049
`
`Overview of Phase II Trials of MT A in Solid Tumors
`
`Peter J. O'Dwyer, Katrina Nelson, and Donald E. Thornton
`
`MTA (L Y231 S 14, multitargeted antifolate) represents
`a new class of folate antimetabolltes and inhibits mul(cid:173)
`tiple enzymes in the purine and thymidine biosynthetic
`pathways, including thymidylate synthase, dihydrofo(cid:173)
`late reductase, and glycinamide ribonucleotide formyl
`transferase. Based on the results of phase I investiga(cid:173)
`tion, the dose and schedule of 600 mg/m 2 administered
`intravenously every 21 days was selected to carry into
`the phase II setting. A number of phase II studies are
`completed or ongoing in a wide range of tumor types,
`and encouraging results have been observed in colorec(cid:173)
`tal, breast, non-small cell lung, head and neck, bladder,
`and cervical cancers.
`Semln Oncol 26 (suppl 6):99-104. Copyright © 1999 by
`W.B. Saunders Company.
`
`M TA (L¥231514, multitargeted antifolate), is
`
`a pyrrolo-pyrimidine analog of folic acid
`that inhibits thymidylate synthase, dihydrofolate
`reductase, and glycinamide ribonucleotide formyl
`transferase. 1•2 The antitumor activity of MTA re(cid:173)
`sults from the inhibition of these folate-requiring
`enzymes, which are components of purine and
`thymidine synthesis. MT A enters the cell via the
`reduced folate carrier and, once there, rapidly un(cid:173)
`dergoes polyglutamylation. The more extensively
`polyglutamated species exhibit greater affinity for
`the target enzymes and greater in vitro activity)
`
`RATIONALE FOR PHASE II DOSE AND
`SCHEDULE
`
`Three dosing schedules have been investigated
`in phase I studies. In one study, patients were
`treated on a once-every-21 days schedule (see
`Rinaldi, elsewhere in this supplement); in a sec(cid:173)
`ond study, patients received drug once weekly for
`4 weeks every 6 weeks4 and in a third, patients
`were treated using a schedule of daily XS every 21
`days. 5
`Based on the toxicity profile, the ability to give
`repeat doses, and the ease of administration, the
`ev~ry- 21-days schedule was selected for further
`development of MT A in clinical phase II studies.
`In the phase I trial investigating this dose, 37
`patients were treated at doses ranging from 50 to
`700 mg/m2
`• Dose escalation proceeded by the
`Modified Continual Reassessment Method in this
`study, limiting the number of patients exposed to
`lower, potentially less-effective doses of drug.6
`Dose-limiting toxicities on this schedule were neu-
`
`thrombocytopenia, and fatigue. The
`tropenia,
`maximum tolerated dose on this schedule was de(cid:173)
`termined to be 600 mg/m2, and of the 20 patients
`treated at this dose, National Cancer Institute
`Common Toxicity Criteria grade 4 neutropenia
`and grade 4 thrombocytopenia occurred in four
`and one patient, respectively, in the first cycle.
`National Cancer Institute Common Toxicity Cri(cid:173)
`teria grade 2 toxicities included rash, mucositis,
`nausea, vomiting, fatigue, anorexia, and elevations
`of liver transaminases. Patients who experienced
`rash and were treated in subsequent cycles with 4
`mg of dexamethasone twice daily for 3 days start(cid:173)
`ing the day before MT A therapy experienced a
`decrease in severity or even prevention of the rash.
`The phase I experience is summarized in Table 1.
`Pharmacokinetic calculations based on non(cid:173)
`compartmental methods were performed in 20 pa(cid:173)
`tients who were treated at the maximum tolerated
`dose (600 mg/m2
`). A mean maximum plasma con(cid:173)
`centration of 137 p.g/mL was attained, with an
`effective harmonic mean half-life of 3.1 hours
`(range, 2.2 to 7.2 hours). Mean clearance and
`steady-state volume of distribution values of 40
`mL/min/m2 (24% coefficient of variance) and 7.0
`L/m2 (20% coefficient of variance) were also cal(cid:173)
`culated. This mean clearance value is similar to
`that of creatinine clearance in the age range of the
`patients enrolled (approximately 45 to 55 mL/min/
`m2
`) and the volume of distribution reflects limited
`distribution outside the blood stream. 7 The clear(cid:173)
`ance was invariant with dose over the entire dose
`range (O.Z to 700 mg/m2
`). The clearance of the
`drug is primarily renal, with 2:80% of the dose
`recovered unchanged in the urine during the first
`24 hours after dosing. The disposition of MT A
`does not change after multiple doses and no accu-
`
`From the University of Pennsylvania, Philadelphia, PA and Ully
`Research Laboratories, Indianapolis, IN.
`SjJOnsored by Eli Lilly and Company.
`Dr 0' Dwyer is a consulumt for and has received honoraria and
`research support from Eli LiUy and Company. Dr Thornton is an
`employee and a stockholder of Eli Ully and Company.
`Address reprint requests to Peter]. O'Dwyer, MD, University of
`Pennsylvania, 51 N 39th St, MAB-103, Philadelphia, PA
`19104.
`Copyright© 1999 by W.B. Saunders Company
`0093-7754/99/2602-0616$10.00/0
`
`Seminars in Oncology, Vol 26, No 2, Suppl 6 (April), 1999: pp 99-104
`
`99
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`100
`
`MTA PHASE II OVERVIEW
`
`Table I. Single Agent Phase I Experience
`
`Daily
`
`Every 3 Weeks
`
`Weekly
`
`Schedule (all doses administered
`as a I O.min infusion)
`No. of patients treated
`Dose range (mg/m2)
`Recommended phase II dose
`(mg/m2
`)
`
`DLT
`
`Responses
`
`Daily xs. every 21 d
`38
`0.2-5.2
`
`"'
`Neutropenia
`Minor responses in
`colorectal cancer (I) and
`NSCLC (I)
`
`Once every 21 d
`37
`50-700
`
`600
`
`Neutr'?penia. mucositis, fatigue
`
`Weekly x4, every 6 wk
`2-4
`I ().40
`
`30
`Myelosuppression, particularly
`granulocytopenia
`
`Partial responses in pancreas (2)
`and colorectal (2) cancer
`
`Minor responses in colorectal
`(2) cancer
`
`Abbreviations: DL T, dose-limiting toxicity; NSCLC. non-small cell lung cancer.
`
`mulation appears to occur with multiple courses.
`Initial clinical data indicated that an element of
`cumulative toxicity may have been present (see
`Rinaldi, this supplement), but so far this has not
`been borne out in subsequent clinical experience.
`MT A clearance does appear to decrease with age,
`although this decrease is most likely related to
`decreasing renal function. 7
`
`PHASE II EXPERIENCE
`
`Gastrointestinal Cancers
`
`Clinical activity in metastatic colorectal carci(cid:173)
`noma has been demonstrated in two multicenter
`trials performed in the United States and Canada.
`Because MT A was initially believed to be primar(cid:173)
`ily a thymidylate synthase inhibitor, early phase II
`trials were designed to require a 1-year interval
`from prior treatment with drugs that also inhibit
`thymidylate synthase. For this reason, prior adju(cid:173)
`vant chemotherapy was allowed if completed at
`least 1 year before study entry. In the Canadian
`study, the starting dose of 600 mg/m2 was reduced
`to 500 mg/m2 after dose reductions were required
`in five of the first eight patients. Toxicities leading
`to these reductions included rash, mucositis, neu(cid:173)
`tropenia, and febrile neutropenia. Responses have
`been seen at this reduced dose in six patients, for
`an overall response rate of 20%.8 In the US colo(cid:173)
`rectal study, objective tumor responses have been
`seen in six of 39 patients for an overall response
`rate of 17%.9 The median times to progressive
`disease in the two studies were 4.6 months and 3.3
`
`months, and the median survival times have been
`16.2 months and 15 months.
`Two additional studies were initiated to study
`the antitumor effects of MT A in colorectal cancer
`in patients who had received prior therapy. In
`each of these two trials, 31 patients were evaluated
`for tumor response. In the first, patients must have
`been refractory to both 5-fluorouracil and irinote(cid:173)
`can, defined as having disease progression on or
`within 6 months of prior therapy containing 5-flu(cid:173)
`orouracil and disease progression on or within 6
`months of prior irinotecan therapy. In the second,
`patients must have progressed within 6 months of
`therapy containing 5-fluorouracil. Although sev(cid:173)
`eral patients in these studies have maintained sta(cid:173)
`ble disease for longer than 4 months, objective
`tumor responses have not been observed. Median
`survival times on these studies will be closely mon(cid:173)
`itored as these data mature.
`A study in pancreatic cancer is complete; there
`was one complete and one partial response in 35
`evaluable patients, for an overall response rate of
`6%. Importantly, the median time to progression
`to date is 3.9 months with a median survival of 6.5
`months, and 13 additional patients have main(cid:173)
`tained a status of stable disease for longer than 6
`months of treatment, suggesting a clinical benefit
`not immediately apparent from objective tumor
`measurements.ID
`A study in patients with esophageal cancer was
`conducted in the United Kingdom and South Af(cid:173)
`rica. Patients had inoperable, locally advanced,
`recurrent, or metastatic esophageal cancer and had
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`
`O'DWYER, NELSON, AND THORNTON
`
`101
`
`Table 2. Phase II Activity of MTA in Gastrointestinal Cancers
`
`Colorectal
`
`Colorectal
`
`Colorectal
`
`Colorectal
`
`Pancreas
`
`Esophagus
`
`Tumor
`
`No. of evaluable patients
`CR
`PR
`Overall RR
`Median survival, rna (% Cens)
`Median TIP, rna (% Cens)
`
`41
`I
`5
`15
`16.2 (54%)
`4.6(15%)
`
`29
`0
`5
`17
`15
`3.3
`
`31
`0
`0
`0
`
`-
`-
`Abbreviations: CR. complete response; PR. partial response; RR, response rate; Cens, censored; TIP, time to progression.
`-, Data not available at this time.
`
`31
`0
`I
`3
`-
`-
`
`35
`I
`I
`6
`6.5 (34%)
`3.9(11%)
`
`20
`-
`-
`-
`-
`-
`
`I
`
`not received prior therapy. All patients received a
`dose of 600 mg/m 2 MT A. This study was designed
`with two stages, with an early stopping rule in the
`event of poor antitumor activity, and in fact closed
`after no objective tumor responses were noted in
`the first 20 patients. Although this study was not
`designed to quantify clinical benefit, investigators
`reported some instances of decreased pain and
`improved swallowing. The incidence of toxicity in
`this study was high, with grade 3 and 4 neutrope(cid:173)
`nia experienced by 33% and 23% of patients and
`grade 3 and 4 thrombocytopenia experienced by
`30% and 55% of patients.
`Table 2 illustrates the activity of MT A in gas(cid:173)
`trointestinal cancers.
`
`Breast Cancer
`A study of MT A in locally advanced or meta(cid:173)
`static breast cancer is complete and involved a
`heterogenous population, with five of 38 patients
`having received no prior chemotherapy, 15 of 38
`having received prior adjuvant therapy, and 12 of
`38 who had received prior therapy in the meta(cid:173)
`static setting (additionally, five patients had re(cid:173)
`ceived therapy both in the adjuvant and the met(cid:173)
`astatic setting). Of the 36 patients evaluable for
`response, one complete and 10 partial responses
`have been documented, for an overall response
`rate of 31 o/o. Responses have been seen following
`prior therapy for metastatic disease with a variety
`of treatments, including epirubicin, ifosfamide,
`paclitaxel, gemcitabine, and docetaxel. Neutrope(cid:173)
`nia was the major hematologic toxicity observed,
`with grade 3 seen in 24% of patients and grade 4
`seen in 29% of patients. 11
`An additional study of MT A in metastatic
`
`breast cancer is ongoing in Europe. Patients par(cid:173)
`ticipating in this study must have been previously
`treated with an anthracycline- or anthracenedi(cid:173)
`one-containing regimen and are classified as hav(cid:173)
`ing failed prior therapy ( ie, having disease progres(cid:173)
`sion beyond one cycle length of the final dose of
`this therapy) or as being refractory to prior therapy
`(ie, having disease progression during or within
`one cycle length of the final dose of this therapy).
`While this data set is quite immature at this point,
`two partial responses have been noted within the
`group of 12 evaluable patients in the anthracy(cid:173)
`cline-refractory group and two complete responses
`and four partial responses have been noted within
`the group of 16 patients in the anthracycline fail(cid:173)
`ure group.
`Table 3 illustrates the activity of MT A in breast
`cancer.
`
`Table 3. Phase II Activity ofMTA In Breast Cancer
`
`Ongoing
`
`Complete
`
`A (Anthra
`Refractory)
`
`B (Anthra
`Failures)
`
`No. of evaluable
`patients
`CR
`PR
`
`36
`I
`10
`
`12
`0
`2
`
`16
`2
`4
`
`Overall RR
`
`31
`
`-
`Abbreviations: CR, complete response; PR, partial response;
`RR, response rate.
`-, Data not available at this time.
`
`-
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`102
`
`MTA PHASE II OVERVIEW
`
`Non-Small Cell Lung Cancer
`A study of MT A in patients with locally ad(cid:173)
`vanced or metastatic non-small cell lung cancer
`was carried out by the National Cancer Institute of
`Canada Clinical Trials Group. Patients participat(cid:173)
`ing in this study had not received prior chemo(cid:173)
`therapy. The original starting dose of MT A of 600
`mg/m2 was decreased to 500 mg/m2 after initial
`patients on this study as well as a study of MT A in
`colorectal cancer experienced toxicity leading to
`dose reductions. Of 30 patients evaluable for tu(cid:173)
`mor response, seven partial responses were seen,
`for an overall response rare of 23% (95% confi(cid:173)
`dence interval, 9.9% to 42.3%). Four of these
`responses were in patients with stage IIIb disease
`(of eight patients with stage IIIb disease) and three
`were in patients with stage IV disease (of 25 pa(cid:173)
`tients with stage IV disease). Principal nonhema(cid:173)
`tologic toxicities seen in this study included grade
`3 lethargy (21% of patients) and grade 3 skin rash
`(39% of patients). Subsequent studies have incor(cid:173)
`porated prophylactic administration of dexameth(cid:173)
`asone, which has served to ameliorate or prevent
`this type of rash. Principal hematologic toxicities
`included grade 3 and 4 neutropenia in 27% and
`12% of patients and grade 4 thrombocytopenia in
`3% of patients. Grade 3 febrile neutropenia was
`experienced by 12% of patients.12
`A similar study of MT A in previously untreated
`non-small cell lung cancer was carried out jointly
`between Australia and South Africa. All patients
`in this study received a starting dose of MT A of
`600 mg/m2
`• Of the 42 patients evaluable for re(cid:173)
`sponse, seven partial responses (six in patients
`with stage IV disease and one in a patient with
`
`stage Illb disease) were noted for an overall re(cid:173)
`sponse rate of 17%. The median survival to date is
`9.8 months, median time to disease progression is
`4.5 months, and 42% of patients were alive after 1
`year. As these data mature, the time to event
`intervals are expected to increase. Hematologic
`toxicity seen on this study included grades 3 and 4
`neutropenia in 24% and 8% of patients. Rash was
`the most common nonhematologic toxicity, expe(cid:173)
`rienced by 21% (grade 3) and 11% (grade 4) of
`patients. Other grade 4 nonhematologic toxicities
`included vomiting (2% of patients) and diarrhea
`(4% of patients).D
`Additionally, a study of MTA in second-line
`non-small cell lung cancer is currently ongoing in
`Europe. All patients in this study are receiving a
`starting dose of 500 mg/m2
`• Patients are classified
`into two groups according to whether prior che(cid:173)
`motherapy did (group A) or did not {group B)
`contain a platinum agent. Of the 27 patients en(cid:173)
`rolled to date, 15 are currently evaluable for re(cid:173)
`sponse. Four patients have experienced a partial
`response, for a preliminary response rate of 27%.
`No responses have been seen in the group of
`patients who had received prior platinum therapy,
`but this is most likely a function of the small
`sample size, as response to MT A following plati(cid:173)
`num failure has been noted in other tumor types.
`Grade 3 or 4 neutropenia occurred in 27% of
`cycles and grade 3 or 4 thrombocytopenia occurred
`in 4% of cycles. Grade 3 or 4 infection occurred in
`8% of cycles. Skin rash was frequent, although
`mostly mild, with moderate to severe rash occur(cid:173)
`ring in only 2% of cycles.
`
`Table 4. Phase II Activity of HTA in Non-Small Cell Lung Cancer
`
`First-Une Canada,
`Complete
`
`First-Line Australia/
`South Africa,
`Complete
`
`Second-Line, Ongoing
`
`A (Prior Treatment
`Not With Platinum)
`
`B (Prior Treatment
`With Platinum)
`
`No. of evaluable patients
`CR
`PR
`Overall RR
`Median survival (% Cens)
`Median TTP (% Cens)
`
`30
`0
`7
`23
`9.6 (33%)
`3.8
`
`42
`0
`7
`17
`9.7(61%)
`4.4(18%)
`
`10
`0
`3
`
`-
`-
`-
`
`9
`0
`0
`-
`-
`-
`
`Abbreviations: CR, complete response; PR, partial response; RR, response rate; Cens, censored; TTP, time to progression.
`-, Data not available at this time.
`
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`
`O'DWYER, NELSON, AND THORNTON
`
`103
`
`Table 4 illustrates the activity of MTA in non(cid:173)
`small cell lung cancer.
`
`Head and Neck Cancer
`A phase II study of MT A in advanced or recur(cid:173)
`rent squamous cell carcinoma of the head and
`neck is ongoing in France. Patients may have
`received chemotherapy in the neoadjuvant or ad(cid:173)
`juvant setting and the minimum chemotherapy(cid:173)
`free interval is 6 months. All patients are receiving
`a starting dose of 500 mg/m2
`, although 17% of 51
`total courses have been reduced or delayed. To
`date, there have been seven responses to MT A in
`19 patients treated. Although these data are pre(cid:173)
`liminary, this is an encouraging level of activity.
`Toxicity that has been observed to date includes
`grade 3/4 neutropenia in 48% of courses, moderate
`and severe nausea in 22% of courses, and rash in
`13% of courses. Febrile neutropenia has also oc(cid:173)
`curred in 5% of courses. The toxicity seen in this
`study is possibly related to nutritional status in this
`patient population. This hypothesis is supported
`by the work of Niyikiza et al, 14 who have shown
`that functional folate status is highly correlated to
`the incidence of hematologic toxicity in patients
`who receive MT A.
`
`Genitourinary Cancers
`A phase II study ongoing in Spain has enrolled
`25 patients with advanced transitional cell carci(cid:173)
`noma of the urothelium. Six patients received the
`standard phase II dose of MT A, which was reduced
`to 500 mg/m2 in subsequent patients due to unac(cid:173)
`ceptable toxicities. Twenty patients are currently
`evaluable for response and toxicity. There have
`been seven partial remissions, for a response rate of
`35%. National Cancer Institute Common Toxic(cid:173)
`ity Criteria grade 3 or 4 neutropenia has been seen
`in 75% of patients, with five patients developing
`neutropenic fever. Nonhematologic toxicities in(cid:173)
`cluded grade 3 diarrhea in 10 of patients and grade
`4 mucositis in 5% of patients. 15 Although MTA
`has definitive activity in transitional cell carci(cid:173)
`noma, toxicities appear to be severe and results
`from patients receiving the lower dose are awaited
`with interest.
`A phase II study ongoing in Germany has en(cid:173)
`rolled 26 patients with renal cell carcinoma. All
`patients had stage IV disease and had not received
`prior therapy. Nephrectomized patients were re(cid:173)
`quired to have evidence of disease progression
`
`TableS. Phase II Activity of MTA in Head and Neck,
`Genitourinary, and Gynecologic Cancers
`{All Ongoing Studies)
`
`Tumor
`
`Head and
`Neck
`
`Renal
`Bladder Cell Cervi><
`
`No. of evaluable patients
`CR
`PR
`Overall RR
`
`15
`I
`6
`47
`
`20
`0
`7
`29
`
`21
`0
`2
`9
`
`24
`0
`6
`25
`
`Abbreviations: CR, complete response; PR, partial response;
`RR, response rate.
`
`'
`
`before study entry. Of 21 evaluable patients, there
`have been two durable partial responses, one last(cid:173)
`ing for 15 months to date and the other lasting 6
`months to date, for a response rate of 9%. Disease
`stabilization has been experienced by 59% of pa(cid:173)
`tients. In this study, MT A has been quite well(cid:173)
`tolerated, with grades 3 and 4 thrombocytopenia
`seen in 12% and 8% of patients.
`
`Gynecologic Cancers
`A phase II study of MT A in patients with FIGO
`stage IIIB or IV cervical cancer is currently ongo(cid:173)
`ing in South Africa. Patients in this study were not
`permitted to have received prior chemotherapy.
`Of the 24 patients who are evaluable for response,
`there have been six confirmed partial responses.
`Responses have been quite durable, lasting from 4
`to 17+ months. Toxicity in patients with cervical
`cancer has been greater than that experienced in
`other tumor types. Grade 3 or 4 neutropenia was
`seen in 63% of patients and grade 3 or 4 throm(cid:173)
`bocytopenia in 8%. Nearly half of all patients
`ultimately were discontinued from the study be(cid:173)
`cause of decreased creatinine clearance, presum(cid:173)
`ably due to ureteral obstruction, which precluded
`further dosing. In an attempt to improve the tox(cid:173)
`icity profile in patients with this tumor, the study
`protocol has been recently amended to lower the
`starting dose to 500 mg/m2 (from 600 mg/m 2
`).
`Table 5 shows the activity of MT A in head and
`neck, genitourinary, and gynecologic cancers.
`
`CONCLUSION
`MT A has shown a broad spectrum of clinical
`activity in multiple tumor types, including colo(cid:173)
`rectal, breast, non-small cell lung, pancreatic,
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`104
`
`MTA PHASE II OVERVIEW
`
`head and neck, bladder, and cervical cancers. The
`toxicity profile of MT A is typical of an antifolate,
`with myelosuppression being the most common
`toxicity and mucositis, rash, and fatigue occasion(cid:173)
`ally being dose-limiting. While roughly half of all
`patients treated to date have experienced grade 3
`or 4 neutropenia, this toxicity has proven to be
`noncumulative and reversible. Work by Zervos et
`al 16 supports the position that toxicity may be
`increased in patients with poor nutritional status.
`Additional studies are under way to explore the
`relationship between folate status and toxicity.
`
`REFERENCES
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`folate analogue lacking a chiral center at C-6,N-(4 (2-(2-
`amino-3 ,4-dihydro-4-oxo· 7H-pyrrolo( 2,3-d)pyrimidin-5-yl)
`ethyl)benzoyl)-L-glutamic acid, is an inhibitor of thymidylate
`synthase. J Med Chern 35:4450-4454, 1992
`2. Shih C, Chen VJ, Gossett LS, eta!: LY231514, a pyrrolo(cid:173)
`[2,3-d]pyrimidine based antifolate that inhibits multiple folate
`requiring enzymes. Cancer Res 57:1116-1123, 1997
`.3. Chen VJ, Bewley JR, Gossett L, et al: Activity of
`L YZ.31514 against several enzymes in the folate-dependent
`pathways. Proc Am Assoc Cancer Res 37:A2598, 1996 (abstr)
`4. Rinaldi DA, Burris HA, Dorr FA, et a!: Initial phase I
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`5. McDonald AC, Vasey PA, Adams L, era!: A phase I and
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`late. Clin Cancer Res 4:605-610, 1998
`6. Zervos PH, Faries D, Dorr FA, et al: Practical use of the
`modified continual reassessment method (mCRM) for dose
`escalation in a phase I trial with LY231514. Proc Am Soc Clin
`Oneal 14:A473, 1995 (abstr)
`
`7. Woodworth J, Rinaldi D, Burris H, et al: Assessments of
`hemotoxicity and relationships to pharmacokinetics from a
`LY231514 phase I study. Proc Am Soc Clin Oncol16:A734,
`1997 (abstr)
`8. Cripps MC, Burnell M, )olivet J, eta!: Phase II study of a
`multi-targeted antifolate (LY2.31514) (MTA) as first-line ther(cid:173)
`apy in patients with locally advanced or metastatic colorectal
`cancer (MCC). Proc Am Soc Clin Oneal 16:A949, 1997
`(abstr)
`9. John W, Clark J, Burris H, et al: A phase II trial of
`LY231514 in patients with metastatic colorectal cancer. Proc
`Am Soc Clin Oneal 16:Al038, 1997 (abstr)
`10. Miller KD, Loehrer PJ, Picus J, et al: A phase II trial of
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`NEPTUNE GENERICS 1015-00006
`APOTEX 1015-0006