Original arthle
`
`Annals ofOncology 14: 138371390, 2003
`DOI: 10.1093/annonc/mdg368
`
`Randomized, double-blind, multicenter trial comparing two doses
`
`of arzoxifene (LY353381) in hormone-sensitive advanced or
`
`metastatic breast cancer patients
`
`J. Baselga1*, A. Llombart-Cussacz, M. Belletl, V. Guillem-Portaz, N. Enas3, K. Krejcy“, E. Carrascos,
`L. Kayitalire6, M. Kuta7, A. Lluchs, P. Vodvarka9, P. Kerbratlo, M. Namer11 & L. Petruzelka12
`
`JVall D’Hebron University Hospital, Barcelona; ZInstituto Valenciano de Oncologia, Valencia, Spain; 3Eli Lilly & Co., Indianapolis, IN, USA;
`4Eli Lilly & Co., Vienna, Austria; 5Eli Lilly & Co., Madrid, Spain; 5Eli Lilly & Co., Suresnes, France; 7Nemocnice Chomutov, Chomutov, Czech Republic;
`8Hospital Cli’nico Universitario, Valencia, Spain; 9Fakultni Nemocnice S Poliklinikou, Ostrava-Poruba, Czech Republic;
`”Centre Eugene Marquis, Rennes; ”Centre Antoine Lacassagne, Nice, France; ”Charles University, Prague, Czech Republic
`
`Received4 February 2003; revised 2] April 2003; accepted 14 May 2003
`
`Background: This randomized, double—blind, phase II study assessed two doses of the selective estrogen
`receptor modulator arzoxifene in women with advanced breast cancer. The primary end point was to choose the
`best of two doses of arzoxifene based on the response rate or the clinical benefit rate (CBR). Pharmacokinetics
`and toxicities were also assessed.
`
`Patients and methods: Ninety—two patients with advanced breast cancer received arzoxifene 20 or 50 mg/day.
`Tumor response was assessed using World Health Organization criteria. Toxicities were graded according
`to the National Cancer Institute Common Toxicity Criteria (NCl—CTC) system. Pharmacokinetic data were
`analyzed using the NONMEM® software program (GloboMax, Hanover, MD, USA).
`Results: Response rates in the 20 mg arm were numerically higher than the 50—mg arm according to the inves—
`tigator (40.5% versus 36.4%) and the independent review panel (42.9% versus 27.3%). CBR was higher in the
`20 mg arm according to the investigator (64.3% versus 61.4%) and the independent review panel (59.5% versus
`47.7%). Arzoxifene was well tolerated. There were no study drug—related deaths. Mean observed steady—state
`plasma concentrations of arzoxifene were 3.62 and 7.48 ng/ml for the 20 and 50 mg doses, respectively.
`Conclusions: There were no significant differences in efficacy or safety between 20 and 50 mg of arzoxifene.
`Accordingly, arzoxifene 20 mg/day was selected for further study in patients with breast cancer.
`Key words: arzoxifene, breast cancer, LY353381, selective estrogen receptor modulator
`
`Introduction
`
`For many years tamoxifen has been the mainstay of hormonal
`therapy for patients with breast cancer [1, 2]. As tamoxifen use has
`increased, so has the importance of its toxicity. Although tamox—
`ifen is generally a well—tolerated drug, it does have significant
`side—effects, such as thromboembolism, oculopathy and endo—
`metrial cancer
`[1, 3—11]. Tamoxifen has both anti—estrogenic
`(breast) and estrogenic (uterus, bone, lipids and cardiovascular
`system) effects, which are mediated predominantly by nuclear
`estrogen receptors (ERs) [12]. The differential effects of tamoxifen,
`depending upon target organ and hormonal milieu, and other
`selective estrogen receptor modulators (SERMs) are thought to be
`due to subtle differences in the steric binding of these compounds
`to the ER [12]
`
`
`Due to the potential side—effects related to the estrogen—agonist
`effects of tamoxifen, considerable attention has been paid to
`developing SERMs. The SERM arzoxifene (LY353381) was
`designed to have potent ER antagonistic activity on the breast and
`endometrium, while maintaining beneficial estrogen—agonist effects
`on bone and lipids. Both the parent compound and the active
`desmethly metabolite bind to the ER with high affinity and inhibit
`estrogen—dependent growth of MCF—7 breast cancer cells [13].
`Arzoxifene is approximately 1200—fold more potent than tamox—
`ifen in inhibiting the growth of MCF—7 cells. Arzoxifene showed
`dose—dependent inhibition of MCF—7 xenograft growth in nude
`. M
`.
`1.
`.
`1
`t di
`’f
`bl k d
`t
`mice.
`oreover, m prec inica S u es, arzoxr ene
`oc e es rogen—
`induced uterine stimulation In ovariectomized rats and did. not
`stimulate the uterine endometrrum as indicated by a minimal
`effect on uterine weight in ovariectomized rats treated [14].
`In a phase I study in 32 patients with previously treated advanced
`
`*Correspondence to.“ Dr J. Baselga, Vall D’Hebron University Hospital,
`P. Val] D’Hebron 119—129, 08035 Barcelona, Spain. Tel: +34-93-2746085;
`FaX: +34—93-2746059; E-maili jbaselga@Vh6br0n~net
`
`breast cancer, four doses of arzoxrfene were tested: 10, 20, 50 and
`100 Dag/day [151 The mOSt common adVerse eVent (56%) W35 hOt
`flashes, as expected for this class of agent. Prospective evaluation
`
`© 2003 European Society for Medical Oncology
`
`AstraZeneca Exhibit 2088 p. 1
`lnnoPharma Licensing LLC v. AstraZeneca AB lPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB lPR2017-01910
`
`

`

`1384
`
`of uterine safety was performed at baseline and on completion of
`12 weeks of treatment and showed no evidence of endometrial
`
`hyperplasia. There was no evidence of dose—dependent toxicity.
`Neither complete nor partial responses were seen in this study;
`however, six patients had stable disease (SD) lasting 26 months.
`In addition, SD lasting 23 months was demonstrated in at least one
`patient from each dose cohort, suggesting possible antitumor activ—
`ity at all tested doses. This study also established that arzoxifene
`has a linear pharmacokinetic profile [15].
`The current study was conducted to select the best of two doses
`of arzoxifene (20 and 50 mg) for breast cancer treatment by com—
`paring their efficacy and safety in patients with advanced breast
`cancer and to assess the compound for evidence of endometrial
`stimulation. The primary end point of dose selection was chosen
`on the basis of response rate or clinical benefit rate (CBR). Second—
`ary study end points included response duration, time to progres—
`sive disease (TTP), overall survival and toxicity.
`
`Patients and methods
`
`Study design and treatment
`
`A randomized, double—blind phase II study was carried out of arzoxifene 20 or
`50 mg (Eli Lilly & Co., Indianapolis, IN) taken orally once daily by patients
`with advanced breast cancer for 12 weeks or until disease progression. Ran—
`domization was performed and balanced with respect to the treatment in each
`stratum using the Pocock and Simon algorithm [16] for three prognostic factors:
`number of metastatic disease sites (<3 or 23 sites), prior tamoxifen therapy
`(yes or no) and degree of ER positivity (high, low or unknown).
`To preserve the blinding of the study, an assessment committee was
`appointed. No patients or investigators were inadvertently unblinded. How—
`ever, patients treated with arzoxifene 20 mg/day, upon disease progression,
`received further arzoxifene treatment at a dose of 50 mg daily, in an open—label
`manner, at the investigator’s discretion until further disease progression.
`In the event of any National Cancer Institute Common Toxicity Criteria
`(NCI—CTC) grade 3 toxicity, dosing was omitted for a maximum of 2 weeks;
`upon resolution of the toxicity, treatment was re—initiated with a 50% dose
`reduction. Patients who had any study drug—related grade 4 toxicity or who
`progressed after 8 weeks of treatment were discontinued from the study.
`
`Eligibility criteria
`
`Women, at least 18 years of age, with a documented diagnosis of breast cancer
`(locally advanced or metastatic disease) who had not received any systemic
`therapy or relapsed >l2 months after stopping adjuvant tamoxifen were elig—
`ible for this study. Patients with inoperable, locally advanced breast cancer
`were enrolled only if they were ineligible for primary chemotherapy. Prior
`neo—adjuvant or adjuvant chemotherapy was permitted if completed 26 months
`prior to the diagnosis of metastatic disease. Patients had to have evaluable or
`bidimensionally measurable tumors that were ER or progesterone receptor
`(PgR) positive (>10 fmol/mg by biochemical assay or 210% positive cells by
`imrnunohistochemistry).
`Patients were excluded from the study if they had received prior hormonal
`therapy or chemotherapy for metastatic breast cancer; had rapidly progressive
`disease or known central nervous system metastases; inadequate end organ
`function [bilirubin >l.5 >< upper limit of normal (ULN), aspartate aminotrans—
`ferase/alanine aminotransferase >2.5 >< ULN; serum creatinine 21.5 X ULN);
`hypercalcemia (corrected calcium of >1 1.0 mg/dl or 2.7 mmol/l); were preg—
`nant or breast—feeding; or had used any investigational agent within 4 weeks of
`study enrollment].
`
`The study was conducted in accordance with the ethical principles of the
`Declaration of Helsinki. The protocol and consent process were approved by
`all relevant ethics review boards and all patients gave written informed consent
`prior to study enrollment.
`
`Study assessments
`All patients were assessed with the following tests: clinical evaluation, hemat—
`ology, blood chemistry and coagulation profiles, hormone levels, bone
`markers (osteocalcin and type I collagen fragment) and radiological assessment.
`All clinical assessments were repeated every 4 weeks for the first 12 weeks of
`the study. Radiological assessment of involved disease sites was repeated after
`12 weeks, or at discontinuation if sooner than 12 weeks, and every 2—3 months
`thereafter. The same assessment method used to determine the disease status at
`
`baseline was used consistently for efficacy evaluation throughout the study.
`To prospectively evaluate gynecological safety, patients underwent trans—
`vaginal ultrasounds (TVUs) at baseline, 12 weeks and every 6 months there—
`after while on arzoxifene treatment. If endometrial thickness >8 mm was
`
`noted, or had increased 25 mm from baseline, additional evaluation was
`required. To evaluate the effects of arzoxifene on the hypothalarnic—pituitary—
`gonadal axis, patients also underwent hormonal evaluation [follicle stimulat—
`ing hormone (FSH), luteinizing hormone (LH), estradiol and sex hormone
`binding globulin (SHBG)] at baseline and every 2 to 3 months during study
`treatment. To evaluate the effects of arzoxifene on bone metabolism, serum
`osteocalcin and type 1 collagen fragment were measured at baseline and every
`2—3 months during study participation.
`Bidimensionally measurable disease was defined as tumor measurements
`consisting of the diameter of the widest portions of the tumor and the greatest
`diameter perpendicular to that line. Evaluable disease comprised unidimen—
`sionally measurable lesions, masses without clearly defined margins, lesions
`with both diameters <0.5 cm, lesions on scan with either diameter smaller than
`the distance between cuts, palpable lesions with either diameter <2 cm or lytic
`bone disease. Unmeasurable disease was defined as lesions in previously irra—
`diated fields, ascites, pleural effusions, blastic or mixed bony metastases, or
`abdominal masses that could be palpated but not measured.
`Patients who had baseline staging and tumor measurements, at least one
`tumor measurement on treatment and had received at least 4 weeks of treat—
`
`ment were eligible for efficacy analyses. Tumor response [complete response
`(CR) plus partial response (PR)] was assessed by the investigator and the
`independent review panel using World Health Organization (WHO) criteria
`[17]. Tumor response data collected during the open—label dose escalation
`phase were not included in the primary analysis of tumor response. Tumor
`response had to be confirmed at least 4 weeks after a documented response. An
`independent review panel, consisting of three radiologists, reviewed the data
`for all patients with a response or SD according to the investigator. Clinical
`benefit response was defined as CR plus PR plus SD lasting 26 months. TTP
`was measured from the time of randomization until time of documented pro—
`gressive disease (PD), including death by any cause. Response duration was
`identical to TTP but applied only to patients who exhibited a tumor response.
`Survival was defined as the time from randomization until death by any cause.
`Analyses of secondary end points were based on investigator—determined
`assessments.
`Patients who received at least one dose of arzoxifene were evaluated for
`
`safety and toxicity. Safety was assessed by recording all clinical adverse events
`at each patient visit, as well as routine hematological and biochemical monitor—
`ing. Toxicities were assessed using the NCI—CTC grading system (version 1) [l 8].
`
`Pharmacokinetic analysis
`
`Heparinized plasma samples were obtained from each patient during each
`visit for determination of concentrations of unconjugated arzoxifene and its
`desmethyl metabolite LY335562. Data were pooled and analyzed using a
`population pharmacokinetic program (NONMEM).
`
`AstraZeneca Exhibit 2088 p. 2
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`1385
`
`Assessed for eligibility (n=95)
`
`
`Excluded (n=3)
`
`Protocol inclusion criteria not met (=1)
`
`
`Patient decision (n=l)
`Adverse event (n=l)
`
`
`
`
`Randomized (n=92)
`
`Allocated to 20 mg/day (n=46)
`
`Allocated to 50 mg/day (n=46)
`
`
`
`Discontinued treatment (n=43)
`
`Discontinued treatment (n=42)
`Progressive disease (n=25)
`Progressive disease (n=27)
`
`
`
`Clinical relapse (n=8)
`Clinical relapse (n=5)
`
`
`
`Investigator decision (n=4)
`Physician decision (n=7)
`
`
`
`Patient decision (n=2)
`Patient decision (n=4)
`
`
`
`Continued treatment (n=4)
`Protocol inclusion criteria not met (n=l)
`
`
`
`Adverse event (n=l)
`
`
`Death (n=l)
`
`Continued treatment (n=3)
`
`
`
`
`
`
`Analysed (n=44)
`0
`Analysed (n=42)
`
`Excluded from analysis (n=4)
`Excluded from analysis (n=2)
`
`
`
`No bidimensionally measurable disease (n=l)
`Insufficient treatment (n=l)
`
`
`
`No follow-up X-ray (n=l)
`Protocol inclusion criteria not met (n=2)
`
`
`
`No follow-up X-ray (n=l)
`
`
`
`Hi
`
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`
`EEh:
`
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`
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`g
`
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`a.
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`
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`'5
`g
`
`Figure 1. Patient characteristics.
`
`Statistical methods
`
`This study design was based on a ranking and selection methodology [19] in
`which the treatment arm with the larger observed response rate is selected as
`the best treatment. This design ensured that if the true response rate for one
`dose was 215% higher than the other dose, there was at least a 90% probability
`that this more effective dose would be selected. To fulfill this condition, 37
`evaluable patients per dose needed to be enrolled.
`Tinie—to—event distributions were estimated using the Kaplan—Meier method
`[20] and the log—rank test was used to compare treatment groups. The Mantel—
`Haenszel 02 test was used to compare the incidence of toxicities accounting for
`severity. Changes from baseline to study discontinuation at various end points
`(e.g. hormone levels and bone markers) were assessed within study arms using
`the nonparametric sign test to allow for non—syrnmetrical distributions and
`between study arms using the Wilcoxon rank sum test. Exact binomial con—
`fidence intervals were computed for response rates and all confidence intervals
`and P values used a two—sided significance level of 0.05.
`
`Results
`
`Patient characteristics
`
`The study was conducted at 18 European centers and 95 patients
`with advanced or metastatic breast cancer were entered from July
`
`1998 to March 1999 (Figure 1). Three patients were not ran—
`domized: one patient did not meet protocol inclusion criteria, one
`patient experienced an adverse event and one patient decided not
`to enroll. Ninety—two patients were randomized: 46 in the 20 mg
`arm and 46 in the 50 mg arm. All patients were Caucasian. Not—
`ably, the median age for the patient population was 69.5 years and
`92% were postmenopausal. The percentage of patients who had
`received adjuvant therapy was low. Baseline patient character—
`istics were well balanced between the two arms (Table 1).
`
`Response rate and CBR
`
`Forty—two patients in the 20 mg arm and 44 in the 50 mg arm were
`evaluable for efficacy; no bidimensionally measurable disease, no
`follow—up radiological assessment, inclusion criteria not fulfilled
`and insufficient therapy were reasons for non—evaluability.
`Table 2 provides a summary of response rates and CBRs as
`determined by the investigators and the independent review panel.
`Response rate (40.5% versus 36.4%) and CBR (64.3% versus
`61.4%) were numerically higher in the 20 mg arm compared with
`the 50 mg arm, as determined by the investigator as well as the
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`1386
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`Table 1. Baseline patient and disease characteristics
`
`Characteristic
`Arzoxifene [n (%)]
`
`20 mg
`50 mg
`
`No. of randomized patients
`
`46 (100)
`
`46 (100)
`
`Age (years)
`Median
`
`Range
`
`Menopausal statusa
`
`Postmenopausal
`
`Premenopausal
`Disease stage
`
`Locally advanced (111B)
`
`Metastatic (IV)
`Site of metastasis
`
`Liver
`
`Lung (no liver mets)
`
`Bone (no liver or lung mets)
`
`Other
`
`23 metastatic sites
`
`Zubrod performance status
`0
`
`1
`
`ER/PgR status
`
`ER+ (regardless of PgR)
`
`ER—/PgR+
`
`ER unknown/PgR unknown
`
`Time since diagnosis (months)
`Median
`
`Range
`
`70
`
`44—86
`
`41 (89)
`
`4 (9)
`
`18 (39)
`
`28 (61)
`
`5 (11)
`
`7 (15)
`
`12 (26)
`
`22 (48)
`
`15 (33)
`
`26
`
`20
`
`34
`
`2
`
`10
`
`69
`
`37—94
`
`44 (96)
`
`2 (4)b
`
`14 (30)
`
`32 (70)
`
`4 (9)
`
`11 (24)
`
`10 (22)
`
`21 (46)
`
`15 (33)
`
`32
`
`14
`
`34
`
`0
`
`12
`
`1.2
`
`0—232
`
`1.4
`
`0—247
`
`9
`7
`Prior adjuvant chemotherapy
`Prior tamoxifen therapy 4 4
`
`
`
`
`
`“One 20 mg patient was excluded from the algorithm since
`insufficient information was given to classify her status.
`bOne patient had follicle stimulating hormone and estradiol levels
`compatible with the postmenopausal state; however, she was
`deemed to still be menstruating in the previous year and was
`categorized as perimenopausal.
`11, number of patients; mets, metastases; ER, estrogen receptor;
`PgR, progesterone receptor.
`
`independent review panel (Table 2). Thus, the arzoxifene 20 mg
`dose was chosen for further study. Two patients randomized to
`arzoxifene 20 mg/day had disease progression and were subse—
`quently administered open—label arzoxifene 50 mg/day. During
`double—blind therapy with arzoxifene 20 mg, one patient had a
`best study response of PR prior to progression, while the other
`patient progressed without response. During open—label therapy
`with arzoxifene 50 mg, both patients experienced disease progres—
`sion within 4 months.
`
`Time to event measures
`
`The average follow—up time from study enrollment to last known
`contact was 22 months. The median response duration was
`22.0 months [95% confidence interval (CI) 16.8—24.6 months] for
`17 responders in the 20 mg arm and 22.3 months (95% CI, insuf—
`ficient for calculation) for 16 responders in the 50 mg arm. There
`was no statistically significant difference between treatment
`arms. TTP is displayed in Figure 2. In the 20 mg arm, the median
`TTP was 10.7 months (95% CI 8.6—16.8 months) with 43% of
`the patients censored; in the 50 mg arm, the median TTP was
`8.6 months (95% CI 5.6—14.4 months) with 46% of the patients
`censored. Based on the log—rank test, the difference between treat—
`ment arms was not statistically significant. Median survival analy—
`sis was not performed as >80% of the enrolled patients were still
`alive at the time of the final analysis. However, the average sur—
`vival time, from study enrollment to last contact or death due to
`any cause, of patients in the 20 and 50 mg arms, were 21.8 and
`22.4 months, respectively.
`
`General safety
`
`Table 3 summarizes the frequency of adverse events. There was a
`similar frequency of adverse events, irrespective of relationship to
`study drug,
`in both arms. Vasodilatation,
`the most common
`adverse event assessed as related to study drug, occurred more
`frequently in the 20 mg arm compared with the 50 mg arm (48%
`versus 26%), but this difference was not statistically significant.
`Non—serious adverse events resulting in study discontinuation did
`not occur.
`
`Serious adverse events (SAEs) were reported in 14% of patients,
`with a slightly higher frequency in the 20 mg arm compared with
`the 50 mg arm (17 versus 11%). However, there was only one
`SAE assessed by the investigator as possibly related to study
`therapy (uterine perforation complicating surgical removal of an
`endometrial polyp, occurring in a patient treated with arzoxifene
`50 mg/day for approximately 13 months). Dyspnea, the most
`common SAE, occurred in three patients, all of whom had lung
`or pleural involvement from their breast cancer at baseline; for
`all three patients, the event was assessed as disease—related. Two
`patients discontinued the study due to SAEs: one SAE was unex—
`pected but assessed as possibly related to study therapy and the
`other SAE was assessed as unrelated to study therapy (cardiac
`insufficiency in one patient in the 20 mg arm). Although one
`patient (20 mg arm) died at home from gastrointestinal hemor—
`rhage after approximately 7 weeks of study therapy, her death was
`not attributed to study drug or procedure. There were no study
`drug—related deaths.
`NCI—CTC toxicities were mild. There were no statistically
`significant differences in reported toxicities between the two
`arms. There were no reported grade 4 laboratory or non—laboratory
`toxicities during this study. Notably, lymphopenia was the only
`grade 3 laboratory toxicity, reported in one patient in the 50 mg
`arm. There were no grade 3 or 4 clinical toxicities. Grade 1 and 2
`hot flashes, the most common toxicity, were reported in 27 and
`12% of patients in the 20 and 50 mg arms, respectively. Two
`patients in the 20 mg arm developed deep venous thrombosis
`
`AstraZeneca Exhibit 2088 p. 4
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`1.0
`
`0.9
`
`0.8
`
`0.7
`
`Log-Rank P-Value
`Wilcoxon P-Value
`
`0.8784
`0.5015
`
`
`
`0.6
`
`0.5
`
`
`
`ProportionSurviving 0.3
`
`0.1 0.0
`
`0.4
`
`0.2
`
`5
`0
`Patients at risk
`42
`30
`43
`30
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Months
`
`20
`16
`
`1 2
`12
`
`7
`9
`
`2
`4
`
`0
`0
`
`SRM 20mg
`SRM 50mg
`
`Therapy Group ' SRM 20mg
`
`SRM 50mg
`
`Figure 2. Time to progression.
`
`while on the study drug and one patient in the 20 mg arm, with a
`pre—study history of phlebitis, developed thrombophlebitis. Appro—
`ximately 2 months after study discontinuation due to disease pro—
`gression, one patient in the 20 mg arm developed a pulmonary
`embolus that was assessed as unrelated to the study drug by the
`investigator.
`
`Gynecological safety
`
`Table 4 summarizes endometrial data for 52 postmenopausal
`patients who underwent baseline and at least one follow—up TVU.
`Overall, the majority of postmenopausal women did not have evi—
`dence of endometrial stimulation. In the 50 mg arm, one 70—year—
`old postmenopausal woman developed an ovarian microcyst,
`which was unassociated with increased estradiol levels.
`
`thickness was observed in
`Although increased endometrial
`three of six premenopausal patients, timing of the TVU with
`respect to the patients’ menstrual cycle was not reported. ()ne
`50—year—old premenopausal patient in the 20 mg arm developed
`ovarian cysts (maximum diameter, 29 mm) associated with a peak
`estradiol level of 2586 pmol/l.
`
`Endocrinological and bone metabolism evaluation
`
`Among postmenopausal patients in the 20 and 50 mg arms, there
`was a statistically significant decrease from baseline in FSH
`(median change, 9.0 and —13.0 IU/l, respectively) and estradiol
`(median change, 11.5 and —4.0 pmol/l) in both arms, and a statistic—
`ally significant decrease in LH from baseline in the 50 mg arm
`(median change, 4.0 U/l). However, there was no statistically
`significant difference between the two doses of arzoxifene. Simi—
`larly, SHBG levels significantly increased from baseline in both
`arms (median change, +25.0 and +19.0 nmol/l, respectively), with
`no significant difference between arms.
`
`1387
`
`There were six premenop ausal patients. Four of the six premeno—
`pausal patients had increases from baseline in estradiol levels
`without significant changes from baseline in FSH, LH and SHBG
`levels.
`
`Among postmenopausal patients, there were statistically sig—
`nificant reductions in the 20 and 50 mg arms in serum osteocalcin
`(median change, —5 .4 and —3.5 mg/l, respectively) and type 1 col—
`lagen fragment (median change, —1707.0 and —1173.5 pmol/l,
`respectively), which are consistent with a skeletal anti—resorptive
`effect of arzoxifene. However, the difference in reductions between
`
`treatment groups did not achieve statistical significance.
`The small number of premenopausal patients precludes reliable
`statistical analysis or interpretation.
`
`Pharmacokinetic evaluation
`
`The mean observed steady—state plasma concentrations of arzo—
`xifene were 3.62 and 7.48 ng/ml for the 20 and 50 mg doses,
`respectively, with <1% of the samples obtained being below the
`limit of quantitation (<0.05 ng/ml) for both dose groups. How—
`ever, for desmethyl metabolite LY335562, approximately 46%
`and 37% of the samples obtained were below the limit of quantita—
`tion (<0.05 ng/ml) for the 20 and 50 mg doses, respectively, with
`resulting mean observed steady—state concentrations ranging from
`0.050 to 0.499 ng/ml and from 0.051 to 1.118 ng/ml, respectively.
`
`Discussion
`
`This randomized double—blind phase II trial was designed to com—
`pare the efficacy and safety of two doses of arzoxifene in patients
`with locally advanced or metastatic breast cancer.
`The 20 mg arm exhibited a numerically higher response rate,
`CBR and TTP than the 50 mg arm. Therefore, the 20 mg dose of
`arzoxifene was recommended for further study. However,
`the
`study design did not control for statistical type—1 error; thus, the
`observed efficacy could also be consistent with no efficacy differ—
`ence between doses.
`
`in aromatase
`there has been a renewed interest
`Recently,
`inhibitors in the hormonal treatment of breast cancer in postmeno—
`pausal women [21, 22]. Their presumed mechanisms of action are
`inhibition of the aromatase enzyme complex, which is responsible
`for non—ovarian estrogen synthesis in postmenopausal women, as
`well as inhibition of intra—tumor aromatase enzymes. Two double—
`blinded randomized phase III studies [23, 24] have compared
`the non—steroidal aromatase inhibitor anastrozole with tamoxifen
`
`in the treatment of advanced breast cancer in postmenopausal
`patients. In these studies, anastrozole appeared to be equivalent
`or superior to tamoxifen in its effects on overall response rate
`(32.9%/21.0% versus 32.6%/17.0%, respectively) and median
`TTP (8.2/11.1 months versus 8.3/5.6 months,
`respectively)
`[23, 24]. Letrozole, another non—steroidal aromatase inhibitor,
`
`appeared to be superior to tamoxifen in its effects upon overall
`response rate (30% versus 20%, respectively) and median TTP
`(41 weeks versus 26 weeks, respectively) [25]. The efficacy in
`terms of response rate demonstrated in this randomized phase II
`study of arzoxifene is very interesting. Randomized trials against
`
`AstraZeneca Exhibit 2088 p. 5
`
`

`

`1388
`
`Table 2. Tumor response and CBR
`Investigator assessed Arzoxifene Independently reviewed Arzoxifene
`
`
`
` 20 mg (n = 42) 50 mg (n = 44) 20 mg (n = 42) 50 mg (n = 44)
`
`Objective tumor responsea
`3 + 14
`1 + 15
`3 + 15
`2 + 10
`
`Response rate (%)
`
`40.5
`
`36.4
`
`95% CI (%; within group)b
`95% CI (%; between group)c
`
`Clinical benefit responsed
`Clinical benefit rate (%)
`
`22.4 to 52.3
`25.6 to 56.8
`—16.4 to 24.7
`
`3 +14 +10
`64.3
`
`1+ 15 +11
`61.4
`
`42.9
`
`27.2 to 59.0
`
`3 +15 + 7
`59.5
`
`27.3
`
`15.0 to 42.8
`—4.3 to 35.5
`
`2 +10 + 9
`47.7
`
`32.5 to 63.3
`43.3 to 74.4
`45.5 to 75.6
`48.0 to 78.5
`95% CI (%; within group)b
`
`
`—17.5 to 23.395% CI (%; between group)c —9.1 to 32.7
`
`“Objective tumor response 2 CR + PR.
`bWithin group confidence interval is an ‘exact’ discrete interval based on the binomial distribution.
`CBetween group confidence interval is based on an unadjusted normal approximation for the difference of two binomial
`proportions .
`dClinical benefit response: CR + PR + SD 26 months.
`11, number of patients; CR, complete response; PR, partial response; CI, confidence interval; SD, stable disease.
`
`Table 3. Adverse events
`
`
`
`Event
`All patients [n (%)]
`Arzoxifene [n (%)]
`
`(n = 92)
`20 mg (n = 46)
`50 mg (n = 46)
`
`Most frequent adverse event (210%)
`irrespective of relationship
`
`Any adverse event
`
`Vasodilatation
`
`Pain
`
`Nausea
`
`Back pain
`
`Dyspnea
`
`Weight gain
`
`Related adverse events with frequency of 23%
`
`Vasodilatation
`
`Weight gain
`Nausea
`
`Breast pain
`
`Alopecia
`
`80 (87.0)
`
`34 (37.0)
`
`22 (23.9)
`
`15 (16.3)
`
`14 (15.2)
`
`12 (13.0)
`
`10 (10.9)
`
`33 (35.9)
`
`9 (9.8)
`8 (8.7)
`
`4 (4.3)
`
`3 (3.3)
`
`41 (89.1)
`
`22 (47.8)
`
`10 (21.7)
`
`9 (19.6)
`
`7 (15.2)
`
`8 (17.4)
`
`3 (6.5)
`
`21 (45.7)
`
`3 (6.5)
`4 (8.7)
`
`1 (2.2)
`
`2 (4.3)
`
`39 (84.8)
`
`12 (26.1)
`
`12 (26.1)
`
`6 (13.0)
`
`7 (15.2)
`
`4 (8.7)
`
`7 (15.2)
`
`12 (26.1)
`
`6 (13.0)
`4 (8.7)
`
`3 (6.5)
`
`1 (2.2)
`
`1 (2.2)
`2 (4.3)
`3 (3.3)
`Asthenia
`Pruritis 2 (4.3) 3 (3.3) 1 (2.2)
`
`
`
`
`
`
`
`11, number of patients.
`
`current standards are warranted to define better the role of
`arzoxifene in the breast cancer scenario.
`
`Generally arzoxifene was well tolerated. There were no study
`drug—related deaths. Hot flashes, nausea, breast pain and weight
`gain were among the most commonly reported events causally
`related to study drug. Serious adverse events, irrespective of caus—
`ality, were infrequent; only one serious adverse event was assessed
`
`as related to arzoxifene. For the majority of women, regardless
`of menopausal status, there was no evidence of endometrial or
`ovarian stimulation. Notably, only two patients developed deep
`venous thrombosis while receiving therapy. These findings are
`particularly encouraging when compared with those of tamoxifen,
`which include significant side—effects such as thromboembolism
`and endometrial cancer [1, 3—1 1].
`
`AstraZeneca Exhibit 2088 p. 6
`
`

`

`Table 4. Summary of endometrial data for postmenopausal patients
`Variable
`Arzoxifene arm
`
`
`m
`423
`44
`86
`
`Total patients
`
`Hysterectomy
`
`Missing data
`Abnormal baseline ET
`
`Patients with baseline and
`follow—up data
`FU <5 mm increase
`
`FU 25 mm increase
`
`FU >8 mm
`
`Focal abnormality
`
`Total requiring investigation
`Normal tissue
`
`Atrophy only
`
`Endometrial polyp
`Insufficient tissue
`
`3
`
`14
`1
`
`24
`
`19
`
`2
`
`3
`
`0
`
`5
`1b
`
`2
`
`0
`0
`
`4
`
`12
`0
`
`28
`
`24
`
`1
`
`2
`
`1
`
`5
`0
`
`0
`
`2
`1
`
`7
`
`26
`1
`
`52
`
`43
`
`3
`
`5
`
`1
`
`10
`1“
`
`2
`
`2
`1
`
`
`
`No follow—up 4 2 2
`
`
`
`
`
`3One 20 mg patient was excluded from the algorithm since insufficient
`information was given to classify her status.
`bReported as endometrial hyperplasia but no tissue diagnosis. ET,
`endometrial thickness; FU, follow—up.
`
`Although the incidence of vasodilatation was higher in the
`20 mg arm, this difference was not statistically significant and the
`overall safety profiles, particularly drug—related adverse events,
`were similar for both treatment arms. Notably, the only SAE that
`was considered to be possibly related to the study drug, and the
`only grade 3 laboratory toxicity, occurred in the 50 mg arm.
`The outcomes of the ancillary analyses in this study were
`consistent with those associated with the SERM class effect. The
`
`hormonal changes (FSH, LH and estradiol) noted in this study
`were qualitatively similar to those described with tamoxifen, and
`are consistent with a weak estrogen—agonist effect on the pituitary
`in postmenopausal women [1]. In the premenopausal patients,
`interpretation of FSH, LH and estradiol was hampered somewhat
`by lack of information on timing in relation to the menstrual cycle.
`However,
`the noted increase in estradiol has been previously
`reported in premenopausal women administered SERM therapy
`and may represent an estrogen—antagonist effect on the premeno—
`pausal pituitary or direct ovarian stimulation by SERMs [1]. Over—
`all, the pharmacokinetic data were consistent with the known
`linear pharmacokinetic profile of arzoxifene and wide interpatient
`variability [15].
`In conclusion, this study showed no significant differences in
`efficacy or safety between the 20 and 50 mg doses of arzoxifene.
`The 20 mg dose of arzoxifene, however, resulted in efficacy
`(response rate, CBR and TTP) that was numerically higher than
`and a toxicity profile that was similar to the 50 mg dose. Thus, the
`20 mg dose of arzoxifene has been selected for future studies in
`breast cancer.
`
`1389
`
`Acknowledgements
`
`Appreciation is expressed to Drs Sarah Hatty and Claire Barton
`for technical assistance, and to Ms Erica Rappold for editorial
`assistance with the manuscript. Principal investigators for the
`study (in addition to the listed authors) were as follows: V. Cocquyt,
`C. Kirkove, M. Piccart and I. Vergote (Belgium); M. Ambrus,
`I. Bustova, J. Finek, J. Nemec, J. Prausova (Czech Republic);
`T. Petit, D. Serin, M. Speilmann (France); H. Cortes—Funes (Spain).
`This study was sponsored by Eli Lilly & Co.
`
`References
`
`1.
`
`Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med
`1998; 339: 16091—16098.
`. Hortobagyi GN. Treatment of breast cancer. N Engl J Med 1998; 339:
`974—984.
`
`. Hendrick A, Subramanian VP. Tamoxifen and th