`
`22
`
`NUMBER 5&
`
`MARCH 1
`
`2004
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`NAL REPORT
`
`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 Laverdiére, Louise Provencher,
`Martin Potvin, Yvan Drolet, Michael Pollak, Lawrence Panasci, Bernard L’Espérance, Jean Dufresne,
`Jean Latreille, Jean Robert, Benoit Samson, Jacques Jolivet, Louise Yelle, Lionel Cusan, Pierre Diamond,
`and Bernard Candas
`
`Purpose
`To determine the efficacy and safety of EM-800 (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 = 1 year, and had relapsed were treated ina
`prospective, multicenter, phase || study with EM-800 (20 mg/d [n = 21] or 40 mg/d [n = 22] orally).
`Results
`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-800 was 12%, with one
`complete response and four partial responses. Ten patients (23%) had stable disease for = 3
`months, and 7 patients (16%) had stable disease for = 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-800 was well tolerated. No significant adverse events related to the study drug were observed
`clinically or biochemically.
`Conclusion
`EM-800 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 22:864-871. © 2004 by American Society of Clinical Oncology
`
`From the Laval University Medical Re-
`search Center and Centre Hospitalier
`Universitaire de Québec; Hopital du
`Saint-Saerement; Hépital Laval, Québec
`City; McGill University; Hopital Sacre
`Coeur, Centre Hospitalier Universitaire
`de Montréal (CHUM), Hopital Charles-
`Lemoyne, Montreal; Centre Hospitalier
`Universitaire de Sherbrooke, Sher-
`rooke, Ouébec, Canada
`
`Submitted May 19, 2003, accepted
`December 9, 2003.
`
`
`
`Authors’ disclosures of potential con-
`licts of interest are found at the end of
`this article
`
`Address reprint requests to Fernand
`Labrie, MD, Oncology and Molecular En-
`docrinology Research Center, Laval Unt
`versity Medical Center, 2705 Laurier
`Blvd, 1-3-67, Quebec City, Quebec, G1V
`AG?2, Canada; Email:
`fernarid.labrie@
`erchul.ulayal.ca.
`
`© 2004 by American Society of Clinical
`Oncology
`0732-183X/04/2205-864/$20.00
`DOE 10.1200/JCO.2004.05.122
`
`tients is as a result, at least in part, of the
`
`response to tamoxifen in breast cancer pa-
`
`Although 30% to 40% of patients with ad-
`intrinsic estrogenic activity of the com-
`vanced breast cancer show an initial re-
`pound orits metabolites [7-12]. It has also
`sponse to tamoxifen, the duration of re-
`been shown that the inhibitoryeffect of ta-
`sponseis usually limited to 12 to 18 months,
`moxifen is limited to the hormone-depen-
`with subsequent developmentof resistance
`dent activation function (AF) of the estro-
`to further administration of the antiestro-
`gen receptor, known as AF-2, while this
`gen [1]. Based on manyclinical observations
`compound does not inhibit the hormone-
`[2-6], and demonstrated inaseries of stud-
`independent pathway of activation known
`as AF-1 [13,14]. Therefore, to test the hy-
`ies performed with humanbreast cancercell
`lines in vitro as well as in vivo with xeno-
`pothesis that a morespecific and potent an-
`grafts, it is believed that the loss of positive
`tiestrogen completely devoid of estrogenic
`
`864
`
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`Copyright © 2004 American Society of Clinical Oncology. All rights reserved.
`
`AstraZeneca Exhibit 2032 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLCv. AstraZeneca AB IPR2017-01910
`
`
`
`EM-652/Tamoxifen-Resistant Breast Cancer
`
`activity in human breast or endometrial carcinomacells
`[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
`therapyfailure.
`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 ofthe knownantiestrogens and, to our knowledge,it
`is the only nonsteroidal antiestrogen shown to have no
`estrogenic activity either in human Ishikawa endometrial
`carcinomacells, 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-1 and
`AF-2 activities of the estrogen receptor [14], thus poten-
`tially decreasing the resistance to hormonaltherapy.
`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 highestaffinity 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 anddiethylstibestrol in displacing[*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 wasat least 30-fold
`more potent than tamoxifen in inhibiting estrogen-stimulated
`uterine growth. In addition, the maximalinhibitoryeffect on
`uterine weight achieved with EM-800is 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 thefind-
`ing that tamoxifen-resistant human breast cancercell lines
`remain sensitive to compounds showing pure antiestro-
`genic activity on cell proliferation in the mammarygland,
`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 March21, 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-provenor 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 afterits discontinuation
`(four patients) were also eligible. For these 22 patients, differenti-
`ation between acquired and de novo tamoxifen resistance could
`not be madesince 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 discontinuedat 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.
`Adjuvant chemotherapy was allowed but must have been com-
`pleted = 1 year before study entry. Eligible patients had Eastern
`Cooperative Oncology Group performance status of = 2, a life
`expectancy = 6 months, and measurable lesion(s) according to
`WHOcriteria [36]. Tumors had to be ER-positive, progesterone
`receptor-positive (>10 fmol/mg cytosolic protein or positive by
`immunocytochemistry), or ofunknownstatus. 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.
`Exclusion criteria included cancer other than breast carci-
`noma (except successfully treated in situ carcinomaofthe cervix
`or skin carcinoma other than melanoma), CNS involvement by
`cancer, lymphangitic pulmonary metastases, severe infection, and
`severeliver or kidney disease. Patients with neutropeniaor 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 mLof 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 palients were treated with 20 mg/d EM-800. Following con-
`firmation by an independent review board of the tolerance and
`safety of the 20-mgdosein at least four patients treatedforat least
`1 month, a second group ofeight patients were treated with 40
`mg/d EM-800. Thereafter, patients were randomly allocated to
`receive either 20 mg or 40 mg EM-800. Patients and investigators
`were blinded to the doselevel. Patients were to be removed from
`the study for any of the following: development ofserious 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 WHOcrite-
`ria [36]. Chest radiography, computed tomography scan oflung
`for lesionsless than 2 cm in diameter, abdominal ultrasound and
`computed tomography scan ofliver (in cases having a positive
`ultrasound), bone radiography, andisotopic bone scan were per-
`formed at start of treatment. In patients with locally advanced
`
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`AstraZeneca Exhibit 2032 p. 2
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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 ofunknown ERstatus. The
`mean ERlevel 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 observedin five of 43 (12%) patients (Table
`2), including one CR and four PRs; 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 ofthefive responders (20%) continues to respondafter
`71 months. Amongthe 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. Amongpatients 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. Twopatients continue
`torespond at 71 and 77 months,respectively. No significant
`dose effect was observed.
`
`Patterns ofFailure
`At the start of EM-800 administration, the predomi-
`nantsites 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 onesite in 19 patients, at twosites in
`17 patients, andat three sites or more in sevenpatientsat the
`start of EM-800 treatment. Most responses were observed
`
`66
`43-86
`
`7
`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,
`*>10 fmol/mg cytosolic protein or positive by immunocytochemistry.
`‘Based on 34 patients for whorma quantitative measurementof 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 performedat start of treatment, at 1, 2, and 4 weeks, and at
`monthly intervals thereafter. Vital signs were measured and a
`tolerability questionnaire wasfilled 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 andbaseline 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
`
`20 mg (n = 21)
`40 mg (n = 22)
`Response Duration
`
`Best Response
`No.
`%
`(months)
`No.
`%
`Response Duration (months)
`CR
`0
`0
`_
`|
`5
`oF
`PR
`2
`10
`6. 71+
`2
`S
`7,8
`SD
`8
`14
`8,9, 19
`Z
`32
`3,4, 6, 16, 16,17, 77
`
`16 76 _— 12 54PD _
`
`
`
`
`
`
`Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; +, responsestill ongoing.
`
`
`866
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`AstraZeneca Exhibit 2032 p. 3
`
`
`
`
`
`EM-652/Tamoxifen-Resistant Breast Cancer
`
`Table 3. Disease Site(s) at Start and at Failure to EM-800 Therapy and Best Response by Disease Site
`No. of Patients
`Best Response
`At Start of
`PD fany
`At Failure to
`
`
`
`
`
` Site(s) of Disease Treatment CR PR SD site) EM-800
`
`
`
`
`
`
`
`1
`-
`_
`
`17
`2)
`7
`—
`29
`Bones)
`5
`10
`]
`1
`15
`Node(s)
`g
`g
`2
`—
`1
`Liver
`5
`8
`1
`_—
`10
`Lung
`2
`2
`2
`1
`—
`5
`Skin
`—_—
`1
`—
`1
`—
`2
`Breast
`8
`2
`2
`—
`_
`6
`Others
`_—
`10
`6
`2
`1
`19
`One organ site
`—
`13
`3
`1
`=
`1
`Twoorgan sites
`
`Three organ sites _— q — ‘| | 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 CRs or PRs were observed in patients with
`liver metastases. Nine of 11 (82%) patients with liver me-
`tastases andeight 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 samesite during
`the study. In the majority of cases, patients who failed
`EM-800 therapy progressed at the samesite(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 monthsof 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-800, 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 advanceddisease 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 offive (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 (improvementor 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 respectto sites
`of metastases, with 43% of patients 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
`=
`ie
`22°
`Adjuvant
`g
`6
`1
`—
`16
`Advanced disease
`
`Adjuvant + advanced disease 2 5 = = 2
`
`
`
`
`Abbreviations: CR, complete response; PR, partial response; SD, stable disease: PD, progressive disease,
`*Eighteen patients had progressed while receiving tarnoxifen while four progressed following cessation of tamoxifen.
`‘was progressing under tamoxifen.
`*One patient was progressing under tamoxifen, while one progressed 3 years and 5 monthsafter having received tamoxifen for 4: years and 3 months, while
`the other patient had progressed 3 years after having received tamoxifen for 5 years.
`
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`
`
`
`Labrie et al
`
`Table 5. Summary of Adverse Events Occurring in =10% of Patients at Either Dose Level by WHO Grade
`
`20 mg (n = 21)
`40 mg (n = 22)
`GradeI/ll
`
`GradeIII/IV
`
`Grade|/ll
`
`No. of
`No. of
`No. of
`Adverse Event
`Patients
`%
`Patients
`%
`Patients
`%
`
`
`Bone/muscle pain
`ausea
`
`14
`i
`
`67
`Se
`
`15
`9
`
`68
`41
`
`2
`2
`
`9
`9
`
`
`
`
`=
`ne
`45
`10
`24
`5
`Fatigue
`—
`—
`ae
`7
`S
`4
`Asthenia
`14
`o
`14
`2
`24
`5
`Vomiting
`_—
`_—
`14
`3
`2
`4
`Hot flashes
`—
`—
`23
`5
`0
`2
`Heartburn
`5
`1
`14
`3
`0
`2
`Abdominal pain
`—
`—
`18
`4
`0
`2
`Flu-like symptoms
`_—
`—
`14
`3
`4
`3
`Decreased appetite
`5
`|
`18
`2
`0
`Z
`Constipation
`_—
`_—
`18
`4
`0
`2
`Depression
`_
`_
`5
`1
`4
`3
`Diarrhea
`—
`—
`23
`5
`24
`5
`Headache
`_—
`_
`_
`_—
`0
`2
`Soft stools
`_—
`_
`_—
`_—
`0
`2
`Urinary tract infection
`—
`—
`—
`_—
`0
`2
`Decreased hemoglobin
`=
`_—
`_—
`_—
`0
`2
`Paresthesias
`
`
`Safety
`No clinically significant adverse event (AE) related to
`the study drug was observedat either dose level. Commonly
`reported AEs are shown in Table 5. At the 20-mg doselevel,
`no WHOgrade 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 doselevel, 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.
`Nopatient 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, abdominalpain, and consti-
`pation (one patient each). One death from breast cancer
`occurred in the 40-mg dose group within 30 days oftreat-
`ment interruption.
`
`The present data show that EM-800, a novelselective estro-
`gen receptor modulator (SERM) having pure antiestro-
`genic activity in the mammarygland, 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%ofpatients 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 amedian 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% hadclinical benefit rates (CR + PR + SD
`= 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,
`althoughfive patients (36%) had SD [42].
`
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`
`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 hadfailed 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 areits oral bioavailability and its protective effect
`on boneloss [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 stimulatoryeffect of
`estrogen precursors on human breast cancer cells (MCF-
`7186) [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 resistanceis 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 occurredin
`patients with bone, lymph node, skin, and. breast metastases,
`whereas no objective tumor response was observedin 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 numbersare small, patients treated with tamoxifen
`in the adjuvant setting appeared more likely to achieve an
`objective response to EM-800; the proportion ofpatients who
`achieved an objective response or SD was 27% in the patients
`whohad tamoxifen in the advanced disease state compared to
`44% in the adjuvantsetting. It might be proposed that patients
`whoexperienced adjuvant tamoxifenfailure may have had less
`advanced disease than patients whofailed to respond to ta-
`moxifen for the treatment of advanced metastatic disease.
`However, a comparison of these subgroups reveals no major
`differencesin 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 ofsites 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 observedin 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
`
`www.jco.org
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`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 | 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-800 (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 whoreceived daily doses of EM-800 up to 40 mgfor
`up to 14 days. As indicated above, long-term follow-up of
`patients in the present study who remained on EM-800ther-
`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 numerouspreclini-
`cal studies. In fact, while hormonal therapyofbreast 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 amore complete inhibition of the estrogen recep-
`tor [14,16,19,20,26], the tumorocidal action of alcobifene is
`anew paradigm ofestrogen blockade. Moreover, alcobifene
`and fulvestrant not only completely inhibit the stimulatory
`effect of estradiol on theproliferation ofMCF-7/S6 cells but
`further inhibit cell growth by 80% below basalvalues [44].
`Taken together, these data suggest that EM-800 may im-
`prove therate, 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 front-line treatmentof 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-
`
`869
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`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 serum cholesterol andtriglycerides 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 beactively investigated
`for the treatment ofER-positive breast cancer and other estro-
`gen-sensitive malignancies. Moreover, the characteristics of
`EM-800 makeit an ideal compound for prevention ofbreast
`and endometrial cancer because ofthe potential added benefits
`in termsof prevention of osteoporosis and cardiovascular dis-
`ease in postmenopausal women.
`
`
`Acknowledgment
`Wethank Dr Alain Bélanger for his supervision of the
`analytic procedures and Dr Luc Deschénesfor his clinical
`implication and advice.
`
`Authors’ Disclosures of Potential
`Conflicts of Interest
`The following authorsor their immediate familymem-
`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.
`
`agaeas)
`
`
`
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