.08)
`0.79
`(0.64-0.97)
`0.75
`(0.51-1.08)
`
`0.83
`(0.67-1.01)
`0.73
`(0.57-0.93)
`
`0.92
`(0.73-1.16)
`0.68
`(0.55-0.85)
`
`107
`
`148
`
`87
`
`67
`
`201
`
`72
`
`187
`
`155
`
`67
`
`216
`
`0.76
`(0.52-1.12)
`0.66
`(0.47-0.91)
`0.90
`(0.59-1.36)
`
`0.73
`(0.45-1.18)
`0.74
`(0.56-0.98)
`0.73
`(0.46-1.16)
`
`0.72
`(0.54-0.97)
`0.77
`(0.56-1.06)
`
`0.83
`(0.59-1.18)
`0.71
`(0.54-0.93)
`
`Patient Subset
`• No. of Positive Nodes
` 1-3
`
` 4-9
`
` 10+
`
`•• Tumor Size (cm)
` £ 2
`
` > 2 and £ 5
`
` > 5
`
`•• Menopausal Status
` Pre
`
` Post
`
`•• Receptor Status
` Positivea
`
` Negative/Unknown b
`
`a Positive for either estrogen or progesterone receptors.
`b Negative or missing for both estrogen and progesterone receptors (both missing: n=15).
`
`These retrospective subgroup analyses suggest that the beneficial effect of TAXOL is clearly
`
`established in the receptor-negative subgroup, but the benefit in receptor-positive patients is not yet clear. With
`
`respect to menopausal status, the benefit of TAXOL is consistent (see Table 4 and Figures 5-8).
`
`13
`
`

`
`FIGURE 5FIGURE 5
`
`DISEASE-FREE SURVIVAL - RECEPTOR STATUS NEGATIVE/UNKNOWN
`DISEASE-FREE SURVIVAL - RECEPTOR STATUS NEGATIVE/UNKNOWN
`
`AC VERSUS AC+TAC VERSUS AC+T
`
`4
`4
`
`4
`
`AC
`
`N
`N o . e v e n t s
`H R
`( 9 5 % C I )
`
`AC+T 469
`AC
`440
`
`AC+T
`
`A C
`5 3 3
`1 9 2
`
`A C + T
`5 2 2
`1 3 9
`
`0.68
`( 0 . 5 5 - 0 . 8 5 )
`Number at Risk
`259
`106
`242
` 90
`
`1
`
`2
`YEARS
`
`3
`
`14
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`PROPORTION DISEASE FREE
`
`0
`
`0
`
`

`
`FIGURE 6FIGURE 6
`
`
`DISEASE-FREE SURVIVAL - RECEPTOR STATUS POSITIVEDISEASE-FREE SURVIVAL - RECEPTOR STATUS POSITIVE
`
`AC VERSUS AC+TAC VERSUS AC+T
`
`AC+T
`
`AC
`
`N
`No. events
`HR
`(95% CI)
`
`AC
`1018
`149
`
`AC+T
`1048
`144
`
`0.92
`(0.73-1.16)
`
`AC+T 1002
`AC
` 961
`
`0
`
`1
`
`Number at Risk
`617
`226
`577
`231
`
`2
`YEARS
`
`3
`
`17
` 6
`
`4
`
`15
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`PROPORTION DISEASE FREE
`
`

`
`FIGURE 7
`FIGURE 7
`DISEASE-FREE SURVIVAL - PREMENOPAUSAL
`DISEASE-FREE SURVIVAL - PREMENOPAUSAL
`
`AC VERSUS AC+TAC VERSUS AC+T
`
`AC
`
`N
`No. events
`HR
`(95% CI)
`
`AC+T
`
`AC
`966
`201
`
`AC+T
`963
`173
`
`0.83
`(0.67-1.01)
`
`AC+T 905
`AC
`883
`
`Number at Risk
`570
`221
`529
`224
`
`1
`
`2
`YEARS
`
`3
`
`13
` 4
`
`4
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`PROPORTION DISEASE FREE
`
`0
`
`0
`
`16
`
`

`
`FIGURE 8
`FIGURE 8
`DISEASE-FREE SURVIVAL - POSTMENOPAUSAL
`DISEASE-FREE SURVIVAL - POSTMENOPAUSAL
`
`AC VERSUS AC+TAC VERSUS AC+T
`
`AC+T
`
`AC
`
`N
`No. events
`HR
`(95% CI)
`
`AC
`580
`140
`
`AC+T
`603
`110
`
`0.73
`(0.57-0.93)
`
`AC+T 562
`AC
`514
`
`Number at Risk
`304
`111
`289
` 97
`
`1
`
`2
`YEARS
`
`3
`
`8
`6
`
`4
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`PROPORTION DISEASE FREE
`
`0
`
`0
`
`17
`
`

`
`The adverse event profile for the patients who received TAXOL subsequent to AC was consistent with that seen
`
`in the pooled analysis of data from 812 patients (Table 9) treated with single-agent TAXOL in 10 clinical studies.
`
` These adverse events are described in the ADVERSE REACTIONS section in tabular (Tables 9 and 12) and
`
`narrative form.
`
`After Failure of Initial Chemotherapy
`
`Data from 83 patients accrued in three Phase 2 open label studies and from 471 patients enrolled in a Phase
`
`3 randomized study were available to support the use of TAXOL in patients with metastatic breast carcinoma.
`
`Phase 2 open label studies: Two studies were conducted in 53 patients previously treated with a maximum of
`
`one prior chemotherapeutic regimen. TAXOL was administered in these two trials as a 24-hour infusion at initial
`doses of 250 mg/m2 (with G-CSF support) or 200 mg/m2. The response rates were 57% (95% Cl: 37 to 75%)
`
`and 52% (95% Cl: 32 to 72%), respectively. The third Phase 2 study was conducted in extensively pretreated
`
`patients who had failed anthracycline therapy and who had received a minimum of two chemotherapy regimens
`for the treatment of metastatic disease. The dose of TAXOL was 200 mg/m2 as a 24-hour infusion with G-CSF
`
`support. Nine of 30 patients achieved a partial response, for a response rate of 30% (95% Cl: 15 to 50%).
`
`Phase 3 randomized study: This multicenter trial was conducted in patients previously treated with one or two
`
`regimens of chemotherapy. Patients were randomized to receive TAXOL (paclitaxel) at a dose of either 175
`mg/m2 or 135 mg/m2 given as a 3-hour infusion. In the 471 patients enrolled, 60% had symptomatic disease
`
`with impaired performance status at study entry, and 73% had visceral metastases. These patients had failed
`
`prior chemotherapy either in the adjuvant setting (30%), the metastatic setting (39%), or both (31%). Sixty-
`
`seven percent of the patients had been previously exposed to anthracyclines and 23% of them had disease
`
`considered resistant to this class of agents.
`
`The overall response rate for the 454 evaluable patients was 26% (95% Cl: 22 to 30%), with 17
`
`complete and 99 partial responses. The median duration of response, measured from the first day of treatment,
`
`was 8.1 months (range: 3.4-18.1 + months). Overall for the 471 patients, the median time to progression was
`
`3.5 months (range: 0.03-17.1 months). Median survival was 11.7 months (range: 0-18.9 months).
`
`18
`
`

`
`Response rates, median survival and median time to progression for the 2 arms are given in the
`
`following table.
`
`EFFICACY IN BREAST CANCER AFTER FAILURE OF INITIAL CHEMOTHERAPY
`OR WITHIN 6 MONTHS OF ADJUVANT CHEMOTHERAPY
`
`TABLE 5
`
`$ Response
` ---rate (percent)
` ---p-value
`
`$ Time to Progression
` ---median (months)
` ---p-value
`
`$ Survival
` ---median (months)
` ---p-value
`
`175/3
`(n=235)
`
`135/3
`(n=236)
`
`28
`
`4.2
`
`11.7
`
`22
`
`3.0
`
`10.5
`
`0.135
`
`0.027
`
`0.321
`
`The adverse event profile of the patients who received single-agent TAXOL in the Phase 3 study was
`
`consistent with that seen for the pooled analysis of data from 812 patients treated in 10 clinical studies. These
`
`adverse events and adverse events from the Phase 3 breast carcinoma study are described in the ADVERSE
`
`REACTIONS section in tabular (Tables 9 and 13) and narrative form.
`
`Non-Small Cell Lung Carcinoma (NSCLC)
`
`In a Phase 3 open label randomized study conducted by the ECOG, 599 patients were randomized to either
`TAXOL (T) 135 mg/m2 as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2, TAXOL (T) 250 mg/m2
`as a 24-hour infusion in combination with cisplatin (c) 75 mg/m2 with G-CSF support, or cisplatin (c) 75 mg/m2
`on day 1, followed by etoposide (VP) 100 mg/m2 on days 1, 2, and 3 (control).
`
`Response rates, median time to progression, median survival, and one-year survival rates are given in
`
`the following table. The reported p-values have not been adjusted for multiple comparisons. There were
`
`statistically significant differences favoring each of the TAXOL plus cisplatin arms for response rate and time
`
`to tumor progression. There was no statistically significant difference in survival between either TAXOL plus
`
`cisplatin arm and the cisplatin plus etoposide arm.
`
`19
`
`

`
`TABLE 6
`EFFICACY PARAMETERS IN THE PHASE 3 FIRST-LINE NSCLC STUDY
`VP100a
`T135/24
`T250/24
`c75
`c75
`c75
`(n=198)
`(n=201)
`(n=200)
`
`$ Response
` ---rate (percent)
` ---p-valueb
`
`$ Time to Progression
` ---median (months)
` ---p-valueb
`
`$ Survival
` ---median (months)
` ---p-valueb
`
`25
`0.001
`
`4.3
`0.05
`
`9.3
`0.12
`
`$ One-Year Survival
` ---percent of patients
`
`36
`a Etoposide (VP) 100 mg/m2 was administered IV on days 1, 2, and 3.
`b Compared to cisplatin/etoposide.
`
` 23
`<0.001
`
`4.9
`0.004
`
`10.0
`0.08
`
`40
`
`12
`
`2.7
`
`7.4
`
`32
`
`In the ECOG study, the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire had
`
`seven subscales that measured subjective assessment of treatment. Of the seven, the Lung Cancer Specific
`Symptoms subscale favored the TAXOL 135 mg/m2/24 hour plus cisplatin arm compared to the
`
`cisplatin/etoposide arm. For all other factors, there was no difference in the treatment groups.
`
`The adverse event profile for patients who received TAXOL in combination with cisplatin in this study
`
`was generally consistent with that seen for the pooled analysis of data from 812 patients treated with single-
`
`agent TAXOL in 10 clinical studies. These adverse events and adverse events from the Phase 3 first-line NSCLC
`
`study are described in the ADVERSE REACTIONS section in tabular (Tables 9 and 14) and narrative form.
`
`AIDS-Related Kaposi's Sarcoma
`
`Data from two Phase 2 open label studies support the use of TAXOL as second-line therapy in patients with
`
`AIDS-related Kaposi=s sarcoma. Fifty-nine of the 85 patients enrolled in these studies had previously received
`
`systemic therapy, including interferon alpha (32%), DaunoXome7 (31%), DOXIL7 (2%), and doxorubicin
`
`containing chemotherapy (42%), with 64% having received prior anthracyclines. Eighty-five percent of the
`
`pretreated patients had progressed on, or could not tolerate, prior systemic therapy.
`In Study CA139-174 patients received TAXOL at 135 mg/m2 as a 3-hour infusion every 3 weeks
`(intended dose intensity 45 mg/m2/week). If no dose-limiting toxicity was observed, patients were to receive 155
`mg/m2 and 175 mg/ m2 in subsequent courses. Hematopoietic growth factors were not to be used initially. In
`Study CA139-281 patients received TAXOL at 100 mg/m2 as a 3-hour infusion every 2 weeks (intended
`
`_____________________________________
`DaunoXome7 is a registered trademark of NeXstar Pharmaceuticals, Incorporated.
`DOXIL7 is a registered trademark of Sequus Pharmaceuticals, Incorporated.
`
`20
`
`

`
` dose intensity 50 mg/m2/week). In this study patients could be receiving hematopoietic growth factors before
`
`the start of TAXOL therapy, or this support was to be initiated as indicated; the dose of TAXOL was not
`
`increased. The dose intensity of TAXOL used in this patient population was lower than the dose intensity
`
`recommended for other solid tumors.
`
`All patients had widespread and poor risk disease. Applying the ACTG staging criteria to patients with
`prior systemic therapy, 93% were poor risk for extent of disease (T1), 88% had a CD4 count <200 cells/mm3
`(I1), and 97% had poor risk considering their systemic illness (S 1).
`
`All patients in Study CA139-174 had a Karnofsky performance status of 80 or 90 at baseline; in Study
`
`CA139-281, there were 26 (46%) patients with a Karnofsky performance status of 70 or worse at baseline.
`
`TABLE 7
`EXTENT OF DISEASE AT STUDY ENTRY
` Percent of Patients
`
`Prior Systemic Therapy
`(n=59)
`
`Visceral + edema + oral + cutaneous
`Edema or lymph nodes
` oral + cutaneous
`Oral + cutaneous
`Cutaneous Only
`
`42
`
`41
`10
` 7
`
`Although the planned dose intensity in the two studies was slightly different (45 mg/m2/week in Study
`CA139-174 and 50 mg/m2/week in Study CA139-281), delivered dose intensity was 38-39 mg/m2/week in both
`
`studies, with a similar range (20-24 to 51-61).
`
`Efficacy: The efficacy of TAXOL was evaluated by assessing cutaneous tumor response according to
`
`the amended ACTG criteria and by seeking evidence of clinical benefit in patients in six domains of symptoms
`
`and/or conditions that are commonly related to AIDS-related Kaposi=s sarcoma.
`Cutaneous Tumor Response (Amended ACTG Criteria): The objective response rate was 59% (95%
`
`CI: 46% to 72%) (35 of 59 patients) in patients with prior systemic therapy. Cutaneous responses were
`
`primarily defined as flattening of more than 50% of previously raised lesions.
`
`OVERALL BEST RESPONSE (AMENDED ACTG CRITERIA)
`
`TABLE 8
`
`
`
` Percent of Patients
`
` Prior Systemic Therapy
`(n=59)
`
`Complete response
`Partial response
`Stable disease
`Progression
`Early death/toxicity
`
`3
`56
`29
` 8
` 3
`
`21
`
`

`
`The median time to response was 8.1 weeks and the median duration of response measured from the
`
`first day of treatment was 10.4 months (95% CI: 7.0 to 11.0 months) for the patients who had previously received
`
`systemic therapy. The median time to progression was 6.2 months (95% CI: 4.6 to 8.7 months).
`
`Additional Clinical Benefit: Most data on patient benefit were assessed retrospectively (plans for such
`
`analyses were not included in the study protocols). Nonetheless, clinical descriptions and photographs
`
`indicated clear benefit in some patients, including instances of improved pulmonary function in patients with
`
`pulmonary involvement, improved ambulation, resolution of ulcers, and decreased analgesic requirements