VOLUME
`
`22
`
`NUMBER 5
`
`MARCH 1
`
`2004
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`
`
`R | G | N A L
`
`R E P O R T
`
`From the Laval Universny Medical Re
`search Center and Centre Hospitalier
`Unrversrtaire de Québec, Hopital du
`SainteSacrement, Hopital Laval, Quebec
`City; McGill Universrty, Hopital Sacre
`Coeur, Centre Hospitalier UniverSitaire
`de Montreal (CHUM), Hopital Charles
`,emoyne, Montreal, Centre Hospitalier
`Universrtaire de Sherbrooke, Sheri
`rooke, Quebec, Canada
`
`Submitted May 19, 2003, accepted
`December 9, 2003
`
`
`
`Authors' disclosures of potential cone
`licts of interest are found at the end of
`this article
`
`Address reprint requests to Fernand
`,abrie, MD, Oncology and Molecular En,
`docrinology Research Center, Laval Uni
`versity Medical Center, 2705 Laurier
`Blvd, T7367, Quebec City, Quebec, 61V
`462, Canada; Email fernand labrie@
`crchul ulaval ca
`
`© 2004 by American Society of Clinical
`Oncology
`07327183X’04/22057864/392000
`DQI 10 'l200/JCO 2004 05.122
`
`Activity and Safety of the Antiestrogen EM—800, the
`Orally Active Precursor of Acolbifene, in Tamoxifen—
`Resistant Breast Cancer
`
`Fernand Labrie, Pierre Champagne, Claude Labrie, Jean Roy, Jacques Laverdiere, Louise Provencher,
`Martin Port/in, Yi/an Drolet, Michael Pollak, Lawrence Panasci, Bernard L’Espérance, Jean Dufresne,
`Jean Latreille, Jean Robert, Benoit Samson, Jacques Jolivet, Louise Yelle, Lionel Casan, Pierre Diamond,
`and Bernard Candas
`
`Purpose
`To determine the efficacy and safety of EM—8OO (SCH—57050), the precursor of acolbifene, a new, highly
`potent, orally active, pure antiestrogen in the mammary gland and endometrium, for the treatment of
`tamoxifen—resistant breast cancer.
`
`_
`_
`_
`_
`_
`Patients and Methods
`Forty—three post menopausal/ovariectomized women With breast cancer who had received tamOXIfen,
`either for metastatic disease or as adjuvant to surgery for 2 1 year, and had relapsed were treated in a
`prospective, multicenter, phase II study with EM—8OO (20 mg/d [n = 21] or40 mg/d [n = 22] orally).
`Resuhs
`Thirty—seven patients had estrogen receptor (ER)—positive tumors (>10 fmol/mg; mean, 146 fmol/mg
`cytosolic protein), three patients had ER—negative/progesterone receptor—positive tumors, and three
`patients had undetermined ER status. The objective response rate to EM—8OO was 12%, with one
`complete response and four partial responses. Ten patients (23%) had stable disease for 2 3
`months, and 7 patients (16%) had stable disease for 2 6 months. With a median follow—up of 29
`months, median duration of response was 8 months (range, 7 to 71+ months). Treatment with
`EM—8OO was well tolerated. No significant adverse events related to the study drug were observed
`clinically or biochemically.
`Conclusion
`EM—8OO produced responses in a significant proportion of patients with tamoxifen—resistant breast
`cancer,
`thus showing that this highly potent, selective estrogen receptor modulator, which lacks
`estrogenic activity in the mammary gland and endometrium, has incomplete cross—resistance with
`tamoxifen, thus suggesting additional benefits in the treatment of breast cancer.
`
`J Clin Oncol 22:864—87 7. © 2004 by American Society of C/inica/ Oncology
`
`
`Although 30% to 40% of patients with ad—
`vanced breast cancer show an initial re—
`
`sponse to tamoxifen, the duration of re—
`sponse is usually limited to 12 to 18 months,
`with subsequent development of resistance
`to further administration of the antiestro—
`
`gen [1] . Based on many clinical observations
`[2—6], and demonstrated in a series of stud—
`ies performed with human breast cancer cell
`lines in vitro as well as in Vivo With xeno—
`
`grafts, it is believed that the loss of positive
`
`response to tamoxifen in breast cancer pa—
`tients is as a result, at least in part, of the
`intrinsic estrogenic activity of the com—
`pound or its metabolites [7—12]. It has also
`been shown that the inhibitory effect of ta—
`moxifen is limited to the hormone—depen—
`dent activation function (AF) of the estro—
`gen receptor, known as AF—2, while this
`compound does not inhibit the hormone—
`independent pathway of activation known
`as AF—l [13,14]. Therefore, to test the hy—
`pothesis that a more specific and potent an—
`tiestrogen completely devoid of estrogenic
`
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`
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`
`AstraZeneca Exhibit 2032 p. 1
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`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01913
`
`

`

`EM-652/Tamoxifen-Resistant Breast Cancer
`
`activity in human breast or endometrial carcinoma cells
`[14—30] would have improved clinical efficacy, we have
`administered the novel, orally active antiestrogen EM—800
`(SCH—57050) to women who had experienced tamoxifen
`therapy failure.
`EM—800 is the precursor of EM—652 [16]. This com—
`pound acts as a pure and highly potent antiestrogen in
`human breast and uterine cancer cells in vitro as well as in
`
`vivo in nude mice [15—30]. In fact, EM—800 is the most
`potent of the known antiestrogens and, to our knowledge, it
`is the only nonsteroidal antiestrogen shown to have no
`estrogenic activity either in human Ishikawa endometrial
`carcinoma cells, as assessed by changes in alkaline phospha—
`tase activity, or in human breast carcinoma cells, as shown
`in cell proliferation studies [14—16,19,20,23—30]. Moreover,
`as mentioned above, EM—800 blocks both the AF—l and
`
`AF—2 activities of the estrogen receptor [14], thus poten—
`tially decreasing the resistance to hormonal therapy.
`The high potency of EM—800 derives in part from
`the high affinity of its active metabolite (EM—652 [SCH—
`57068]) for the estrogen receptor (ER)
`[24,26]. In fact,
`EM—652 has the highest affinity for ER of any known com—
`pound to date, with a low dissociation constant of 0.05
`nmol/L. In fact, EM—652 is 1.5— to 3.0—fold more potent than
`17 beta—estradiol and diethylstibestrol in displacing [3 H] es—
`tradiol from the ER in human breast cancer and normal
`
`uterine tissue. EM—652 is 200—fold more potent than tamox—
`ifen, and is five—fold more potent than hydroxytamoxifen
`(the active metabolite of tamoxifen). In comparison to
`other antiestrogens. EM—800 has also demonstrated high po—
`tency in vivo. In a murine model, EM—800 was at least 30—fold
`more potent than tamoxifen in inhibiting estrogen—stimulated
`uterine growth. In addition, the maximal inhibitory eflfect on
`uterine weight achieved with EM—800 is 2.5—fold greater than
`the maximum effect achieved with tamoxifen [18].
`The clinical potential of an antiestrogen more potent
`and more specific than tamoxifen is supported by the find—
`ing that tamoxifen—resistant human breast cancer cell lines
`remain sensitive to compounds showing pure antiestro—
`genic activity on cell proliferation in the mammary gland,
`under in vitro conditions [10,31—33] and when grown as
`xenografts in nude mice [12,15,34,35]. This compound has
`been shown to inhibit human breast cancer tumor growth
`in nude mice below the inhibition achieved with tamoxifen
`
`[15,27,28]. The current phase II study was conducted to
`assess the activity and safety of EM—800 in patients with
`tamoxifen—resistant breast carcinoma.
`
`
`Patients
`
`Forty-two post menopausal or ovariectomized women and
`one premenopausal woman with tamoxifen—resistant breast can—
`cer were enrolled between March 21, 1996, and June 13, 1997. The
`
`WWW.jco. org
`
`study was approved by the institutional review board of each
`hospital or university, and all patients gave informed consent
`Eligible patients had progressive metastatic or locally advanced
`biopsy—proven or fine needle aspiration—proven inoperable breast
`cancer that had responded to tamoxifen (complete response [CR]
`or partial response [PR]) or had remained stable for at least 6
`months before progression. Thus, 21 patients had acquired ta—
`moxifen resistance while being treated with tamoxifen for ad—
`vanced disease. Patients originally treated with adjuvant tamox—
`ifen for at least 1 year after surgery who subsequently progressed
`either while on tamoxifen ( 18 patients) or after its discontinuation
`(four patients) were also eligible. For these 22 patients, differenti—
`ation between acquired and de novo tamoxifen resistance could
`not be made since a possible response before progression cannot
`be detected. In fact, this tamoxifen resistance could be acquired or
`existing (de novo) before the start of treatment. Tamoxifen ther—
`apy must have been discontinued at least 1 month before initiating
`treatment with EM—800, unless the investigator judged that the
`disease was rapidly progressing. Eligible patients could not have
`received previous treatment for metastatic disease (including sys—
`temic cytostatic or hormonal treatment) other than tamoxifen.
`Adj uvant chemotherapy was allowed but must have been corn—
`pleted Z 1 year before study entry. Eligible patients had Eastern
`Cooperative Oncology Group performance status of S 2, a life
`expectancy Z 6 months, and measurable lesion(‘s) according to
`WHO criteria [36]. Tumors had to be ER—positive, progesterone
`receptor—positive (>10 fmol/mg cytosolic protein or positive by
`irnrnun ocytochemistry), or of unknown status. All patients under—
`went a baseline staging evaluation. Baseline hematology, clinical
`chemistry, and urinalysis had to be normal according to the ac—
`cepted values of each hospital.
`Exclusi0n criteria included cancer other than breast carci—
`
`noma (except successfully treated in situ carcinoma of the cervix
`or skin carcinoma other than melanoma), CNS involvement by
`cancer, lymphangitic pulmonary metastases, severe infection, and
`severe liver or kidney disease. Patients with neutropenia or throm—
`bocytopenia unrelated to chemotherapy were also excluded.
`
`Treatment
`
`Patients were treated with a daily oral dose (20 or 40 mg) of
`EM—800. The drug was administered with 240 mL of tap water in
`the evening (at bedtime, at least 2 hours after the last meal) for 6
`months or until progression or unacceptable toxicity. The first
`eight patients were treated with 20 mg/d EM—SOO. Following con—
`firmation by an independent review board of the tolerance and
`safety of the 20—mg dose in at least four patients treated for at least
`1 month, a second group of eight patients were treated with 40
`mg/d EM—SOO. Thereafter, patients were randomly allocated to
`receive either 20 mg or 40 mg EM—SOO. Patients and investigators
`were blinded to the dose level. Patients were to be removed from
`
`the study for any of the following: development of serious drug—
`related adverse event, poor compliance (ie, treatment interruption
`for 7 consecutive days), or disease progression confirmed on two
`observations at least 1 month apart.
`
`Evaluation of Response
`Tumor response was evaluated according to the WHO crite—
`ria [36]. Chest radiography, computed tomography scan of lung
`for lesions less than 2 cm in diameter, abdominal ultrasound and
`computed tomography scan of liver (in cases having a positive
`ultrasound), bone radiography, and isotopic bone scan were per—
`formed at start of treatment. In patients with locally advanced
`
`365
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`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
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`

`

`
`
`Table 1. Patient Characteristics at Study Entry
`Baseline Characteristics
`
`Labrie et al
`
`ER—positive tumors (> 10 fmol/mg cytosolic protein), three
`patients had ER—negative/progesterone receptor—positive
`tumors, and three patients were of unknown ER status. The
`mean ER level was 146 fmol/mg (range, 7 to 686 fmol/mg)
`in 34 patients for whom a quantitative determination was
`available. Twenty—two patients had been treated with ta—
`moxifen in the adjuvant setting only, 16 patients had been
`treated with tamoxifen for advanced metastatic disease
`
`only, and five patients had received the antiestrogen both as
`adjuvant therapy and then for advanced metastatic disease.
`The median time to relapse from the start of tamoxifen
`therapy was 34 weeks (range, 5 to 159 weeks).
`
`Response to Therapy
`In the total study population, objective tumor re—
`sponses were observed in five of 43 (12%) patients (Table
`2), including one CR and four PR5; 10 patients (23%) had
`stable disease (SD) for at least 3 months, and seven patients
`(16%) had SD for at least 6 months. With a median fol—
`low—up of 29 months, the median duration of response for
`the five responders was 8 months (range, 7 to 71+ months);
`one of the five responders ( 20%) continues to respond after
`71 months. Among the patients treated with 20 mg EM—800,
`two patients (10%) had a PR, with a response duration of 8
`to 71+ months, and three patients (14%) had SD for a
`duration of 8 to 10 months. Among patients treated with 40
`mg EM—800, one patient had a CR and responded for 57
`months; two patients (9%) had a PR, with a response dura—
`tion of 7 and 8 months, while seven patients (32%) had SD,
`with a duration of 3 to 77+ months. Two patients continue
`to respond at 71 and 77 months, respectively. N0 significant
`dose effect was observed.
`
`Patterns of Failure
`
`At the start of EM—800 administration, the predomi—
`nant sites of metastasis following tamoxifen failure were (in
`decreasing order of occurrence): bone (29 patients), lymph
`nodes (15 patients), liver (11 patients), lung (10 patients),
`skin (five patients) and breast (two patients; Table 3). Me—
`tastases were present at other sites in six patients. Progres—
`sion was present at only one site in 19 patients, at two sites in
`17 patients, and at three sites or more in seven patients at the
`start of EM—800 treatment. Most responses were observed
`
`66
`43-86
`
`37
`3
`3
`
`Age, years
`Mean
`Range
`ER status, No. of patients
`ER positive“
`ER negative/PR positive"
`Not determined
`ER level, fmol/mgt
`Mean
`Range
`Time to relapse from start of tamoxifen, weeks
`Median
`Range
`Setting of prior tamoxifen therapy, No. of patients
`22
`Adjuvant therapy
`16
`Advanced metastatic disease
`
`Adjuvant and metastatic disease 5
`Abbreviations: ER, estrogen receptor; PR, progesterone receptor.
`*>1O fmol/mg cytosolic protein or positive by immunocytochemistry.
`lBased on 34 patients for whom a quantitative measurement of ER level
`was made.
`
`
`146
`7-686
`
`34
`5-159
`
`disease with no evidence of metastases, these tests were repeated
`after 6 months of treatment unless the patient developed particu—
`lar signs or symptoms of progression during the study. If exams
`were positive for metastases at the start of treatment, the exams
`were repeated at 1, 3, and 6 months for evaluation of response.
`Superficial or palpable lesions (cutaneous metastases,
`lymph
`nodes) were measured in two dimensions at monthly intervals.
`Hematology and blood chemistry analysis, as well as urinalysis,
`were performed at start of treatment, at 1, 2, and 4 weeks, and at
`monthly intervals thereafter. Vital signs were measured and a
`tolerability questionnaire was filled out at the same time intervals.
`
`
`Patient and Treatment Characteristics
`
`Forty—three patients were enrolled; 21 patients received
`20 mg/d EM—800, and 22 patients received 40 mg/d EM—
`800. The demographic and baseline clinical characteristics
`of the patients are shown in Table 1. The median age was 66
`years (range, 43 to 86 years). Thirty—seven patients had
`
`
`
`
`Table 2. Best Response to EM-800 and Response Durations by Dose
`40 mg (n : 22)
`20 mg (n : 21)
`Response Duration
` Best Response No. % (months) No. % Response Duration (months)
`
`
`
`
`
`
`CR
`0
`O
`—
`1
`5
`57
`PR
`2
`10
`8, 71 +
`2
`9
`7, 8
`SD
`3
`14
`8, 9,10
`7
`32
`3,4,5,16,16-,17,77+
`
`16 76 — 12 54PD —
`
`
`
`
`
`
`Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; +, response still ongoing.
`
`366
`
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`
`

`

`
`
`EM-652/Tamoxifen-Resistant Breast Cancer
`
`Table 3. Disease Site(s) at Start and at Failure to El\/|-8OO Therapy and Best Response by Disease Site
`No. of Patients
`Best Response
`At Start of
`PD (any
`At Failure to
`
`
`
`
`
` Site(s) of Disease Treatment CR PR SD site) El\/|-800
`
`
`
`
`
`
`
`17
`21
`7
`1
`—
`29
`Bone(s)
`5
`1O
`1
`3
`1
`15
`Node(s)
`9
`9
`2
`—
`—
`11
`Liver
`5
`8
`1
`1
`—
`10
`Lung
`2
`2
`2
`1
`—
`5
`Skin
`—
`1
`—
`1
`—
`2
`Breast
`3
`2
`2
`—
`—
`6
`Others
`—
`1O
`6
`2
`1
`19
`One organ site
`—
`13
`3
`1
`—
`17
`Two organ sites
`
`Three organ sites — 7 — 1 1 5
`
`
`
`
`
`Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
`NOTE. Eighteen patients had progressed while receiving tamoxifen while four progressed following cessation of tamoxifen.
`
`
`in patients with bone, skin, breast, and/ or nodal metastases
`(Table 3). No CR5 or PRs were observed in patients with
`liver metastases. Nine of 11 (82%) patients with liver me—
`tastases and eight of 10 (80%) patients with lung metastases
`at start of treatment progressed at those initial sites of
`disease. Seventeen of 29 (59%) patients with progression in
`the bones at start of study progressed at the same site during
`the study. In the majority of cases, patients who failed
`EM—800 therapy progressed at the same site(s) where they
`were progressing at the start of EM—800 treatment.
`
`Response Based on Previous
`Tamoxifen Therapy
`No correlation was observed between response to EM—
`800 therapy and duration of prior tamoxifen therapy. The
`single CR occurred after 2 months of treatment with 40 mg
`EM—800 in a patient who had progressed in a right axillary
`lymph node while receiving tamoxifen after 42 months of
`adjuvant tamoxifen therapy. Among the four PRs, three
`patients had received adjuvant tamoxifen therapy for 5, 61,
`and 64 months, respectively, while one patient had received
`tamoxifen for advanced disease for 8 months. Among the
`five patients who responded to EM—SOO, three progressed
`
`while receiving tamoxifen (one CR and two PR) while two
`progressed 3 and 3.5 years after having received tamoxifen
`for 5 years, 4 years, and 3 months, respectively. Among
`patients with SD, two patients had received adjuvant ta—
`moxifen therapy for 70 and 73 months, six patients had
`received tamoxifen for advanced disease for periods ranging
`from 10 to 92 months, and two patients had received ta—
`moxifen both as adjuvant therapy and for advanced disease.
`With respect to any association between response to
`EM—800 and the disease stage before tamoxifen therapy,
`four of five (80%) objective tumor responses to EM—800
`were observed in patients who had received adjuvant
`tamoxifen therapy (Table 4). However, when SD is in—
`cluded in the comparison, the proportion of responding
`patients (improvement or stabilization of disease follow—
`ing EM—800 treatment) was similar between subgroups:
`six of 22 (27%) patients who had received tamoxifen as
`adjuvant therapy, and seven of 16 (44%) patients who
`had received tamoxifen for advanced disease. Both of
`
`these subgroups were well balanced with respect to sites
`ofmetastases, with 43% ofpatients in each group having
`liver or lung metastases.
`
`
`
`Table 4. Best Response Based on Disease Stage of Previous Tamoxifen Therapy
`Best Response
`No. of
`
`CR
`PR
`SD
`PD
`Previous Treatment Setting
`Patients
`
`16
`2
`3*
`1 T
`22*
`Adjuva nt
`9
`6
`1
`—
`16
`Advanced disease
`
`Adjuvant + advanced disease 3 5 — — 2
`
`
`
`
`Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
`*Eighteen patients had progressed while receiving tamoxifen while four progressed following cessation of tamoxifen.
`Twas progressing under tamoxifen.
`fOne patient was progressing undertamoxifen, while one progressed 3 years and 5 months after having received tamoxifen for 4 years and 3 months, while
`the other patient had progressed 3 years after having received tamoxifen for 5 years.
`
`
`mww.jca. mg
`
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`
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`

`
`
`Labrie et al
`
`Table 5. Summary of Adverse Events Occurring in 210% of Patients at Either Dose Level by WHO Grade
`
`20 mg (n:21)
`40 mg (n:22l
`Grade II“
`
`Grade lll/lV
`
`Grade l/ll
`
`No. of
`No. of
`No. of
`
`Adverse Event
`Patients
`%
`Patients
`%
`Patients
`%
`
`Bone/muscle pain
`ausea
`
`14
`7
`
`67
`33
`
`15
`9
`
`68
`41
`
`2
`2
`
`9
`9
`
`—
`—
`45
`1O
`24
`5
`:atigue
`—
`—
`32
`7
`9
`4
`Asthenia
`14
`3
`14
`3
`24
`5
`Vomiting
`—
`—
`14
`3
`9
`4
`-lot flashes
`—
`—
`23
`5
`0
`2
`-leartburn
`5
`1
`14
`3
`O
`2
`Abdominal pain
`—
`—
`18
`4
`Q
`2
`:lu-like symptoms
`—
`—
`14
`3
`4
`3
`Decreased appetite
`5
`1
`18
`3
`O
`2
`Constipation
`—
`—
`18
`4
`O
`2
`DepreSSion
`—
`—
`5
`1
`4
`3
`Diarrhea
`—
`—
`23
`5
`24
`5
`-leadache
`—
`—
`—
`—
`O
`2
`Soft stools
`—
`—
`—
`—
`O
`2
`Jrinary tract infection
`—
`—
`—
`—
`O
`2
`Decreased hemoglobin
`—
`—
`—
`—
`0
`2
`Daresthesias
`
`
`
`
`
`Safety
`No clinically significant adverse event (AE) related to
`the study drug was observed at either dose level. Commonly
`reported AEs are shown in Table 5. At the 20—mg dose level,
`no WHO grade 3/4 AE was observed. Bone and muscle pain
`was the most common grade 1/2 AE, occurring in 14 pa—
`tients (67%). Headache, vomiting, and fatigue each oc—
`curred in five patients (24%). At the 40—mg dose level, grade
`3/4 vomiting occurred in three patients (14%), while severe
`nausea and bone/muscle pain each occurred in two patients
`(9%). The most common grade 1/2 AE was also bone/
`muscle pain reported in 15 patients (68%) in the 40—mg
`dose group. The next most frequent mild to moderate AEs
`were fatigue, nausea, and asthenia that occurred in 10
`(45%), nine (41%), and seven (32%) patients, respectively.
`No patient complained of vaginal dryness or altered libido.
`In long—term follow—up of patients who remained on EM
`800 therapy for at least 2 years, 10 various AEs were reported
`by eight patients, including nausea and vomiting (two pa—
`tients), pleural effusion (two patients), bone pain, dyspnea,
`melena, chest pain, back pain, abdominal pain, and consti—
`pation (one patient each). One death from breast cancer
`occurred in the 40—mg dose group within 30 days of treat—
`ment interruption.
`
`
`
`The present data show that EM—800, a novel selective estro—
`gen receptor modulator ( SERM) having pure antiestro—
`genic activity in the mammary gland, was well tolerated and
`
`induced clinical responses in a significant proportion of
`patients with advanced—stage,
`tamoxifen—resistant breast
`cancer. A 12% objective response rate (CRs + PRs) was
`observed, with a median response duration of 8 months at
`29 months of median follow—up, with one of these five
`patients continuing to respond at 71 months. In addition,
`23% of patients had SD for a median duration of 9 months,
`one of these seven patients still responding at 77 months.
`Similar results were observed in a series of 19 tamoxifen—
`
`resistant patients treated with monthly intramuscular injec—
`tions of the pure steroidal antiestrogen fulvestrant [37]. In
`that small preliminary study, seven patients ( 36%) had a
`PR, and six patients (31%) had SD for a median duration of
`25 months. In two large—scale studies performed in a com—
`parable population of patients who had failed tamoxifen
`and received the pure steroidal antiestrogen fulvestrant,
`44.6% and 42.2% had clinicalbenefit rates (CR + PR + SD
`2 24 weeks), respectively. [38,39].
`These results appear superior to those obtained with
`other antiestrogens or SERMs that have been investi—
`gated as salvage therapy in tamoxifen—resistant patients.
`For example,
`two large phase II studies of high—dose
`toremifene in patients with tamoxifen—refractory ad—
`vanced breast cancer demonstrated objective response
`rates of only 4% and 5%, thus leading the authors to
`conclude that there is significant cross—resistance be—
`tween toremifene and tamoxifen [40,41]. Salvage therapy
`with raloxifene in 14 patients produced no CR or PR,
`although five patients (36%) had SD [42].
`
`368
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Downloaded from jco.ascopubs.org on January 6, 2016. For personal use only. No other uses without permission.
`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
`AstraZeneca Exhibit 2032 p. 5
`
`

`

`EM-652/Tamoxifen-Resistant Breast Cancer
`
`As mentioned above, these studies performed with ful—
`vestrant have shown an efficacy comparable to the aro—
`matase inhibitor anastrazole in women who had failed en—
`
`docrine therapy [38,39]. While both acolbifene (EM—652,
`EM—800) and fulvestrant exert pure antiestrogenic activity
`in the mammary gland and uterus, the possible advantages
`of EM—652 are its oral bioavailability and its protective effect
`on bone loss [16,43]. In addition to its protective effect on
`bone, the other potential advantages of EM—652 compared
`to aromatase inhibitors are the observations that aromatase
`
`inhibitors do not completely block the stimulatory effect of
`estrogen precursors on human breast cancer cells (MCF—
`71S6) [44] and do not prevent the stimulatory effect of the
`estrogenic steroid androstene—3 beta, 17 beta—diol [45], two
`effects achieved with EM—652.
`
`The responses to EM—800 observed in the present
`study, and those observed with fulvestrant, are consistent
`with the suggestion that progression in patients treated with
`tamoxifen may be as a result, at least in part, of the partial
`estrogenic effects of tamoxifen, which can lead to stimu—
`lation of
`the proliferation of breast
`cancer
`cells
`[4—16,23,25—29]. A potentially important mechanism of
`tamoxifen resistance is related to the finding that tamox—
`ifen does not inhibit the ligand—independent AF—1 activ—
`ity of ER, whereas EM—800 does [14]. This observation
`further suggests a possible mechanism by which EM—800
`and fulvestrant can induce responses in patients with
`tamoxifen—refractory tumors.
`Consistent with other studies, most responses occurred in
`patients with bone, lymph node, skin, and breast metastases,
`whereas no objective tumor response was observed in patients
`with liver metastases. Others have also documented the unfa—
`
`vorable prognosis of patients with liver metastases [5]. There
`was, however, no apparent association between EM—800 re—
`sponse and the duration of previous tamoxifen therapy. Al—
`though the numbers are small, patients treated with tamoxifen
`in the adjuvant setting appeared more likely to achieve an
`objective response to EM—800; the proportion of patients who
`achieved an objective response or SD was 27% in the patients
`who had tamoxifen in the advanced disease state compared to
`44% in the adjuvant setting. It might be proposed that patients
`who experienced adjuvant tamoxifen failure may have had less
`advanced disease than patients who failed to respond to ta—
`moxifen for the treatment of advanced metastatic disease.
`
`However, a comparison of these subgroups reveals no major
`differences in sites ofdisease. In the two groups, 45% and 38%
`of patients had liver and/or lung metastases. Moreover, no
`clear association was observed between best response and the
`number of sites of progression at the start of EM—800 treat—
`ment. Finally, no clear dose—response relationship was ob—
`served in this study; two objective responses occurred in the
`20—mg, while three were observed in the 40—mg dose group.
`The majority of the AEs observed in the present study
`were mild to moderate in severity and were not considered
`
`mww.jca. mg
`
`by the investigators to be related to the study drug. Al—
`though nausea and vomiting were considered possibly re—
`lated to treatment with EM—800, phase I studies performed
`in normal healthy women showed a similar incidence of
`nausea and vomiting in the EM—800 and placebo groups
`(unpublished data). Serious AEs, including grade 3/4 bone
`and/or muscle pain, nausea, abdominal pain, vomiting, and
`constipation occurred in a total of nine patients in the
`40—mg dose group but were not considered by the investi—
`gators to be related to the study drug. These results are
`consistent with the absence of significant findings in pre—
`clinical toxicology studies performed in female rats and
`monkeys with EM—SOO (25 mg/kg body weight), a dose
`approximately 35—fold higher than the highest dose used in
`the present study. No toxic effects were observed in animals
`tested daily for 12 months other than the endocrine changes
`expected from a pure antiestrogen. EM—800 was also well
`tolerated in a phase I study in 145 normal postmenopausal
`women who received daily doses of EM—800 up to 40 mg for
`up to 14 days. As indicated above, long—term follow—up of
`patients in the present study who remained on EM—800 ther—
`apy for more than 5 years also demonstrates the safety of
`EM—800 during long—term use. The AEs observed in the
`present study are not different from those observed in two
`large studies comparing fulvestrant and anastrozole in a simi—
`lar category of patients [38,39]. Fulvestrant and anastrozole
`were also well tolerated, with the most common AEs being
`nausea, vasodilatation, asthenia, vomiting, and bone pain.
`The present data are supported by numerous preclini—
`cal studies. In fact, while hormonal therapy of breast cancer
`was believed to be limited to a tumorostatic action as orig—
`inally described with tamoxifen [7,8], it has recently been
`observed that alcobifene ( EM—652) achieves the cure of 60%
`
`of human breast tumors in nude mice [30]. Probably as a
`result of a more complete inhibition of the estrogen recep—
`tor [14,16,19,20,26] , the tumorocidal action of alcobifene is
`a new paradigm of estrogen blockade. Moreover, alcobifene
`and fulvestrant not only completely inhibit the stimulatory
`effect of estradiol on the proliferation of MCF —7/86 cells but
`further inhibit cell growth by 80% below basal values [44].
`Taken together, these data suggest that EM—800 may im—
`prove the rate, quality, and duration of responses in patients
`with tamoxifen—resistant advanced breast cancer. In addition,
`
`given the highly potent antiestrogenic activity, lack of any
`estrogenic stimulatory effect in the mammary gland and endo—
`metrium, as well as the good tolerability demonstrated in pre—
`clinical and clinical studies, EM—800 or its active metabolite
`
`EM—652 should also be investigated in the neoadjuvant and
`adjuvant settings and as front—line therapy for metastatic dis—
`ease. It is reasonable to expect that EM—800 may be more
`effective than tamoxifen for the fiont—line treatment of breast
`
`and endometrial cancer, and its use should also decrease or
`
`eliminate the risk of carcinogenicity associated with the long—
`term use of tamoxifen [46]. EM—800 has been shown to pre—
`
`1369
`
`Downloaded from jco.ascopubs.org on January 6, 2016. For personal use only. No other uses without permission.
`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
`AstraZeneca Exhibit 2032 p. 6
`
`

`

`Labrie et al
`
`vent bone loss in the ovariectomized rat [16,43] and to de—
`
`crease serurn cholesterol and triglycerides in the rat [47].
`In conclusion,
`this orally bioavailable, nonsteroidal
`SERM having pure and highly potent antiestrogenic activity in
`the mammary gland has a number of important advantages
`over all other antiestrogens and should be actively investigated
`for the treatment of ER—positive breast cancer and other estro—
`gen—sensitive malignancies. Moreover, the characteristics of
`EM—800 make it an ideal compound for prevention of breast
`and endometrial cancer because ofthe potential added benefits
`in terms of prevention of osteoporosis and cardiovascular dis—
`ease in postmenopausal women.
`
`
`Acknowledgment
`We thank Dr Alain Bélanger for his supervision of the
`analytic procedures and Dr Luc Deschenes for his clinical
`implication and advice.
`
`Authors’ Disclosures of Potential
`Conflicts of Interest
`
`The following authors or their immediate family mem—
`bers have indicated a financial interest. No conflict exists for
`
`drugs or devices used in a study if they are not being evalu—
`ated as part of the investigation. Owns stock (not including
`shares held through a public mutual fund): Fernand Labrie,
`Schering—Plough. Performed contract work within the last 2
`years: Fernand Labrie, Schering—Plough.
`
`
`
`(REFEREE. Iii
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`Ingle JN, Ahmann DL, Green SJ, et al:
`Randomized clinical trial of diethylstilbestrol ver-
`sus tamoxifen in postmenopausal women with
`advanced breast cancer. N Engl J Med 304:16-
`21, 1981
`2. Pritchard KI, Thomson DB, Myers RE, et
`al: Tamoxifen therapy in premenopausal patients
`with metastatic breast cancer. Cancer Treat Rep
`64:787-796, 1980
`3. Hoogstraten B, Gad el Mawla N, Maloney
`TR, et al: Combined modality therapy for
`irst
`recurrence of breast cancer. A Southwest Oncol-
`ogy Group study. Cancer 54:2248-2256, 1984
`4. Canney PA, Griffiths T, Latief TN, e al:
`Clinical signifi