0 5
`
`'l'~LANClff
`
`Refere~~~~~~~~~~~~~~~~
`I Davis LG, Weber DJ, Lemon SM. Horizontal transmissfon of hepatitis
`8 virus. Um= 1989; i: 889- 93.
`2 Bernle:r RH, Sampliner R, Gerecy R, Tabor E, Hami1too F,
`Nathanson N . Hepatitis B ln!cction in households of chronic carriers of
`hepatitis B surface antigen: focton associated with prevalence of
`infection. Am J Epidemiol J 982; 116: 199-21 J.
`3 Franks A, Berg CJ, Kane MA, et al. Hepatitis 8 virus infection among
`children born io the United Stale$ to Southeast Asian refugees. N Engl
`J Mui 1989; 321: 1301--05.
`4 Friede A, Harris JR, Kobayashi JM, Shaw FE, Scboemaker-Nawas PC,
`Kane M . Troo8missioo of hepatitis B virus from adopted Asian
`children to their families Am J Pub/it: H.alth 1988; 78: 26-29.
`van Dillhuysen Th JM, De Witte-van Der Schoor E, van Loon AM,
`Rijnties PJM, Yap SH. Hepatitis 8 in an instirution for the mentally
`rewdcd. Am J EpidmUql 1988; 128: 629-38.
`6 Hayashi], Kuh.iwagi S, Nomura H, Kajiyama W, Otetnatsu H .
`Hepatitis B virus transmission in nursery schools. Am J Epidemiol J 987;
`12S1 492-98.
`
`7 Van Damme P, Meneus A. Hepatitis B In mental handicap hospitals.
`Lan«r 1989; i: 840-41.
`8 McPhillips JC, Collliu JC, Spigl and I. Hepatitis B virus infections
`transmitted from retarded children to their families during brief home
`exposure:. J Prdiau Gosrrwmerol Nurr 1984; 31 69-71.
`9 Jenison SA, Leman SM, Bater LN, Newbold JE. Quantitative analysis
`of hepatitis B virus DNA in saliva and semen of chronically ID.fccted
`homosexual men. J Jn/ta Dis 1987; 156: 299-307.
`10 Cancio-Bello TP, de Medina M, Shorey J, Vallcdor MD, Schiff ER. An
`institutional outbreak of hepatitis B related to 1 human biting carrier.
`J lnfoa Dis 1982; 1461 652-56.
`
`Depart ment of Epldemlolor;y and Community Medicine, University
`of Antwerp, 2610 Antwerpen, Belglum (P Van Damme MD,
`M Cramm MD, J..c Van Der AlNlera. A Meheus PhO); and lnstlltute or
`Hygiene and Epldemloloty, 8 russet., Betclum (R Vranckx PhD)
`COlfMpondenc• to: Dr Pierre Van Damme
`
`19 posanenopausal patients less than 81 years old with
`advanced, histologically verified, breast cancer resist.ant to
`ramoxifen were treated with rcr 182780. The srudy was
`approved by the ethics coo:unittees of each clinical centre.
`Patients were in.eluded if they h ad been tre11ted with tamoxifen as
`an adjuvant to surgery for more than two years and then relapsed
`or treated with tamoxifen for advanced disease, had a complete
`or partial remission, or no change for at least six months• and
`subsequently progressed. Patients were excluded if they had
`serious intercurrent disease, a WHO performance status of
`greater than 2 and a life expectancy of less than 3 months, or had
`received other chemotherapy. One patient had adjuvant therapy
`for only 9 months a.od progressed, and wa• thus a protocol
`violation but is included in the analysis. She had progressive
`disease when treated with ICI 182780. The predominant sites of
`disease at the time of relapse on tamo.xifcn were: breast/chest wall
`(7), lymph nodes (1), bone (9). and lung/pleura (2). After giving
`informed consent, all patients underwent baseline staging
`investigations before starting
`treatment with ICI 182780;
`including radiographs, liver ultrasound or computed tomograph
`scan (all every 1- 2 months), and isotope bone scan (every 6
`months). ICI 182780 was administcz:cd as a
`long--acting
`in a
`castor oil-based vehicle by monthly
`formulation
`intramuscular injection into a b uttock. For safety appraisal, the
`first 4 patients received escalating doses of ICJ 182780, starting
`with 100 mg the first month and increasing to 250 mg from
`month 2 onwards, following confirmation of lack of local or
`systemic drug toxicity at the 100 mg dose. Patients 5-19 received
`250 mg/month from the outset. lreaanem with ICI 182780 was
`continued until cancer progression occurred. Patients were seen
`every 3-7 days during the first month to monitor local and
`systemic drug tolerability and to collect blood samples for
`pharmacokinetic studies. Thereafter, review was done monthly to
`evaluate response and to monitor local and systemic drug
`tolerability. Blood samples were tllkcn before treatment and at
`monthly intervals thereafter for measurement of full blood count,
`biochemistry, serum hormones, and lipids. Cancer response was
`evaluated according to UICC criteria. Tu qualify for the "no
`change" category, cancer growth had to stabilise for more than
`sixmonw.•
`
`R~to
`ICJ 182780
`
`Number!")
`
`Response to a specific antloestrogen
`(ICI 182780) In tamoxlfen-reslstant
`breast cancer
`
`( ',Anthony Howell, David DeFriend, John Robertson,
`Roger Blarney, Peter Walton
`
`We treated 19 patients with advanced breast cancer
`resistant to tamoxifen with a new specific antioestrogen
`(ICI 182780) which, in animal studies. has no agonist
`activity. 13 (69%} patients responded (7 had partial
`to monthly
`resPonses and 6 showed no change}
`intramuscular injections of ICI 182780 after progression on
`tamoxlfen. for a median duration of 18 months with
`minimum side effects. Prellmfnary evidence suggests that
`the agent
`is without effects on
`the
`liver or the
`hypothalamic-pituitary axis. ICI 182780 appears to be a
`promising new agent for treatment of advanced and early
`breast cancer.
`Lancet 1995; 345: 29-30
`
`Although half of all patients with advanced breast cancer
`bave cancers which either regress or remain stable when
`ueated with tamoxifen, tumours eventually becom e
`resistant after a median duration of remission of fifteen
`months. Although an antagonist with respect to the
`cancer, tamoxifcn is an oestrogenic agonist with respect to
`bone, liver, and endometrium. One cause of resistance
`may be the cancer reacting to tamoxifen as an agonist or
`that tamoicifen is, in some way, rendered unavailable to
`oestrogen receptors so that endogenous oestradiol is able
`to restimulate cancer growth. To test this hypothesis, we
`treated patients with cancers resistant to tamoxifen with
`(ICI
`182780:
`7a-[9(4,4,5,5,5
`an
`antioestrogen
`pentafluoropentylsulfinyl)nonyl]oestra-1,3,5 ,(I O)-triene-
`3, 1713-cliol) which, in animal studies, has been shown to
`have no agonist activity. i
`ICI 182780 is a steroidal antioestrogen with an
`alkylsulphioyl side chain in the 7o. position. There is
`evidence that the side cb.ain prevents dimerisation of two
`molecules of the oestrogen
`receptor which
`is a
`In contrast,
`prerequ1stte
`for gene
`transcription.~
`tamoxifcn, like oestrogens, causes receptor dimerisation
`and partly initiates gene transcription; which is the basis
`of its partial agonist activity.•
`
`Partial
`
`No change
`
`7 (37)
`
`6 (32)
`
`Progn•ssoon
`
`6 (31)
`
`20-+{PR 19), 18+(NC 8), 17+(A67), 17 (PR24)
`12 (A 74). 8 (A20), 3 (A77)
`23+(NC8), 18•(A74), 1~(A71), 16+(NC 48),
`16+(A23), 9 ( NC 34)
`All pauems progressed on <8 weeks. Pr.,.,ious
`treatment wtth temoxl fen A48, A45, NC 7,
`PR 8. 9. NC12
`letters In brackets Indicate response to tamoxofen when given for advanced disease
`(PR=part1al remission, NC"'no change, PIFprogressove disease) or of gl\len as an
`ad)uvanl therapy (A). Numbers In \Jfackets Indicate duration of treatmen1 with
`tamoxifan.
`Table: Response rate and durations of response t o ICI 182780
`
`MYLAN PHARMS. INC. EXHIBIT 1012 PAGE 1
`
`

`
`...
`
`THEl.ANC&f
`
`All 19 patients were evaluable (table). 13 (69%)
`responded IO treaunem for a median duration of more
`than 18 months. 9 are still responding and continuing
`treatment with IC! 182780 after 16-23 months. Sites of
`response were soft tissue (4), bone (7), and lung (3).
`Responses were seen in 6 of 9 women who had progressed
`whilst receiving tamoxifen for advanced disease and in 7
`of 10 women who had re1;civcd tamoxifen as adjuvant
`therapy. There appeared to be no association between
`duration of treatment with tamoxifen and subsequent
`response to ICI 182780. No serious drug-related adverse
`events occurred; minor adverse events were reported by 2
`patients--transient blood-stained vaginal discharge and a
`subjective feeling of living in a "dream like state" (similar
`to that she had whilst talcing tamoxifen) in one patient,
`and alteration of body odour (noticed by her husband for
`one month), possibly associated with increased hair
`greasiness, in the other. There was no alteration in the
`frequency of night sweats or hot flushes, if already
`present, and none were initiated. None of the patients
`reported vaginal dryness or altered libido on direct
`questioning at each out-patient attendance. ICI 182780
`appeared well tolerated at the site of injection despite the
`relatively large 5 mL volume administered, with only 3
`patients developing bruising or erythema on one occasion
`each. There were no clinically significant changes in full
`blood count or unexpected changes in biochemical tests.
`Our study shows that patients with advanced breast
`cancer respond to a specific antioesttogen after failure of
`treatment with a partial-agonist antioestrogen. There
`appeared to be no cross resistance between ICI 182780
`and tamoxifen in 69% of patients, whereas studies where
`tamoxifen-resistant patients were treated with another
`triphenylethylene antioestrogen, toremifine, have reported
`much higher rates of cross resistance.' The median
`duration of response to ICI 182780 has not yet been
`reached, but is already longer than we might expect from
`other second-line endocrine therapies such as megestrol
`acetate.
`ICI 182780 is thought to act exclusively as an
`antioestrogen via the oestrogen receptor.' Thus response
`to treatment with I CI 182780 suggests that oestrogen
`receptors remain functional and that tamoxifen therapy
`fails because cancer regrowth is produced
`by an
`oestrogenic stimulus. The cancer may acquire
`the
`capacity to respond to the partial agonist activity of
`tamoxifen and/or
`its various metabolites. This
`is
`supported by the ability of tamoxifen
`to stimulate
`proliferation of primary human breast cancer cells grown
`in-vitro,• and also by the occasional clinical findings of
`patients whose cancers respond to withdrawal of
`tamoxifen at the time of treannent failure. 1 Alternatively,
`changes in the intracellular handling of tamoxifen may
`reduce its ability to block oestrogen receptors and allow
`stimulation of cancer growth by endogenous oestrogens.
`This might occur as a result of cancer cells acquiring the
`ability
`to
`inactivate
`tamoxifen by
`intracellular
`degradation, intracellular sequestration to proteins other
`than oestrogen receptors, or by increased drug exclusion
`from the cell.•·• Our data do not distinguish between these
`resistance mechanisms.
`Preliminary data (not shown) from this study show an
`initial rise in serum gonadotropin during the first three
`months of treatment with ICI 182780 (probably as a
`result of cessation of tamoxifen therapy) but no further
`changes thereafter. In view of the lack of initiation or
`
`alteration of hot flushes and hot sweats seen in the study,
`these data suggest that, as was predicted from anin1al
`studies,' ICI 182780 may be without effect on the
`hypothalamus and pituitary gland. ICI 182780 may also
`be peripherally selective with respect to the liver since no
`significant effects on sex-hormone-binding globulin and
`lipid have been seen in the present study. In primates and
`in shon-term studies jn women,10 ICI 182780 inhibited
`endometrial proliferation at similar serum concentrations
`to those seen in this study. H a similar inhibitory effect of
`ICI 182780 were shown in longer-term studies, this
`would be a further therapeutic advantage of the specific
`antioestrogen, since tamoxifen is known to be associated
`with proliferation and endometrial cancer.•
`Our study suggests that ICI 182780 may improve the
`rate and duration of response when used as a first-line
`treatment for advanced breast cancer, since it has no
`demonstrable agonist activity. Furthermore, the lack of
`toxicity or effect on serum lipids identify ICI 182780 as a
`candidate agent with which to investigate the potential
`benefits of specific antioestrogens in the adjuvant setting.
`
`We thank Sisters Julie Kiernan and Nicki Seon for services in the clinical
`srudy; Mr E Hoare, Mr I MT Howat, and Mr R J Williams for rcferrina
`patients; Jean Miller for help with preparing the manuscript; and Zenec.a
`Phannaceuticals for financial support.
`
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`antioestrogen !Cl 164,384 appears to be mediated by impaittd receptor
`dimerization. Proc Nazi AUid Sci USA 1990; 87: 6883-87.
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`antioestrogen binding site activity. Cancer R~s 1992; 52• 4106-12.
`10 Thomas EJ, Walcon PL, Thomas NM, Do~ett M. The effects ofIC!
`182780, a pure antiocstrogen, on the hypothalamic-pituitary-gonada!(cid:173)
`axis and on cndomeirial proliferation in premenopausal women.
`Hum Reprod 1994; 9: (in press).
`
`CRC Department of Medical Oncology, University of Manchester,
`Christle Hospital, Manchester M20 9BX, UK (A Howell f RCP);
`Department of Surgery, University Hospital of South Manchester,
`Manchester, UK (0 J DeFriend FRCS); Department of Surgery,
`City Hospital, Nottingham (Prof R W Blarney Files,
`J F Robertson FRcs); and Zeneca Pharmaceutlcais, Macclesfield,
`Cheshire, UK (P Walton PnD)
`Correspondence to: Dr Anthony Howell
`
`MYLAN PHARMS. INC. EXHIBIT 1012 PAGE 2