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`
`Pemetrexed Disodium: A Novel Antifolate Clinically
`Active Against Multiple Solid Tumors
`
`AXEL—R. HANAUSKE, VICTOR CHEN, PAOLO PAOLETTI, CLET NIYIKIZA
`
`Eli Lilly and Company. Indianapolis, Indiana, USA
`
`Key Words. Multi-zargeied unlifoiaze - Tliymidylate synthase inhibitor ’ Amimetabolite
`
`
`
`ABSTRACT
`
`being the dose-limiting toxicity. Folic acid added to
`Pemetrexed disodium tALlMTA‘“. “pemetrexed”)
`the diet in preclinical studies reduced toxicities while
`is a novel. multi-targeted antifolate that has demon-
`maintaining antitumor activity. Based on this obser-
`strated promising clinical activity in a wide variety of
`vation and clinical toxicities, folic acid and vitamin
`solid tumors, including non-small cell lung, breast,
`Bu dietary supplementation has been recently intro-
`mesothelioma, colorectal, pancreatic, gastric. blad-
`der, cervix, and head and neck. Pemetrexed inhibits
`duced into all ongoing trials. Studies combining
`pemetrexed with other active chemotherapeutic
`multiple t‘olate-dependent enzymes involved in both
`agents demonstrate that these combination therapies
`purine and pyrimidine synthesis including thymidy-
`may become important treatment regimens in a vari-
`late synthase, dihydrofolate reductase, glycinamide
`ety of cancer types. Currently. pemetrexed phase III
`ribonucleotide formyltransferase, and aminoimida—
`trials are ongoing in mesothelioma and non-small cell
`zole carboxamide ribonucleotide formyltransferase.
`lung cancer with future trials planned to explore this
`As a single agent, pemetrexed exhibits a moderate
`unique multitargeted antifolate. The Oncologist
`toxicity profile at a dose 01'500 mg/m2 by 10-minute
`200] :63363-3 73
`infusion once every 21 days with myelosuppression
`
`
`lN’rimnr‘C’rtox
`
`Fol-citefldependent pathways are key targets in the develop-
`ment of effective anticancer agents. Unlike most other vital
`enzyme systems within the body. there is little redundancy in
`the Mate—dependent systems that
`lead to DNA synthesis.
`Research into the development of antiiolates as untitumor
`agents has been actively pursued since the l9SOs and has led
`to the most successful anti tolate to date. methotrexate (MIX).
`In 1992. a report by Taylor er (Ii. [l] described the discoxu
`cry of pemetrexed disodium (lALlMTA‘E‘. "pentetrexed"l,
`LY23l5l4; Eli Lilly and Company; Indianapolis. lN‘), a mul—
`titargeted folute analogue that suppresses tumor growth by
`impeding both DNA synthesis and folnte metabolism. By its
`nature. pcmetrexed is a broadly acting agent and because of
`this. multiple clinical indications are currently being pursued.
`in phase ll trials. penietrexed has demonstrated single-agent
`activity in a variety of tumor types. including non-small cell
`lung [2—3], breast [4’5]. colorectal [6-7]. head and neck [8]. gas—
`tric l9}. bladder HO}. cervix ill}. and pancreas cancers {l2}.
`
`liemetrexeo‘ is currently in phase ill studies for rnesotheliotna
`and non small cell lung cancer (NSCLC).
`
`CHEMICAL STRUCTURE AND NIECHANISM or ACTION
`
`l’emetrexed is a novel pyrrololZ.3~dlpytiinidine-based
`nntiiolate (Fig.
`l). lt gains entry to the cell via the reduced
`folate carrier. Once inside the cell, the antifolate is poly/gluta—
`mated by tolylpolyglutamate synthetse. an enzyme for which it
`shows high affinity. Pemetrexed and its tri- and pentagluta—
`mate derivatives demonstrate significant inhibitory activity for
`multiple enzyme systems (Table I). Like S-tluorouracil (Li—FL“)
`and raltitrexed. inhibition of thymidylate synthase (TS) is the
`primary mechanism of action ll3.
`l4} (Fig. 2‘). TS. a rotate»
`dependent enzyme. catalyzes the transfonnation of deoxytxri»
`dine monophosphate to deoxythymidine monophosphaie.
`Inhibition of TS results in a decrease in the available thy/mi»
`dine necessary for DNA synthesis leading to a subsequent
`decline in cellular proliferation. of particular significance in
`rapidly proliferating tumor cells [ii in]. Pentetrexed and its
`
`Co;'i‘espandence; Axcle. Harman/m. Mil, Phil, Eli UN} and Company, DCt’)0()5, Indianapolis, Indiana 46285. USA.
`Telephone: 317—433-6977; For 317276-7234; e-mail: Humans/(e.lND~5ynergcn@t-wilincdc Received January 15, 200];
`acceptedfur publication May 22, 2001, 63.4 [plead/[ed Press 1083—7/59/2001/3500/0
`
`The Oncologist 20iil;ti:363~f73 wwaheOncologist.com
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz V. Eli Lilly, Exhibit 1083-0001
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1083-0001
`
`

`

`Hanautke. Chen, Paoletti et al.
`
`
`
`364
`
`polyglutamated derivatives also potently inhibit dihydrotolate
`reductase (:DHFR). which produces tetrahydrofolate and is the
`primary target for MTX. and glycinamide ribonucleotide
`formyl
`transferase (GARFT),
`involved in de novo purine
`biosynthesis [17]. To a lesser extent, pemetrexed and its polyg—
`lutainated forms inhibit aininoimidaxole carboxamide
`
`ribonucleotide formyltransferase (AICARFT), Like GARFIX
`this enzyme is involved in purine biosyntliesisr The pen
`taglutamate derivative is the predominant intracellular form
`and is >60—fold more potent in its inhibition of TS than its
`antimetabolite parent In fact. with the exception of DHFR
`the tri~ and pentaglutaniate tonne exhibit markedly higher
`antagonistic activity against folate—dependent enzymes than
`the parent compound [18}. Separate from the increased
`inhibitory activity polyglutamation bestows on penietrexed.
`glutamation also increases cellular retention of the molecule,
`which translates into both a longer exposure time and increased
`intracellular concentrations of the drug.
`
`PRECLINICAL STUDIES
`
`Preclinical studies demonstrated that pemetrexed is
`
`cytotoxic against a number of cell lines including CCRF~
`CEM leukemia. GC3/Cl colon carcinoma. and HCT-X
`ileocecal carcinoma cells {19. 20]. In CCRF-CEM cells,
`
`the inhibition was only partially reversed upon the addi~
`tion of thyrnidine. suggesting the importance of the sec-
`ondary Sites. of action for the activity of pernetrexed.
`Further MCFTDX and H630RIO cells. which overex~
`
`press TS and are resistant to the TS inhibitorsi FU and
`raltitrexed. were shown to be Zl—o and LES‘)fold less
`
`resistant to pemetrexed than to raltitrexetl. These findings
`suggest the importance of secondary inhibitory pathways
`in the activity of pernetrexed and indicate that the agent
`may be useful in S—FU~ and raltitrexedreSistant tumors.
`Teiciier and coworkers [2H have investigated the ther»
`
`igure 2. Mechanism ofaction Ofpemetrexcd. Kev target enzytrtos include 73.
`DHFR. and GARFT. Primer/"erect ritsodium is a competitive inhibitor of these
`and other enzymes inducing disturbances in both pyrimidirw and purine treaty/r
`thesis.
`apeutic advantage of combining pemetrexed with other
`
`,
`’ M’”’.W“"~—“W‘““’i
`
`’ ”
`and their relyglniznnates ag Streconthinanthuntan tanfIlS.t anDHFR. recombi-
`
`
`
`Compound
`LY2315l4
`
`LY23lSl4vglu3
`LYBHiH-glnfi
`MTX
`
`rHuTS
`l09 : 9
`
`Lott} l
`l}. i ()3
`13.000
`
`Ki (means i SE nM}
`
`rHuDllfll
`7.0 : l9
`
`l i in
`’7
`7216.4
`0.0034
`
`rmt } ARI’T
`0,300 i 690
`
`380192
`65 i— 16
`80.000
`
`
`l MTX—gluS
`4,7
`0.00M
`2.509
`
`rHuAlCARFT
`3.580
`
`480
`265
`l 43.000
`
`56
`
`ww—n
`—~wm
`7
`W
`itKi—iahie; 13¢LY23l 5M and its polygglutamates takeii'from H4}. “flfifi
`hKi val ties for MTX and M polyglutamates against all en/ymes except DHFR taken from {50}. The Ki values lor MTX against DHFR taken
`from [51}.
`
`7
`
`
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz V. Eli Lilly, Exhibit 1083-0002
`
`thatLuotipopetnunou
`
`
`
`:7‘‘<
`r:—
`EZ:
`Zo4a
`B7.(t
`
`5;t a
`
`Ca
`
`O
`
`(DE/OH
`
`N H
`
`
`
`N-ia-{z-{zxamlno-SA—dihyndxo-pryrrotofz,3~d}pyrimidin.
`5-yt)ethyi}benzoyI}-L-gtmamic acid
`
`MilliNN
`
`H
`
`
`
`Figure 1. Structure quemetrexed.
`
`l
`
`Pemetrexed
`
`mflmw‘e
`
`aw 4..., DNfi
`l
`GHQTHF-5to-Cfiz-THF
`x-Dm Mubarak;
`main.
`i
`mater-'1'
`aura
`“AW“
`a”;
`2
`RifiPi-
`l
`
`roan
`\wmpemp-h-rmmna
`
`l
`‘
`3
`l
`
`TS: myrtaéylate syntnase
`DHFR nihydmtelate reductase
`QARFT r. gtyeinamécte finamrctsotioe tarmghransterase
`
`
`l F
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1083-0002
`
`

`

`365
`
`Petnetrexcd Disodium: Clinical Activity of a Note] Maid-Targeted Antilolate
`
`antitumor agents in human tumor xenografts (breast or
`NSCLC). When pemetrexed was combined with S—FU or
`paclitaxel. a synergistic antitumor effect was achieved.
`Notably. the antitumor effect obtained with pemetrexed/S—FU
`was greater than that achieved with the combination of 5—H)
`and MTX.
`In a similar manner. when human tumor
`
`xenografts were incubated in the presence of combinations of
`pemetrexed with gemcitabine or one of the platinum—contain-
`ing compounds (carboplatin. cisplatin, or oxaliplatin), these
`regimens produced additive or synergistic antitumor effects.
`Additive antitumor effects were seen when pemetrexed was
`combined with vinorelbine, cyclophosphamide, or doxorubin.
`The effects on tumor suppression were additive when penter—
`trexed was given prior to fractionated radiation. Combined
`treatment resulted in a strong increase of efficacy with an
`enhancement ratio of 3.3 [22]. The success of combining
`petnetrexed with other anticancer agents or radiotherapy in
`human tumor xenografts suggested that exploration of these
`same combinations might prove clinically beneficial.
`The mechanism by which natural folates protect in vitro
`cell cultures from the toxic effects of antifolates is generally
`believed to be the result of competition at the levels of trans—
`port
`into the cell. polyglutamation, or target
`interaction.
`either independently or in combination [23]. However, the
`results from the in vitro studies done using single cell types
`are not readily translated into them vivo situation where
`multiple cell types are involved. Protection against toxicities
`without impairment of drug efficacy implies a differential
`response to the folate/drug combination between tumor cells
`and normal cells such that the outcome favors the survival of
`normal cells. Studies to address such a differential in folare
`
`types are difficult. Clinical
`for various cell
`requirement,
`attempts to combine pemetrexed and folic acid have been
`designed on an empirical basis. However, preliminary data
`gathered are encouraging and support the notion that folate
`supplementation is beneficial and reduces toxicities.
`
`CLINICA I. PHARMA COM )GY
`
`Single-Agent Phase I Studies and Pharmacokinetic
`Parameters
`
`Given the schedule dependency observed in animal mod—
`els. phase I studies were conducted exploring three treatment
`schedules: daily X 5 on a 3-week cycle [24]; weekly x 4 on a
`(3—week cycle [25]; and once every 21 days {26]. McDonald
`er a]. [24} administered pemetrexed beginning at 0.2 mgfmj
`as a daily lO-minute infusion for the first 5 days of each 3-
`week cycle. The maximum tolerated dose on this schedule
`was 5.2 trig/m3, with neutropenia being the dose—limiting toxi—
`city. However, the inconvenience of repeated i.v. administra—
`tion (and decreased patient compliance.) combined with the
`
`less than optimal dose intensity achievable widi this regimen
`made this dose and schedule of pemetrexed undesirable. espe-
`cially in light of success of the once every 2l day cycle.
`Rhutldi er al. [25] investigated a schedule of pemetrexed in a
`weekly X 4 every 6 weeks cycle beginning at a dose of 10
`mg/ml. The maximum tolerated dose was 40 ngnfi with neu-
`tropenia again being the dose-limiting toxicity. This reversible
`neutropenia limited the escalation of the dose beyond 40
`mg/m2 and thus, limited the dose intensity achievable with this
`regimen. Another schedule. which was carried forward in all
`subsequent trials. was studied by Rinaldi 61 a]. [26}. These
`investigators administered pemetrexed beginning at 50 mg/m3
`in a 10—minute infusion once every 3 weeks. The maximum
`tolerated dose was 700 trig/m3, with the dose-limiting toxici»
`ties being neutropenia,
`thrombocytopenia. and cumulative
`fatigue. Based on this study. the recommended phase II dose
`for pemetrexed was 600 tug/ml. Of the total 100 patients eval—
`uated during phase I studies. six deaths were considered drug—
`related. Toxicities associated with these drug-related deaths
`included neutropenia, mucositis. diarrhea, and severe nausea
`and vomiting [24—26].
`Phannacokinetic parameters were investigated in two
`separate studies by Rinaldi er al. [26] and One/let er a].
`[27]
`(Table 2). Pemetrexed plasma concentration—time
`functions followed a two—compartment model. The upper
`ent volume of distribution was 6.8 mm, which is rather
`
`small and suggests that pernetrexed is primarily confined
`to the plasma and interstitial compartments. The relatively
`rapid clearance from the body may play a role in the small
`volume of distribution. More significantly. petnetrexed is a
`polar—charged compound which must use a transporter to
`gain access to the cell. and this inability to readily pene-
`trate biomembranes probably is the major determining facr
`tor for the small volume of distribution. The peak plasma
`concentration at the recommended dose of 600 mg/m2 was
`I37 rig/ml. Linear relationships exist between dose and
`peak plasma concentration and between dose and area
`under the curt-e (ABC). The hallllife of peinetrexed was
`3.0 hours and the clearance was 40 nil/'min/mz, with
`
`approximately 78% excreted unchanged in the urine in the
`first 24 hours. All pemetrexcd studies exclude patients
`whose calculated creatinine clearance is below 45 mlr‘min
`
`(modified Cockcrofr and Garth formula; corresponds to 60
`nil/min using the standard Cor‘kr'mft and (Fault formula).
`Additionally, patients whose creatinine clearance drops
`below 45 ml/min may not be retreated until their clearance
`rises above this threshold.
`
`Oral bioavailability has not been evaluated since peme—
`trexed is
`intended for use by short-term i.v.
`infusion.
`However, oral absorption was evaluated in mice using 20
`rug/kg iv. and oral doses of 14C radiolabeled pemetrexed.
`
`Co
`$.
`E0fi
`r;a
`a.
`:.
`95
`
`
`
`om“;3a,].toqtquoNnowoulddoi:
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz V. Eli Lilly, Exhibit 1083-0003
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1083-0003
`
`

`

`
`Half-life
`Clearance
`
`Hanauske. Chen. Paoletti et al.
`
`
`366
`
`, ”Pharmacolttnene
`
`i
`
`
`
`
`
`11
`Patients
`l
`l
`2
`l
`l
`l
`a
`20
`5
`
`150
`225.
`350
`525
`600*
`700
`Mean values
`
`
`Volume of
`distribution (l/ml)
`7
`10
`6
`5
`6
`h
`?
`7
`h
`6.8
`
`Maximum plasma
`concentration (ml/min/mli
`12
`ll)
`27
`39
`(i4
`9 l
`2 l
`l 37
`75
`ND“:
`
`AUC
`(ugh/ml)
`22
`l 4
`39
`54
`[20
`l 58
`23 l
`ZhS
`397
`ND
`
`(h)
`2.5
`l .5
`2.4
`2.2
`2.7
`2.7
`3.9
`3. l
`3,7
`3.0
`
`tml/min/mz)
`38
`92
`42
`46
`3 l
`37
`4 l
`40
`34
`40
`
`l.
`2“ Recommended phase ll dosc it e
`** Not determined
`
`
`Results from mice indicate that the oral absorption is low
`
`with only 13% of an oral dose absorbed in mice.
`
`Single-Agent Phase 11 Studies
`
`NSCLC
`
`Pentetrexed as a smgle agent has been investigated for
`antiturnor activity in patients with advanced NSCLC who
`were either previously untreated {2. 3} or previously treated
`i28] (Table 3'). Penietrexed 500 or hilt} mglml was adminis-
`tered as a ill-minute infusion once every 2i days. The
`l wer dose of 500 tug/m?- was instituted due to toxicities
`seen both in the study by Rust/town m a]. {'3} and a col—
`orectal study by Cripps er al. [6] conducted at the same
`institution Results from the study by Rust/rover? er al. [3]
`
`and one by Clarke er al, [2] were consistent with regard to
`end points. with an overall response rate of 23% [3] and
`18% [2} (Table 3). Sixty—seven percent of patients with
`
`stage lllh responded to therapy compared to 13% with stage
`IV [3]. Duration of response was 3.l months in the study by
`Rust/invert er a]. and 5.6 months in the study by Clarke er
`a1. Overall survival in the two studies was similar. with 9.2
`
`In the study by
`respectively.
`months and 9.8 months.
`Rust/invert et al,, principal toxicities were grade 3/4 neu~
`tropenia {39% of patients) and grade 3 rash (39% of
`patients). in addition. l3% of patients experienced febrile
`neutropeniu. Similarly. the study by Clarke er til. reported
`principal
`toxicities to be grade 3/4 neutropenia (45% of
`patients) and grade 3/4 rash (349'? of patients}. Later analy
`sis of these data led to subsequent addition of prophylactic
`corticosterords. which has reduced the severity and ire»
`
`quency of skin rash. These studies suggest that pemetrexed
`
`has clinically meaningful antitumor activity with moderate
`toxicity and is similar to other single agents used in the
`treatment of NSCLC. Further, these results indicate that
`combination studies are warranted.
`
`A third single-agent study investigated the safety and
`efficacy of pemetrexed in NSCLC patients who had
`relapsed after either platinum» or non-platinum-hased regiw
`mens E28}. Patients who had tailed treatment with nonpist—
`
`inurn agents (such as gemcitabine. vinorelbine. paclitaxeli
`achieved an objective response rate of 30% (including one
`complete response iCRl) compared to a response rate of
`only l3% for those who had previously failed platinum—
`based therapies. Principle grade 3’4 toxicities in this study
`were neutropenia (23% of cycles) and leukopenia (22%}.
`The findings from this study suggest that second—line then
`apy with peinetrexed is feasible and carries promise.
`
`Breast Cancer
`
`Three studies investigating the safety and efficacy of
`pemetrexed as a salvage regimen in locally advanced or
`metastatic breast cancer have been reported [4. 5. 29]. In all
`
`of these studies. pernetrexcd was administered without folic
`acid and vitamin 8,3 supplementation. Pcmetrexed at 500 or
`600 nag/in2 was administered as a lO-minute infusion once
`every 2i days. Lind et al.
`[4} reported the effect of petite—
`trexed when given to patients with either locally advanced or
`metastatic breast cancer. with 33 of 38 patients having recur—
`rence after primary chemotherapy. An objective response
`rate of 31% was achieved. including l CR and duration of
`response was 8+ months, Primary grade 3/4 toxicities
`included neutropenia (50%), thrombocytopenia t l5%‘). and
`rash ( lQC/ci. In this mixed population, penietrexed showed
`
`9H).
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz V. Eli Lilly, Exhibit 1083-0004
`
`
`
`«'tuotipopuoiumoql
`
`0*“
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`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1083-0004
`
`

`

`367
`
`
`
`Pernetrexed Disotliutn: Clinical Actit'itt‘ 0111 Notel Multi-Targetcd Antiiolate
`
`
`
`
` ' Table 13. Rest; I’
`
`\
`L'
`m phase-Hiring witiiirtemetrexedhdminin ,1
`Duration
`Phase H
`u Patients
`Objective
`trials
`evaluable
`response
`of response
`rate
`response/toxicity
`
`
`
`Overall
`survival"t
`
`Principle
`toxicities?
`
`NSCLC
`
`Rust/lover; [311
`
`30/33
`
`C[or/re [211
`
`34/41}
`
`Poxtmnt 128]:
`
`Breast
`
`Lind [4]"
`
`Theodott/ou {201‘
`
`Spirlmann [5F
`
`Colorectal
`
`Cripps [6]
`
`43
`
`36
`
`24
`
`69
`
`29
`
`500130 patients):
`600 {3 patients)
`
`500
`
`500
`
`600
`
`3M
`6011
`
`3.] months
`(23-135 months)
`
`9.2 months
`
`5.6 months
`14.6-14.1 months;
`
`9.8 months
`(ii-141+ months)
`
`18%
`
`309‘? 1’1" arm
`13% NP arm
`
`31%(1CR)
`
`8+ months
`
`19%
`29% AF
`1992 AR
`28% T
`
`1 7%
`
`4.3 months
`12.1-10.4 monthsl
`
`15.1 months
`(_ 1.4-le months)
`
`03/4 neutrOpenia (399‘?)
`Febrile neutropenin ( 13%}
`G3 rash {39%)
`
`03/4 neutropenia (459311
`(33/4 rash (349?)
`
`G314 neutropenia (23%)
`03/4 leukopenia (22%;:
`
`63/4 neutropenia (50%)
`(13/4 thrombocytopenia (15%)
`G3/4 rash (19%;
`
`(33/4 neutropcnia £29922)
`
`63/4 neutropenia (7%)
`
`
`
`
`
`
`
`,—uC
`2s
`
`E.a
`S.
`:27C3_.
`
`
`
`
`
`
`‘1‘1.tnqtquoNno$0115A‘q‘2C
`
`9111
`
`
`
`
`11
`
`,
`
`Pancreas:
`
`Mi/t'nr {12}
`
`Ceriix
`
`1
`
`1 Gard/rah [111
`
`Bladder
`
`Fag-Areas 110}
`
`Head and neck
`
`John 171
`
`30/40
`
`1992-,
`
`9.1 months
`
`16.2 months
`
`in: (t CR)
`
`12 months
`
`6.5 rnonthx
`
`600 19 patients)
`500 (23 patients)
`
`600
`
`6th
`
`601.1
`
`5001 17 patients)
`{1% 153‘ patient-5';
`
`306/1“
`
`63/4 neutropenia (30%)
`03/4 leukopenin 146%,!
`(33/4 thrombocytopenia t 13% )
`
`(33/4 neutropcnia (692}
`
`it
`(13/4 leukopenia t 5
`63/4 thromhocytopenia t 38%}
`
`(33/4 neutropenin {40%;}
`(33/4 teukopenia (439%)
`(33/4 anemia (19%)
`63/4 thromhocytopenin it??? t
`
`63/4 nontropenia 184%)
`03/4 leuhopenia (62%)
`03/4 anemia (35%)
`63/4 vomiting (8%)
`
`G4 neutropenia (35%)
`{3/4 anemia t
`t it
`03/4 thronihoeytopenia 19‘2“;
`
`34.142
`
`24
`
`23
`
`Prim; [8}
`
`26/2?
`
`L11 ‘5
`
`
`
`
`
`
`
`63/4 neutropenia (43% )
`(33/4 anemia {12%)
`
`
`
`
`
`
`‘’Febrile neotropenia (13% of ‘ ‘
`
`Abbreviations: Pi" = previously treated with platinum-hosed regimens: AF : anthracycline t‘nilurcx; NP = pretiouxly treated with nonplzttintzm-hascd regimens: T = mane-refractory: AR
`2 anthracyclinc refractory: CR = complete response: G = grade.
`
`IChemotherapy naive patientt.
`lPatientx‘ who had received prior chemotherapy with or without platinum.
`ihiixed population _, no more than two prior chemotherapies.
`1Patients who had rcceited anthracyclinet and taxanesi
`‘Pntients who had received anthracyclines.
`*Ohicctit'e response rate. duration of response. and overall surrivnl are based on n of patients evaluable for each study.
`
`'i‘Principtc toxicities are boxed on ll of patients evaluable for torit‘it)‘ for each study,
`
`
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz V. Eli Lilly, Exhibit 1083-0005
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1083-0005
`
`

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`promising antitumor activity with acceptable toxicity. Two
`other studies have investigated pemetrexed when adminis—
`tered to metastatic breast cancer patients previously treated
`with anthracyclines and/or taxanes. leeodou/ou er al. [29]
`evaluated pemetrexed as a third-line therapy in metastatic
`breast cancer patients who had failed previous treatment with
`both taxanes and anthracyclines. In a preliminary report.
`
`19% of patients achieved an objective response. The major
`adverse event was grade 3/4 neutropenia (29% of patients).
`Spielmamz er al. [5] conducted a study with a similar patient
`population. All patients in this study had metastatic breast
`cancer and had previously received an anthracycline. A sub—
`set, of patients (42%) had also received previous taxane ther-
`apy. For analysis, patients were divided into either
`anthracyclinc-refractory (progression S30 days after treat—
`ment) or anthracycline failures (progression >30 days after
`treatment). Andiracycline-failure patients achieved an objec—
`tive response rate of 29% and anthracycline~refractory
`patients achieved an objective response rate of 19%. Of those
`patients who had also received a taxane in previous therapy.
`28% responded to treatment with pemetrexed. regardless of
`whether they were anthracyCline—refractory or anthracycline
`failure patients. Toxicity in the study was quite mild. with
`only 7% of patients experiencing grade 3/4 neutropenia.
`These studies support the conclusion that pentetrexed, as a
`single agent, is effective as a second- or thirddine regimen in
`the treatment of locally advanced or metastatic breast cancer
`As with NSCLC, further investigation of pentetrexed in
`combination with other agents appears to be warranted.
`
`Gastrointestinal Cancers
`
`Colorecuzl Studies
`
`Clinical activity of pemetrexed t without folic acid and
`vitamin Big supplementation) in metastatic colorectal carci»
`noma has been demonstrated in two rnulticenter trials per-
`
`formed by Cripps er a]. lo] and John er a]. {7]. The US.
`study used penietrexed at 6th mg/m2 tl’n‘oughour the trial.
`while the Canadian study reduced the starting dose of (300
`mg/m2 to 500 mg/m2 after dose reductions w ere required in
`five of the first nine patients Toxicities leading to these
`reductions included neutropenia,
`febrile neutropenia.
`mucositis. and rash.
`in the study by John er (11.. objective
`
`tumor responses were observed in 15% of patients (with 1
`CR) and in l??? of patients (with l CR) in the study by
`Cripps er a]. The median duration of response was
`markedly different with 4.3 months in the trial by Crippr er
`a}. and 9.1 months in the trial by John ct at. Overall survival
`was Lil months and 16.2 months. respectively.
`in the
`
`study by John at (1].. 569/} of patients experienced grade 3/4
`neutropenia. 54% grade 3/4 leukopenia. and l8% grade 3/4
`
`368
`
`thrombocytopenia. In the study by Cripps ct 511.. of the nine
`patients who received a starting dose of 600 ngmB. five
`patients experienced grade 3/4 neutropenia. four patients
`experienced grade 3/4 leukopenia. and three patients expe-
`rienced grade 3/4 thrombocytopenia. Hematologic toxici-
`ties were less frequent after the dose of pemetrexed was
`reduced to 500 mg/mz. Of the 23 patients receiving this
`dose. ll patients developed grade 3/4 neutropenia. seven
`patients developed grade 3/4 leukopenia. and one patient
`grade 3/4 thrombocytopenia. One patient died due to neu-
`tropenic sepsis. Additional trials investigated pemetrexed in
`patients with colorectal cancer refractory to S—FU and 5—
`FU/in'notecan {30} with only minor responses reported. These
`studies demonstrated that pemetrexed has activity in metasta—
`tic colorectal cancer in a magnitude similar to that of other
`agents. Studies are under way which will investigate the Clio"
`ical benefit of combining pemetrexed with other agents active
`in colorectal cancer. including irinotecan.
`
`Pancreatic Cancer
`
`Thus far. only one phase II study has investigated the
`clinical usefulness of pemetrexed in advanced pancreatic
`cancer [12]. Miller et a1. administered pemetrexed 600
`mg/m2 to patients with unresectable or metastatic pancre-
`atic cancer. While direct antitumor activity was modest (60/?
`objective response rate). 1 CR lasted to months. Also. 40%
`or“ patients achieved disease stabilizz‘ition. Median survived
`was 7 months. which compares well to the most frequently
`used chemotherapy with gerncitahine. Principal grade 3/4
`toxicities included neutropenia t4t’)%i.
`leultopenia (43%}.
`anemia if 39%}. and thrombocytopenia “7%). Based on the
`preliminary observation of activity in pancreatic cancer,
`combination regimens using pemetrexed and gemcitabine
`have been initiated and randomized phase ill studies appear
`to be warranted.
`
`Gastric Cancer
`
`Celia er til. :9; have reported encouraging preliminary
`findings when pemetrexed is given to patients with gastric
`cancer. Several
`responses have been reported.
`initially.
`pemetrexed 500 mg/m2 was administered to six patients, as a
`ill-minute infusion every 2i days without t‘olic acid and vit—
`amin B}: supplementation. Each of these patients reported at
`least one grade 3/4 toxicity. Three of these patients died due
`to treattnentrelated side effects. Subsequently.
`seven
`
`patients have been given high—dose intermittent folic acid
`(5. mg daily. days ~2 to +2) during pemetrexed treatment and
`no deaths or serious toxicities have been observed thus far.
`
`Although this is a limited series of patients. these data indi»
`cate that folic acid supplementation is associated with a
`decrease in serious side effects, while the antitumor activity
`
`Sandoz Inc. IPR2016-00318
`
`Sandoz V. Eli Lilly, Exhibit 1083-0006
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1083-0006
`
`

`

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`Pemetrexetl Disndinm: Clinical Activity of a Notel Multil‘argeted Antifolate
`
`of pemctrexed appears to be preserved. This study is ongoing
`using the above folic acid dose schedule. and mature results
`are awaited before final conclusions can be determined.
`
`Other Cancers
`
`Cervical Cancer
`
`Goed/za/s and van Wijk [1 ll presented the results of a
`phase II trial investigating the antiturnor activity of peme-
`trexed (without folic acid and vitamin Bi; supplementation)
`in women with advanced cervical cancer. Initially, patients
`received pemetrexed 600 trig/n13. but with evidence of high
`toxicity. the dosage was reduced to 500 trig/m2 and folic acid
`supplementation was added. At present. only data for patients
`receiving 600 mg/m2 are available for review. The overall
`response rate for these patients was 2192. with 71% of patients
`achieving stable disease. Of the patients with stable disease.
`25% had unconfirmed partial responses However.
`in this
`patient population. there was a high incidence of decreasing
`creatinine clearance that necessitated withdrawal from the
`
`study. Grade 3/4 hematologic toxicities included neutropenia
`(84%). leukopenia (62%). and anemia (35%). Grade 3/4 non-
`hematologic toxicities included vomiting (8%). Additionally.
`one death was related to study drug. The clinical benefit
`obtained with pemetrexed in advanced cervical cancer must
`be balanced against the compounds toxicity protile. if the
`reduction in dose and the supplementation with tolic acid can
`moderate the frequency and intensity of adverse events
`observed here. then pemetrexed may be pursued as a single
`agent or in combination regimens against ceor'ical cancer.
`
`Bladder Cancer
`
`Par-A res et a]. l i (ll investigated pemetrexed (without folic
`acid and vitamin B}; supplementation)
`in patients with
`advanced transitional cell carcinoma of the bladder. The initial
`
`starting dose of pemetrexed was 600 trig/m3. but subsequently
`the dose was reduced to 500 rug/m2 due to toxicities.
`Pemetrexed showed remarkable clinical activity with an objec~
`tive response rate of 30% Additionally. stable disease was
`achieved in 35% of patients. Main toxicities included grade
`4 neutropenia (35%). grade 3/4 anemia 0797:). and grade
`3/4 thrombocytopenia (WE). Twenty—two percent of
`patients developed febrile neutropenia and two patients
`died from either renal failure or sepsis related to study drug.
`Pemetrexed thus appears to also be active in advanced
`bladder cancer.
`
`Head and Neck Cancers
`
`Pivot er (1]. {8] administered pemetrexed 500 mg/m2
`(without folic acid and vitamin B13 supplementation) to
`patients with squamous cell carcinoma ot‘the head and neck
`
`with a response rate of 33% and an equal percent achieving
`stable disease. Grade 3/4 hematological toxicities were neu-
`tropenia (43%) and anemia 02%). Additionally. febrile
`neutropenia occurred in 13% of the cycles, with one patient
`death from neutropenic sepsis. These data suggest
`that
`pemetrexed is active as a single agent and that combination
`regimens that include pemetrexed may prove to be clini-
`cally beneficial in advanced head and neck cancers.
`
`PHASE I COMBINATION STUDIES
`
`Based on the activity of pemetrexed as a single agent in a
`number of tumor types. combination activity demonstrated in
`human tumor xenografts l2l ]. and the unique mechanism of
`action of pemetrexed. regimens combining this antifolate with
`other active agents have been explored clinically. Phase I
`combination regimens investigated thus far have included
`penietrexed with platinum-containing agents (cisplatin [31).
`carboplatin [32], oxaliplatin [33}, and gemcitabine {34)}.
`Additional combinations under investigation include peme—
`trexed with S—FU, irinotecan. taxanes. and anthracyclines [35-
`37}. These phase 1 studies, like the single—agent phase 1 trials
`discussed above, determined feasible and alternative schedul»
`
`ing and dosing regimens. The recommended schedule and
`dosing for the combination of pemetrexed with cisplatin and
`gemcitabine have been determined. For penietrexed/cisplatin.
`the recommended schedule was pemetrexed 500 trig/m4
`without folic acid and vitamin B}; supplementation) admin
`istered as a lilminute infusion. followed by a 30~minute
`wash-out period. and then cisplatin 75 rug/m: administered
`over a l2tl~minute period given on day l of a Zl’datv cycle,
`that nnann oral. {El l observed it objective responses out of
`the 40 patients who were administered the day l dose and
`schedule. Responders included patients with head and neck
`cancer ( l CR and 2 partial responses [PRlL and PR in patients
`with colorectal cancer t' l l. mesothelioma t5). and NSCLC (ll.
`
`Of particular interest. 5 PR were documented from 1 l patients
`assessable with pleural malignant mesothelioma, Based upon
`these data. a randomized phase ill study with pernetrexedfcisv
`platin versus cisplatin has been initiated.
`Final results from the pernetrexedfcarboplatin combina»
`tion by Calvert er a]. in patients with mesothelioma {32} are
`not available at the time of this review. However. in a prelim—
`inary report. 27 patients enrolled with malignant mesothelioma
`treated with pemetrexed/carboplatin (ranging from petite»
`trexed 400 mg/nfi carboplatiu AUC 4 to 500/6). have shown
`toxicities u ere generally manageable and responses have been
`noted in it) out of the 20 evaluable patients to date. Final
`results of this phase I trial are awaited to define the recom—
`mended dose and schedule for this promising combination.
`For the pentetrexed/gemcitabine combination. the rec
`ommended dose and schedule for future phase ll studies
`
`Sandoz Inc. IPR2016-00318
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`Sandoz V. Eli Lilly, Exhibit 1083-0007
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1083-0007
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`

`

`Hanauske, Chen. Paoletti et Ell.
`
`370
`
`
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