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`Tif
`
`810-Medical
`
`Library
`
`.4
`
`EXHIBIT
`
`tJ
`
`Lilly Ex. 2022
`Sandoz v. Lilly IPR2016-00318
`
`

`
`PHASE
`
`TRIALS
`
`560
`
`1558
`PHASE
`ii DeVore
`
`.jotte
`
`is
`
`IL-8
`
`attenuated
`
`treatment
`
`STUDY OF THE ANTINEOVASCULARIZATION
`Wamil
`Hellerqvist
`Wakefield
`Yan
`Carter Y-F Wang
`York
`Vanderbilt University Nashville TN 37232
`CM-i0i
`induces
`neovascular
`polysaccharide that
`bacterial
`inflammation in malignant tumors Twenty seven patients with refractory
`study of CM-i 01 The first
`15
`were enrolled in
`malignancies
`phase
`received CM-iOl
`patients Group 11
`15-minute infusion
`intravenously by
`every other day three times in one week
`at doses
`ranging from
`units/Kg Cycles were repeated every 3-4 weeks
`Twelve
`l7.Spgl/Kg to
`additional patients Group 21 were treated on
`10 schedule of
`weekly
`of CM-lOi
`which
`six received
`3.3 units/Kg
`and
`received
`units/Kg
`of CM-lOi
`1gM
`Serum was
`the development
`lgG and
`snslyzed for
`Inflammatory cytokines were analysed
`following each treatment
`For
`the
`patients the maximally tolerated dose was 3.3 units/Kg
`and dose
`Group
`limiting toxicities included grade IV dyspnes and arrhythmia encountered
`the
`level
`12 hours
`Toxicities occurred primarily within the first
`units/Kg
`following therapy snd included mild to moderate fever/chills nausea cough
`headache
`flushing dyspnea myslgiss and acute tumor-related pain
`fscial
`No patient
`CM-lOi
`developed
`detectable
`antibodies
`patients
`All
`time- snd dose-dependent elevations in all cytokines
`marked
`experienced
`studied Peak cytokine ranges pg/mI were as follows TNFa 1243 49221
`mip-io 1535- 8.174 lL-6 1212- 10150 IL-8 11582-161551
`180-
`1149- 1259 ng/ml
`In both patient groups peak TNFo
`14631 sE-selectin
`snd
`responses occurred
`following the
`but were
`treatment
`first
`following the 2nd and 3rd treatments However when Group
`2-3 week rest
`treatment cycles
`following
`patients received
`subsequent
`to those observed
`peak cytokine levels were similar
`following their
`that more treatment
`This may indicate
`is necessary
`interval
`to
`CM-101 can be
`response
`the desired
`repetitive inflammatory
`generate
`for severe and possibly
`safely administered at doses that produce evidence
`tumor specific inflammation Supported by CarboMed Inc and GCRC MOb
`RR00095
`
`DRUG CM-i 01
`Thurman
`Sundell
`Zhang and
`Johnson
`
`unit
`
`at
`
`IL-b
`
`initial
`
`regimens
`
`TRIAL TO EVALUATE ORALLY ADMINISTERED
`PHASE
`EVERY WEEKS
`IRINOTECAN HCL CPT-I1 GIVEN DAILY
`IN PATIENTS WITH REFRACTORY MALIGNANCIES
`Dreneler
`Burns
`Eckhardt
`Hodges
`Kraynak
`Dietz
`Eckardt
`Kuhn
`Smith
`Peacock
`Rizzo
`Schaaf
`Rinaldi
`Rodriguez
`Von Hoff
`The University of Texas Health Science
`Thurman
`Center San Antonio TX Cancer Therapy
`Research Center San Antonio
`TX Brooke Army Medical Center Ft Sam Houston TX and The Upjohn
`Company Kalamazoo MI
`Irinotecan CPT-1
`soluble camptothecin
`semi-synthetic water
`inhibitor with substantial
`antitumor activity
`derivative is
`topoisomerase
`variety of dosing schedules
`by the
`It has been studied clinically
`in
`route The development
`of an oral
`formulation would provide
`intravenous
`therapy enhance quality of
`the opportunity for cost-effective outpatient
`for intravenous
`at cancer
`by preventing prolonged
`stays
`life
`clinics
`of chronic dosing
`administration
`and allow for convenient
`infusions
`The objectives
`of
`this study were to determine the maximally-
`tolerated dose MTD and the dose limiting toxicity of
`irinotecan when
`days to characterize
`day for five consecutive
`administered orally once
`of irinotecan and its metabolite SN-38 and to detect
`the phannacokinetics
`To date 13 patients pts
`male
`any evidence of antitumor activity
`female ages 29-74 with advanced
`refractory solid tumors have received
`dose levels 20 40 66 and 100 mg/m2/day
`40 courses of treatment over
`The majority of patients
`weeks schedule
`treated
`on
`every
`had 5-FU refractory metastatic colon cancer 12/13
`Entry criteria
`good
`status 0-2 adequate
`included
`performance
`organ function
`hematologic status and absence of any condition which could impalr oral
`Irinotecan was administered diluted in 50 ml of Cran
`medication intake
`Grape juice Patients
`his prior and
`his post oral administration
`fasted
`Dose
`Grade
`included diarrhea and neutropenia
`limiting toxicities
`diarrhea despite use of aggressive
`loperamide support occurred
`in 1/1 Pt
`occurred
`at 100 mg/m2/d and 2/6 pts at 66 mg/m2/d
`Grade
`neutropenia
`Pt at 100 mg/m2/d and 1/6 pts at 66 mg/m2/d
`Further patient accrual
`in I/I
`to better define the dose recommended
`for phase II studies
`is currently in
`All other
`toxicities were
`or
`less
`Pharmacokinetic
`grade
`progress
`of lactone total and glucuronide forms
`analysis including concentrations
`of irinotecan and its metabolite SN-38 quantified by high performance
`by the Upjohn Company
`liquid chromatography is ongoing
`Supported
`
`daily
`
`561
`
`is
`
`EVERY OTHER WEEK IRINOTECAN CPT-l1 RESULTS
`OF
`AND PHARMACOKINETIC PK STUDY ML Rothenbere
`PHASE
`D.A Rinaldi LS Smith
`Hodges A.M Thurman N.K Ichhpurani
`Schaaf
`SO Eckhardt 0.1 Rodriguez
`Drengler AJ Dietz T.C Murphy
`Villalona
`HA Burns III D.D Von Hoff The University of Texas Health Science Center at
`San Antonio TX Cancer Therapy and Research Center San Antonio TX Brooke
`Army Medical Center FL Sam Houston TX and The Upjohn Co Kalamazoo MI
`Irinotecan hydrochloride CPT-1
`water-soluble camptothecin analog with
`small cell and non-small cell lung ovarian and
`promising activity agalnst colorectal
`week wk schedule
`allows administration of
`cervical cancers While
`once every
`and results in
`higher single doses
`slightly higher dose intensity weekly drug
`administration allows for more frequent dosing which may be important
`for
`cell-
`an every other wk drug
`cycle specific drag such
`as this
`is possible that
`It
`could combine the most
`favorable aspects of dose intensity
`administration schedule
`We are conducting
`and PK trial
`Phase
`and
`dose
`this thug
`of
`frequency
`administration schedule To date 20 patients jsts have been enrolled 13
`and
`Median age 53.5 range 29-77 WHO
`all are evsluable for toxicity during cycle
`PS 013 16 21 Thirteen
`pta have colon cancer
`adenoca of the
`rectal cancer
`adenoca of unknown primary Clinical
`toxicities are as follows
`small bowel and
`Medisn ANc
`Nadir cycle
`cells/mm
`reese
`
`Dose
`
`Level
`
`Pts
`
`cycles
`
`Evsluable/
`
`Administered
`
`mg/rn2
`
`Eatered
`
`Pa With
`ItT
`Type of DLT
`
`125
`
`4/4
`
`3/3
`
`22
`
`31
`
`2825 1417-5548
`
`LY23 1514 N-
`
`1559
`NOVEL MUL11-
`OF
`EVALUATION
`PHASE
`LY23 1514
`EVERY 21 DAYS 1A
`ADMINISTERED
`TARGETED ANTIFOLATE
`Rodriguez SO Eckhardt SM Fields JR
`Rinnidi HA Burns PA Don
`Lu DD Von Hoff From the
`Woodworth JO Kuhn
`Langley
`Clark
`and Research Center and Brooke Army Medical Center San
`Cancer Therapy
`Antonio TX and Eli Lilly and Company Indianapolis IN
`
`pyrimidin -5-yl ethyl benzoyl-L-glutamic
`
`acid disodium salt
`
`is multi-
`
`which
`
`inhibits
`
`the enzymes thymidylate
`doses were administered
`
`antifolate compound
`targeted
`synthase and dihydrofolate reductase
`Escalating
`to patients with advanced
`21 days
`refractory
`and determine the maximally-tolerated
`antitumor activity of the
`profile and potential
`was
`escalation
`based
`
`intravenously every
`tumors to assess toxicities
`
`solid
`
`dose
`
`the Modified
`
`Continual
`
`patient
`
`MTD pharmacokinetic
`Dose
`compound
`on
`treated at each minimally toxic dose
`Reassessment Method with
`total of 37 patients 27 males 10 females median age 59 yo median
`level
`PS 90% were treated with 132 courses at
`dose levels ranging from 50 to
`The MTD of LY23 1514 was 600 mglm2 with reversible
`700 mg/m2
`neutropenia thrombocytopenia and fatigue
`as the dose-limiting toxicities
`included mild to moderate
`observed
`
`Nonhematologic
`
`toxicities
`
`fatigue
`
`anorexia
`
`nausea
`
`diarrhea mucusitis
`
`transaminase
`
`elevations
`
`Pharmacokinetic
`
`and
`
`reversible
`
`the 600 mg/m2 dose level demonstrated
`treatment at
`life maximum plasma concentration clearance
`area under
`
`and
`
`Partial
`
`and in
`
`obtained
`
`in
`
`promising agent
`
`volume of distribution at steady-state
`apparent
`41.7 mI/minim2 293.3 meg-hr/mI
`meg/mI
`and 26.55
`percent of the compound was excreted
`Seventy-eight
`patients with advanced pancreatic
`responses were achieved in
`cancer Minor
`patients with advanced
`patients with advanced
`for the treatment of gastrointestinal malignancies
`
`hepatic
`rash
`course of
`analysis after the first
`mean harmonic half-
`the curve AUC
`of 5.07 hours
`L1m2 respectively
`in the urine
`
`142
`
`unchanged
`
`colorectal
`
`colorectal
`
`cancer
`
`cancer
`
`responses were
`LY23 1514 is
`
`150
`
`175
`
`200
`
`225
`
`6/6
`
`6/6
`
`1/1
`
`46
`
`32
`
`1699 3473574
`
`2831 160-4935
`
`2t72 300-3637
`
`4500
`
`Febrile nest and
`ANC
`days
`
`grade
`
`Febnle nest asd
`
`grade
`
`disarhea
`
`Other common toxicitics
`have been nausea vomiting fatigue and anorexia none of
`which have been dose limiting Preliminary PK data from the first
`dose levels
`max and AUC for CPT-l
`linear relationship between
`drug dose
`reveal
`once MTD is reached
`for SN-38 Phsnnacodynamic relationships
`will
`evaluated
`in CEA
`confirmed PR and
`One pt with colon cancer has had
`others have had
`50% With an MTD
`200 mg/m2 this schedule
`dose intensity that will
`of
`has
`wk schedule
`vs 116.7 mg/m2/wk
`or exceed
`100 mg/m2/wk
`approach
`the
`drug 33% more frequently
`to the 225
`Accrual
`while administering
`respectively
`every other wk administration of
`mg/m2 dose level
`In conclusion
`is ongoing
`dose intensity and
`CPT- 11 is feasible and may provide the optimal balance
`between
`dose frequency This study was sponsored by The Upjohn Company
`
`but not
`
`fall
`
`PROCEEDINGS OF ASCO VOL 15 MAY 1996
`
`489
`
`Lilly Ex. 2022
`Sandoz v. Lilly IPR2016-00318