sis Monday 15 September 1997
`
`flesuits:inapriorstuthrwherepatlerrtereceivedRCTaslriarrnA
`but without A. 12/14 (86%) patient developed grade 34 mucoeitis and
`all patients developed grade 2 acute xeroetomle (Buntzel. Blood 80 (10)
`suppi1).inthieeti.idy nopstlenta liiarrns A. Borcdeveloped gradeale
`muooeitie and only 1 patient in am 3 developed grade 2 acute xeroetornla.
`i-taemetologicai toxicity was rnirllmd.
`conclusion: A. stostantialy reduces the toiucitiss associated with RCT
`tor HAN cancer and allows the administration oi intensive treatmere. Ad-
`ditlonelexpenericeisrequiredtoesseesttieberielitsolaeplltdceeot
`A.
`
`62
`
`POSTER
`
`Functional Folate status as a Prognostic indicator or Toxicity
`in clinical Trials oi‘ the Iilultitargeied Antitolate LY231514
`gem.-i._zm‘. Robert H. Allen’. Donald E. Thomton'. Patricia
`A. Thiem‘. '5» Lilly and co. Indianapolis W.; ‘University at Colorado
`Health sciences center. Dept. olsiochemlslm Biophysics and Genetics,
`Denver. Ca USA
`Stories in aniriiai models and humans have revealed that lohte nutritional
`status may be correlated with toxicity and antitumor activity ot mtilolatee.
`Supplemental tctic acid may play a role it protecting against the toxicities
`associated with entitolate (tugs.
`LY23t514 is a rnuiti-targeted antilclate that hhibits Thyrnidylale eynthsse,
`Dirrycvotoiate reductaee and Glycinamide rbonucteotide iorrnyitrarieleraae.
`Functional lolete status, based on serum concentraione ct hcrnocystaine
`(HCYS). cystathiorie (CYSTAT). and melhyimaicnic acid (MMA), was as-
`sessed in 118 patients Dlrildliathg in Phase 2 studies ct LY231514.
`sampieeweretelren prlorto Initlatlcnol therapy andprlortothestartot
`each cyde. CTC toxicity scores (hematologic and non-hematologic) were
`assigned at the and at each cycle at therapy. Fotate deficiency (elevated
`HOYS and CYSTAT and norrnai MMA) was observed it 11 patients. Elu-it
`otthetoiate deiicientptshad CTcgrade aeretoiricltyandsottheioiate
`deficient pts had only minor toxicity. Elfllt oi the 11 pte experienced grade
`4 neutropenia and 5 ot the 11 pts experienced grade 4 thrornbocytopenla.
`From this data, we would concside that functional tolete status may be
`a reliable prognostic Indicator cl hematoiogc toxicity in pro treated with
`W231 514. Further investigation h warranted to support this conclusion.
`
`33
`
`POSTER
`
`Prevention ot anti-androgen Induced gynecomsstia in
`prostate cancer: Clinical experience In 85 patients treated
`with 12GY single dose electron irradiation
`
`gjmgg, B.F. schmld, M. Camera. Department of Flsdoerrcology
`Kamerlnerihcsnllal $10398". Germany
`
`Purpose: The most common side etlects of endocrine treaenent in prostate
`cancer are breast tendemeae and gynecornaetia. Pre-irradiation prevents
`gynecomastia in males who receive tsrrinizlng lionnones. Recommended
`doses rangetrem 9to23. 758v inonetothree tractiona using ii-raysor
`Co-omuttieiekriownrbetattiestliclencyandpoesioieletssequeiaot
`single dose electron therapy and the role at pre-irradiation in androgen
`withdrawal.
`Methods: From 1January to 31Dezember 1990 2l7pta with prostate
`cancer received pre-irradiation at the breast In our Department. Median
`age: 75 yrs. Dose: may or taey. Field size: 6 cm. All patients were treated
`with single dose 4 May or 8 my electrons. in autumn 1996 a qiestionnaire
`was rnaiied to the surviving patients to evaluate etiiciency and long-terrn
`tolerance.
`Results: 85pts. (39.2%) underwent evaluation. 79pie. (38.4%) had died
`and sapts. (24.4%) wereioet totoiiow-up. 11/85 showed a rriild gynecorrias-
`tia (12.9%). No rnammalgie occurred. Erytherru was reported by 13I85pts.
`(15.3%). in alsspts. rriild pigmentation persisted (9.4%).
`conctuelone:(1) Slngledosaeiearontreetrnentwith 12Gy Isesetlective
`as lractionated schedules to prevent gynecomaetls and rnarnrnalgia.
`2) Side eiiects are mild and wel tolerated
`(3) The single dose treatrnsrit is easier accepted by elderly patients. A
`major protrlem ot fractionated therapy. namely withdrawal of the patient
`daring therapy. is avoided.
`
`34
`
`Proffcrcd Papers
`
`POSTER
`
`Etficacy and safety at oral granlsctron vs N ondansetron in
`prevention of moderately ernetogenic
`chemotherapy-induced nausea and vomiting
`
`EA. Pggg‘. s.r>. Chawla', P.K. Kaywin’, J. San®ad'I‘, K. Yocorn’.
`A. Preston‘. c. Friedman‘. ‘Mayo Clinic. Jadrsonvlllo. FL.‘ ‘UCLA School
`orltledicine. Santa Monica. CA; "0ricology~I-ierrrarology GrvUP°'3°W'
`Florida. Miami. FL;‘ramonooIo9M Btausun. rx: Srruthlaino
`Beecham Pharrrraautlmle, Collegevllle, PA. USA
`
`Purpose: A multicenter. double-blind. parallel-group study compared the
`prophylactic efficacy and salary oi 2-mg oral grariisetmn (G) V3
`‘V
`ondaneetron (0) given once before cycicphosphamide- or carooplatrn-based
`chemotherapy.
`Methods: Chemo-naive pts(&86F.219Ml) recelvedtwoi-m0GNbi913(i|
`-5-t2)orpiaceboatoominpre-cherrto.enda15-rririiriluetonol0(n-543)
`or placebo at 30 mm pre-chemo Dexamethaeone or rriethylprednlsolono
`were permitted. Primary endpoint was total control (no emeals. nausea. or
`use of antiemetic rescue medication} at 24 and 48 h after start
`chemo.
`Secondary endpoints were Incidence of emesis and nausea (+ Incidence
`oterrtiemetic rescua)at24and4Bh. Satetywesassessod UP 30 1168?!
`poetohemo
`Results: Conparahie etlicacy was shown tor al endpoints (P < 0-0001):
`
` as Hours so i-loure
`OraIG
`we
`omit:
`we
`59.4
`5&0
`40 7
`43-8
`71.0
`72 e
`5s.7
`se.1
`one
`so 4
`47 s
`«.4
`
`‘kill Control (90
`No Ernesie (as)
`Ne Nausea (as)
`
`Adverse experiences were similar in both woups. IX09Pi '0' <'53i"°°3
`(5.4% G- vs 9.6% 0-treated pie: p =oo11) and abnomial vision (0.6% G-vs
`4.295 0-treated P18; P < o.oo1).
`conclusion: (3 tablets provided corrparaiiie etllcacy to IV 0 in chemo-
`nalve pts receiving moderately einetegenic chemotherapy. B00’! 809013
`were well tolerated. (stpported by smIthKiine Beecham)
`
`as
`
`POSTER
`
`Cardiac function late after anthrscycline (AX) therapy tor
`pediatric cancer. A rnuiticentric study ot the gemtan society
`or pediatric oncology and hematology (GPOI-I)
`§. Bieia_c_l;. K. Kargue. G. Andthger. J. Beck. G. l-tausdort. Project-Group
`Heano!iheLaieE!IectsiM:vldrrgGIoupoIdieGPOH.Gennarry
`
`Purpose: To detine the Incidence or cardiac abncrmailues among pre-
`viously esyrnptonntic patients lets alter AX therapy lor pedetric cancer
`given aocordhg to GPOH protocols. To evaluate follow-up techniques in a
`muiucentric setting.
`Ilethode: Multicentrlc evaluation at relapse-tree survivors who had no
`congerital heart-disease. no medastinal irradiation. and did not receive car-
`d flOfl byqueetionaire. physical exam. ECG. and echocardiograrn
`(
`)-
`Results: 129 eligible patients vlic had been 0.5 :t 5.5 years ct age at
`diagnosis ct malignancy were evaluated 7.8 A 3.2 alter receiving a mean
`ournuleuve AX dose 250 a 126 rnglm’ (all < 500). while no patient had
`cinicai signs suggestive ot congestive heart failure, the iracilonal shortening
`rate FS measured by ECHO was eubnormal (<2B%) in 14 (10.9%). Higher
`titan average cumulative Ax dose (p - 0.001) and longer toilaal-up (p <
`0.06). to a lesser extent higher indivlmal AX dose (p < 0.1) and younger
`age at treatment (p < 0.1). but not patient sex. were associated with
`lower rs values. Various other echocardlographlc or electrocardiographlc
`measurements (hot. corrected OT-interval) did not show similarly strong
`correiatioris to known rtelt tactore tor Ax cardiornyopattiy.
`Conclusion: Subciinicai cardiac damage is treouent lalie alter presumably
`sale cumulative Ax dceee. even when patents are asymptomatic. in g
`rnuiticentrlc setting. more sophisticated measures oi cardiac luriction were
`not swericr to es detemiination by ECHO.
`
`Lilly Ex. 2063
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2063
`Sandoz v. Lilly IPR2016-00318
`
`flesuits:inapriorstuthrwherepatlerrtereceivedRCTaslriarrnA
`but without A. 12/14 (86%) patient developed grade 34 mucoeitis and
`all patients developed grade 2 acute xeroetomle (Buntzel. Blood 80 (10)
`suppi1).inthieeti.idy nopstlenta liiarrns A. Borcdeveloped gradeale
`muooeitie and only 1 patient in am 3 developed grade 2 acute xeroetornla.
`i-taemetologicai toxicity was rnirllmd.
`conclusion: A. stostantialy reduces the toiucitiss associated with RCT
`tor HAN cancer and allows the administration oi intensive treatmere. Ad-
`ditlonelexpenericeisrequiredtoesseesttieberielitsolaeplltdceeot
`A.
`
`62
`
`POSTER
`
`Functional Folate status as a Prognostic indicator or Toxicity
`in clinical Trials oi‘ the Iilultitargeied Antitolate LY231514
`gem.-i._zm‘. Robert H. Allen’. Donald E. Thomton'. Patricia
`A. Thiem‘. '5» Lilly and co. Indianapolis W.; ‘University at Colorado
`Health sciences center. Dept. olsiochemlslm Biophysics and Genetics,
`Denver. Ca USA
`Stories in aniriiai models and humans have revealed that lohte nutritional
`status may be correlated with toxicity and antitumor activity ot mtilolatee.
`Supplemental tctic acid may play a role it protecting against the toxicities
`associated with entitolate (tugs.
`LY23t514 is a rnuiti-targeted antilclate that hhibits Thyrnidylale eynthsse,
`Dirrycvotoiate reductaee and Glycinamide rbonucteotide iorrnyitrarieleraae.
`Functional lolete status, based on serum concentraione ct hcrnocystaine
`(HCYS). cystathiorie (CYSTAT). and melhyimaicnic acid (MMA), was as-
`sessed in 118 patients Dlrildliathg in Phase 2 studies ct LY231514.
`sampieeweretelren prlorto Initlatlcnol therapy andprlortothestartot
`each cyde. CTC toxicity scores (hematologic and non-hematologic) were
`assigned at the and at each cycle at therapy. Fotate deficiency (elevated
`HOYS and CYSTAT and norrnai MMA) was observed it 11 patients. Elu-it
`otthetoiate deiicientptshad CTcgrade aeretoiricltyandsottheioiate
`deficient pts had only minor toxicity. Elfllt oi the 11 pte experienced grade
`4 neutropenia and 5 ot the 11 pts experienced grade 4 thrornbocytopenla.
`From this data, we would concside that functional tolete status may be
`a reliable prognostic Indicator cl hematoiogc toxicity in pro treated with
`W231 514. Further investigation h warranted to support this conclusion.
`
`33
`
`POSTER
`
`Prevention ot anti-androgen Induced gynecomsstia in
`prostate cancer: Clinical experience In 85 patients treated
`with 12GY single dose electron irradiation
`
`gjmgg, B.F. schmld, M. Camera. Department of Flsdoerrcology
`Kamerlnerihcsnllal $10398". Germany
`
`Purpose: The most common side etlects of endocrine treaenent in prostate
`cancer are breast tendemeae and gynecornaetia. Pre-irradiation prevents
`gynecomastia in males who receive tsrrinizlng lionnones. Recommended
`doses rangetrem 9to23. 758v inonetothree tractiona using ii-raysor
`Co-omuttieiekriownrbetattiestliclencyandpoesioieletssequeiaot
`single dose electron therapy and the role at pre-irradiation in androgen
`withdrawal.
`Methods: From 1January to 31Dezember 1990 2l7pta with prostate
`cancer received pre-irradiation at the breast In our Department. Median
`age: 75 yrs. Dose: may or taey. Field size: 6 cm. All patients were treated
`with single dose 4 May or 8 my electrons. in autumn 1996 a qiestionnaire
`was rnaiied to the surviving patients to evaluate etiiciency and long-terrn
`tolerance.
`Results: 85pts. (39.2%) underwent evaluation. 79pie. (38.4%) had died
`and sapts. (24.4%) wereioet totoiiow-up. 11/85 showed a rriild gynecorrias-
`tia (12.9%). No rnammalgie occurred. Erytherru was reported by 13I85pts.
`(15.3%). in alsspts. rriild pigmentation persisted (9.4%).
`conctuelone:(1) Slngledosaeiearontreetrnentwith 12Gy Isesetlective
`as lractionated schedules to prevent gynecomaetls and rnarnrnalgia.
`2) Side eiiects are mild and wel tolerated
`(3) The single dose treatrnsrit is easier accepted by elderly patients. A
`major protrlem ot fractionated therapy. namely withdrawal of the patient
`daring therapy. is avoided.
`
`34
`
`Proffcrcd Papers
`
`POSTER
`
`Etficacy and safety at oral granlsctron vs N ondansetron in
`prevention of moderately ernetogenic
`chemotherapy-induced nausea and vomiting
`
`EA. Pggg‘. s.r>. Chawla', P.K. Kaywin’, J. San®ad'I‘, K. Yocorn’.
`A. Preston‘. c. Friedman‘. ‘Mayo Clinic. Jadrsonvlllo. FL.‘ ‘UCLA School
`orltledicine. Santa Monica. CA; "0ricology~I-ierrrarology GrvUP°'3°W'
`Florida. Miami. FL;‘ramonooIo9M Btausun. rx: Srruthlaino
`Beecham Pharrrraautlmle, Collegevllle, PA. USA
`
`Purpose: A multicenter. double-blind. parallel-group study compared the
`prophylactic efficacy and salary oi 2-mg oral grariisetmn (G) V3
`‘V
`ondaneetron (0) given once before cycicphosphamide- or carooplatrn-based
`chemotherapy.
`Methods: Chemo-naive pts(&86F.219Ml) recelvedtwoi-m0GNbi913(i|
`-5-t2)orpiaceboatoominpre-cherrto.enda15-rririiriluetonol0(n-543)
`or placebo at 30 mm pre-chemo Dexamethaeone or rriethylprednlsolono
`were permitted. Primary endpoint was total control (no emeals. nausea. or
`use of antiemetic rescue medication} at 24 and 48 h after start
`chemo.
`Secondary endpoints were Incidence of emesis and nausea (+ Incidence
`oterrtiemetic rescua)at24and4Bh. Satetywesassessod UP 30 1168?!
`poetohemo
`Results: Conparahie etlicacy was shown tor al endpoints (P < 0-0001):
`
` as Hours so i-loure
`OraIG
`we
`omit:
`we
`59.4
`5&0
`40 7
`43-8
`71.0
`72 e
`5s.7
`se.1
`one
`so 4
`47 s
`«.4
`
`‘kill Control (90
`No Ernesie (as)
`Ne Nausea (as)
`
`Adverse experiences were similar in both woups. IX09Pi '0' <'53i"°°3
`(5.4% G- vs 9.6% 0-treated pie: p =oo11) and abnomial vision (0.6% G-vs
`4.295 0-treated P18; P < o.oo1).
`conclusion: (3 tablets provided corrparaiiie etllcacy to IV 0 in chemo-
`nalve pts receiving moderately einetegenic chemotherapy. B00’! 809013
`were well tolerated. (stpported by smIthKiine Beecham)
`
`as
`
`POSTER
`
`Cardiac function late after anthrscycline (AX) therapy tor
`pediatric cancer. A rnuiticentric study ot the gemtan society
`or pediatric oncology and hematology (GPOI-I)
`§. Bieia_c_l;. K. Kargue. G. Andthger. J. Beck. G. l-tausdort. Project-Group
`Heano!iheLaieE!IectsiM:vldrrgGIoupoIdieGPOH.Gennarry
`
`Purpose: To detine the Incidence or cardiac abncrmailues among pre-
`viously esyrnptonntic patients lets alter AX therapy lor pedetric cancer
`given aocordhg to GPOH protocols. To evaluate follow-up techniques in a
`muiucentric setting.
`Ilethode: Multicentrlc evaluation at relapse-tree survivors who had no
`congerital heart-disease. no medastinal irradiation. and did not receive car-
`d flOfl byqueetionaire. physical exam. ECG. and echocardiograrn
`(
`)-
`Results: 129 eligible patients vlic had been 0.5 :t 5.5 years ct age at
`diagnosis ct malignancy were evaluated 7.8 A 3.2 alter receiving a mean
`ournuleuve AX dose 250 a 126 rnglm’ (all < 500). while no patient had
`cinicai signs suggestive ot congestive heart failure, the iracilonal shortening
`rate FS measured by ECHO was eubnormal (<2B%) in 14 (10.9%). Higher
`titan average cumulative Ax dose (p - 0.001) and longer toilaal-up (p <
`0.06). to a lesser extent higher indivlmal AX dose (p < 0.1) and younger
`age at treatment (p < 0.1). but not patient sex. were associated with
`lower rs values. Various other echocardlographlc or electrocardiographlc
`measurements (hot. corrected OT-interval) did not show similarly strong
`correiatioris to known rtelt tactore tor Ax cardiornyopattiy.
`Conclusion: Subciinicai cardiac damage is treouent lalie alter presumably
`sale cumulative Ax dceee. even when patents are asymptomatic. in g
`rnuiticentrlc setting. more sophisticated measures oi cardiac luriction were
`not swericr to es detemiination by ECHO.
`
`Lilly Ex. 2063
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2063
`Sandoz v. Lilly IPR2016-00318
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