2056
`
`Perspectives in Bladder Cancer
`Supplement to Cancer
`
`Review of a Promising New Agent-Pemetrexed
`Disodium
`
`1
`
`Luis Paz-Ares, M.D., Ph.D.
`Susana Bezares, M.D.1
`Jose M. Tabernero, M.D?
`1
`Daniel Castellanos, M.D.
`Hernan Cortes-Funes, M.D., Ph.D.
`
`1
`
`1 Department of Medical Oncology, Doce de Oc(cid:173)
`tubre University Hospital, Madrid, Spain.
`
`2 Department of Medical Oncology, Vall D'Hebron
`University Hospital, Barcelona, Spain.
`
`Based on a Satellite Symposium held in conjunc(cid:173)
`tion with the First European Conference on Per(cid:173)
`spectives in Bladder Cancer, Monte Carlo, Monaco,
`November 16-17, 2001.
`
`Luis Paz-Ares and Hernan Cortes-Funes have
`given lectures with honorarium paid by Eli Lilly and
`Company.
`
`Address for reprints: Luis Paz-Ares, M.D., Ph.D.,
`Servicio de Oncologfa Medica, Hospital Universita(cid:173)
`rio Doce de Octubre, Avenida de Cordoba Km 5,4,
`28041 Madrid, Spain; Fax: 011 (34) 914603310;
`E-mail: Ipaz@hdoc.insalud.es
`
`Received May 6, 2002; revision received Septem(cid:173)
`ber 30, 2002; accepted January 13, 2003.
`
`© 2003 American Cancer Society
`
`Pemetrexed disodium (ALIMTa™, [pemetrexed], LY231514; Eli Lilly and Company;
`Indianapolis, IN), a novel antifolate antimetabolite with multiple enzyme targets
`involved in both pyrimidine and purine synthesis, has entered clinical trials due to
`its favorable pleclinical profile. Many studies utilizing the drug, as a single or
`combination agent, are currently ongoing, including Phase III trials in mesotheli(cid:173)
`oma, nonsmall cell lung carcinoma (NSCLC) and pancreatic cancer. Promising
`feasibility and activity data have been obtained with pemetrexed in combination
`with platinum compounds and gemcitabine. The supplementation with daily oral
`folate could reduce the incidence of hematologic toxicities while preserving the
`antitumor activity of pemetrexed. Cancer 2003;97(8 Suppl):2056-63.
`© 2003 American Cancer Society.
`DOl 1O.1002/cncr.11279
`
`KEYWORDS: antifolate antimetabolite, pyrimidine synthesis, purine synthesis, thy(cid:173)
`midylate synthase.
`
`Since the discovery of the ability of aminopterin to induce remis(cid:173)
`
`sions in children with acute leukemia 6 decades ago, folate de(cid:173)
`pendent pathways have been pursued as key targets in the develop(cid:173)
`ment of new and effective anticancer agents. 1 The antifolates interfere
`with the binding of natural folate co factors to important biosynthetic
`enzymes, such as thymidylate synthase (TS), dihydrofolate reductase
`(DHFR), glycinamide ribonucleotide formyl transferase (GARFT), and
`aminoimidazole carboxamide formyl transferase (AICARFT). Inhibi(cid:173)
`tion of these enzymes results in impeded synthesis of nucleotides
`and, thus, in DNA and RNA synthesis inhibition. Several agents of this
`class, including methotrexate, 5-fluorouracil, and raltitrexed, are now
`used extensively in the treatment of patients with a variety of solid
`and hematologic malignancies, and others are being developed.
`Pemetrexed disodium (ALIMTATM [pemetrexed], LY231514; Eli
`Lilly and Company; Indianapolis, IN) is a novel antifolate antimetab(cid:173)
`olite with multiple enzyme targets involved in both pyrimidine syn(cid:173)
`thesis and purine synthesis.2
`4 Due to its favorable preclinical profile,
`-
`the agent has entered clinical trials and has shown encouraging
`activity in a wide range of tumors, including nonsmall cell lung
`carcinoma (NSCLC), malignant mesothelioma, and carcinomas of the
`breast, colorectum, uterine cervix, head and neck, and bladder. Many
`studies with the drug as a single agent or in combination with other
`agents are currently ongoing, including Phase III trials in patients
`with mesothelioma, NSCLC and pancreatic carcinoma.
`
`Preclinical Studies
`Pemetrexed disodium (N -[4- [2- (2-amino-3,4-dihydro-4-oxo-7H -pyr(cid:173)
`rolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid) is a struc-
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1079-0001
`
`

`
`A Promising New Agent: Pemetrexed Disodium/Paz-Ares et al.
`
`2057
`
`H
`
`FIGURE 1. Chemical structure of pemetrexed disodium (N-[4-[2-(2-amino-
`3, 4-d ihydro-4-oxo-7H-pyrrolo[2,3-d] pyri mid in -5-yl)ethyl] be nzoyl]-L -g lutamic
`acid).
`
`PEMF:':I'{{E~~J).··· - - - - -+ . C ts)
`'~ ,'T' < T -00 "
`
`___________ 5.10-CH2-THF
`
`DHF
`
`r~~R' NADPH
`lO-~~.. .
`~ ~
`
`~--,--~~,-------+THF
`
`NADP+
`
`PRPP
`L-DHF
`
`fGAR
`
`_
`
`AMP. GMP - - - . DNA. RNA
`
`FIGURE 2. The mechanism of action of pemetrexed disodium.
`
`turally novel analog of the classic antifolate GARFT
`inhibitor lometroxol (Fig. 1). It has a pyrrole ring that
`replaces the pyrazine ring in the pterine portion of
`folic acid and a methylene group that replaces the
`benzylic nitrogen in the bridge portion of folic acid.
`Inhibition of TS is the primary mechanism of action of
`pemetrexed dis odium, resulting in a decrease in the
`available thymidine necessary for DNA synthesis (Fig.
`2).5-7 In addition, pemetrexed potently inhibits DHFR,
`which catalyzes the synthesis of tetrahydrofolate and
`is the primary target for methotrexate, and GARFT. To
`inhibits
`lesser extent, pemetrexed disodium
`a
`AICARFT, an enzyme involved in the "de novo" pu(cid:173)
`rine biosynthesis like GARFT. These targets are related
`to the cytotoxicity of pemetrexed, because both thy(cid:173)
`midine and hypoxanthine are required to circumvent
`cellular death caused by pemetrexed. 6
`Pemetrexed gains entry to the cell through the
`reduced folate carrier; and, once inside the cell, the
`antifolate is polyglutamated by folylpolyglutamate
`synthase, an enzyme for which it shows high affinity.
`The pentaglutamate form of pemetrexed is the pre-
`
`dominant intracellular form and is > 60-fold more
`potent in its inhibition of TS compared with mono(cid:173)
`glutamate. 8 In addition, whereas the latter has little
`activity against GARFT and AICARFT, the pentagluta(cid:173)
`mate is much more active. The inhibitory activity of
`pemetrexed against DHFR is not increased by polyglu(cid:173)
`tarnation. Pemetrexed pentaglutarnate is most active
`against TS followed by DHFR, GARFT, and AICARFT;
`and its inhibition is competitive with respect to the
`natural folate in all instances. Glutamation increases
`cellular retention of the molecule, which translates
`into both a longer exposure time and increased intra(cid:173)
`cellular concentrations of the drug.
`Cell cycle experiments indicate that pemetrexed
`disodium induces cell cycle arrest in Gl/S phase, as
`expected by its antifolate effects, and cell death, which
`did not appear to be mediated by P53. Cell culture
`studies demonstrated that pemetrexed is cytotoxic
`against a number of cell lines, including CCRF-CEM
`leukemia cells, GC3/Cl colon carcinoma cells, and
`HCT-8 ileocecal carcinoma cells? In addition, in vitro
`activity has been demonstrated against human-tumor
`colony-forming units obtained from patients with co(cid:173)
`lon carcinoma, renal carcinoma, hepatoma, carcinoid
`tumor, and lung carcinoma. 9 Pemetrexed disodium
`also was established as an effective antitumor agent
`against murine tumors and against several human
`tumor xenografts, including VRC5 colon carcinoma
`cells, GC3 colon carcinoma cells, BXPC3 pancreatic
`carcinoma cells, LX-I NSCLC cells, and MX-l breast
`carcinoma cells. 10 Furthermore, the drug has signifi(cid:173)
`cant activity in cell lines and xenografts that are resis(cid:173)
`tant to methotrexate, 5-fluorouracil, and raltitrexed. 3
`These findings are consistent with the multitargeted
`mechanism of action of pemetrexed and suggest that
`the agent may be useful in 5-fluorouracil-resistant,
`raltitrexed-resistant, and methotrexate-resistant tu(cid:173)
`mors.
`Several dose administration schedules for pem(cid:173)
`etrexed were tested in toxicology studies in dogs. Uni(cid:173)
`formly, the predominant toxicities were gastrointesti(cid:173)
`nal and hematologic. Marked schedule dependence
`was noted, with the best toxicity profile found using
`once-weekly dosing compared with daily dosing.ll
`
`Single-Agent Phase I Studies
`Given the schedule dependency observed in animal
`models, Phase I studies were conducted exploring
`three treatment schedules: daily X 5 every 3 weeks,
`weekly X 4 on a 6-week cycle, and once every 3 weeks
`(Table 1).9.12.13 The predominant toxicity on each
`schedule was hematologic, particularly neutropenia,
`which was dose limiting. Other side effects encoun(cid:173)
`tered included fatigue, diarrhea, mucositis, cutaneous
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1079-0002
`
`

`
`2058
`
`CANCER Supplement April 15, 2003/ Volume 97/ Number 8
`
`TABLE 1
`Single-Agent Phase I Trials
`
`Authors
`
`McDonald et al.12
`
`Rinaldi et aU 3
`
`Rinaldi et al.'
`
`No. of
`patients
`
`38
`
`24
`
`37
`
`DLT: dose limiting toxicity.
`
`Schedule
`
`Dose (mg/m2)
`
`Recommended
`dose
`
`DLT
`
`Daily X 5, 3-week
`cycle, 10-minute
`infusion
`Weekly X 4, 6-
`week cycle 10-
`minute infusion
`Once every 3
`weeks, 10-
`minute infusion
`
`0.2-5.2/ day
`
`4 mg/m2 day
`
`Neutropenia, liver
`enzymes elevation
`
`10-40/week
`
`40 mg/m2/week
`
`Neutropenia
`
`50-700
`
`600 mg/m2
`
`Neutropenia,
`thrombocytopenia,
`cumulative fatigue
`
`Other toxicities
`
`Mucositis,
`diarrhea, rash,
`fatigue
`Anorexia, nausea,
`fatigue
`
`Rash, mucositis,
`nausea,
`emesis,
`vomiting,
`fatigue,
`anorexia
`
`rash, and transient transaminitis. Given the conve(cid:173)
`nience for the patient, the higher dose intensity at the
`recommended dose, and the antitumor activity seen
`during the Phase I trial, with partial responses in two
`patients with pancreatic cancer and in two patients
`with advanced colorectal cancer, the 3-weekly sched(cid:173)
`ule was chosen for further development in Phase II
`trials.
`Pharmacokinetic determinations were made in 20
`patients who were treated at the recommended dose
`(600 mg/m2) in the trial performed by Rinaldi et al.9,13
`Pemetrexed plasma concentration-time functions fol(cid:173)
`lowed a two-compartment model. The mean peak
`plasma concentration at the recommended dose of
`600 mg/m2 was 137 fLg/mL, and the mean half-life was
`3.1 hours (range, 2.2-7.2 hours). The apparent steady(cid:173)
`state volume of distribution was 6.8 Llm2, which sug(cid:173)
`gests that pemetrexed is confined primarily to the
`plasma and interstitial compartments. This is consis(cid:173)
`tent with the polar nature of the compound and the
`relatively high clearance (40 mL per minute per m 2).
`The clearance of pemetrexed is primarily renal, with
`78% of the dose recovered unchanged in the urine in
`the first 24 hours after administration.14 No accumu(cid:173)
`lation appears to occur with multiple courses, and the
`linear disposition of pemetrexed over the range stud(cid:173)
`ied does not change after multiple doses. Protein
`binding in human plasma is approximately 81 %.
`
`Single-Agent Phase II Studies
`In Phase II trials, pemetrexed (500-600 mg/m2 every 3
`weeks) has demonstrated single-agent activity in mul(cid:173)
`tiple solid tumors, including NSCLC and tumors of
`the breast, colorectum, pancreas, uterine cervix, blad(cid:173)
`der' and head and neck (Table 2). Two trials in pa-
`
`tients with advanced NSCLC, including 78 untreated
`patients, resulted in a remarkable overall response
`rate (RR) of 20% and a median survival of 9.2-9.8
`months.15,16 A third trial was completed in pretreated
`patients with NSCLC who had an overall RR of 30% in
`patients who had not been previously exposed to plat(cid:173)
`inurn compounds and of 13% in patients who had
`received platinum as first-line treatment.17 With these
`data in mind, a Phase III trial has been started com(cid:173)
`paring pemetrexed disodium with docetaxel as sec(cid:173)
`ond -line treatment in patients with NSCLC. Pem(cid:173)
`etrexed exhibited activity in patients with colorectal
`cancer similar to the activity of other agents, produc(cid:173)
`ing RRs of 15% and 17% in two independent Phase II
`trials in untreated patients.18,19 Pemetrexed disodium
`has been evaluated in patients with advanced breast
`carcinoma in three trials as second-or third -line treat(cid:173)
`ment.20-22 The antifolate showed promising activity,
`with an overall RR that exceeded 25%, and the drug
`was effective in subsets of patients with prior failure to
`anthracyclines (RR, 29%), failure to taxanes (RR, 28%),
`and failure to anthracyclines and taxanes (RR, 19%).
`Pemetrexed has also shown promising activity in pa(cid:173)
`tients with bladder cancer (RR, 32%; see below) and in
`patients with squamous cell carcinomas arising in the
`uterine cervix (RR, 21 %) and the head and neck (RR,
`33%).23-25 The single-agent activity of pemetrexed di(cid:173)
`sodium in patients with advanced pancreatic carci(cid:173)
`noma was marginal (RR, 6%).26
`A pooled toxicity analysis of 872 patients entered
`on Phase II trials is presented in Table 3.2- 4,27 Myelo(cid:173)
`suppression, as may be predicted by the antifolate
`nature of pemetrexed, was the predominant side ef(cid:173)
`fect. Grade 3-4 neutropenia was observed in 50% of
`patients, and febrile neutropenia and neutropenic
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1079-0003
`
`

`
`TABLE 2
`Single-Agent Phase II Trials with Pemetrexed
`
`A Promising New Agent: Pemetrexed Disodium/Paz-Ares et al.
`
`2059
`
`Authors
`
`Rusthoven et aP 5
`NSCLC
`First line
`Clarke et aP6
`NSCLC
`First line
`Postmus et aP'
`NSCLC
`Second line
`Cripps et aP 8
`Colorectal
`John et aI.19
`Colorectal
`Miller et aI.26
`Pancreas
`
`Lind et aI.2O
`Breast
`Second line
`Theodoulou et aI.21
`Breast
`Third line
`Spielmann et aI.22
`Breast
`Second or third line
`Goedhals and van Wijk24
`Cervix
`Pivot et aI.25
`Head and neck
`Paz-Ares et aI.23
`Bladder
`
`No. of
`patients
`
`33
`
`40
`
`43
`
`29
`
`40
`
`42
`
`36
`
`24
`
`69
`
`24
`
`35
`
`31
`
`Dose mg/m2
`
`600 (3 patients)
`500 (30 patients)
`
`500
`
`500
`
`600 (9 patients), 500 (23 patients)
`
`600
`
`600
`
`600
`
`500
`
`600
`
`600
`
`500
`
`600 (6 patients), 500 (25 patients)
`
`Response rate
`(%)
`
`Overall survival
`(months)
`
`23
`
`18
`
`P13
`NP30
`
`17
`
`15
`
`40
`
`31
`
`19
`
`26
`
`21 (71% SD)
`
`26.5
`
`32
`
`9.2
`
`9.8
`
`4.3
`
`12
`
`12.8
`
`6.4
`
`9.5
`
`NSCLC: nonsmall cell lung carcinoma; P: previously treated with platinum-based regimens; NP: previously treated with nonplatinum-based regimens; SD: stable disease.
`
`sepsis were relatively uncommon. The incidence of
`Grade 3-4 thrombocytopenia and anemia was 15%
`and 17%, respectively. The most common nonhema(cid:173)
`tologic toxicity was hepatic enzyme elevations (Grade
`1-2 in 60-70% of patients, Grade 3 in 12% of patients).
`Elevations of transaminase levels were more frequent
`than alkaline phosphatase and bilirubin abnormalities
`and typically returned to baseline levels before the
`start of the subsequent course. A diffuse maculopap(cid:173)
`ular rash with a predominantly truncal distribution
`was frequent but was preventable with steroid pre(cid:173)
`medication in subsequent cycles. Other toxicities,
`usually mild to moderate, included emesis, fatigue,
`mucositis, and diarrhea.
`From December 1999, a requirement for daily oral
`folic acid 350-600 fLg per day and vitamin Bl2 was
`added to all pemetrexed studies. The rationale for this
`requirement was based on some compelling data sug(cid:173)
`gesting an improvement in the therapeutic index of
`
`this drug when given with vitamin supplementation.
`Some investigators have established a correlation be(cid:173)
`tween the folic acid status of patients and the inci(cid:173)
`dence of toxicity with other antifolates. 28
`29 These
`•
`studies concluded that the addition of folate to these
`treatments markedly decreased the incidence of tox(cid:173)
`icity while maintaining efficacy. More recently, Wor(cid:173)
`zalla et al. reported that, in mice that were given folic
`acid with pemetrexed, the incidence and severity of
`adverse events were lowered dramatically, whereas
`the antitumor activity was preserved.3D Concurrent
`with that study, Niyikiza et al. assessed the correlation
`between vitamin metabolites (homocysteine, cystathi-
`0nine' and methylmalonic acid), systemic pemetrexed
`exposure, and patient toxicities.31 Those authors ob(cid:173)
`served that high homocysteine pretreatment levels,
`which reflect poor folate status, were related closely to
`an increased risk of Grade 4 neutropenia or thrombo(cid:173)
`cytopenia, Grade 3-4 mucositis, or diarrhea. A subse-
`
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`
`

`
`2060
`
`CANCER Supplement April 15, 2003/ Volume 97/ Number 8
`
`TABLE 3
`Hematologic and Nonhematologic Toxicity in 872 Patients Treated in
`the Phase II Program of Pemetrexed (500-600 mg/m2 every 3 weeks)a
`
`NCI-CTC toxicity grade (worst per patient, %)
`
`Toxicity
`
`ANC
`Hemoglobin
`Platelets
`Nausea
`Emesis
`Stomatitis
`Diarrhea
`Alk phos
`ALI
`ASI
`Bilirubin
`Creatinine
`Cutaneous
`Fatigue
`Infection
`Pulmonary
`
`2
`
`17
`37
`8
`22
`20
`12
`
`21
`20
`
`27
`19
`
`10
`31
`22
`28
`15
`20
`15
`32
`39
`47
`< 1
`11
`19
`16
`
`3
`
`23
`14
`8
`
`12
`
`< 1
`5
`6
`
`4
`
`27
`3
`
`< 1
`2
`< 1
`2
`
`< 1
`< 1
`2
`
`< 1
`2
`
`NCI-CTC: National Cancer Institute Common Toxicity ANC: absolute neutrophil count; Alk phos:
`alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase.
`
`quent study explored combining pemetrexed and
`high-dose, intermittent, oral folic acid (5 mg daily on
`Days - 2 to Day + 2 of every cycle) in a Phase I triaL32
`Preliminary data have indicated that folic acid ame(cid:173)
`liorates toxicities, permitting dose escalations ofpem(cid:173)
`etrexed up to ::,. 925 mg/m2 in heavily pretreated pa(cid:173)
`tients_ A recent report of an ongoing Phase II trial of
`pemetrexed with or without folic acid in patients with
`gastric cancer also indicates that the addition of the
`vitamin substantially improves the safety profile of
`pemetrexed_33 Furthermore, a preliminary compara(cid:173)
`tive toxicity analysis of patients treated in different
`trials with (78 patients) or without (246 patients) vita(cid:173)
`min supplementation showed that the addition of fo(cid:173)
`lic acid and vitamin Bl2 substantially reduced the in(cid:173)
`cidence of adverse events, such as Grade 4
`neutropenia (2_6% vs_ 32%), Grade 4 thrombocytope(cid:173)
`nia (0% vs_ 8%), Grade 3-4 mucositis (1.3% vs_ 5%),
`Grade 3-4 diarrhea (2_6% vs_ 6%), and toxic death (0%
`vs_ 5%)_2
`
`Combination Studies
`Once an anticancer drug has shown clinical activity as
`single agent and has been associated with a manage(cid:173)
`able toxicity profile, like pemetrexed disodium, the
`next logical step in its development is to perform
`combination studies with other active compounds,
`particularly those with different mechanisms of action
`and nonoverlapping toxicity_ Xenograft studies ini-
`
`tially performed showed that the most effective com(cid:173)
`binations of pemetrexed were with platinum com(cid:173)
`pounds and 5-fluorouraciL Synergistic or additive
`antitumor effects were also achieved with gemcitab(cid:173)
`ine, methotrexate, and paclitaxeL3-1o Additive re(cid:173)
`sponses were seen with doxorubicin, vinorelbine, cy(cid:173)
`clophosphamide, and fractional radiation_
`Clinical trials of pemetrexed in combination with
`cisplatin and other analogs, including gemcitabine,
`irinotecan, taxanes, anthracyclines, and 5-fluoroura(cid:173)
`cil, have been initiated_ Initials results are available for
`some regimens, although many studies are still ongo(cid:173)
`ing_ Thodtmann et aL performed a Phase I trial with
`the combination of pemetrexed and cisplatin in which
`neutropenia and delayed fatigue were the observed
`toxicities_34 Those authors
`dose-limiting
`recom(cid:173)
`mended the following dose and schedule for future
`trials: pemetrexed 500 mg/m2 followed, after a 30-
`minute wash-out period, by cisplatin 75 mg/m2_
`Eleven of 40 assessable patients in that trial showed an
`objective remission, including one complete response_
`It is interesting to note that 5 of 11 patients with
`malignant mesothelioma obtained a partial response_
`Based on these data, a large Phase III trial comparing
`cisplatin with pemetrexed plus cisplatin has been per(cid:173)
`formed in patients with malignant mesothelioma_ The
`results of that trial were presented recently at the 2002
`annual meeting of the American Society of Clinical
`Oncology and showed that the combination regimen
`improved survival significantly compared with cispla(cid:173)
`tin alone (hazard ratio [HR], 0_77; P < 0_020)_ In addi(cid:173)
`tion, combined pemetrexed and cisplatin also showed
`significant improvements in the response rate (41 % vs_
`17%; P < 0_001), the time to disease progression (HR,
`0_64; P < 0_008), lung function, and subjective indica(cid:173)
`tors of quality of life_
`The pemetrexed/ cisplatin regimen has been
`tested as front-line treatment in patients with ad(cid:173)
`vanced NSCLC in two Phase II studies_ Manegold et aL
`reported an overall response rate of 39% and a median
`survival of 10_9 months in 36 patients who were in(cid:173)
`cluded in their study_ The main toxic effects were
`Grade 3-4 neutropenia (59%), Grade 3-4 thrombocy(cid:173)
`topenia (17%) and Grade 3-4 diarrhea (6%)_35 Com(cid:173)
`parable results were obtained in another study that
`was conducted in Canada_ 36
`The combination of pemetrexed 400-600 mg/m2
`and carboplatin (area under the serum concentration(cid:173)
`time curve, 4-6 mg/mL per minute) has been studied
`in a Phase I trial in patients with malignant mesothe(cid:173)
`lioma_37 The toxicities were manageable, including
`predominantly short-lived myelosuppression, and re(cid:173)
`sponses were observed in 10 of 20 patients who were
`evaluated_ According to that study, the recommended
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1079-0005
`
`

`
`A Promising New Agent: Pemetrexed Disodium/Paz-Ares et al.
`
`2061
`
`dose for Phase II trials is pemetrexed 500 mg/m2 and
`carboplatin 5 mg/mL per minute. In another ongoing
`trial, the doublet pemetrexed plus oxalipaltin has been
`investigated.38 The regimen seems to be well tolerated,
`with hematologic dose-limiting toxicities, and 2 partial
`responses have been observed in 28 patients who are
`participating. The recommended schedule for further
`testing consists ofpemetrexed 500 mg/m2 followed by
`oxaliplatin 120 mg/m2.
`A Phase I study of sequences of gemcitabine and
`pemetrexed was completed recently.39 The recom(cid:173)
`mended dose and schedule for this combination was
`gemcitabine 1250 mg/m2 on Days 1 and 8 and pem(cid:173)
`etrexed 500 mg/m2 on Day 8 (administered 90 min(cid:173)
`utes after gemcitabine) every 3 weeks. The most com(cid:173)
`mon toxicity was neutropenia, and other toxicities
`included emesis, fatigue, and transaminitis. The re(cid:173)
`sults were encouraging, with responses observed in 13
`of 35 patients who had a variety of solid tumors. An
`ongoing Phase III trial is comparing single-agent gem(cid:173)
`citabine with the gemcitabine plus pemetrexed com(cid:173)
`bination in patients with advanced pancreatic cancer.
`
`Pemetrexed Disodium in Patients with Bladder Cancer
`The safety and efficacy of pemetrexed in patients
`with advanced bladder cancer was explored in a
`recently concluded Phase II study in a chemother(cid:173)
`apy naIve population.23 Thirty-three patients (31
`men and 2 women; median age, 65 years) with met(cid:173)
`astatic or recurrent, inoperable bladder carcinoma
`who had measurable disease and a World Health
`Organization performance status <s 2 were included.
`Two patients were ineligible, because one patient
`had received prior chemotherapy, and the other
`patient had low creatinine clearance. Treatment
`consisted of pemetrexed 600 mg/m2 (the first 6 pa(cid:173)
`tients) or 500 mg/m2 (the remaining patients) ad(cid:173)
`ministered as a 10-minute infusion every 21 days.
`No vitamin supplementation was given.
`A total of 114 cycles of pemetrexed were admin(cid:173)
`istered to 31 patients. Patients underwent a median of
`3 cycles (range, 1-12 cycles) of therapy. The 25 pa(cid:173)
`tients who were administered pemetrexed 500 mg/m2
`received a median of 4 cycles (range, 1-9 cycles), with
`a median dose intensity of 483 mg/m2. The 6 patients
`who were administered pemetrexed 600 mg/m2 re(cid:173)
`ceived a median of 2 cycles (range, 1-12 cycles), with
`a median dose intensity of 577 mg/m2. Toxicity in this
`trial was significant and was predominantly hemato(cid:173)
`logic, including Grade 3-4 thrombocytopenia (6%),
`anemia (23%), neutropenia (71 %), and febrile neutro(cid:173)
`penia (26%). Nonhematologic toxicity consisted of
`mild-to-moderate mucositis, diarrhea, and lethargy.
`Three early deaths were observed due to sepsis and
`
`renal failure or mucositis (two patients) and atrial
`fibrillation and cardiac failure (one patient). We spec(cid:173)
`ulate that two factors may have contributed to the
`higher incidence of toxicity observed in our trial com(cid:173)
`pared with other Phase II studies in solid tumors. First,
`patients with bladder cancer often have some degree
`of renal impairment associated with their disease
`state. This may have conditioned a decreased pem(cid:173)
`etrexed clearance and, subsequently, an increase in
`the incidence of certain toxicities, such as neutrope(cid:173)
`nia.9,13 Second, the nutritional status and, in particu(cid:173)
`lar, the folate status of the patients in this study may
`have been poorer compared with other cohorts, Many
`patients with bladder cancer in Spain have a history of
`heavy alcohol consumption, Furthermore, the typical
`diet in Spain does not include the vitamin-enriched
`breakfast cereals consumed in the United States,
`Twenty-eight patients who received at least two
`cycles were evaluable for efficacy according to the
`protocoL Nine patients (32%; 95% confidence interval
`[95%CI], 16-52%) achieved a partial response, Ten
`patients (36%) had disease stabilization, and 6 pa(cid:173)
`tients (21 %) had a best study response of progressive
`disease, Tumor response was not evaluated in three
`patients (11 %), The response rate on an intent -to-treat
`basis was 29% (95%CI, 14-48%), Responses were seen
`at all disease sites, including the liver, and were more
`frequent in patients with better performance status (0
`vs, 1-2; P = 0,013) and with nonvisceral metastasis (P
`= 0,01) but were not related to the starting dose (500
`mg/m2 vs, 600 mg/m2; P = LO), The antitumor activity
`observed in this trial was encouraging and identified
`pemetrexed as the only new drug with activity against
`urothelial bladder cancer since studies demonstrated
`the activity of gemcitabine, paclitaxel, and docetaxeL 40
`The median response duration (8,0 months; 95%CI,
`7.4-10.5 months) and overall survival (9.4 months;
`95%CI, 5,7-12,8 months) compare favorably with most
`single agents in this setting and are similar to those
`noted with novel combination regimens, such as car(cid:173)
`boplatin plus paclitaxeL 41 These results are particu(cid:173)
`larly appealing considering the fact that all patients in
`our series had metastatic or recurrent disease, and
`61 % of patients had visceral metastases,
`Based on this study, a new single-agent pem(cid:173)
`etrexed trial (500 mg/m2 with vitamin supplementa(cid:173)
`tion) has been initiated in pretreated patients, In ad(cid:173)
`dition, and taking into account the combination
`regimen data in other patient populations, doublets
`and triplets of pemetrexed with platinum compounds,
`gemcitabine, and other active agents (such as taxanes)
`merit further investigation,
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1079-0006
`
`

`
`2062
`
`CANCER Supplement April 15, 20031 Volume 971 Number 8
`
`Conclusions
`Pemetrexed disodium is a new and multitargeted an(cid:173)
`tifolate that exhibits significant antitumor activity in a
`wide range of solid tumors, including NSCLC, me(cid:173)
`sothelioma, and carcinomas of the breast, colon, uter(cid:173)
`ine cervix, head and neck, and bladder. Promising
`feasibility and activity data have been obtained with
`pemetrexed in combination with platinum com(cid:173)
`pounds and gemcitabine. The supplementation with
`daily oral folate may reduce the incidence of hemato(cid:173)
`logic toxicities while preserving the antitumor activity
`of pemetrexed disodium. The role of this agent in the
`management of patients with solid tumors will be
`determined by randomized Phase III studies, like the
`recent study performed in patients with malignant
`mesothelioma that has been closed to accrual.
`
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