Annals of Oncology
`
`Annals of Oncology 24: 2543—2548, 2013
`doi:10.1093/annonc/mdt2) 6
`Published online 20 June 2013
`
`Randomized phase II study of lonaprisan as second-line
`therapy for progesterone receptor-positive breast
`
`cancer
`
`W. Jonat”, T. BachelotZ, T. Ruhstaller3, l. Kuss4, U. Peimann4 &J. F. R. Robertson5
`7Department of Gynaecology and Obstetrics, University Hospital Schleswig—Holstein, Campus Kiel, Kiel, Germany; 2Department of Medical Oncology and Lyon Cancer
`Research Centre, Centre Leon Berard, Lyon, France; 3Breast Centre St. Gallen, Kantonsspital St. Gallen, St. Gallen, Switzerland; 4Bayer Pharma AG, Berlin, Germany;
`5Academic Division of Breast Surgery, University of Nottingham, Royal Derby Hospital, Derby, UK
`
`Received 26 November 2012; revised 25 April 2013; accepted 26 April 2013
`
`Background: The progesterone—receptor (PR) antagonists onapristone (type I) and mifepristone (type II) showed
`modest activity in hormone—receptor—positive breast cancer; however, onapristone in particular was associated with
`hepatotoxicity. Lonaprisan is a novel, type III PR antagonist that was well tolerated in phase I studies.
`Patients and methods: This randomized, open—label, phase II study evaluated the efficacy and tolerability of lonaprisan
`
`as second—line endocrine therapy in postmenopausal women with stage IV, PR—positive, H ER2—negative, metastatic
`breast cancer.
`
`Results: Patients received once—daily lonaprisan 25 mg (n : 34) or )00 mg (n : 34). The primary objective was not met
`(235% clinical benefit rate: complete/partial responses at any time until month 6 or stable disease [SD] for 26 months
`from start of treatment). There were no complete/partial responses. In the 25 mg and )00 mg groups, 6 of 29 patients
`(2) %) and 2 of 29 patients (7%), respectively, had SD 26 months. Overall, 6) of 68 patients (90%) had 2) adverse event
`
`(AE), the most frequent (2) 0% overall) being fatigue, hot flush, dyspnoea, nausea, asthenia, headache, constipation,
`
`vomiting, and decreased appetite; 33 patients had serious AEs.
`Conclusion: Lonaprisan showed limited efficacy as second—line endocrine therapy in postmenopausal women with
`PR—positive metastatic breast cancer.
`Key words: antiprogestin, breast cancer, lonaprisan, progesterone—receptor antagonist, progesterone—receptor positive
`
`introduction
`
`Endocrine therapy is the most important systemic treatment for
`patients with hormone—receptor—positive breast cancer (BC),
`and multiple endocrine therapies are available in this setting.
`However, all these agents aim at oestrogen deprivation.
`Furthermore, the effectiveness of current endocrine therapies is
`limited by the development of drug resistance [1]. This
`resistance is thought to be mediated, at least in part, by
`interactions between oestrogen—receptor (ER) and growth—
`factor—receptor signalling pathways—so—called molecular cross—
`talk—that lead to modulation of hormone receptor function [2].
`Therefore, there is an unmet need for therapies with novel
`mechanisms of action for postmenopausal women with
`hormone—receptor—positive, stage IV, systemic BC.
`
`*Corresponclence to: Prof. Dr med Walter Jonat, Department of Gynaecology and
`Obstetrics, UniverSity Hospital SchleSWigiHolstein, Campus Kiel, Michaelisstrasse )6,
`24) 05 Kiel, Germany. Tel: +4943) 75977204) : Fax: +4943) 75972) 46;
`Email: walter.lonat@ul<sh.de
`
`As well as agents that target oestrogen deprivation, various
`agents targeting the progesterone receptor (PR) have been
`investigated. PR modulators compete with progesterone for the
`PR ligand—binding site. There are three types of steroidal PR
`antagonist. Type I agents prevent DNA binding and inhibit PR
`phosphorylation. Type 11 agents promote DNA binding and
`promote PR phosphorylation. Type III agents promote DNA
`binding, recruit co—repressors, and strongly promote PR
`phosphorylation. Studies with onapristone (type I) and
`mifepristone (type 11) suggested that PR antagonism, either
`alone or in combination therapy, may be a viable treatment
`strategy in postmenopausal women with advanced BC [3—6].
`Both were studied in first— and second—line settings, and
`mifepristone has also been used as a third—line treatment.
`Beneficial effects were mainly observed in patients with PR—
`positive tumours. Together, the study of mifepristone as second-
`line therapy (71 = 11) and the study of onapristone as second-
`line therapy (71 = 90) reported an objective response rate (ORR;
`complete response plus partial response) of around 10% [3, 6].
`The first—line studies reported ORRs of 11% for mifepristone
`
`© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
`All rights reserved. For permissions, please email: journals.permissions@oup.com.
`
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`Annals of Oncology
`
`and 56% for onapristone [4, 5]. However, transient liver
`function test abnormalities in some patients (mainly during the
`first 6 weeks) halted the clinical development of onapristone [4].
`Lonaprisan (ZK230211) is a type III PR antagonist. In vitro
`studies show that lonaprisan has strong antiproliferative
`properties that are greater than those of rnifepristone and
`onapristone [7—9]. In two randomized, placebo—controlled,
`phase I studies in healthy postmenopausal women, lonaprisan
`(single dose of 1—200 mg or repeated doses of 5—100 mg) was
`well tolerated without hepatotoxicity [10]. The aim of the
`present prospective, multicentre, randomized, open-label,
`parallel-group, phase II study was to evaluate the efficacy,
`tolerability, and pharmacokinetics of lonaprisan, 25 or 100 mg
`once daily, as second—line endocrine therapy for
`postmenopausal women with stage IV, PR—positive,
`human epidermal growth factor receptor 2 (HER2)—negative,
`metastatic BC.
`
`computerigenerated list produced by the sponsor using randomization
`blocks. Patients were equally distributed between treatment groups with
`stratification for disease status (measurable/nonimeasurable disease) and
`previous chemotherapy (yes/no).
`The primaiy eflicacy outcome was clinical benefit, defined as the
`proportion of patients with: complete response or partial response at any
`time up to month 6; or stable disease for 6 months from the start of study
`treatment. Secondary eflicacy outcomes were: ORR (best overall response out
`of partial response or complete response in patients with measurable
`disease); progressionifree survival (PFS); duration of response; duration of
`clinical benefit; and overall survival (OS). Tumour response was evaluated at
`37monthly intervals until study end, and lesions were evaluated according to
`RECIST1.0[11].
`Safety outcomes included adverse events (AEs), serious AEs (SAEs),
`laboratory assessments, and electrocardiograms (ECGs).
`Other outcomes included pharmacokinetic analysis of lonaprisan and its
`metabolites (subgroup of patients at selected centres only).
`
`materials and methods
`
`study design
`This was an openilabel, prospective, randomized, paralleligroup, phase II
`study (clinicaltrialsgov identifier: NCT00555919; EudraCT Number:
`20057005581736), carried out at 28 centres in Austria, Finland, France,
`Germany, UK, Italy, Poland, Spain, Sweden, and Switzerland. It was conducted
`in accordance with the principles of the Declaration of Helsinki, the ICIIGCP
`guidelines, and appropriate local regulatory authorities. The objective of the
`study was to evaluate the eificacy, safety, tolerability, and pharmacokinetics of
`two doses of lonaprisan, 25 and 100 mg, given orally, once daily.
`
`study population
`Patients included were postmenopausal women with: PRipositive,
`histologically, or cytologically confirmed metastatic (stage IV, Union
`Internationale Contre le Cancer [UICC] criteria version 6) BC; disease
`progression after fii‘strline endocrine therapy for advanced BC (i.e. with
`tumour remission or stabilization lasting at least 3 months under endocrine
`therapy); at least one measurable or nonrmeasurable tumour lesion
`(according to Response Evaluation Criteria in Solid Tumours [RECIST]
`[11]); WHO performance status score 31.
`Postmenopausal was defined as: aged 250 years with amenorrhoea for
`212 months; or aged 350 years with 6 months of spontaneous amenorrhoea
`and follicleistimulating hormone levels within postmenopausal range (>40
`mIU/ml); or having undergone bilateral oophorectomy. This is a standard
`definition for postmenopausal, and is consistent with, for example, draft
`guidance from the FDA regarding clinical evaluation of hormone
`replacement therapy to treat the symptoms of the menopause [12].
`Exclusion criteria included: more than one prior endocrine treatment for
`advanced BC; previous combination of endocrine treatment with any other
`type of treatment (except chemotherapy); previous sequential endocrine
`treatments (if there was disease progression between treatments); HERZ
`status positive or unknown.
`
`interventions and outcomes
`
`Patients were randomized to receive lonaprisan 25 mg once daily (one 257
`mg tablet) or 100 mg once daily (two 507mg tablets) until they had disease
`progression, became unable to tolerate therapy, developed any condition
`that precluded study treatment, were nonicompliant with therapy, withdrew
`consent, or died. Treatment was taken as a fasting morning dose at least 1 h
`before food. Randomization was carried out centrally according to a
`
`statistical methods
`
`Planned enrolment was 72 patients (36 per dose group). This was based on
`oneisided significance testing within each group at test level 10%. With 36
`assessable patients per group, a power of 290% was guaranteed if the
`anticipated clinical benefit rate of 35% were met. The primary objective of
`the study was not inferential comparison between the two groups, but
`hypothesis testing within each group. The study was designed to
`demonstrate a positive eifect of lonaprisan (within each group) compared
`with a threshold clinical benefit rate of 15%. Within each treatment group,
`the primary eflicacy outcome was analysed in a singleistage design. The
`outcome was considered successful if 9 of 36 assessable patients in one
`treatment group showed clinical benefit. The main analysis of eflicacy was to
`be carried out after all patients had been treated for 6 months or had
`dropped out before month 6, whichever came soonest. The analysis sets for
`efficacy and safety were consistent (all patients with at least one intake of
`study drug). Data are displayed by descriptive statistics.
`
`results
`
`patients
`
`The first patient enrolled in March 2008. The study was
`terminated earlier than planned (April 2010) owing to slow
`recruitment and anticipation of negative study findings;
`expected futility was based on a data review carried out by two
`senior investigators (the coordinating investigator and a site
`principal investigator) when 68 of the proposed 72 patients had
`been treated. Of 83 patients screened, 69 were randomized
`(supplementary Figure S1, available at Annals of Oncology
`online). All but one patient (100 mg group) received at least one
`dose of lonaprisan; the full analysis set as well as the safety
`analysis set included 68 patients.
`Overall, the median (range) patient age was 66 (42—94) years
`(Table 1). All patients except one were Caucasian and all had
`UICC stage IV BC. Initial diagnosis for 72.1% of patients was
`ductal carcinoma (including invasive ductal carcinoma, ductal
`carcinoma in situ, and inflammatory, mucinous, scirrhous,
`papillary, or other subtypes) and for 23.5% of patients was
`lobular carcinoma (including invasive lobular carcinoma with
`lobular carcinoma in situ). The remaining 4.4% of patient had
`other subtypes of BC. Overall, the two treatment groups were
`
`2544 I Jonat et al.
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`Annals of Oncology
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`Table 1 . Baseline patient characteristics and demographics (full analysis set)
`
`Lonapriszn 25
`
`34:)
`
`Lenaprisan 100 nag/day.
`
`:34)
`
`Total (n, = 63‘)
`
`64.5 (42782)
`
`67.0 (54794)
`
`66.0 (42794)
`
`33 (97.1)
`1 (2.9)
`
`25 (73.5)
`8 (23.5)
`1 (2.9)
`
`31 (91.2)
`0 (0)
`3 (8.8)
`
`32 (94.1)
`0 (0)
`2 (5.9)
`
`29 (85.3)
`2 (5.9)
`3 (8.8)
`
`34 (100)
`0 (0)
`
`24 (70.6)
`8 (23.5)
`2 (5.9)
`
`33 (97.1)
`0 (0)
`1 (2.9)
`
`34 (100)
`0 (0)
`0 (0)
`
`31 (91.2)
`3 (8.8)
`0 (0)
`
`67 (98.5)
`1 (1.5)
`
`49 (72.1)
`16 (23.5)
`3 (4.4)
`
`64 (94.1)
`0 (0)
`4 (5.9)
`
`66 (97.1)
`0 (0)
`2 (2.9)
`
`60 (88.2)
`5 (7.4)
`3 (4.4)
`
`35 (51.5)
`28 (41.2)
`18 (26.5)
`44 (65.7)g
`
`Age (years)
`Median (range)
`Race, 11 (%)
`Caucasian
`
`Hispanic
`Histology at initial diagnosis, 11 (%)
`Ductal carcinomaa
`Lobular carcinomab
`OtherC
`
`HER2 receptor status, 11 (%)
`Negative
`Positive
`
`Unknown/missingc1
`Progesterone receptor status, n (%)
`Positive
`
`Negative
`Unknown/missinge
`Oestrogen receptor status, n (%)
`Positive
`
`Negative
`Unknown/missing
`Previous breast cancer therapy, 11 (%)
`Adj uvant/neoadjuvant hormone therapy
`Adj uvant/neoadjuvant chemotherapy
`Chemotherapy for advanced/metastatic disease
`Radiotherapy
`Previous endocrine therapy for metastatic/advanced
`disease, 11 (%)h
`Aromatase inhibitors
`Letrozole
`Anastrozole
`Exemestane
`
`Oestrogen receptor antagonists
`Tamoxifen
`Fulvestrant
`
`Number of sites of metastasis, n (%)
`
`1 2 2
`
`3
`
`Most commoni sites of metastasis, n (%)
`Bone
`Liver
`
`Lymph nodes
`Lung
`Breast
`Pleura
`
`
`aIncludes ductal carcinoma, e.g. ductal carcinoma in situ, and all subtypes, such as inflammatory, mucinous, papillary, scirrhous, and other subtypes.
`bIncludes lobular carcinoma, e.g. invasive and carcinoma in situ.
`CIncludes Paget’s disease and breast carcinoma (not otherwise specified).
`c1Although this was an exclusion criterion, four patients with unknown/missing HER2 status were enrolled (minor protocol deviation in three patients; no
`protocol deviation in one patient, as HER2 was available at screening).
`6Although this was an inclusion criterion, two patients with unknown/missing progesterone receptor status were enrolled (major protocol deviation in one
`patient; no protocol deviation in one patient as PR was available at screening).
`{11 : 33.
`gn :67.
`
`hPatients could have received more than one previous endocrine therapy for metastatic/advanced disease.
`i> 10% of total patients.
`HER2, human epidermal growth factor receptor 2.
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`comparable in terms of demographics and baseline
`characteristics.
`
`efficacy
`
`The primary efficacy variable was clinical benefit (defined as the
`proportion of patients with complete or partial response at any
`time point up to month 6 or stable disease for 6 months from
`the start of study treatment). Of the evaluable patients (n = 58),
`8 (14%) had stable disease 26 months: 6 of 29 (21%) in the 25
`mg group and 2 of 29 (7%) in the 100 mg group. There were no
`confirmed complete or partial responses. Therefore, the primary
`objective of at least 35% clinical benefit rate was not met.
`The best overall response during the study was stable disease
`for 23 months in 18 patients (9 of 29 [31.0%] in each group).
`For the remaining patients, best overall response was therefore
`progressive disease (20 of 29 [69.0%] in each group). Time—to—
`event analyses were omitted due to the lack of responders. Some
`patients had prolonged stable disease: three in the 25 mg group
`and one in the 100 mg group still showed stable disease at
`month 12.
`
`pharmacokinetics
`
`Dose-related increases in exposure to lonaprisan and its
`metabolites occurred when the lonaprisan dose increased from
`25 to 100 mg.
`
`safety
`
`Twenty-nine (85.3%) of the 34 patients in the 25 mg group and
`32 (94.1%) of the 34 patients in the 100 mg group experienced
`at least one AE (Table 2). The most common AEs (210%
`overall) were fatigue, hot flush, dyspnoea, nausea, asthenia,
`headache, constipation, vomiting, and decreased appetite. Drug—
`related AEs were reported for 18 patients (52.9%) in the 25 mg
`group and 24 patients (70.6%) in the 100 mg group; the most
`common (210% overall) were fatigue and hot flush.
`In all, 21 patients (30.9%) experienced an SAE (9 [26.5%] in
`the 25 mg group and 12 [35.3%] in the 100 mg group). SAEs
`reported in more than one patient were endometrial
`
`Table 2. Adverse events (safety analysis set)
`
`Annals of Oncology
`
`hypertrophy (one patient in the 25 mg group and two patients
`in the 100 mg group); myocardial infarction (MI; two patients
`in the 100 mg group); and ascites, subileus, and dyspnoea (one
`patient in each group for each).
`Treatment was discontinued due to AEs in three patients in
`the 25 mg group (increase of alanine aminotransferase and
`gamma—glutamyl transpeptidase, increase of endometrial
`thickness, elevated liver enzymes) and in three patients in the
`100 mg group (non—ST-elevated MI, fatigue/chills, liver failure
`due to disease progression).
`There were no consistent trends observed for any laboratory
`parameters in either dose group. Most laboratory abnormalities
`were CTCAE grade 1 or 2. Few notable changes in heart rate or
`blood pressure were observed.
`Twelve patients died during the study (four in the lonaprisan
`25 mg group and eight in the lonaprisan 100 mg group). In the
`25 mg group, all four deaths were due to disease progression. In
`the 100 mg group, six deaths were due to disease progression,
`one to cardiorespiratory distress, and one to ‘other’ (‘reduced
`general condition’ with ‘nausea, upper abdominal pain’). No
`deaths were considered related to study treatment.
`
`discussion
`
`This prospective, multicentre, randomized, open—label, parallel-
`group, phase II study evaluated the efficacy, tolerability, and
`pharmacokinetics of once—daily lonaprisan 25 or 100 mg as
`second-line endocrine therapy for postmenopausal women with
`stage IV, PR—positive, HER2—negative metastatic BC. Although
`disease stabilization was observed in some patients for a
`clinically useful period (overall 14% of patients had stable
`disease for 26 months), the study did not meet its primary end
`point. The study terminated earlier than planned owing to slow
`recruitment and anticipation of negative study findings (futility
`analysis).
`Based on observations for second—line therapy with type I and
`II PR antagonists in hormone—receptor—positive BC, an overall
`clinical benefit rate of ~35%—50% was expected for lonaprisan, a
`type III steroidal PR antagonist [3, 6, 13, 14]. In our study, no
`
`
`1.90
`(22 “z 343?
`
`29 (85.3)
`
`Patients with any adverse event, 11 (%)
`Most common adverse events, 11 (%)a
`2 (5.9)
`11 (32.4)
`1 (2.9)
`6 (17.6)
`Fatigue
`0
`6 (17.6)
`1 (2.9)
`7 (20.6)
`Hot flush
`1 (2.9)
`7 (20.6)
`1 (2.9)
`5 (14.7)
`Dyspnoea
`o
`6 (17.6)
`0
`6 (17.6)
`Nausea
`1 (2.9)
`2 (5.9)
`o
`9 (26.5)
`Asthenia
`0
`3 (8.8)
`0
`5 (14.7)
`Headache
`0
`3 (8.8)
`0
`4 (11.8)
`Constipation
`0
`3 (8.8)
`0
`4 (11.8)
`Vomiting
`0
`4 (11.8)
`1(29)
`3 (8.8)
`Decreased appetite
`1 (2.9)
`2 (5.9)
`1 (2.9)
`1 (2.9)
`Ascites
`
`0 2 (5.9) 2 (5.9)
`
`Myocardial infarction
`0
`
`
`Lanade 2:5 mgfdax‘én : 34:2
`(384:1: 23‘
`8 (23.5)
`
`Any gfadif:
`32 (94.1)
`
`12 (35.3)
`
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`aAny grade adverse events occurring in 210% of patients overall, or glade 23 adverse events occurring in 22 patients overall.
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`Annals of Oncology
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`objective responses were observed, compared with ORRs of
`~10%—50% in previous studies of second—line endocrine
`therapy [3, 6, 13—15]; thus, the clinical benefit rate here included
`only patients who had stable disease. The limited efficacy
`demonstrated by lonaprisan in this study suggests that either the
`drug is ineffective in this population or it is effective in only a
`limited number of patients. In our study, four patients had
`prolonged stable disease (>12 months); however, there is
`considerable debate about the value of stable disease as a
`
`measure of efficacy in BC. Given our findings, a clinical benefit
`rate of <20% should be the definition of an ineffective second—
`
`line therapy after an aromatase inhibitor. While there is an
`argument for setting this at <15% (the clinical benefit rate across
`both doses of lonaprisan) we feel that the more conservative
`figure of <20% is appropriate.
`This study differs from studies of other PR antagonists in
`postmenopausal women with metastatic BC in terms of study
`design and patient population, but the results of the studies may
`also vary because of the type of PR antagonist used—i.e. a type
`III agent compared with a type I or II agent (such as
`onapristone and mifepristone, respectively). Further
`investigation would require a deeper understanding of the
`mechanism of action of lonaprisan, especially of the
`implications of being a type III PR antagonist, and which
`characteristics make tumour cells sensitive to type III PR
`antagonism. Understanding the effects of therapy and selecting
`individuals who are likely to respond to treatment are two key
`challenges we face in using endocrine therapies for BC [16].
`Clinical and molecular factors may both have led to the
`limited efficacy of lonaprisan. Potentially relevant clinical
`factors include advanced metastatic disease, multiple sites of
`metastases, large tumour burden, poor performance status, and
`aggressive tumour biology. Notably, there were 10 deaths from
`progressive disease, emphasizing the advanced BC stage of the
`enrolled patients. In terms of molecular factors, cross—talk
`between ER and growth—factor—receptor signalling pathways is
`thought to be a significant cause of de novo or acquired
`resistance to endocrine treatment for hormone—receptor—
`positive BC [2]. These alterations in signalling may induce not
`only the development of an endocrine—insensitive phenotype
`but also a cellular phenotype with enhanced migratory and
`invasive behaviour [1]. Cross—talk between PR and growth—
`factor signalling pathways also occurs [17] and this cross—talk,
`or dysregulation of this mechanism, may underlie the limited
`efficacy of lonaprisan in this study.
`Five patients had ER—negative, PR—positive disease. There has
`been much debate on this topic, with compelling arguments
`both for [18, 19] and against [20, 21] the existence of ER—
`negative, PR-positive disease. Either way, we do not believe
`that the ER status of patients in our study affected our results,
`given that we assessed a PR antagonist in patients with PR—
`positive BC.
`In conclusion, lonaprisan showed very limited efficacy as
`second-line endocrine therapy in postmenopausal women with
`PR—positive metastatic BC. Our findings set a definition for an
`ineffective agent (clinical benefit rate <20%) in the second—line
`setting after an aromatase inhibitor—a setting for which no
`endocrine agent has a licensed indication. While there may be a
`number of potential reasons for the observed lack of eflficacy,
`
`
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`7. EU‘rmann L, HesseS umpp H, Cleve A et al Synthesis and biological activity of a
`iovel, highly potent p ogesterone receptorantagonist. J Med Chem 2000; 43:
`50‘ (P5016.
`
`8. 3Lsia L, Fa s H, Hotlnann J et al The antiprogestin Lonaprisan inhibits breast
`ca"cercell proliferation by inducing p21 expression. Mol Cell Endocrinol 2011;
`333: 3746.
`
`future research should look to find a deeper understanding of
`the mechanism of action of lonaprisan, including better
`comprehension of the implications of being a type III PR
`antagonist.
`
`acknowledgements
`
`Editorial support provided by 7.4 Limited (supported by Bayer
`HealthCare Pharmaceuticals). The authors thank the patients
`involved in the study and the staff of all the centres that
`participated in the trial. The following investigators participated
`in the study: Austria: C. Dittrich, R. Greil, C. Marth,
`H. Samonigg; Finland: V. Kataja, O. Paija; France: D. Azria,
`T. Bachelot, I. Bonneterre, M. Campone, ].—C. Eymard,
`I. Gligorov; Germany: B. Gerber, W. Ionat, M.P. Lux,
`K. Schwedler, D. Wallwiener; Italy: A. Santoro; Poland:
`B. Czartoryska—Arlukowicz, A. Iagiello—Gruszfeld, P. Tomczak,
`I. Wojcik—Tomaszewska; Spain: ].A.G. Saenz; Sweden:
`S. Bergenfelt, L. Carlsson, L. Klint; Switzerland: T. Ruhstaller;
`United Kingdom: ].F.R. Robertson.
`
`funding
`
`This work was supported by Bayer HealthCare Pharmaceuticals.
`
`disclosure
`
`W] has received honoraria and consulting and lecture fees from
`AstraZeneca, Novartis, and Pfizer Oncology. IFRR has received
`research grants from Bayer HealthCare Pharmaceuticals and has
`been a member of Advisory Boards for Bayer HealthCare
`Pharmaceuticals. IK and UR are employees of Bayer HealthCare
`Pharmaceuticals. TB and TR have declared no conflicts of
`interest.
`
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`Annals of Oncology 24: 2548—2554, 2013
`doi:10.1093/annonc/mdt213
`Published online 24 June 2013
`
`N0539 phase II trial of fulvestrant and bevacizumab in
`
`patients with metastatic breast cancer previously
`treated with an aromatase inhibitor: a North Central
`
`Cancer Treatment Group (now Alliance) trial’r
`
`W. W. Tani, A. C. Dueck2, P. Flynn3, P. Steen4, D. Anderson3, K. Rowland? D. Northfelt6 &
`E. A. Perez”
`
`7Division of Hematology/Oncology, Mayo Clinic, Jacksonville; 2Section of Biostatistics,‘ Mayo Clinic, Scottsdale; 3A/letro Minnesota COOP; St Louis Park; 4Sani‘ord Medical
`Center; Fargo; 5Car/e Cancer Center; Urbana,‘ SDivison of Hematology/Oncology; Mayo Clinic, Scottsdale, USA
`
`Received 10 August 2012; revised 24 April 2013; accepted 29 April 2013
`
`Background: Based on preclinical studies, the vascular endothelial pathway is an important mechanism for estrogen
`receptor resistance. We conducted a phase II study of fulvestrant and bevacizumab in patients with aromatase inhibitor
`pretreated metastatic breast cancer.
`Patients and methods: A single—stage phase II study was conducted with these objectives: 6—month progression—free
`survival (PFS), tumor response, toxic effect, and overall survival. Regimen: 250 mg fulvestrant days 1 and 15 (cycle 1) then
`day 1 (cycle 2 and beyond) and 10 mg/kg bevacizumab days 1 and 15 of each 4—week cycle.
`Results: At interim analysis, 20 eligible patients initiated treatment, 1 1 were progression free and on treatment at 3
`months, not meeting the protocol—specified efficacy requirements (at least 12 of 20). Accrual remained open during
`interim analysis with 36 patients enrolling before final study closure. Among the 33 eligible patients, the median PFS was
`
`*Correspondence to: Dr Edith A. Perez, DiViSion of Hematology/Oncology,
`Mayo Clinic, 4500 San Pablo Road, JacksonVille 32224, USA. Tel: +17904795370118;
`Fax: +17904795376233; Email: perez.edith@mayo.edu
`
`TPartially presented at San Antonio Breast Cancer SympOSium 2009.
`
`© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
`All rights reserved. For permissions, please email: journals.permissions@oup.com.
`
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