MuItitargeted Antifolate LY231514 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
`
`Purpose: To evaluate the efficacy and safety of the
`multitargeted antifolate LV231514 (MTA) in patients
`receiving initial chemotherapy for unresectable, ad(cid:173)
`vanced non-small-cell lung cancer (NSCLC).
`Patients and Methods: Patients with measurable, ad(cid:173)
`vanced NSCLC who had not received previous chemo(cid:173)
`therapy for advanced disease were considered for this
`study. Eligible patients who gave written informed con(cid:173)
`sent initially received MTA 600 mg/m2 intravenously
`(IV) for 10 minutes every 3 weeks. After three patients
`received treatment at this dose, the dose was reduced to
`500 mg/m2 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(cid:173)
`ceived up to four cycles after complete or partial remis(cid:173)
`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 0 or 1, 18 patients (55%) had adenocarci(cid:173)
`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 responses were seen;
`thus, the overall response rate was 23.3% (95% confi(cid:173)
`dence interval, 9.9% 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 (39%) experienced grade 3 or 4
`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 oftoxicity.
`Conclusion: MTA seems to have clinically meaningful
`activity as a single agent against advanced NSCLC.
`Toxicity is 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 17:1194-1199.
`Society of Clinical Oncology.
`
`1999 by American
`
`T HYMIDYLATE SYNTHASE (TS) is the primary tar(cid:173)
`
`get of the fluoropyrimidines fluorouracil (5-FU) and
`fluorodeoxyuridine, long-established active agents in the
`treatment of gastrointestinal cancers, breast cancer, and
`other malignancies. I ,2 Biomodulation of 5-FU by leucovo(cid:173)
`rin? interferon,3 or methotrexate4 has resulted in greater
`inhibition ofTS and, consequently, improved response rates5
`and survival,6 particularly among patients with colorectal
`cancer. However, the fluorinated pyrimidines, such as 5-FU,
`
`From the Hamilton Regional Cancer Centre, Hamilton, Queen 5
`University, Kingston, and Eli Lilly and Company, Scarborough, On(cid:173)
`tario; and Nova Scotia Cancer Treatment and Research Foundation and
`Dalhousie University, Halifax, Nova Scotia, Canada.
`Submitted May 18, 1998; accepted November 23, 1998.
`Supported by the National Cancer Institute of Canada Clinical Trials
`Group, Kingston, and Eli Lilly and Company, Scarborough, Ontario,
`Canada.
`Address reprint requests to james J. Rusthoven, 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/99/1704-1J94
`
`are indirect inhibitors ofTS, requiring metabolic activation,
`and are linked to other effects, such as alteration of RNA
`metabolism. I Such non-TS-inhibiting effects may lead to a
`low therapeutic index due to increased toxicity or loss of
`efficacy. In addition, inhibition ofTS results in an increase in
`intracellular deoxyuridine monophosphate that can compete
`with pyrimidine analogs for binding to TS. 8
`Direct and more specific inhibitors of TS have been
`developed that interact with the folate-binding site ofTS. 9-11
`These folate analogs have been designed to improve the
`specificity for TS inhibition; furthermore, deoxyuridine
`monophosphate would enhance rather than competitively
`reverse their binding to TS. Multitargeted antifolate
`LY231514 (MTA) was designed as a folate-based TS
`inhibitor with a glutamate side chain in this new class of
`folate antimetabolites. 12,13 Although MTA itself only moder(cid:173)
`ately inhibits TS, polyglutamation of the parent drug and its
`metabolites readily occurs, and the polyglutamated form of
`MTA is lOO-fold more potent than MTA itself. In addition,
`other folate-requiring enzymes may act as targets for this
`drug, including dihydrofolate reductase, glycinamide ribo(cid:173)
`nucleotide formyltransferase, aminoimidazole carboxamide
`
`1194
`
`Journal of Clinical Oncology, Vol 17, No 4 (April), 1999: pp 1194-1199
`
`Downloaded from jco.ascopubs.org on January 30, 2015. For personal use only. No other uses without permission .
`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`Sandoz Inc.
`Exhibit 1052-0001
`
`JOINT 1052-0001
`
`

`
`MULTI-TARGETED ANTIFOLATE FOR ADVANCED NSCLC
`
`ribonucleotide fonnyltransferase, and Cl tetrahydrofolate
`synthase. 14,15
`MTA has demonstrated activity in a wide range of tumor
`types. The drug is highly active against CCRF-CEM human
`leukemia cells in vitro; the activity is partially reversible
`with the addition of thymidine. 12-14 The 50% inhibitory
`concentration in CCRF -CEM cells was 7 ng/mL.13 It is also
`cytotoxic in human tumor colony-fonning unit assays against
`human colon, renal, small-cell lung and non-small-cell lung
`cancers, hepatomas, and carcinoid tumors. 16 MTA can
`inhibit tumor growth in mice transplanted with human colon
`xenografts resistant to methotrexate. 17 In beagle dogs treated
`with a weekly and/or single-dose intravenous (IV) schedule,
`major toxicities included anorexia, emesis, diarrhea, mucosi(cid:173)
`tis, weight loss, neutropenia, lymphopenia, and mild anemia.
`Plasma concentrations increased linearly with increasing
`doses, with the tenninal half-life occurring at about 2.3
`hours. IS Early studies have suggested that dietary supplemen(cid:173)
`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(cid:173)
`pleted in which patients were treated by lO-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 neutropenia and grade 3 or 4 thrombocy(cid:173)
`topenia. In patients who received 500 to 600 mg/m2 MTA,
`serum peak concentrations were 70 to 200 flg/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/m2 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 colorectal cancer. 19
`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 ofthe latter study are reported here.
`
`PATIENTS AND METHODS
`
`Patient Selection
`
`Eligible patients were accrued between September 1995 and Febru(cid:173)
`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(cid:173)
`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
`
`1195
`
`Group performance status of 0 to 2, (3) serum creatinine level within
`normal limits, (4) good hepatic function (ie, serum bilirubin :s 1.5 times
`the upper normal limit and AST :s two times the upper normal limit or
`:s five times 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(cid:173)
`ments.
`
`Drug Administration
`
`MTA was supplied as a lyophilized powder in 1 OO-mg vials and was
`reconstituted by adding 10 mL of 0.9% sodium chloride. The appropri(cid:173)
`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
`:s 2) toxicity. Patients with grade :s 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
`:s 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 (2: 50 X 1 09/L) also received a 25% dose
`reduction for the next cycle. The use of nonsteroidal anti-inflammatory
`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(cid:173)
`inflammatory agents.) Supportive-care agents, such as colony(cid:173)
`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 ofMTA and had
`follow-up measurements performed to assess change in tumor size were
`assessable for response. Response was assessed on day 1 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 tumor 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
`
`Downloaded from jco.ascopubs.org on January 30 , 2015. For personal use only. No other uses without permission .
`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`Sandoz Inc.
`Exhibit 1052-0002
`
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`

`
`1196
`
`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(cid:173)
`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/m2 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/m2 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/m2 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.)
`
`Antitumor 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 2l.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 I-year survival rate
`was 25.3% (95% confidence interval, 9.7% to 40.9%). A
`higher response was seen among stage IllB patients (four
`[67%] of six) compared with those who entered the study
`with stage IV disease (three [12.5%] of24).
`
`RUSTHOVEN ET AL
`
`Table 1. Patient Characteristics
`
`No. of Patients
`
`63
`42-74
`
`Age, years
`Median
`Range
`Sex
`Female
`Male
`Performance status"
`o
`
`2
`Histology
`Adenocarcinoma
`Squamous
`Undifferential
`Prior therapy
`Radiation therapy
`Sites of disease
`Lung
`Lymph nodes
`Liver
`Bone
`Adrenal
`Pleural effusion
`Subcutaneous
`Spleen
`Stage at study entry
`IIiB
`IV
`No. of organ sites involved
`1
`2
`3
`"':4
`
`7
`26
`
`13
`19
`
`18
`9
`6
`
`11
`
`27
`24
`8
`7
`7
`5
`
`8
`25
`
`7
`11
`10
`5
`
`'Eastern Coopoerative 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 ai,
`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(cid:173)
`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(cid:173)
`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
`
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`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
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`Exhibit 1052-0003
`
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`
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`
`MULTI-TARGETED ANTIFOLATE FOR ADVANCED NSCLC
`
`1197
`
`Table 3. Nonhematologic Toxicity (n = 33)
`
`'"
`c: .;;
`.~
`" en
`c:
`0
`'2
`0
`Q. e
`c..
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`0
`33
`
`Grade (no. of patients)
`
`Median survival: 9.61 months
`
`Toxicity
`
`Skin rash
`Lethargy
`Anorexia
`Diarrhea
`Nausea
`Arthralgia
`Stomatitis
`Vomiting
`Tearing
`Edema
`Febrile neutropenia
`Infection
`
`3
`5
`8
`9
`13
`
`5
`8
`6
`5
`
`3
`
`10
`15
`10
`2
`9
`4
`4
`5
`3
`5
`
`3
`
`13
`9
`4
`3
`4
`3
`2
`3
`2
`3
`4
`4
`
`5
`30
`
`10
`16
`Time (months)
`#At Risk
`
`15
`
`20
`
`4
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`0
`
`% Drug-
`Total No. of %of
`Patients
`Patients Related Only
`
`26
`29
`22
`14
`26
`8
`11
`16
`11
`13
`4
`10
`
`79
`88
`67
`42
`79
`24
`33
`49
`33
`39
`12
`30
`
`79
`76
`58
`33
`76
`0
`33
`46
`30
`21
`12
`6
`
`Fig 1. Overall survival of all patients.
`
`DISCUSSION
`
`adverse event; one experienced a cerebrovascular accident,
`and the other patient developed a deep vein thrombosis and
`pulmonary thromboembolus associated with severe short(cid:173)
`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 dexamethasone,
`93% of cycles with skin rash, 47.5% grade 3; with dexametha(cid:173)
`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).
`
`Initial results from preclinical animal studies and phase I
`trials suggested clinical activity for MTA primarily against
`colorectal and pancreatic cancer. 19,20 The level of activity
`seen in the present study in NSCLC was higher than initially
`anticipated, and independent reviewers confirmed all re(cid:173)
`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 IllB patients. In another phase II study of
`MTA in patients with NSCLC by Clarke et al,21 all patients
`were initially treated with 600 mg/m 2 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(cid:173)
`tween the two studies; in addition, toxicity seen in the phase
`I studies was similar to that reported for other drugs in this
`class. 19,2o,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(cid:173)
`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 severe,
`
`Table 2. Hematologic Toxicity (n = 33)
`
`Table 4. Biochemical Changes (n = 31)
`
`Nadir (x 10' III
`
`Toxicity Grade
`
`Toxicity Grade
`
`Median
`
`Range
`
`Hemoglobin, giL
`WBC
`Granulocytes
`Platelets
`
`111
`2.5
`1.1
`152
`
`73-149
`0.4-8.1
`0.0-4.0
`20-278
`
`0
`
`6
`6
`7
`17
`
`14
`5
`3
`14
`
`10
`9
`10
`
`3
`11
`9
`0
`
`4
`
`0
`2
`4
`
`Test
`
`Serum creatinine
`Bilirubin
`AST
`Alkaline phosphatase
`
`0
`
`29
`26
`5
`14
`
`0
`17
`16
`
`4
`7
`
`0
`
`2
`0
`
`4
`
`0
`0
`0
`0
`
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`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
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`
`1198
`
`and physician discretion was pennitted for prophylaxis
`based on the low emetogenic potential projected from phase
`I 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 dexamethasone given in
`cycle 1 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(cid:173)
`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
`
`RUSTHOVEN ET AL
`
`is similar to that seen in the study of Clarke et al,2l in which
`all patients started at a dose of 600 mg/m2. Furthennore, it is
`interesting that all responding patients were treated at an
`initial dose of500 mg/m2.
`MTA clearly has relevant clinical activity in patients with
`advanced NSCLC and toxicity that is tolerable with conven(cid:173)
`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 Gl/S interface
`initially, followed by synchronous entry of treated cells into
`S phase II 4 hours after initial drug exposure in vitro.23 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. 24 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 efficacy
`against NSCLC, such as the taxanes and platinum com(cid:173)
`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. Cormier, Hopital Laval, Quebec
`City; A. Neville, Hamilton Regional Cancer Centre, Hamilton; and F.
`Shepherd, The Toronto Hospital, Toronto, Canada.
`
`REFERENCES
`
`I. Rustum YM, Harstrick A, Cao S, et al: Thymidylate synthase
`inhibitors in cancer therapy: Direct and indirect inhibitors. J Clin Oncol
`15:389-400, 1997
`2. Poon MA, O'Connell MJ, Moertel CG, et al: Biochemical
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`Sandoz Inc.
`Exhibit 1052-0005
`
`JOINT 1052-0005
`
`

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`Downloaded from jco.ascopubs.org on January 30 , 2015. For personal use only. No other uses without permission .
`Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
`
`Sandoz Inc.
`Exhibit 1052-0006
`
`JOINT 1052-0006