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`Journal Title: Journal of clinical oncology : official ODYSSEY ENABLED
`journal of the American Society of Clinical
`.
`Oncology
`Charge
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`Maxcost: $15.00
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`Volume: 17 Issue: 4
`MonthIYear: 1999Pages: 1194—9+TOC+acq
`
`Article Author: Rusthoven et al.
`Article Title: Multitargeted Antifolate LY231514 as
`1st+TOC+datestamp/cvr
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`‘mprmt:
`Number: 38232390
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`llililllllllllllllllllllllllllllllllllllllllllllll
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`
`Multitargeted Antifolate LY23l514 as First-Line
`Chemotherapy for Patients With Advanced Non—Small-Cell
`Lung Cancer: A Phase II Study
`
`By James J. Rusthoven, Elizabeth Eisenhauer, Charles Butts, Richard Gregg, Janet Dancey, Bryn Fisher,
`and Jose Iglesias for the National Cancer Institute of Canada Clinical Trials Group
`
`Purgs : To evaluate the efficacy and safety of the
`multitargeted antifolate LY231514 (MTA)
`in patients
`receiving initial chemotherapy for unresectcible, ad-
`vanced non-small-cell lung cancer (NSCLC).
`Patients and Methods: Patients with measurable, ad-
`vanced NSCLC who had not received previous chemo-
`therapy for advanced disease were considered for this
`study. Eligible patients who gave written informed con-
`sent initially received MTA 600 mg/m’ intravenously
`(IV) for 10 minutes every 3 weeks. After three patients
`received treatment at this close, the dose was reduced to
`500 mg/m1 IV at the same infusion time and frequency
`because of toxicity seen in this study and another
`Canadian MTA trial in colorectal cancer. Patients re-
`ceived up to four cycles after complete or partial remis-
`sion or six cycles after stable disease was documented.
`Results: Thirty-three patients were accrued onto the
`study. All were assessable for toxicity, and 30 patients
`were assessable for response. All but one patient had
`an Eastern Cooperative Oncology Group performance
`status score of O or 1, 18 patients (55%) had adenocarci-
`noma, and nine patients (27%) had squamous cell
`carcinoma. Twenty-five patients (76%) had stage IV
`disease, and the remainder had stage IIIB disease at
`
`trial entry. Seven patients experienced a confirmed
`partial response and no complete response: were seen;
`thus, the overall response rate was 23.3% (95% confi-
`dence interval, 9.9°/o to 42.3%). The median duration of
`response was 3.1 months (range, 2.3 to 13.5 months)
`after a median follow-up period of 7.9 months. Four
`(67%) of six patients with stage IIIB disease and three
`(12.5%) of 24 with stage IV disease responded to
`treatment. Four patients (13.3%) experienced febrile
`neutropenia and 13 (89%) experienced grade 3 or A
`neutropenia, whereas only one patient (3%) developed
`grade 4 thrombocytopenia. Nonhematologic toxicity
`was generally mild or moderate, but 39% of patients
`developed a grade 3 skin rash. Most other toxicities
`comprised grade 1 or 2 stomatitis, diarrhea, lethargy,
`and anorexia. Ten patients stopped protocol therapy
`because of toxicity.
`Conclusion: MTA seems to have clinically meaningful
`activity as a single agent against advanced NSCLC.
`Toxicityis generally mild and tolerable. Further study of
`this agent in combination with cisplatin and other active
`drugs is warranted in this disease.
`J Clin Oncol 17:7 194-1 199. 0 1999 by American
`Society of Clinical Oncology.
`
`HYMIDYLATE SYNTHASE (TS) is the primary tar-
`get of the fluoropyrimidines fluorouracil (5—FU) and
`fluorodeoxyuridine, long-established active agents in the
`treatment of gastrointestinal cancers, breast cancer, and
`other malignancies.’-2 Biomodulation of 5-FU by 1eucovo-
`rin,2 interferon} or methotrexate4 has resulted in greater
`inhibition of TS and, consequently, improved response rates5
`and surviva1,° particularly among patients with colorectal
`cancer. However, the fluorinated pyrimidines, such as 5-FU,
`
`From the Hamilton Regional Cancer Centre, Hamilton, Queens
`University, Kingston, and Eli Lilly and Company, Scarborough, On-
`tario; and Nova Scotia Cancer Treatment and Research Foundation and
`Dalhousie University, Halifax, Nova Scotia, Canada.
`Submitted May 18, 1998; accepted November 23. I998.
`Supported by the National Cancer Institute ofCanada Clinical Trials
`Group, Kingston, and Eli Lilly and Company, Scarborough, Ontario,
`Canada.
`Address reprint requests to James J. Rusthovén, MD, Eli Lilly and
`Company, Lilly Research Laboratories, Lilly Corporate Center, DC
`2202, Indianapolis, IN 46285.
`© 1999 by American Society of Clinical Oncology.
`0732-183X/99/1 704-I194
`
`are indirect inhibitors of TS. requiring metabolic activation.
`and are linked to other effects, such as alteration of RNA
`metabolism.‘ Such non-TS—inhibiting effects may lead to a
`low therapeutic index due to increased toxicity or loss of
`efficacy. In addition, inhibition of TS results in an increase in
`intracellular deoxyuridinc monophosphatc that can compete
`with pyrimidine analogs for binding to TS.’
`Direct and more specific inhibitors of TS have been
`developed that interact with the folalc—binding site ol'TS.‘“‘
`These folate analogs have been designed to improve the
`specificity for TS inhibition;
`furthermore, dcoxyuridine
`monophosphate would enhance rather than competitively
`reverse their binding to TS. Multitargctcd antifolate
`LY231514 (MTA) was designed as a folate-based TS
`inhibitor with a glutamate side chain in this new class of
`folate antimetabolitcs.‘3~‘3 Although MTA itself only moder-
`ately inhibits TS, polyglutamation of the parent drug and its
`metabolites readily occurs, and the polyglutamated form of
`MTA is 100-fold more potent than MTA itself. In addition,
`other folate-requiring enzymes may act as targets for this
`drug, including dihydrofolate reductase, glycinamide ribo-
`nucleotide formyltransferase, aminoimidazole carboxamide
`
`H94
`
`Journal olCllnical Oncology, Vol 17, No A (April), i999: pp 1 l9d~l 199
`
`Teva – Fresenius
`Exhibit 1033-00002
`
`

`
`MULTI-TARGETED ANTIFOLATE FOR ADVANCED NSCLC
`
`H95
`
`ribonucleotide formyltransferase, and Cl tetrahydrofolate
`synthase.’4~‘5
`MTA has demonstrated activity in a wide range of tumor
`types. The drug is highly active against CCRF-CEM human
`lfillkemifl C6115 in Vitro; the activity is partially reversible
`with the addition of thymidine.”'” The 50% inhibitory
`concentration in CCRF-CEM cells was 7 ng/mL.13 It is also
`cytotoxic in human tumor colony-forming unit assays against
`human colon, renal, small-cell lung and non-small-cell lung
`cancers, hepatomas, and carcinoid tumors.“ MTA can
`inhibit tumor growth in mice transplanted with human colon
`xenografts resistant to methotrexate.” In beagle dogs treated
`with a weekly and/or single—dose intravenous (IV) schedule,
`major toxicities included anorexia, emesis, diarrhea, mucosi—
`tis, weight loss, neutropenia, lymphopenia, and mild anemia.
`Plasma concentrations increased linearly with increasing
`doses, with the terminal half-life occurring at about 2.3
`hours.” Early studies have suggested that dietary supplemen-
`tation with folic acid may improve the therapeutic index by
`reducing toxicity in mice.
`A phase I trial of single-agent MTA was recently com-
`pleted in which patients were treated by 10-minute IV
`infusion every 3 weeks. Starting at 50 mg/m2, doses were
`escalated to 700 mg/m2, at which point three of six patients
`developed grade 4 ueutropenia and grade 3 or 4 thrombocy—
`topenia. In patients who received 500 to 600 mg/m2 MTA,
`serum peak concentrations were 70 to 200 pg/mL, values
`well above the 50% inhibitory concentration in CCRF—CEM
`cells (data for peak concentrations provided by J. Walling,
`personal communication, October 1998). Twenty patients
`were treated at the 600-mg/n12 dose level, and 25% of them
`developed grade 4 neutropenia, 10% developed grade 3 or 4
`thrombocytopenia, and 50% developed grade 2 pruritic skin
`rash. Four partial responses (four [11%] of 37 patients) were
`seen in patients with pancreatic and col orectal cancer.”
`With these data, the recommended starting dose for phase
`II studies using this schedule was 600 mg/m2. Two phase II
`studies have been conducted through the National Cancer
`Institute of Canada Clinical Trials Group, one in colorectal
`cancer and one in non-small-cell lung cancer (NSCLC). The
`results of the latter study are reported here.
`
`PATIENTS AND METHODS
`P_atient Selection
`Eligible patients were accrued between September 1995 and Febru-
`ary 1997. These patients had histologically or cytologically confirmed
`inoperable, locally advanced, or metastatic NSCLC with evidence of
`bidimensionally measurable disease. Prior radiation therapy was permit-
`ted if acute side effects had resolved. Previous systemic therapy given
`for advanced disease was not permitted, but prior adjuvant therapy was
`allowed if the last dose was given 2 12 months earlier. Other eligibility
`criteria included (1) age 2 16 years, (2) Eastern Cooperative Oncology
`
`Group performance status of 0 to 2, (3) serum creatjnine level within
`normal limits, (4) good hepatic function (ie, serum bilirubin S. 1.5 times
`the upper normal limit and AST 5 two times the upper normal limit 91-
`5 five n'mes the upper normal limit if liver metastases were present), (5)
`adequate bone marrow function and reserve (absolute granulocyte
`count > 1.5 X 109/L and platelet count 2 150 X 109/L), (6) absence of
`clinically detectable third-space fluid collections, (7) absence of clinical
`evidence of brain metastases, and (8) no concurrent treatment with other
`experimental drugs, anticancer therapy, or folinic/folic acid supple-
`ments.
`
`Drug Administration
`MTA was supplied as a lyophilized powder in 100-mg vials and was
`reconstituted by adding 10 mL of 0.9% sodium chloride. The appropri-
`ate dose was then withdrawn, diluted in normal saline, and administered
`intravenously over 10 minutes every 3 weeks. Retreatment at the initial
`dose and on schedule was determined by the lack of hematologic (S
`grade 1 on day of treatment and granulocytopenia 2 0.5 X 109/L and
`thrombocytopenia 2 50 X 109/L at nadir) and nonhematologic (grade
`3 2) toxicity. Patients with grade 5 2 nonhematologic toxicity were
`treated symptomatically without delays, except for cases of grade 2 skin
`rash, in which case treatment was delayed until rash improved to grade
`5 1. Patients with severe (grade 3 or 4) nonhematologic toxicity
`received a 25% dose reduction during subsequent cycles once toxicity
`had subsided. Those with nadir granulocytopenia less than 0.5 but less
`than severe thrombocytopenia (.>_ 50 X 10°/L) also received a 25% dose
`reduction for the next cycle. The use of nonsteroidal anti-inflarnmatory
`drugs and salicylates was permitted but not on or around the day of
`treatment. (This precaution was taken because of previous kinetic data
`suggesting increased drug levels during coadministration of anti-
`inflammatory agents.) Supportive—care agents, such as colony-
`stimulating factors, were permitted but could not be substituted for dose
`reductions required according to protocol. No dose escalations were
`permitted.
`
`Measurements of Study End Points
`All patients were assessable for toxicity from the time of their first
`treatment. Patients who had received at least one cycle of MTA and had
`follow—up measurements performed to assess change in tumor size were
`assessable for response, Response was assessed on day l of each cycle
`by clinical tumor measurements and documentation of the tumor size of
`measurable and nonmeasurable disease, using positive radiographic
`tests. If results were initially negative,
`tests were repeated only if
`clinically indicated. All sites with measurable lesions were followed for
`response. Measurements of undimensional lesions (ie, single largest
`dimensions) and bidimensional lesions (the products of the largest
`diameter and its largest perpendicular) were summed at each assessment
`and the best response on study was recorded.
`A complete response required the disappearance of all clinical and
`radiologic evidence of minor for at least 4 weeks. A partial response
`required a 2 50% decrease in the sum of the products of the diameters
`of all measurable lesions, also for at least 4 weeks. Stable disease
`designated a steady-state of disease, which was a response less than a
`partial response or progression less than progressive disease, both for at
`least 6 weeks from the start of therapy. In addition, there could be no
`new lesions or increases in the size of any nonmeasurable lesions for
`
`Teva – Fresenius
`Exhibit 1033-00003
`
`

`
`Table 1. Patient Characteristics
`
`RUSTHOVEN ET Al
`
`63
`
`Age, years
`Median
`Range
`Sex
`Female
`Male
`Performance status‘
`
`0l2
`
`Histology
`Adenocorcinoma
`Squamous
`Unclifferenliol
`Prior therapy
`Radiation Iiweropy
`Sites of disease
`Lung
`Lymph nodes
`Liver
`Bone
`Adrenal
`Pleural effusion
`Subcutaneous
`Spleen
`Stage at study entry
`lllB
`lV
`No. of organ sites involved
`
`l232
`
`4
`
`‘Eastern Coopoerotive Oncology Group performance status.
`
`Toxicity
`
`After the first three patients were accrued, a decision was
`made to reduce the starting dose to 500 mg/m2 based on the
`combined toxicity of 12 patients entered onto this study and
`a Canadian study of the same initial dose and schedule in
`patients with advanced colorectal cancer (Cripps et 81.
`manuscript submitted for publication). Of the first three
`patients in the present trial, one patient experienced grade 3
`dyspnea, mucositis, and high fever with radiographic suspi-
`cion of pneumonia. The patient recovered but refused further
`therapy. The other two patients completed six cycles of
`therapy at
`the initial dose. Two of the three patients
`experienced grade 3 neutropenia, and none experienced
`higher than grade 2 renal or hepatic toxicity. The hemato-
`logic toxicity experienced by the 30 patients who started at
`the 500-mg/m2 dose level was similar to that of the other
`three patients. Hematologic toxicity, as median nadir counts
`and by worst grade experienced for all patients, is listed in
`Table 2. Overall, only two patients experienced a grade 4
`
`ll96
`
`complete or partial remissions or for stable disease. Progressive disease
`indicated an unequivocal increase of at least 25% in the sum of the
`products of the diameters of all measurable lesions compared with
`baseline or the appearance of new lesions. Nonmeasurable disease was
`not considered in the response assessment, except that new lesions
`would constitute progressive disease; all nonmeasurable lesions had to
`disappear for a designation of complete response to be made.
`Response duration was defined from the time that criteria for
`response were met until disease progression was objectively docu—
`mented, with disease progression measured from the time that response
`was established. Stable disease was measured from the start of therapy
`until disease progression. All reported responses were verified by
`independent radiology review.
`
`RESULTS
`
`Thirty—three patients were accrued onto this study. All
`patients were assessable for toxicity, and 30 patients were
`assessable for response. The three unassessable patients
`came off study before the second treatment because of
`toxicity. One hundred thirty—two cycles were administered;
`13 cycles were given to the three patients at the initial
`600-mg/ml dose (median, six cycles; range, one to six
`cycles), and 75 cycles were given to patients who started at
`the 500—mg/m2 dose (median, four cycles; range, one to
`eight cycles). Of the 30 patients who started at the 500-
`mg/rnz dose, 15 received one cycle at this dose, four received
`two cycles, and 11 received three or more cycles. Fourteen
`patients required a dose reduction to 375 mg/ml for one or
`more cycles. Four patients required a further dose reduction
`to 281 mg/m2. Characteristics of the 33 patients are listed in
`Table 1. The majority were male, presented with excellent
`performance status, and received only radiotherapy as prior
`treatment. A majority (18 of 33) had adenocarcinoma as a
`histologic diagnosis, and 26 of 33 patients had more than
`one site of involvement at study entry. At the time this article
`was written, the median follow-up was 7.9 months (range,
`3.3 to 16.8 months).
`(For patients who died,
`the last
`follow-up date was the date of death.)
`
`/lntitumor Activity
`
`Of the 30 patients assessable for response, none had a
`complete response and seven patients had a confirmed
`partial response; thus, the overall response rate was 23.3%
`(95% confidence interval, 9.9% to 42.3%). When all eligible
`patients are included,
`the response rate is 21.2%. The
`median time to progression for all patients was 3.8 months
`(range, 0.5 to 15.8 months). The median survival time of all
`patients was 9.2 months (Fig 1), and the 1-year survival rate
`was 25.3% (95% confidence interval, 9.7% to 40.9%). A
`higher response was seen among stage IIIB patients (four
`[67%] of six) compared with those who entered the study
`with stage IV disease (three [12.5%] of 24).
`
`Teva – Fresenius
`Exhibit 1033-00004
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`

`
`MULH-TARGETED ANTIFOLATE FOR ADVANCED NSCLC
`
`H97
`
` p_
`Table 3. Nonhematologic Toxicity in = 33}
`-i——j———__
`0
`4°
`0
`% Drugv
`Grocle(no.oFporienIs)
`TMNO 6
`% ‘
`l
`2
`3
`4
`Patients
`Patients Related Only
`26
`79
`79
`10
`29
`88
`76
`15
`l0
`22
`67
`58
`_ l 4
`42
`33
`26
`79
`‘ 76
`8
`24
`0
`ll
`33
`33
`16
`49
`46
`ll
`33
`30
`i3
`39
`21
`4
`l2
`l2
`I0
`30
`6
`
`—
`
`00000 0
`
`OO 00
`
`0
`
`
`
`
`
`ProportionSun:‘wing
`
`Median S|ll'VlV3I1 5.51 MOHUIS
`
`10
`16
`Time (months)
`1: Al Risk
`
`3
`5
`8
`
`‘
`.
`T°x'c'lV
`Skin msh
`Lethargy
`Anorexia
`Diarrhea
`Nausea
`Arlhrclgio
`Stomafitis
`Vomiting
`Tearing
`Edema
`Febrile neutropenia
`lnleciion
`
`Apmmmmwnwnoa
`
`Fig 1. Overall survival of all patients.
`
`DISCUSSION
`
`Initial results from preclinical animal studies and phase I
`trials suggested clinical activity for MTA primarily against
`colorectal and pancreatic cancer.193° The level of activity
`seen in the present study in NSCLC was higher than initially
`anticipated, and independent reviewers confirmed all re:
`sponses. This promising level of clinical activity was seen in
`patients with lung and lymph node involvement as well as in
`those with visceral and bone involvement, although the
`proportion of patients who responded was much higher in
`the group of stage IIIB patients. In another phase II study of
`MTA in patients with NSCLC by Clarke et al,“ all patients
`were initially treated with 600 mg/m2 MTA. Response rates
`were comparable to those in this study; among 12 patients
`assessable for response, the overall response rate was 33%
`(all partial responses). Toxicity profiles were similar be-
`tween the two studies; in addition, toxicity seen in the phase
`I studies was similar to that reported for other drugs in this
`class.‘9=2°’22 Neutropenia was the predominant hematologic
`toxicity, resulting in dose reduction in 12% of patients, but it
`did not lead to treatment delays; only one patient (3%)
`experienced dose-reducing (grade 4) thrombocytopenia.
`Most symptomatic, nonhematologic toxicity was man-
`aged with appropriate supportive care; for 2 grade, 3
`toxicity, the next cycle was delayed until symptoms resolved
`to 2 grade 1 severity and subsequent doses were reduced by
`25%. Nausea and emesis were infrequent and not seven;
`
`Table 4. Biochemical Changes (:1 = 3])
` .&%
`Toxicity Grade
`2
`l
`3
`'o*~—§-.—
`
`at
`
`3
`
`20
`
`Serum creotinine
`Bilirubin
`AST
`Alkaline phosphatase
`
`29
`26
`5
`1 A
`
`1
`0
`17
`1 6
`
`1
`A
`7
`1
`
`adverse event; one experienced a cerehrovascular accident,
`and the other patient developed a deep vein thrombosis and
`pulmonary thromboembolus associated with severe short-
`ness of breath. Neither of these events was considered
`
`related to the MTA therapy. Other than these cases, the most
`severe and prevalent nonhematologic toxicities are listed in
`Table 3. Severe (grade 3) nonhematologic toxicity presented
`most commonly as a skin rash (39%),
`lethargy (27%),
`anorexia (12%), nausea (12%), vomiting (9%), and diarrhea
`(9%), most of which was attributable to the study drug. The
`skin rash was generalized in half of affected patients and
`symptomatic with primarily pruritus in 23 of 26 patients.
`Subsequent retrospective analysis in this and the colorectal
`phase II study of the same agent showed that patients who
`received dexamethasone in their first cycle had a lower
`frequency and severity of skin rash (without dexarnethasone,
`93% of cycles with skin rash, 47.5 % grade 3; with dexametha~
`sone, 56% of cycles with skin rash, 12% grade 3). Four
`patients (12% of all patients) on the study developed febrile
`neutropenia, with one documented severe systemic infection
`considered related to protocol therapy.
`Nonhematologic biochemical changes were mild. Only
`three patients developed transient grade 3 elevations of their
`liver function tests (bilirubin and AST), and only one patient
`developed grade 2 elevation of serum creatinine (Table 4).
`
`Table 2. Hematologic Toxicity (n = 33)
`Nadir (X l0’/L]
`Toxicity Grade
`Median
`Range
`2
`
`0
`
`l
`
`l 4
`
`l0
`9
`
`66
`
`7
`l 7
`
`Hemoglobin, g/l.
`WBC
`Grunulocyles
`Platelets
`
`l l l
`2.5
`l . l
`l 52
`
`73-149
`0.4-8.1
`00-40
`20-278
`
`Teva – Fresenius
`Exhibit 1033-00005
`
`

`
`H98
`
`RUSTHOVEN er AL
`
`and physician discretion was permitted for prophylaxis
`based on the low emetogenic potential projected from phase
`1 studies. Skin rashes were frequent; 30% of patients had
`treatment delayed with no subsequent dose reduction,
`whereas patients with generalized, symptomatic rash (39%)
`were given a 25% dose reduction. Both groups were treated
`prophylactically with dexamethasone for 3 days starting the
`day before each subsequent dose. With this intervention,
`skin toxicity decreased in subsequent cycles. Later in the
`study, it was noted that prophylactic dexarnethasone given in
`cycle I seemed to have a beneficial effect in reducing the
`expected frequency and severity of skin rash. Future trials
`should likely incorporate this premedication at the first dose.
`Thirty percent of patients came off protocol therapy because
`of toxicity, most often gastrointestinal. This highlights the
`considerable interpatient variability of the toxicity experi-
`enced. Nonhematologic biochemical alteration of renal and
`hepatic function was relatively mild and of no clinical
`consequence. In three patients (9%), grade 3 elevation of
`bilirubin or AST levels resulted in dose reduction.
`
`The decision to reduce the starting dose from 600 mg/m2
`to 500 mg/m2 early in this study was based largely on the
`toxicity seen in a larger cohort of patients in a Canadian
`phase II study of colorectal cancer that is using the same
`dose and schedule. The toxicity seen in all other phase II
`trials of lung, breast, and gastrointestinal
`tumors at
`the
`600-mg/m2 dose and schedule has been similar to that seen
`in our study. Factors that may be associated with the more
`severe toxicity seen in the Canadian colorectal trial cohort
`have not yet been identified. The clinical activity in our trial
`
`is similar to that seen in the study of Clarke et al.“ in which
`all patients started at a dose of 600 mg/m2. Furthermore, it is
`interesting that all responding patients were treated at an
`initial dose of 500 mg/ml.
`MTA clearly has relevant clinical activity in patients with
`advanced NSCLC and toxicity that is tolerable with conven-
`tional dose and schedule adjustments. In addition to its effect
`on multiple enzymes in the folate-dependent pathways,
`MTA can synchronize treated cells at the GIS interface
`initially, followed by synchronous entry of treated cells into
`S phase II 4 hours after initial drug exposure in vitro.” A
`recent study suggests that MTA may enhance the cytotoxic
`effect of other drugs, such as gemcitabine, when target
`cancer cells are exposed to MTA 12 to 24 hours earlier.“ A
`phase I combination trial of these two agents is in progress.
`As a result, further studies are planned to test the efficacy of
`MTA in combination with other agents with proven eflicacy
`against NSCLC, such as the taxanes and platinum com-
`pounds. Our group is presently conducting a phase II
`combination study of MTA and cisplatin in advanced
`NSCLC. Ultimately, it is hoped that MTA may contribute to
`an improvement in the survival and quality of life of some
`patients with this disease.
`
`ACKNOWLEDGMENT
`
`We thank the following investigators who, in addition to the authors,
`contributed patients to this study: Y. Connier, Hopitnl Laval. Quebec
`City; A. Neville, Hamilton Regional Cancer Centre, Hamilton; and F.
`Shepherd, The Toronto Hospital, Toronto, Canada.
`
`REFERENCES
`
`'
`
`1. Rustum YM, Harstrick A, Cat) S. et al: Thyrnidylate synthase
`inhibitors in cancer therapy: Direct and indirect inhibitors. J Clin Oncol
`15:389-400, 1997
`2. Poon MA, O’Connell MI, Moertei CG, et al: Biochemical
`modulation of fluorouracil: Evidence of significant improvement of
`survival and quality of life in patients with advanced colorectal
`carcinoma. J Clin Oncol 721407-1413, 1989
`3. Sotos AG, Grogan L, Allegra CJ: Preclinical and clinical aspects
`of biomodulation of 5—fluorouracil. Cancer Treat Rev 20:11-49, 1994
`4. The Advanced Colorectal Cancer Meta-Analysis Project; Meta-
`analysis of randomized trials testing the biochemical modulation of
`fluorouracil by methotrexate in metastatic colorectal cancer. J Clin
`Oncol 12:960-969. 1994
`S. The Advanced Colorectal Cancer Meta-Analysis Project: Modula-
`tion of fluorouracil by leucovorin in patients with advanced colorectal
`cancer: Evidence in terms of response rate. J Clin Oncol 10:896-903,
`1992
`6. Scheithauer W, Depisch D, Kornek G, et al: Randomized compari-
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`MUl.Tl~TARGElED ANTIFOLATE FOR ADVANCED NSCLC
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`Teva – Fresenius
`Exhibit 1033-00007
`
`

`
`Teva — Fresenius
`
`Exhibit 1033-00008
`
`Teva – Fresenius
`Exhibit 1033-00008
`
`

`
`Tex; — Fresenius
`Exhibit 1033-00009
`
`Teva – Fresenius
`Exhibit 1033-00009
`
`

`
`Journal of Clinical Oncology
`
`The Oflicial Journal of the American Society of Clinical Oncology
`
`Vol 17, No 4
`
`,
`
`CONTENTS
`
`April 1999
`
`EDITORIAL: Signaling Inhibitors in the Clinic: New Agents and New Challenges.......................... ..Gary Hudes
`
`1093
`
`Clinical Pharmacology and Pharmacokinetics
`
`ORIGINAL REPORTS
`
`Phase I and Pharmacologic Study of the Tyrosine Kinasc Inhibitor SU101 in Patients With Advanced Solid
`Tumors .................................S. Gail Eckhardt, Jinee Rizzo, Kevin R. Sweeney, Gillian Cropp, Sharyn D. Baker;
`Maura A. Kraynak, John G. Kuhn, Miguel A. Vzllalona—Calero, Lisa Hammond, Geoflrey Weiss, Allison Thurman,
`Lon Smith, Ronald Drengler, John R. Eckardt, Judy Moczygemba, Alison L. Hannah, Daniel D. Von Hojf
`and Eric K. Rowinsky
`
`Gastrointestinal Oncology
`
`Correlation Between Uracil and Dihydrouracil Plasma Ratio, Fluorouracil (5-FU) Pharmacokinetic
`Parameters, and Tolerance in Patients With Advanced Colorectal Cancer: A Potential Interest for
`Predicting S-FU Toxicity and Determining Optimal 5-FU Dosage ..............
`Gamelin, M. Baisdron-Celle,
`1/. Gue’rin—Meyer, R. Delva, A. Lortholary, F, Genevieve, E Larra, N. Ifrah, and J. Robert
`
`Efficacy and Safety of Prolonged-Release Lanreotide in Patients With Gastrointestinal Neuroendocrine
`Tumors and Hormone-Related Symptoms ........ ..A.N.M. Wymenga, B. Eriksson, P.I. Salmela, M.B. Jacol).ven,
`E.J.D. G. Van Cutsem, R.H. Flasse, M.J. Viiliméiki, J. Renstrup, E.G.E. de Vries, and K.E. Oherg
`
`Breast Cancer
`
`5-Year Results of Dose-Intensive Sequential Adjuvant Chemotherapy for Women With High-Risk
`Node-Positive Breast Cancer: A Phase II Study........ .. C. Hudis, M. Farmer; L. Riccio, D. Lebwohl, J. Crown,
`T. Gilewski, A. Surbone, 1/. Currie, A. Seidman, B. Reichman, M. Moynahan, G. Raptis, N. Sklarin, M. Theodoulnu,
`L. Weiselberg, R. Salvaggio, K.S. Panageas, IJ. Yao, and L. Norton
`
`Docetaxel: Standard Recommended Dose of 100 mglmz Is Effective But Not Feasible for Some Metastatic
`Breast Cancer Patients Heavily Pretreated With Chemotherapy-—A Phase II Single-Center Study
`E. Salminen, M. Bergman, S. Huhtala, and E. Ekholm
`
`Journal ofClinical Oncology (ISSN 0732-183X) is published monthly by Lippincott Williams & Wilkins, 351 West Camden Street, Baltimore, MD
`21201-2436. Periodicals postage paid at Hagerstown, MD, and at additional mailing offices.
`’
`Editorial correspondence should be addressed to George P. Cancllos, MD, Journal of Clinical Oncology, 850 Boylston St, Suite 301A, Chestnut
`Hill, MA02467. Telephone: (617) 739-8909. Fax (617) 739-8541. Email: whippei1d@asco.0rg. Internet: http://www.jc0.0rg
`740-0350.
`ZIPOSTMASTER: Send change of address to Journal ofClinical Oncology, c/o Lippincott Williams & Wilkins, PO Box 350, Hagerstown, MD
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