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`
`Seminars in
`Oncology
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`EDITORS
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Overview of Phase I Trials of Multitargeted
`Antifolate (MTA, LY23 I 5 I 4)
`
`David A. Rinaldi
`
`Multitargeted antifolate (MTA, LY23l5I4) is a novel
`antifolate antimetabolite, with antitumor activity via
`inhibition of thymidylate synthase, glycinamide formyl
`transferase, and dlhydrofolate recluctase. Three dosing
`schedules have been investigated in the phase I setting:
`daily X5 every 2| days, weekly x4 every 42 days, and
`once every 2| days. The maximum tolerated doses on
`these schedules were 4.0 mglmz, 30 mglm’, and 600
`mg/m‘, respectively. The major dose-limiting toxicity
`seen on all schedules was neutropenia, with a greater
`degree of reversible liver biochemistry disturbances
`observed on the daily X 5 schedule. Given that toxicities
`were manageable and reversible, the antitumor activ-
`ity exhibited. and the convenience 0! an every-2|-day
`dosing schedule, this schedule was selected for phase II
`evaluation.
`Semin Oncol 26 (suppl 6):82-88. Copyright © I999 by
`W.B. Saunders Company.
`
`(MTA,
`ULTITARGETED antifolate
`LY231514) is a novel compound, represen-
`tative of a new class of folate antimetabolites. Its
`antitumor effect is via inhibition of the enzymes,
`thymidylate synthasc, glycinamide ribonucleotide
`formyltransfcrasc, and dihydrofolate reductase.
`MTA is an excellent substrate for the folylpoly—
`glutamate synthetase, leading to extensive intra-
`cellular polyglutamation. This converts the drug
`from a form that readily effluxes from the cell to a
`form that is retained intracellularly for a prolonged
`period. producing a tnore sustained drug effect. In
`preclinical models, MTA has demonstrated activ-
`ity against a wide spectrum of tumor types.”
`Three phase I clinical trials with three different
`schedules of MTA have now been completed, one
`in the United Kingdom and two in the United
`Stats.” In the three trials, MTA was administered
`as a 10-minute intravenous infusion in escalating
`
`From the Unitersity of Texas Health Science Center, San An-
`tonio, TX; Brooke Army Medical Center, San Antonio, TX; the
`Cancer Therapy and Research Center, San Antonio, TX; and the
`Beatson Oncology Centre, Glasgow, UK.
`Sponsored by Eli Lilly and Company.
`Dr Rinaldi has received hnnoraria and research support from Eli
`Lilly and Company.
`Address reprint requests to I)avid A. Rinaldi, MD, 501 W St
`Mary Blvd, Suite 200, Lafayette, LA 70506.
`Copyright © 1999 by W.B. Saunders Company
`00934754/99/2602-0613$l0.0C/O
`
`doses’ to patients with advanced, refractory, solid
`tumors and relatively normal bone marrow, renal,
`and hepatic function. Patients requiring chronic
`aspirin therapy and those with significant effusions
`were excluded due to the structural similarities of
`MTA and methotrexate. The maximum tolerated
`dose (MTD) was defined as that dose level at
`which 30% of the patient population developed
`unacceptable toxicity. The recommended dose for
`phase II clinical trials was defined as the dose that
`caused moderate reversible toxicity in most pa-
`tients.
`
`DAILY X5, REPEATED EVERY 2| DAYS
`
`Thirty-eight patients were treated in this study‘;
`the clinical characteristics are listed in Table 1.
`One hundred sixteen courses of MTA were admin-
`istered at 10 dose levels, ranging from 0.2 to 5.2
`mg/mz. Myelosuppression and liver biochemistry
`perturbations were dose limiting on this schedule.
`Myelosuppression was not higher than grade 2
`in patients treated at doses less than 2.3 mg/ml. Of
`the three patients treated with 2.3 mg/ml, one
`developed uncomplicated grade 3 neutropenia
`that was not considered dose limiting. One of the
`initial three patients treated with 3.0 mg/m‘, ex-
`perienced grade 3 neutropenia and grade 2 throm-
`bocytopenia; therefore, an additional four patients
`were treated at this dose level. No further dose-
`limiting toxicity was seen at this dose level.
`Of the five patients initially treated at the 4.0
`mg/m2,dose level. one developed grade 3 hepato-
`toxicity (bilirubin), which was considered a dose-
`limiting toxicity, and one developed grade 3 neu-
`tropenia. The treatment dose was then escalated
`to 5.2 mg/mz. with the first patient at this dose
`level experiencing no significant
`toxicity. How-
`ever,
`the second patient died despite aggressive
`medical management after experiencing grade 4
`neutropenia, grade 3 thrombocytopenia, and grade
`4 gastrointestinal toxicities on day 8 of the first
`course of treatment. This event resulted in a re-
`evaluation of the previous dose level and an addi-
`tional patient was treated with 4.0 mg/m2. This
`patient developed uncomplicated, but dose-limit-
`
`Seminars in Oncology. Vol 26. No 2. Suppl 6 (April). I999: pp 82-38
`
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`

`
`MTA PHASE II OVERVIEW
`
`83
`
`Table I. Patient Characlneristiu
`
`Daily X5
`Every 1|
`Days
`
`38
`I 9.1 I 9
`
`Weekly X4
`Every -12
`Day:
`
`24
`|lI|3
`
`Ever}! 2 I
`Days
`
`37
`2}'I|{)
`
`59 (33-73)
`
`59 (20-82]
`
`59 (30-74)
`
`No. of evaluable
`patients
`I'1.I'F
`Median age, yr
`(range)
`Karnofsky
`perforrnance
`status
`|OO%
`90%
`80%
`60%
`No. of prior
`chemodwerapy
`regimens
`
`Tu:-nor types
`Coloreclal
`Pancreas
`Melanoma
`Other
`
`ing grade 4 neutropenia and grade 3 hepatic
`transaminase elevations. Because two of six pa»
`tients at
`this dose level had experienced dose»
`limiting toxicity, the MTD was established at 4.0
`rngfrrlz.
`Hepatotoxicity was frequently observed at most
`dose levels, with grade 3—4 toxicity occurring in at
`least one patients treated at each dose level 22.3
`mgfmz. These abnormalities were observed most
`frequently during either the first or second course
`
`of treatment, did not appear to be progressive, and
`resolved during continued treatment or on discon-
`tinuation of treatment for other reasons.
`
`In patients treated at the 4 rngfmz dose level, no
`patient developed grade 3-4 nonhernatologic, non-
`hepatic toxicity. Grade 1-2 rnucositis occurred in
`two patients, nausea in five patients, vomiting in
`three patients, and diarrhea in four patients. Pro-
`phylactic antiernetics were not routinely used. Ta
`ble 2 summarizes the course 1 toxicity seen at all
`dose levels on this dosing schedule.
`A patient with pancreatic cancer, treated at the
`2.3 mgfrnz dose level, experienced a fatal gastro-
`intestinal hemorrhage Following the second cycle
`of treatment. Coagulation parameters and platelet
`count were normal throughout the time on study,
`although grade
`3
`elevations of
`the hepatic
`transamirlases were noted in association with the
`
`acute event. Extensive inflammatory changes were
`seen in the large intestine at postmortem exami-
`nation, with no focal bleeding source identified.
`Only microscopic evidence of residual tumor was
`seen at this point. While the etiology of the event
`remains unclear, a relationship to MTA adminis-
`tration cannot be excluded.
`
`While no objective tumor responses were noted,
`antitumor effects were observed in three patients.
`The first was a patient with metastatic non»small
`cell lung cancer who was previously treated with
`platinum. Symptomatic and radiologic improve—
`ments, which were observed after six courses of
`MTA at 3.0 mgfmz, persisted through the 10th
`course. A second patient, who had metastatic co—
`lon cancer, experienced a reduction on a nonmea—
`surable hepatic lesion after {our courses of treat-
`ment with MTA at 4.0 lngfmz. The third patient,
`who had pancreatic cancer and was receiving
`MTA at 2.3 mg/ml, developed fatal gastrointesti-
`
`Table 2. Daily X5: Course I Toxicity
`
`Dose T
`Na of
`Neutropenia
`Level
`Patients
`I
`2
`3
`
`Thrombotympenia
`2
`J
`
`D
`I
`I
`I
`0
`
`II3I0
`
`0
`0
`I
`2
`I
`
`22
`
`3 Tnnsaminases
`
`Hyperbiiirulainernia
`3
`
`I
`
`7
`0
`3
`2
`I
`
`2
`
`I
`D
`I
`3
`U
`
`3
`
`I
`I
`0
`I
`0
`
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`
`B4
`
`DAVID A. RINALDI
`
`nal bleeding (as described above) 4 weeks after the
`second course of treatment. This patient’s tumor,
`which had originally been measured at 4 X 4 cm,
`was not macroscopically detectable at necropsy,
`although microscopic tumor was found in biopsy
`specimens taken from the original site of disease.
`Additionally, eight patients had stable disease.
`Two patients with metastatic colon cancer, pro-
`gressing during 5-fluorouracil (5-FU)-based ther-
`apy, achieved disease stabilization for 3 and 6
`months with MTA.
`
`WEEKLY X4, REPEATED EVERY 42 DAYS
`
`Twenty-four evaluable patients enrolled in the
`weekly X4, repeated every 42 days study.‘ Their
`characteristics are listed in Table 1. Fifty-eight
`courses of MTA were administered, with a range of
`one to seven courses per patient. The close-limit-
`ing toxicity of MTA on this schedule was neutro-
`penia. Nonhematologic toxicities observed in-
`cluded mild fatigue, anorexia, and nausea. with no
`instances of grade 3 or 4 side eFFects. There was no
`evidence of cumulative toxicity.
`The dose escalation schema incorporated into
`this study was based on the modified continual
`reassessment method (mCRM).” The initial dose
`level was to include at least three patients, with
`subsequent dose levels of one patient each, and
`planned expansion of those dose levels when mod-
`erate to severe toxicity was observed. The pro-
`jected phase ll dose was to include at least 10
`patients.
`At the initial dose level of 10 mgfmz, one of
`four patients developed grade 4 neutropenia and
`grade 3 thrombocytopenia, while the remaining
`three patients tolerated the treatment without
`significant toxicity. The next patient, who re-
`ceived 20 mgfmz, also experienced no significant
`toxicity, so the dose was escalated to 40 mgfml.
`After the first patient developed grade 4 neutro-
`penia, five additional patients were treated at
`this dose level. Two of these five experienced
`grade 4 neutropenia, which prompted a de-esca-
`lation to 20 mg/ml. Because none of the three
`additional patients at
`this dose level experi-
`enced significant toxicity, an intermediate dose
`level of 30 mgfmz was added. Two of the 10
`patients treated at
`this dose level developed
`grade 4 neutropenia; therefore, this dose level
`was determined to be the MTD and recom-
`
`mended dose for phase II trials using this sched-
`ule.
`
`No major responses were observed; however,
`minor responses were achieved in two patients
`with advanced, refractory colon cancer. A patients
`treated at the 40 mgfmz’ level who had failed 5-FU
`and folinic acid exhibited a 34% reduction in
`measurable disease after two cycles, but had pro-
`gressed by the next computed tomography scan 6
`weeks later. A patient with evaluable liver metas-
`tases, treated at the 30 mglmz level, exhibited a
`decline in carcinoembryonic antigen level from
`945 ngfml. before the study’ to 271 ng}'mL after
`three courses of treatment. Of note, this patient
`
`had been previously treated with 5-FU and le-
`vamisole, 5-FU and folinic acid, and intrahepatic
`artery 5-FU and interferon.
`The inability to deliver scheduled doses due to
`grade 22 myelosuppression at the time of treat-
`ment precluded optimal use of the mCRM and
`also limited dose escalation on this schedule. This
`toxicity predominantly occurred during week 3 or
`4. At the 10 and 20 rngfmz levels, 29 of32 planned
`doses were delivered and six of eight patients re-
`ceived all doses. At the 40 rngfmz levels 18 of the
`24 planned doses were delivered, and at the 30
`mgllmz dose level 30 of the 40 doses were given.
`Only one patient at each of these dose levels
`received all four of the scheduled doses during
`their first course. Table 3 summarizes the course 1
`
`toxicity seen at all dose levels on the treatment
`schedule.
`
`I
`Table 3. Weeldy X1 Every 42 Days: Course I Toxicity
`
`Grade {World Health Organization)
`
`l
`
`Toxicity
`
`Neutropenia
`Thrornb-oc}rtopenia
`Anemia
`Nauseafemesis
`Fatigue
`Transaminasemia
`Anorexia
`Mucositis
`Derrrradfls
`
`0
`
`6
`20
`9
`3
`I3
`20
`I3
`20
`23
`
`I
`
`I
`D
`8
`9
`I0
`3
`I I
`4
`I
`
`2
`
`7
`2
`7
`1
`I
`I
`0
`0
`D
`
`3
`
`5
`I
`D
`0
`U
`D
`D
`O
`O
`
`4
`
`5
`I
`0
`0
`0
`O
`D
`0
`0
`
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`
`MTA PHASE II OVERVIEW
`
`Table 1!. HTA Every 2| Days: Toxicity Course I‘
`
`Dose Level
`(Wm?)
`
`Neutropenia
`
`Thrombocyaopenia
`I
`2
`3
`
`Nonhernatcllogic
`I
`3
`
`
`
`* Number of patients. maximum toxicity World Health Clrganition grade.
`
`SINGLE DOSE EVERY 2| DAYS
`
`Thirty-seven patients were enrolled in the study
`and received MTA as a 10-minute infusion once
`
`every 21 days.” The majority of these patients
`had metastatic colorectal cancer
`refractory to
`5-FU. Additional patient characteristics are listed
`in Table 1. Patients received from one to 12
`courses of therapy; 132 courses of MTA were ad-
`ministered. The dose escalation format
`in this
`
`study was also based on the mCRM,“ with planned
`dose levels ranging from 50 to 700 mgfmz.
`One patient was treated at each of the first
`seven dose levels, which included 50, 75, 100, 150,
`225, 350, and 525 mfmz. At the 150 rngfmz dose
`level, a second patient was treated, as the initial
`patient at this dose level received a dose based on
`ideal weight rather than actual weight. No in-
`stances of grade 3 or 4 toxicities occurred during
`this stage of the study.
`The first patient treated at 700 mglmz devel-
`oped grade 4 neuttopenia, grade 3 thrombocyto—
`penis, and rash, so three additional patients were
`added to the 525 mg/m2 dose level. Because a
`single instance of grade 3 thrombocytopenia and
`no grade 4 toxicity was observed in these patients,
`re—escalarion to 700 mg/m2 occurred and five ad-
`ditional patients were treated at this dose level. Of
`these five, two experienced grade 4 neutropenia
`accompanied by grade 3 or 4 thrombocytopenia.
`Substantial nonhematologic toxicity was also seen,
`with two patients experiencing rnucositis and one
`patient each experiencing fatigue, diarrhea. rash,
`and anorexia. This dose level was therefore not
`considered tolerable.
`
`tropenia, with one of the five requiring hospi-
`talization for infection and one also experienc-
`ing grade 4 thrombocytopenia. While no patient
`developed grade 3 or 4 nonhematologic toxicity
`during the first course of treatment, mild to
`moderate nonhernatologic toxicity occurred in
`most patients at this dose level. The most com-
`mon moderated (grade 2) nonhematologic tox-
`icity was a pruritic rash that occurred in 10
`patients. This was ameliorated with the use of a
`prophylactic course of steroids (dexamethasone
`4 mg orally twice a day for 3 days, starting day 1)
`around subsequent doses. Six patients developed
`moderate nondermal toxicity at this dose level.
`The 600 rngfmz dose was felt to be the MTD and
`recommended dose for phase II clinical
`trials
`using this schedule of MTA. Table 4 summarizes
`the course 1
`toxicity seen at all dose levels on
`this treatment schedule.
`
`Multiple patients treated at the highest dose
`levels experienced mild reversible renal dysfunc-
`tion, with greater toxicity appearing to correlate
`with worsening renal function. Weekly serum cre-
`atinine levels revealed that five of 20 patients who
`received 600 mgfml and two of six who received
`700 mgfmz had a maximal
`serum creatinine
`greater than 50% over baseline. This nephrotox-
`icity appeared to he reversible and nonprogressive,
`despite continued treatment in most of these pa-
`tients. To investigate this further, patients with
`varying degrees of renal dysfunction are receiving
`MTA in an ongoing follow-up study.
`Eight patients enrolled at the 600 Ingftnz dose
`level received four or more total doses of MTA.
`
`An intermediate dose level of 600 rrlgfmz was
`then added and 20 total patients were treated at
`this level. Five of these developed grade 4 neu-
`
`Hematologic toxicity and fatigue appeared to
`become more prominent after repetitive doses
`(Table 5). Hematologic toxicity was more severe
`
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`
`DAVID A. RINALDI
`
`Table 5. HTA Every ll Days: Cumulative Toxicity
`
`Course I
`Nadir
`Serum Creatinine Granulocytes
`(mgJ'dL)
`(per mm?)
`LG
`9|2
`0.9
`969
`L0
`2067
`|.|
`3456
`0.6
`I722
`0.?
`28 I 1
`0.B
`ISJ9
`
`Patient
`N3
`I F5
`I76
`I7?
`131*
`I83‘
`|84*
`
`Dose
`rmgrmi)
`600
`600
`600
`600
`600
`600
`$00
`
`Nadir Platelets
`(per mm‘)
`61
`45
`I89
`ill
`316
`234
`I 27
`
`Dose
`(mynfi)
`350
`350
`350
`SOD
`600
`500
`450
`
`Serum Creafinine
`[rngl‘dL)
`L3
`I .0
`0.8
`|.|
`0.5
`0.8
`I .0
`
`Course 4
`Nadir
`Granule-tyres
`(per mu?)
`2
`I40
`I564
`I856
`777
`I930
`I058
`
`Nadir Platelets
`(per mm’)
`5
`I4
`56
`50
`‘.163
`I43
`l 68
`
`I33
`I450
`L0
`we
`:95
`2527
`L0
`son
`L user
`“‘ Had pharmacokinetic studies after courses I and 4, which showed that MTA disposition was not significandy difierent in those retreated at
`Leon mgrmi.
`
`after the fourth course even though the pretreat-
`ment serum creatinine levels had not changed
`significantly. No changes in MTA disposition
`were demonstrated by repeat pharmacokineric
`analyses after a fourth course of treatment in
`four patients. While these eight patients had
`decreasing biood counts after multiple cycies of
`therapy, Cumulative toxicity has not been ob-
`served in subsequent clinical studies.
`The mean estimated creatinine clearance of
`those patients at the 600 rug/ml dose level devel-
`oping grade 4 neutropenia after their first course
`was 86 mL;'rriin. This compared with 97 rnL['min
`for those not developing grade 4 neutropenia. Two
`of the three patients with a baseline estimated
`creatinine clearance less than 70 rnljmin devel-
`oped grade 4 toxicity after their first dose at the
`600 mg/m2 compared with one of the nine patients
`with an estimated creatinine clearance greater
`than 90 mljmin.
`Twenty-three patients were withdrawn from the
`study because of disease progression. Fatigue led to
`the discontinuation of six patients and thrombo-
`cytopenia led to the discontinuation of one pa-
`tient. None of these patients who withdrew be-
`cause of study drug toxicity had evidence of disease
`progression at the time of discontinuation. Three
`patients died during the study related to drug tox-
`icity, two from neutropenic sepsis, and one from
`acute respiratory distress syndrome. These deaths
`occurred after three,
`four, and eight
`treatment
`courses, respectively.
`
`p
`
`Four patients, all with liver metastases, and all
`treated at the 600 mgfrnz dose level, achieved
`partial responses with MTA. Two of these had
`metastatic pancreatic cancer (of three pancre-
`atic cancer patients) and two had colorectal
`cancer (of 25 colorectal cancer patients). The
`first pancreatic cancer patient, who had previ-
`ously experienced disease progression during
`treatment with 5-FU, achieved a 53% reduction
`in measured disease; the second achieved a 76%
`reduction in measured disease. Both patients
`discontinued because of fatigue,
`the first after
`four courses of MTA and the second after six
`courses. The first colorectal cancer patient, who
`had previously received intrahepatic fluorode-
`oxyuridine, saw a 60% reduction in measured
`disease before withdrawing because of fatigue
`after six courses of treatment. The second pa-
`tient, who had previously experienced disease
`progression during treatment with raltitrexed,
`achieved a reduction of 51% in measured dis-
`ease. This patient
`received eight courses of
`MTA, but developed acute respiratory distress
`syndrome (as previously described). Six patients
`with advanced colorectal cancer also experi-
`enced minor responses, with five of these having
`received prior treatment with 5-FU.
`
`DOSE ESCALATION METHODOLOGY
`
`\)Vhile the study incorporating the daily X5,
`every 21 days schedule used traditional dose esca-
`lation methodology,
`the other two studies dis-
`
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`
`Table 7. Comparative Pharmacol-tinetics
`
`Daily X5
`Every 1| Days
`
`Once
`Every Ii Days
`
`Weekiy X4
`Every -12 Days
`
`Schedule
`MTD
`4
`30
`am
`(main?)
`ass ngimi.
`I
`|.2O pg.lmL
`umo pglmL
`c,,,,,,
`E106 ng.lhrl'mL
`13.61 i.tg,‘hr1mL
`2645 p,g!hrIrnL
`AUG
`in n1Umin.fm1“
`52.3 muminlml
`40.0 muminrm‘
`Clearance
`3.15 um‘
`as-1 um?
`100 um‘
`v,,
`|.I net
`2.02 hr
`3.0% hr
`L cm
`*The inconsistency in these values is due to plasma concen-
`trations reachlng minimurn quantitation limits before establish-
`ment of the apparent terminal elimination phase.
`l_
`
`87
`
`|
`
`J
`
`pear to be linear over a 0.2 to 700 mglmz dose
`range.
`
`SUMMARY
`
`MTA is a novel antifolate compound that
`inhibits the enzymes thymidylate synthase, gly—
`cinamide ribonucleotide formyltransferase, and
`dihydrofolate reductase. It is a schedule—depen—
`dent compound with substantially greater dose
`intensity achieved with a longer dosing interval.
`The MTDs observed were 4 mg/m2, 30 mg/m2,
`and 600 mgfrnl when administered as a daily
`X5, weekly, and every—21—day schedule, respec-
`tively. The major dose—limiting toxicity was
`neutropenia on all schedules, with possibly a
`greater degree of reversible liver biochemistry
`disturbances observed in the daily ><5 schedule.
`and more fatigue and dermatitis see in the every-
`21—day schedule. This latter schedule, however,
`appeared to exhibit more antitumor activity,
`with four patients (pancreas,
`two; colorectal,
`two} achieving partial
`responses. Minor
`re-
`sponses were observed in multiple tumor types
`and on all treatment schedules. Currently, MTA
`is being extensively evaluated in the phase ll
`setting against a variety of tumor types using the
`600 rngfrnz every-Z1«day treatment schedule.
`
`REFERENCES
`
`MTA PHASE II OVERVIEW
`
`cussed here used the rnCRM described by Fariesfi‘
`The goal of the inCRM is to expose fewer patients
`to lower,
`less—efficacious dose levels by updating
`the estimate of the MTD after each patient has
`been treated. The weekly X4, every 6 weeks
`schedule enjoyed only moderate success with this
`method due to the extent of toxicity seen at the
`initial dose levels, but the every-Z1—day schedule
`used the mCRM quite successfully, with 81% of
`enrolled patients being treated at, or close to, the
`projected phase 11 dose. Table 6 compares the
`patient numbers at each dose level in the three
`studies.
`
`COMPARATIVE PHARMACOKI NETICS
`
`Plasma samples for pharrnacokinetic analysis
`were obtained in each of the three studies dis-
`cussed.” Table 7 lists the pharmacokinetic param-
`eters associated with each of the three dosing
`schedules studied. Several general comments can
`be made regarding the pharmacokinetics of MTA
`over these dose ranges and schedules. MTA ex-
`hibits multicompartmental behavior with rapid
`distribution and elimination phases and is roughly
`80% protein hound. MTA has a small steady-state
`volume of distribution, suggesting that it has lim-
`ited tissue distribution. It is eliminated fairly rap-
`idly from plasma with a mean terminal elimination
`half—liFe of approximately 2 to 3 hours at
`the
`higher end of the dose range, and roughly 70% to
`80% of the aclministeredldose is recovered in the
`urine within 24 hours. The pharmacokinetics ap-
`
`Table 6. Dose Escalation Methodology Result:
`
` l Schedule
`
`Weekly X4
`Daily X5
`Every 6
`Every 2|
`Weeks
`Days
`
`Every 2|
`Days
`
`_|
`
`Dose escalation
`rnethocl*
`Range of dose levels
`No. of dose levels
`MTD (rnglmz)
`Patients treated at
`or near. the phase ll
`dose (5%)
`
`rnC.RM
`50-TDD
`7
`600
`
`mCRi'-1
`10-40
`4
`30
`
`T
`0.26.2
`I0
`4
`
`BI
`
`67
`
`29
`
`|_
`
`*T = traditional v mCRi“1.
`
`1. Thymidylate Symhase lnhibitor LY23l514-, Clinical in-
`vestigation Brochurc. Indianapolis, lN, Lilly Research labora-
`tories, Eli Lilly and Company, 1994
`2. Shih C, Chen V], Gossett LS. et al: LY231514. a pyr-
`rolo[2,3-d]pyrimidine»based antifolate that
`inhibits multiple
`folare—requiring enzymes. Cancer Res 5'i’:1116-1123, 1997
`3. Grindcy GB, Shih C, Barnett C], et al: LYZ315l4, a
`
`J
`
`J
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`Lilly Ex. 2030
`Sandoz V. Lilly IPR2016-00318
`
`Lilly Ex. 2030
`Sandoz v. Lilly IPR2016-00318
`
`

`
`88
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`4. McDonald AC. Vase): PA, Adams L, ct al: Phase 1 and
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`fulate. Clin Cancer Res 4:605-610, 1998
`5. Rinaldi DA, Burris HA, Dorr FA, ct al: Initial pll:-we I
`evaluation of the novel rhymidylate synthase inhibitor, MTA.
`utilizing the modified continual reassesalnent method for dose
`escalati0n._I Clin Oncul 131284212350. 1995
`6. Rinaldi DA, Burris HA, Don’ FA, er al: A phase I eval-
`tlatiun of L‘l'2315l4, a novel multiltargetecl antifnlatc admin-
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`istcred every 21 days. Proc Am Soc Clin Crncnl l5:l55‘3‘, I996
`(ahsrr)
`7. Rinalcli DA, Kuhn ]G, Burris HA, er al: A phase [ evalua-
`tion of rnultidargeted antifolzttc (MTA, LY231 514}. administered
`every 21 days, utilizing the modified continual
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`method for dose escalation. (submitted for publication)
`3. Farics D: Practical modifications of the continual reassess-
`merit for phase 1 cancer clinical trials. ] Biopharm Stat 4:147-
`l64, 1994
`9. Sharma A, luhnson RD, Woodworth ]M: Cumparanve
`hum-an pharmacokinetics of MTA in three phase I studies. Proc
`Am Soc Clin Oncol l?:900, 1998 (abstr}
`
`Lilly Ex. 2030
`Sandoz v. Lilly IPR2016-00318
`
`Lilly Ex. 2030
`Sandoz v. Lilly IPR2016-00318