UIIW. Ilf Miflll.
`Bin-Medical
`
`Lilly Ex. 2045
`Sandoz v. Lilly IPR2016-00318
`
`

`
`l 700
`
`‘E50
`
`CLINICAL PHARMACOLOGY
`
`*651
`
`Proceedings of ASCO Volume 18 i999 F
`
`f
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`Bisptalin Dose-Response Relationship. Resistance Mechanisms ll. optimum
`Resistance Modulating strategies in Ovarian (on) Us Nun-Small cell lung
`Cancer (NSCLG). David J. Stewart. Simone Dahrouge. Rernco Donlrer.
`Ottawa Regional Cancer Centre. Ottawa, Ontario. Canada.
`Purpose: To compare cisplatin (Cpl dose-response relationships tDRRsl in
`DC vs NSCLC & to use Dftits to surmise resistance mechanisms and
`optimum resistance modulating strategies. Baci_rground: We postulated
`excess resistance factor l'active resistance‘) would give a shoulder on a
`dose-response curve (DRE)
`8:
`factor deficiency (‘passive resistance‘.
`including resistance due to slow cell division‘: would give a terminal plateau
`lstewart et al.
`invest New Drugs 14:115. 1996). Method: We used
`published response rates in oc & NSCLC to estimate meantla tumor cell kill
`with varying Cp doses. assuming complete, partial, & minor responses.
`stable disease & failures represent >9E‘i‘if=. 83%. 50%. 13% and 0% mean
`cell ltills, respectively. we used studies with single agent (Zn or comparing 2
`Co doses or comparing another drug alone to that drug-t Cp. Results were
`corrected for estimatedis cell kill by any concurrent drug. We plotted log%
`cell survival vs Cp doselcourse & dose intensity. DRCs were extrapolated
`leftvvards to the ‘Op dose=0' line. Results: The DC DRE appeared to be
`steep 8. to cross the 'Cp dose=0‘ line near the 100% cell survival point. For
`NSCLC. the DRG appeared to be flat over the entire Cp dose range studied
`(50—20{l mglmzlcoursel & to cross the ‘Cp dose=0' line below the 100%
`cell survival point. Conclusions: If our assumptions are valid. DRCs suggest
`minimal Cp resistance or low dose active resistance in OS. but passive
`resistance in NSCLC. Active resistance is analogous to competitive inhibi-
`tion of drug. 8: may be inducible with drug exposure. Hence. the optimum
`initial strategy in DC may be to use Co at highest tolerable doses by rapid
`infusion (to achieve high peak ievelsl. Resistance modulating agents
`should be explored for responding patients who fail to be cured. For the
`passive resistance in NSCLC, one should define lowest closes giving
`‘plateau-level‘ response rates. 8. should then use this dose at frequent
`intervals 8: for as many courses as tolerable. along with drugs with other
`mechanisms of action,
`
`Preclinical Synergy of oxaliplatin (Olin). Topoisomerase l-Inhibitor (tupotacany
`and 5-Fluorouracil in sensitive and 5-Fluorouracli Resistant HT29 Bell l.iI'tp_
`M. Taron. C. Plasencia, A. dead. M. Guillot, C. Martin. A. Eernadas.
`.q_
`Rosell. Medical Oncology service and Laboratory of Molecular Biology
`Hospital Germans Trias i Pujof. Cfcanyet sin. O8916~Badalona (Barce,
`Iona). Spain.
`Topotecan (TPT) and Oxaliplatin (OXA) have demonstrated chemotherapeu.
`tic activity in a wide variety of tumors. In our study we have evaluated the
`potential synergism of TPT. OXA and 5-Fluorouracil (SFU) combination in
`variants of sensitive and 5FU resistant human colorectal tumor derived Cell
`lines lHT29lHT295FUFl). The HT295FUl-'t was obtained in our mt"!
`laboratory after administration of increasing concentrations of 5FU until a
`level of Zphll was reached and the doubling times were roughly equivalent to
`those of HT29. The 5i-‘U resistant cell line showed to be 5-fold resistant ya
`5FU and proved to be non resistant to TPT or OXA as compared to the
`parental HT29 cell
`line fl-W29 vs. HT295FUFt: 5FU p < 0.01. mm
`p = 0.25; TPT p = 0,33). Usingthis model, we have analyzed cell toxicity
`in four sequential schedules of administration: OXA —~ TPT. TPT —- OXA
`OXA —- 5FU. 5FU —— OXA. Cell viability was assessed by the l~ll'l'T-test. amt
`isobologrem analysis {Chou and Talalay method) was then performed ya
`determine synergismlantagonism.
`in all schedules drugs were adminis;
`tercd for 24 hours lTPTl5FUl or 4h l0ltA). our results show a highly
`synergistic effect in all schedules, and being also independent from the
`5FU~resistance phenotype. at all Ievelsof fractional survival. (See combina.
`tion Index 3 SD at
`ICSO level summarized below: Cl < 1
`indicates
`synergism. and Cl > 1 antagonism).
`In this assay.
`it has also been
`demonstrated that the addition of OXA in the OXA —> 5FU schedule
`circumvents the 5FU resistant phenotype of HT295FUR. thus showing the
`same degree of sensitivity to 5FU than parental cell line.
`OXA —~ TPT
`TPT H OXA
`OXA -i 5FU
`
`5FU A OXA
`
`0.58 i 0.07 0.40 : 0.04
`0.77 : 0.03 0.78 I 0.07
`HT29
`HT295FUR 0.65 i 0.02 0.55 I 0.007 0.24 : 0.005 0.47 i 0.02_
`
`In conclusion, OXAl'fPT and 0XAl5FU combination have shown a highly
`therapeutic potential
`in sensitive as well as in 5FU resistant human
`colorectal tumor derived cell line. These results may be further exploitedto
`promote new schedules of administration for advanced colorectal cancer
`treatment.
`
`*652
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`‘553
`
`A Phase I and Pharmacokinetic Study of LY309887 Given Every 3 Weeks with
`Folic Acid Supplementation. Sarah Ha/ford, P, Harper, M. Highley, M. Lind,
`A.H. Calvert, R. Johnson, J. Walling. Elitilly. Indianapolis, IN.
`LY3Cl9B87 is a thiophene derivative of lometrexol. and inhibits glycinamide
`ribonucleotide formyltransferase (Gr-‘tRFTl.
`It
`is a specific inhibitor of
`purine biosynthesls. LY309887 is a more potent inhibitor of GAR FT. This
`occurs by virtue of a greater affinity for thealpha form of thefolate receptor.
`Supplemental folic acid reduces the toxicity of lornetrexol in viva and in
`patients (pie), and reduces the toxicity of Lt?-0988? in vivo. we report here
`data from an ongoing phase l study of Li’3[l9t387 given til once every 3
`weeks. with oral folic acid (5 rngldayl given for 14 days, starting 7 days
`prior to L‘l3D988?. There were 2? pts given 86 courses over 5 dose levels
`between 2 and 12 mglm2'. Patient characteristics were: age range. 33 to
`73. median 55; malignancy. colorectal 9; ovary 4; pancreas 4: other 4;
`prior chemotherapy 24; prior radiotherapy 6. Doses were escalated in
`cohorts of 3 pts and doselimiting toxicity (BLT) was n.ot observed until 12
`rnglmz. when the first pt in the cohort expired of septic complications of
`myelosuppresslon. The dose for subsequent pts was dropped to 8 mglm2.
`The first 3 pts in this cohort did not experience DLT and a total of 9 pts were
`accrued at this dose level
`in anticipation that this would be the phase ii
`dose. However. 2 pts had dose-limiting grade 4 neutropenia. and 4 pts
`developed a slowly reversible neuropalhy. characterized by a
`loss of
`temperature sensation and burning dysesthesias perl-orally and in the
`extremities. Two pts had autonomic neuropathy. This dose level was
`therefore defined as the MTD. with a recommended phase II dose of 6
`mglm2. A minor response was observed in a pt with a right parotid primary.
`Based on preclinical observations showing improvement
`in therapeutic
`index with increased dose of folic acid. an extension to the study was
`performed to define a MTD using a 25 mg daily dose of folic acid X14 days.
`No DLT was observed at 6 mglrnz. and at 8 mglmz 4 pts were treated. one
`pt developed parlcylopenia and sepsis and expired. Three pts developed
`neuropathy. LY30988? was cleared rapidly from plasma with an effective
`terminal elimination half-life of 4 to 6 hours. However. plasma concentra-
`tions persist at low levels up to 3 weeks after administration. reflective of a
`prolonged terminal phase. In conclusion. LY30988? hasa long terminal half-iife
`and a toxicity profile characterized by rnyelosuppression and slowly reversible
`neuropathy. Neuropathy was not predicted from previous experience with
`Iometrexol. or from preclinical models. The study continues to characterize the
`safety profile of LY309887 in combination with 25 mg of folic acid.
`
`Phase I Study of 209331 on a 5-Day Slum Infusion schedule Elven Everya
`Weeks. 3.6. Son, MJ. Retain. D. Borfucci, R. Smith, S. Mani, NJ.
`Vogefzang. Rt. Schilslry, M. Hutchlson. M. Smith. S. Averbuch, E.
`Douglass. Eeneca Pharmaceuticals, lrllilmingfon. DE.
`Z0933] is a potent inhibitor of thymidylate synthase {T8} at the folale
`binding site. d lffering lrorn 'Tomudex' in that it does not undergo intraceliu-.
`far polyglutarnation and therefore may have a different spectrum of activlif
`and toxicity. A o_dX5 scheduleevery 3 weeks was studied in this phase 1 iltal
`because of the short (6 hi half-life in dogs. Dose Ecalation followed 3
`2-stage procedure. with initial doubling of the dose until drug-relglefl
`toxicity was seen; dose escalation was subsequently guided by a modlfiyd
`Fibonacci series. Sixty—one patients. of which 56 were evaluable. Wm‘
`refractory cancer have been treated at it dose levels fD.4 mglmzld to 15
`mglmzldl. Myelosuppression was dose-limiting. with grade 4 thrornb0C‘i“‘*
`penia occurring at 4.8 and 15 rnglmzld and febrile neutropenia observed
`in M6 patients at 12 mglmfilcl and 2J8 patients at 16 mglmzlgi N9’;
`dose-limiting neutropenia grade 3 and 4 was observed in 2 other patient} 31
`16 mglmgfd. Grade 3 erythematous maculopapular rash was observed
`‘
`patient at 12 rnglmzld. Other non-hematological toxicities that were “gr
`dose-limiting included fatigue. diarrhea. and reversible elevatI9|"5 up
`transaminases. Pnarrnacokinetic analysis showed non-linearity.
`ivlthsed
`creased clearance and reduced terminal half—life as closes were IHCIB3
`'
`This may reflect saturation of tubular reabsorption processes. Th
`leafed
`clearance and terminal half-life of the drug were 6.8 t 2.4 ml!
`72.8 1 27.7 h. respectively. A significant fraction of the drug W35 C mail
`within 24 hours. and slow terminal phase accoun
`, 3
`“,3...
`fraction of the drug clearance. Hence steady-state concentratlonfi with
`reached within 2-3 doses idoys). Drug clearance correlated bfilifwo
`estimated are than ash. and further evaluation of the drug *"'" Ilateltrl
`fixed dosing. in a multivariate linear regression model. both H33 02% anti
`nadir tr:-0.73. p<[}.OlJ01l and log neulrophil nadir lr=-071' P
`.é with
`correlated with total AUC of ZD9331. nuc correlated bettarthan 0° , was
`log hadir neutrophll. A minor response (<50% shrinkaze °f [U colon.-C‘
`observed in 1 patient with 5-fluorouracil and lrinotecan refracifltl’ cant-‘l
`lal cancer treated at 12 mgjmzld. Two patients with colorectanm5_ H.
`treated at 6 rnymiflld had stable disease for more than 6 Toisirrllh’
`conclusion. the recommended dose for ZD933i on this schedff engyttlrr "E
`range of 12 to 15 mglnf’. based on which a fixed dose of 2-7 '9"... we"
`undergoing evaluation presently. Neutropenia and thrown‘???-.c~:la)led.
`dose-limiting. and efficacy studies in colorectal cancer are II‘!
`'
`’Tomudex' is a trade mark. the property of Zeneca Ltd.
`
`Lilly Ex. 2045
`Sandoz v. Lilly IPR2016-00318