161 SP I Phase 1 study of different sequences of MTA
`
`(LY231514) In combination with clsplatln In patients
`with solid tumours
`R. Th!\Qtm;mn 1•2 , H. Oepenbrock1·2 , H. Dumez', U Ohnmacht3, J. Blatter3,
`A. T. van Oosterom 1 , A.A. Hanauske 1 ·2 • 'UZ Gesthuisberg Le wen, Belgium;
`2 TUM Munich, Ge11T1Bny; 3 Ell Lilly Gennany; Bad Homburg, GefT11Bl1Y
`
`Introduction: The novel multi-targeted anbfolale (MTA) 1s a potent lnh1blt0< of
`thymldylate synthase, dihydrofolale redtx:tase and glycinamlde ribonucieotlde
`formyltransferase. MT A has shown encouraging antitumour aCIJVJly in vitro
`and In vivo and In single-agent phase I and phase II trials. The purpose
`of this study was to determine the maxJmum tolerated dose (MTD) and
`dos&-limlUng toxlcitles (DLT). pharmacoklnetics and amltumour aCIJVJty of MTA
`In combination with cisplatin (C).
`Patients and Methods: Patients (pts) with solid tumours with no proven
`treatment options were entered Into this tnal. In cohort 1, both drugs were
`admln'8tered on day 1; In oohort 2 MTA on day 1 and C on day 2. Treatment
`was repeated f!Very 3 weeks. In cohort 1 the starting dose was MTA 300
`mg/m2 and C 60 mglm2; In cohort 2 the startlng dose was MTA 500 mglm2
`and c 75 mglm2.
`Reaulte: In cohort 1, 40 pts were evaluable f0< toxicity. The MTD was
`reached at MTA 600 mg/m2 and C 100 mgtm2, WTtt1 thrombocytopenla and
`febrile neutropenia as DLTs. In cohort 2, 11 pis were evaluable for loXldty. In
`this schedule, thrombocytopenla grade 4 occurred in 1 pl al MTA 500 mg/m2
`and C 75 mglm2, and in 1 pt at MTA 600 mg/m2 and C 75 mglm2. Grade 4
`Infection was observed In 1 pt at each dose level, rash grade 3 In 1 pt at each
`dose lfNel. Grade 4 diarrhoea occurred In 1 pl al MTA 500 mglm2 and C 75
`mglm2, and grade 4 mucoslbs In 1 pt at MT A 600 mglm2 and C 75 mglm2. Al
`both dose levels 1 pt died due to therapy-related toxlcttles. Pharmacoklnetlc
`parameters of MTA were not Influenced by C administration and hydration
`Several responses were observed: In cohort 1, 11 pts, including 4 of 7 pis wrth
`mesothelloma: In cohort 2, 3 pts had minimal responses, and remain on study
`Concius.lon: The MTD of this combiMtion Is MTA 600 mgtm2 and C 100
`mglm2, If administered on day 1, with mye!osuppresslon as tile DLT. The day 1
`schedule was dlnically superior. This combination of MTA and cisplatin sl1ows
`encouraglng antitumour actMty.
`
`I s19p I Reduction of mlcrometastatlc tumor load by
`
`monoclonal antibody therapy: Influence of tumor
`antigen heterogeneity
`S. Braun. F. Hepp, W. Jann!, H.L Sommer, K. Pante! I. FraufJflklinik and
`Institute fvr Immunology. Univ. of Munich, Germany
`lntroductlon; Disseminated cancer cells In bone marrow (BM), are regarded
`as suitable targets for adiuvant lmmunotllerapy, because they are easily
`accessible for both lmmunoglobullna and Immune effector cells. Thls pllot
`study was designed to examine the Influence of Iha lndMdual antigen profile
`of such target cells on the potentlal treatment efficacy
`Methods: lndlvldual breast cancer cells In BM were Identified by the antl(cid:173)
`cytokeratin (CK) monoclonal antibody (mAb) A45-B/B3. To evaluate the antigen
`profile of these cells, we applied a quantitatlve doobl&-mBrker assay and typed
`10< four potential therapeulic targets ( 17 -1 A, MUC-1, Lew\s v, c-erbB-2). In a
`pllot study, five breast cancer patients wtth e CK• BM finding were trooted with
`a single dose of 500 mg Panorex", and were morntored for the elimination of
`17·1A co-expressing CK• cancer cells after 5-7 days.
`Results: CK• cells from 20 breast cancer patients typed In this study
`f0< the expression of the four antigenic targeta were found to represent a
`heterogeneous cellular population. The mean percentage of double-positive
`cells per total no. of CK• cells was 44% (0-75%) for 17·1A, 41% (o-67%)
`for MUC-1, 34% (0-59%) for Lewisv. and 42% (0-92%) for c-erbB-2. This
`was contrasteo by a mean count of 70% (34-100%) coek1all•tcK· cells If all
`four antigens were targeted simultaneously by the antibody-cocktail consisting
`of all four antigens. Thus, we considered tumor antigen heterogeneity a
`potential cause f0<incomplete tumor cell elimination by monovalent therapeutic
`approaches. This assumption was supported by our pilot study. Prior to
`treatment patients presented with 17, 67, 97, 115, 524 CK• cells per 1()11
`BM cells, and a mean percentage of 61% (range: 41-100%) C017·1A•/CK•
`double-positive cells per total no. of CK• cells. In all five pabents we assessed
`a remarkable reduction In both the no. of CK• cells (17-+5, 67->11, 97-.2,
`115-20. 524-+26) per 106 BM cells, and the percentage of 17·1A•tcK• cells
`(41%-+0%. 48%-.0%, 54%-> 10%, 60%-+ 15%. 100%-+17%) pertolal no. of
`CK• cells eher the administration of Panorex".
`Conclusion: Genomic lnstab1llty of carcinoma cells resuttmg m Iha reported
`pciycional phenotype of the disseminated tumor cell population may hmtt
`the efficacy of monovalent 1mmunogenetlc treatment strategies. Individual
`lmmunocytochemlcal mon1torfng of therapeutic tumor cell elimlnation Is feasible
`and suggest that Panorex" might be able to eliminate 17 -1 A+ breast cancer
`cells.
`
`Novel therapeutics and pharmacology
`I e20P I A phase I and pharmacoklnetlc (PK) study of the
`
`multltargetad antlfolate (MTA, LY231514) with follc acid
`(FA)
`L Hammond', M. Villalona-Calero'. S.G. Ed<han:t1 1 • L. Slu 1 , M. Hidalgo'.
`D. Thomton2, J. Waillng2, S. Baker, C. Cottman 1 , D. Von Hoff'. E. Rowinsky'.
`1 Cancer Theraw and Rosearch Center, San Antonio. TX. and 2 Eli Ulfy,
`Indianapolis, IN, USA
`
`lntroductlon: MTA, a new antJfolate that inhibits thymldy1ate synthasa, dl(cid:173)
`hydrofolate reductase, and glydnamide nbonucleotlde lormyl translerase.
`demonstrated notable broad ant!rumour actMty when Infused 10 min !. v. ev(cid:173)
`ery 21 clays. Myelosuppresslon predudad dose escala!lon above 500-600
`mglm2. As prectlnlcal evaluabons indicate that FA supplementation increases
`the therapeutic Index of MT A, this study was Initiated to determine If FA supple(cid:173)
`mentation permits significant close-escalation above the recommended phase
`II dose of MTA alone. Vrtamln metabol!les were measured to determine their
`value as potential prognostic mari<ers with this combination.
`Metflodll: So far, 33 mlnlmelly- and hsavily-pretreated pis received 90
`courses of FA (5 mg/day) lor 5 days startlng 2 days before MTA at 600, 700,
`800 925 mgim2. Vitamin metaboUtes were evaluated during cycles 1 and 2 as
`potential determinants of principal toxicities encl eflocts.
`Rawltll: Prtnclpal drug-related toxidUes Include neutropenla, anaemia and
`thrombocytopen1e, which were more severe In heavily-pretraated pts. Other
`toxicities (grade (G) 1-2) include rash, somnolence, fatigue, leg oedema,
`and a decrease In creabnlne dearance (CrCI). Severa toxldtles In 2 pis, 1
`who had taken a non steroidal anti-Inflammatory agent and 1 with severe
`hypoalbum1naemla, resolved after administration of klucovorin and thymldine.
`Preliminary vitarmn metabolites In 26 pts reveal: 2 and 3 of 11 pts with
`homocyste!ne 2: 10 had G4 thrombocytopenla and neutropenla, respectively;
`1 and 2 of 15 pis with homocystelne < 10 had G4 thrombocytopenla and
`neulroperna. respectively: 1 and 2 of 9 pts with elevated cystalhlonlne levels
`(cystathlonlne upper limit of normal 342 nMIL) had G2 somnolence and G1-2
`fatigue, respectlvely; 1 and 10 of 16 pts with normal cystalhionlne levels
`tiad G2 somnolence and G1-2 fatigue. respecttvely; 1 of 4 pts with elevated
`methylmalonlc acid (mathylmalonic acid upper llmll of normal 271 nM/L) had
`G2 fatigue while 12 of 22 pts with nonnaJ levels had G1-2 leUgue. 7 of 15
`pis with elevated homocysteine, cystathionine, or methyfmalonlc acid klvels
`tlad a significant decrease In CrCI. Based on lnfonnation from the$e 15 pta,
`addition of FA may reduce the usefulness of vitamin metabolites as predictors
`of toxicity.
`Concluak>ns: FA supplementation appears to pe!Tl11t MTA dose escalation
`by ameliorating toXJCity. Heavily· and mlnlmally-prelreated pts tolerate MTA at
`700 and 925 mgim2 and accrual contlnuas at 600 and 925 mgim2, respecilvely.
`
`Phannacoklnetlc (PK) and phannecodynamlc (PD)
`analysis of a phas~ study of Texof'(T), Carboplatln
`(C) with P-glycoproteln (P-gp) modulator PSC-833
`(PSC)
`M. Michael, A. Oza, M.J. Egonn, A. Patnruk, P. Flrby, LL Siu, M. Utchman,
`M.J. Moore. Princess Margaret Hosp/IBJ, University of Toronto, Toronto,
`Ontario, MSG 2M9, Cafl/'lda, University of Maryland, MD, Novartis
`Phal1'00C6utlcsls, NJ, USA
`
`Introduction: Cyctosporine analogues such as PSC reduce the clearance of
`PilP substrates (I.e. 1) and their maximum tolerated dose (MTD). This trial
`was dealgned to assess the MTD. PK ancl PD ol T and C with oral PSC In
`pallenta (pts) with refractory solid tumors.
`Methods: All patients were planned to receive a fixed dose of PSC (5
`mg/kg, p.a. 6 hr x 12, days 0-3) and T (baseline dose 54 mglm2, 13.5mglm2
`lncraments, 3 hr lnfUSlon, day 1) and C (target AUC 6-9 mg/mLmln, day 1).
`3-weekty. C AUCs derived trom a limited sampling model, and T PK parameters
`fitted to e 2-<::0mpartment model.
`Results: 58 pis entered Into 7 dose levels (DL), 41 had previous chemother(cid:173)
`apy, (34, 1 prior regimen). PK for DL 1-7 summarized below.
`
`DL
`
`2. 6, 7
`3,5
`4
`
`T
`Dose
`mg1rn2
`54
`675
`81
`945
`
`TBl"IJ"t
`C-AUC
`rr¢n.hr
`6
`6, 7.5, 9
`6
`6
`
`#
`pts
`
`3
`28
`23
`4
`
`C-AUC
`mwmt.hr
`
`T·AUC
`µ"1.hr
`
`T-CI
`LJ!u/rn2
`
`5.4
`6.3. 7 15. 7.55
`52
`6.7
`
`4.8
`5.94
`7.-W
`12.1
`
`13.19
`13.31
`13.47
`9.14
`
`llme
`(hr)
`T > 0.05µ"1
`20.46
`26.52
`28.0
`37.32
`
`No PK lnteractloo was noted between C & Tor PSC & C. The T and c doses
`showed a linear correlabon with% change nadir ANC (R2 = 0.95 respectively).
`their AUCs correlated less well with % change nadir ANC or platelets. PSC
`prolonged the time T > 0.05 µM at T 94.5 mg1m2 > than T 175 mg.tm2 alone.
`DL-2 and DL-5 were the MTOs of prior treated & chernonelve pis respectively.
`Concluelone: PSC by redl.ICing Ts clearance, prolongs the IIme T > 0.05
`1<M, wtlhout Influence on C PK. PSC reduced the MTD of the T & Ccomblnation.
`
`Annals of OncoioRY· Supplement 4 10 Volume 9, 1998
`
`(I 1998 Kluwer Acndamc Publisher>, Printed in The Netherlands
`
`129
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