CLINICAL REVIEW
`
`Clinical Review Section
`
`1
`
`
`
`
`AGREEMENTS OR FDA
`INDICATION,
`MEETING,
`RECOMMENDATIONS
`SUBMISSION, OR
`PROTOCOL,
`
`
`
`
`ISSUES
`ACTION
`
`
`
`
`trial; conduct a Phase
`1 trial with MTA +
`vitamins
`
`
`
`
`2. Stop current trial and
`open a new trial with a I
`new protocol and new
`dose
`3. Continue current trial
`with addition of
`vitamins and
`
`
`
`.wfi.-_*————M_—_Wm,_i*
`
`
`recalculate sample size
`
`Lilly opted for #3
`
`After 150 patients are
`treated with vitamin
`
`supplementation, a
`survival analysis will be
`done polling the approx.
`150 patient without
`vitamin supplementation
`
`
`FDA concern about ability
`to determine the benefit of l
`adding vitamins to trial;
`no standard dose of
`i
`vitamins
`
`l |
`
`Lilly to provide patient
`diary and pill count
`
`'
`
`March 8, 2000
`I (serial #212) and
`l April 13, 2000
`' (serial #220)
`
`1
`i
`
`FDA not convinced that
`
`
`
`clinical benefit response
`data will warrant early
`filin
`
`
`
`
`
`Follow-up questions
`2"'-line NSCLC trial
`2n-line NSCLC trial as
`on EOPZ
`as supporting trial for
`supporting trial for
`
`
`
`
`mesothelioma or
`_ mesothelioma
`
`
`
`Phase II data from
`
`mesothelioma trial(s)
`for support of
`
`mesothelioma
`
`
`23
`
`

`

`early submission of
`the NDA based on an
`
`interim analysis of
`clinical benefit
`endoints
`
`2n -line NSCLC trial
`
`to support
`mesothelioma
`indication
`
`acceptance of an
`interim analysis
`secondary endpoints
`on the mesothelioma
`
`trial
`
`l
`
`l I
`
`l l
`
`
`
`' July 6, 2000
`
`SUBMISSION, OR
`ACTION
`
`June 21, 2000
`
`Follow-up to EOPZ re:
`mesothelioma
`
`indication
`
`CLINICAL REVIEW
`Clinical Review Section
`
`1
`
`MEETING,
`
`
`
`AGREEMENTS OR FDA
`
`INDICATION;
`RECOMMENDATIONS
`
`
`PROTOCOL,
`ISSUES
`
`
`
`
`
`
`2“'-line NSCLC trial
`(superiority in survival) to
`
`support mesothelioma
`indication
`
`
`
`
`
`
`
`FDA expects mature
`survival data
`
`
`no double-blinding of ,
`mesothelioma trial
`
`demonstration of an
`
`improved survival
`associated with MTA
`
`
`
`
`
`would provide confidence
`that MTA is an effective
`
`agent providing clinical
`benefit
`
`8/24/2000:
`
`‘l
`
`Demonstrate superiority
`
`Serial #240
`Special Protocol
`assessment of 2nd-Iine
`
`NSCLC trial (JMEI: a
`Phase 3 trial ofalimta
`vs docetaxel in
`
`patients with locally
`advanced or metastatic
`
`As support for
`mesothelioma
`indication:
`
`Demonstrate
`
`superiority
`assessment
`
`Demonstrate non-
`
`inferiority assessment
`
`non-small cell lung
`cancer previously
`treated with
`.
`chemothera
`i
`
`
`
`Serial #242
`
`Statistical analysis
`
`issues, regarding the
`Mesothelioma privotal
`
`
`addition of vitamins
`trial revisions
`
`
`
`to the treatment
`
`
`regimens after the
`study had accrued
`
`about 150 patients
`
`
`Potential a - roval
`
`24
`
`

`

`l
`
`l
`
`July 12, 2000
`
`_
`' March 20, 2001
`
`CLINICAL REVIEW
`
`-
`
`Clinical Review Section
`
`MEETING,
`SUBMISSION, OR
`ACTION
`
`INDICATION,
`PROTOCOL,
`ISSUES
`
`AGREEMENTS OR FDA
`
`RECOMMENDATIONS
`
`
`
`
`
`
`j
`I strategies for MTA
`
`-
`
`Via an mtenm
`
`analysisorthefinal
`
`analysis
`
`430 (75 without
`vitamin-
`
`supplemented
`patients/arm) + (140
`vitamin-
`
`supplemented
`patients/aim)
`Final analysis p-value
`
`
`‘
`
`.
`
`1
`
`
`
`A single-blind
`Revisions: statistical
`
`
`randomized phase 3
`analysis issues,
`trial of MTA plus
`regarding the addition
`
`
`
`cisplatin vs. cisplatin
`of vitamins to
`
`
`treatment regimens
`in patients with
`
`
`
`malignant pleural
`mesothelioma
`
`Special protocol
`assessment: a
`
`
`
`JMEW to support the Comments about strategy
`front-line
`(5/7/2001):
`mesothelioma claim
`
`
`
`0
`
`0
`
`0
`
`Interim analysis of
`JMCH planned later in
`year
`
`Pre—NDA meeting
`scheduled 8/2001
`
`JMEW projected to
`accrue over 15-months
`
`plus 12-months of
`follow-u.
`
`randomized Phase 3
`
`trial comparing alimta
`plus best supportive
`care vs. best
`
`supportive care alone
`in previously treated
`patients with locally
`advanced or metastatic
`
`malignant pleural
`mesothelioma
`
`(JMEW)
`
`Interim database lock
`
`August 23, 2001
`
`‘
`
`Orphan drug status
`-ranted
`
`Ii
`
`
`Indication: treatment
`Conclusion: follow the
`Communication of
`
`of mesothelioma
`statistical analysis plan as
`data safety monitoring
`
`
`board conclusions
`' stated in orotocol and base
`
`
`
`‘ October 29,2001
`i
`I
`
`
`
`25
`
`

`

`
`'
`CLINICAL REVIEW
`Clinical Review Section
`
`MEETING,
`SUBMISSION, OR
`ACTION
`
`INDICATION,
`PROTOCOL,
`ISSUES
`
`AGREEMENTS OR FDA
`RECOMMENDATIONS
`
`
`
`
`
`
`
`
` .
`
`
`the final primary analysis
`on the mixed population
`of both supplemented and
`non-supplemented
`patients; final significance
`level of' -= 0.0476
`
`
`
`
`
`
`Last patient on-study _Visit
`'
`Pre-NDA meeting
`Alimta in combination
`
`
`
`with cisplatin is indicated
`
`for patients with advanced
`malignant pleural
`
`mesothelioma
`
`Lilly proposed to
`provide for electronic
`
`reader capability at
`
`the FDA and
`
`providing images for
`
`responders at baseline
`
`and at best response
`
`
` Proposal for Protocol
`
`V
`
`)'
`
`I November 7, 2001
`l January 30, 2002
`
`I
`
`March 19, 2002
`
`March 26, 2002
`
`for Treatment: alimta
`
`
`+ cisplatin, alimta +
`carboplatin, alimta
`
`alone
`
`
`Serial #394
`Change in
`formulation I
`
`
`
`
`
`
`formulation-Myophili
`zed product); CMC
`package and data -
`
`
`delayed until 2“d
`
`uarter 2003
`
`
`
`lSI single patient IND
`for compassionate and
`emergency use for
`malignant
`mesothelioma based
`on results from JMCH
`
`(JMCH to be
`
`26
`
`

`

` MEETING,
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`INDICATION,
`PROTOCOL,
`ISSUES
`
`AGREEMENTS OR FDA
`RECOMMENDATIONS
`
`SUBMISSION, OR
`ACTION
`
`presented at the
`plenary session of
`ASCO annual
`
`meeting
`Protocol for treatment
`for chemonaive
`patients with
`malignant pleural
`'
`mesothelioma
`
`
`
`Supported by JMCI—I
`Request for fast track
`data in abstract
`designation
`
`
`submitted to ASCO
`
`for 2002 annual
`meetin
`
`
`Presentation of the
`
`results ofJMCH at
`
`FDA: aiimta + cisplatin
`
`Regimens: alimta +
`cisplatin, alimta +
`carboplatin, alimta
`alone
`
`'
`
`
`
`
`
`plenary session of
`ASCO annual meeting
`
`;
`5 April 3, 2002
`i
`!
`Ii
`
`
`
`
`
`
`
`:LO
`
`
`June 10 2002
`
`
` Abstract was one of
`top five out of 3500
`
`
`abstracts submitted
`
`Fast track designation
`granted for malignant
`
`,
`
`l
`
`’
`Rolling submission of'
`October 31,2002
`NDA be - ins
`
`
`indication
`
`pleuralmesothelioma
`
`'
`
`4. Other Relevant Information
`
`Alimta is not approved in the United States or in any other country
`
`5.
`
`Important Issues m‘th Pharmacologically Related Agents
`
`5.1
`
`Introduction of folic acid and vitamin BIZ for safety reasons
`
`The introduction of folic acid and BIZ into the pivotal tn'al, IMCl-I, was based on a Lilly
`initiated multivariate analysis conducted in late 1997 to assess the relationship of vitamin
`metabolites, drug exposure, and other pre-specified baseline patient characteristics to
`toxicity following therapy with MTA. Data were examined from 139 Phase 2 patients '
`
`27
`
`

`

`CLINICAL REVIEW
`
`Clinical Review Section
`
`with tumors of the colon, breast, pancreas, and esophagus who had been treated with
`MTA at 600 mg/mZ intravenously over 10 minutes once every 21 days. These patients
`had homocysteine (Hcys), cystathionine, and methylmalonic acid levels measured at
`baseline and once each cycle thereafter. Stepwise regression modeling, multivariate
`analysis of variance and discriminant analysis were implemented to determine which
`predictors might correlate with severe toxicity, and to predict which patients were at high
`risk of experiencing such toxicity. Prognostic factors then considered were age, gender,
`prior therapy, baseline albumin, liver enzymes, ANC, platelets, vitamin metabolites, and
`AUC,
`
`C
`
`The findings from this investigation led to the following conclusions:
`
`{Toxicity resulting from therapy with MTA appeared to be higher in patients
`with elevated pre-therapy homocysteine levels.
`
`0 Elevated baseline homocysteine levels (210 ' mol/L, for the 139 patients
`included in this initial analysis) highly correlate with severe hematological and
`nonhetnatological toxicity following therapy with MTA.
`
`- Homocysteine was found to be better than baseline albumin (another predictor
`oftoxicity identified in the analysis) at predicting toxicity and was not altered
`with MTA therapy.
`
`Because of the observation that pre-therapy homocysteine levels were critically important
`'in predicting toxicity, the same multivariate analysis was repeated on data from 305
`patients who had their baseline homocysteine levels measured and recorded using a
`single laboratory. To eliminate the confounding factor ofthe effect of folic acid
`supplementation on toxicity, patients on Study IMAS who received folic acid
`supplementation (n=3 8) were removed from the analysis, leaving a final sample size of
`267 patients. Prognostic factors considered in this second wave of analysis were age,
`gender, baseline albumin, liver enzymes, ANC, platelets, vitamin metabolites, pretherapy
`weight, AUC, tumor type, and prior treatment. Baseline homocysteine was identified as
`a highly statistically significant predictor of febrile neutropenia (p <0.00001), Grade 4
`. neutropenia (p = 0.0191), Grade 4 thrombocytopenia (p <0.00001'), and Grade 3 or 4
`diarrhea (p (0.00001). According to Lilly, these results confirmed the original findings
`and supported the conclusion that homocysteine may provide an ideal prognostic variable
`for predicting toxicity during MTA therapy.
`,
`‘
`
`During the conduct of the JMCH trial, a programmatic change was made by Lilly in the
`clinical development of MTA whereby every patient treated with MTA must be
`supplemented with folic acid and vitamin B12 to improve patient safety. Initiation of
`vitamin supplementation in this study was done in both treatment arms and at the same
`time point to preserve study blinding at the patient level. By this time a total of 112
`patients had been randomized in the study and received therapy without vitamin
`supplementation from the start, while a total of 40 patients received vitamin supplements
`
`28
`
`

`

`l
`
`-
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`1
`
`after at least one cycle of study therapy. For the purpose of this study, a patient was
`classified as supplemented with vitamins if he/she received study vitamin supplement
`during his/her entire study participation. The two groups of patients described above were
`classified as not supplemented with vitamins in this study while those who received
`vitamin supplementation with all cycles of study therapy were be classified as
`supplemented with vitamins. As such, approximately 150 patients were considered
`treated without study vitamin supplementation (initial study cohort) while an anticipated
`280 qualified patients were considered treated with vitamin supplementation on the
`revised protocol.
`
`52
`
`. The effect of folic acid and vitamin B12 on the efficacy of an antifolate
`
`The narrative above does not take into account the potential negative effect on efficacy
`by the addition of folic acid + B 12. The commentarybelow seeks to understand the
`enhanced efficacy from the addition ofa folate to an antifolate.
`
`Natural folates and antifolates have two important properties, such as: l) the requirement
`for cellular uptake via a reduced folate carrier (RFC); and 2) the ability to be
`polyglutamylated.
`Increased extracellular folate concentrations and expanded
`intracellular folate pools may contribute to decreased antifolate sensitivity due to
`competition for transport and polyglutamylation, thus, decreasing the inhibitory effect on
`TS and GARFTase.6
`
`5.3
`
`Transport
`
`In comparison to all other transport routes identified in rodent and human neoplastic cell
`types, the basic kinetic properties and preferences among structurally related folates and
`their analogues as permeants for the one-carbon, reduced-folate system are remarkably
`similar. 7 Enhanced RFC activity promotes the efficient transport of RF C-dependent
`antifolates and thus, more potent TS inhibition.8 Folic acid is a poor substrate for RFC]
`and enters cells by other mechanisms.9
`
`Carrier—mediated systems transporting folates have a variety of properties in common.
`The internalization (influx) of folates by these systems is saturable, conforming to
`Michaelis-Menten kinetics. However, they exhibit differences in preferences for
`structurally related folates and their analogues, which are competitive inhibitors.‘0 The
`carrier was encoded by the RFCI gene.H There is also a receptor-mediated process. The
`
`6 Bachus et al. 1m .1 Cancer. 2000;87:771-778.
`7 Sirotnak FM. Annual Review ofNutIition. l999;19:91~122
`s Baehus et al. Int J Cancer. 2000;87:771-778.
`9 Zao, Babani, Gao, Liu, Goldman. Clin Cancer Res. 2000; 613687-3695
`1° Sirotnak FM. Annual Review ofNutrition. 1999,19: 91-122
`” Khokhar, Lam, Rusch, Sirotnak. J Thoracic Cardiovasc Surg. 2002; 123:862-868
`
`29
`
`

`

`CLINICAL REVIEW
`
`Clinical Review Section
`
`extent to which carrier— or receptor-mediated processes contribute to net translocation of
`folates in cell types where both processes are found is comroversial, but it will depend on
`the level of expression ofthe corresponding gene in each cell type. Because the
`translocation efficiency of carrier-mediated processes is much greater than that of
`receptor-mediated processes, the relative level of expression required for the latter to
`contribute significantly to net translocation of folates is proportionally greater.‘2 The
`exact mechanism of transport has not been established for MTA. MTA does have high
`affinity for RFCl and folate receptor-alpha.13
`
`In one cell type, L1210, free levels of folates and antifolates are governed by RFC] .14 For
`mesothelioma cells, there are varying views on MTA transport. One reason for MTA
`activity in mesothelioma may be due to a highly expressed, high-affinity alpha folate
`receptor on mesothelioma cells of all histolog’ic subtypes. This type of highly expressed
`eceptor was thought to contribute to MTA transport into mesothelioma cells.15
`However, other evidence suggests that human mesothelioma cell lines predominately
`internalize tritiated methotrexate (MTX shares a transport routle6and is polyglutamylated
`in tumor cellsin a manner similar to natural folate compounds 6) by means ofa carrier-
`mediated mechanism, with little transport by a receptor--mediated mechanism. 17
`Recently, a high-affinity transport activity in three human mesothelioma cell lines was
`characterized. The researchers reported that the transport activity was specific for MTA
`and had low affinity for other antifolate inhibitors of dihydrofolate reductase (MTX,
`,aminopterin, PT523) and thyrnidylate synthase (ZD1694, ZD9331); also, this activity
`ma} be another transport routefor mesothelioma cellsof5—meth}l-tetrahydtofolate, the
`predominatefolate in the plasma ofman and rodents.8 The degree of expression of this
`transport activity in comparison to the RFC] has not been elucidated.
`
`5.4
`
`Polyglutamylation
`
`Pharmacological activity of MTA depends on conversion to polyglutamylated derivatives
`inside the cell; polyglutamylation increases the affinity ofthe MTA derivative.
`Polvglutamylated forms also ensure cellular retention Only inhibition of DHFR is not
`affected by the degree of polyglutamylaion. 9The effect of polvglutamylation on the
`inhibitory activity of MTA15 shown below.19
`
`‘3 Sirotnak l-‘M. Annual Review ofNutrition. 1999;19: 91-122
`‘3 Zao, Babani, Gao, 1.1g Goldman. Clin Cancer Res. 2000; 6:3687-3695
`_ H 230. Babani, Gao. Liu, Goldman. Clin Cancer Res. 2000; 6:3687-3695
`‘ Scagliotti etal JClin Oncol 2003,21: 1556 1561
`'6 Egan MG, Sirlin S, Rumberger BG, Garrow TA, Shane B, Sirotnak FM .1 Biol Chem 1995.270(10): 54628.
`’ Khokhar NZ, Lam AF, Rusch VW, Sirotnak FM JThorac Cardimasc Surg. 2002. 123(5): 862 8.
`“Wang, Zhao, Chattopadhyay, Goldman. Cancer Res. 2002;62:6434—6437
`’9 Zao, Babani, Gao, Liu, Goldman.
`c1111 Cancer Res. 2000; 63687-3695
`
`30
`
`

`

`CLINICAL REVIEW
`
`Clinical Review Section
`
`PENTAGLUTAMATE
`
`MTA
`
`. 5.5
`
`The effect ofincreased folate levels
`
`Antifolates, under conditions of increased extracellular folate levels, have decreased
`sensitivity due to competition for transport and polyglutamylation. This diminishes the
`effect on thymidylate synthase (TS) and GARFTa'se. Cells grown in low folate
`conditions are more sensitive to antifolates, including MTA, than cells grown in high
`folate conditions.20
`'
`
`Intracellular folates rise as extracellular 5-formyl-THF increased and MTA sensitivity
`decreased in an inverse relationship. Intracellular levels of THF cofactors modulate the
`growth-inhibitory activity ofMTA (figure below). THF cofactor pool size plays a critical
`role in modulating the growth-inhibitory effects of MTA.” In this system, an increase in
`folate pool size required an increase in MTA concentration for comparable inhibition.
`
`10
`
`l
`
`15-34.t
`
`
`
`{a
`
` I.5 (term"soJoin/mutt){00d«2'0;unnuaaenut
`
`
`
`'15.,..
`
`
`
`
`Extracellular S-CHOJHF (nM)
`
`Fig. 7 Relatiaisltip; 3mm; MTA cl MIX ICM intmmllubt‘ folatc
`pm! size. and ntnwllubr S-(‘HLLTHF cmuntmtim In Ll 2l0 cells.
`LUIO cells were 31mm in (“late-free RPM! I440 sunrkmaued with
`different concentrations tiff-C HO-THF fora! least I week before MTA
`or MTX K‘g..\ were determined. Intracellular fol-ate pools were meas-
`ured after cell: were grown exponentially for 1 week in. folate‘free
`medium wpplaucntcd “III! different cmmntntions of l'l-flS-CHO~
`'l'lll’. The data an the mean 7 SE from three separate experiments.
`
`MTA activity is modulated within cells by natural folates that compete for
`polyglutamation at the level of folylpolyglutamate synthetase. Contraction of the cellular
`folate pool decreases suppression of MTA polyglutamation.22
`
`2° Bachus et al. Int J Cancer. 2000;87:771-778.
`E1 230, Babani, Gao, Liu, Goldman. Clin Cancer Res. 2000; 6:3687-3695
`‘2 Goldman ID, Zhao R. Semin Oncol. 2002 Dec;29(6 Suppl 18):3-l7.
`
`31
`
`

`

`CLINICAL REVIEW
`
`Clinical Review Section
`
`Changes in folate levels influence the competition between antifolates and natural folates.
`Below are processes that may be affected.
`
`Natural folate pools within the cell may modulate MTA activity by:
`c
`competing with and inhibit MTA polyglutamation at the level of folyl—poly-gamma-
`glutamate synthetase
`competing with antifolates at the level of target enzymes
`
`o
`
`For example, increased folate pools (i.e., byfolic acid supplementation) may prevent
`polyglutarnylation, resulting in faster efflux and a decrease in sensitivity of MTA.
`
`Below is an in vitro example of the biochemical perturbations on MTA activity, resulting
`from changing folate levels.
`'
`
`In the murine colon cancer cell lines (541x23), human colon cancer cell lines (1.2
`x), and the human head and neck cancer lines (1.8-22x), ICSO values for MTA
`were higher in cells grown in standard folate media (8.8 uM folic acid and 2.2 uM
`folic acid, respectively) compared to cells grown in low folate media (2.5 nM
`leucovorin for murine colon cancer cells; 1 nM leucovorin for the human colon
`cancer cells; 0.5 nM leucovorin for head and neck cancer cell lines). FdUMP
`binding capacity and TS protein expression (by Western blotting) was lower in
`cells grown in low folate media. RFC activity was increased several fold (2-7x)
`in cells grown in low folate media compared to high folate media. In the case of
`lower activity of TS, lower concentrations of TS inhibitors are required for
`inhibition. No significant changes in polyglutamylation activity were found.24
`
`MEDICAL OFFICER NOTE: It appears that in cell culture, MTA
`has biochemical advantages under low folate conditions.
`In marked
`contrast, in patients, i.e., the randomized JMCH trial, the addition of
`folic acid to the regimens increased efficacy without increasing the
`dose of MTA.
`
`, Below is an in vilro example of the inhibitory activity ofMTA, resulting from increasing
`folate levels. Again, note that for a comparable ICSO, the concentration of MTA is
`increased as the folic acid concentration is increased.
`
`The table below illustrates that a several fold increase in MTA is required to give
`comparable inhibition of the cancer cell lines (none are mesothelioma cell lines)
`when folic acid is added to the media.25
`
`33 Refers to lC50
`3" Bachus et al. Int J Cancer. 2000;87:771-778.
`
`:5 Worzalla et al. Anticancer Research. 1998; 18:3235-3240
`
`32
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`

`

`CLINICAL REVIEW
`
`Clinical Review Section
`
`
`
`Hrnin: “been {“am‘ Ir. K}.
`
`Fui's 3:}: pa. I'I Ndn‘
`
`n: .M
`13
`
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`
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`:5
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`(mnzu
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`‘( ymmmq in Ara-nub; v‘r‘l’nu: ml) Miami. u-L\Z’:.‘H (nu minus-m nuts-uW 1-me
`fink a: hint and u. .130! I») run. plk u. l YTPHM mire
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`
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`179
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`n»
`b
`z
`
`It is known that the MTD of antifolates in folated-depleted mice is much lower (50x)
`compared to mice on a standard diet.26 Below is an in vivo example of the changes in
`MTA lethality, resulting from changing folate in the diet.
`
`In mouse strains, CD 1 nu/nu and DEA/2 (figure below), the MTA LDSOS were
`250x and 60x greater, respectively, in mice fed a standard diet (1-2 mg
`folate/kg/day) compared to a low folate diet (0.00l~0.008 mg folate/kg/day)
`(figure below). Inspection of the figure shows that the two mouse strains had
`approximately the same MTA LDSO same on standard diet. On a low folate diet,
`the strains could be differentiated; there was a 10-fold difference in MTA LDSO,
`i.e., DBA/Z > CD 1 nu/nu.27 In view ofthe data in the next figure, a MTA LD50
`study with low folate + folate supplement (15 mg folate/kgx’day) would have been
`helpful.
`
`¢r_- -w?;_,_ _ _.__cs/'
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`2: Bachus et al. Int J Cancer. 2000;87:771—778.
`'2’ \K'orzalla et al. Anticancer Research. 1998; 18:3235-3240
`
`33
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`

`

`CLINICAL REVIEW
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`Clinical Review Section
`
`In mouse strain DBA/Z on a low folate diet, there was 100% inhibition of
`
`L5 1 78Y/TK-/HX- lymphoma (figure below), at a MTA dose of 0.3 and I
`m g/kg/day administered intrapen'toneal for 10 days, starting the day after tumor
`transplant. In mice fed a low fat diet + folate supplementation, 100% inhibition of
`L5178Y/TK-/HX- lymphoma was achieved at MTA doses of 30 -
`lOOO
`mgx’kg/day or the dose ofMTA had to be increased 3 0x to obtain comparable
`eflicacy wit/ifolale supplememalion(figure below).
`
`WWI“) .
`
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`
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`
`MEDICAL OFFICER NOTE: These preclinical results are counterintuitive
`to the results of the pivotal clinical trial, JMCH. In JMCH, after accrual of
`70 of patients to the trial, subsequent patients were supplemented with folic
`acid + BlZ without an increase in the dose of MTA. In comparison to the
`never supplemented group, efficacy parameters appear to have improved
`with folic acid + BIZ supplementation, including in the cisplatin arm. Similar
`clinical findings ofincreased efficacy with the addition of folic acid + B12
`were reported from a Phase 2 trial of MTA alone in mesothelioma patients;
`i.e., in the non-supplemented patients the median survival was 8 months and
`in the supplemented patients the median survival was 13 months.28
`
`In mice, folic acid supplementation required a significant increase in the
`dose of MTA to obtain comparable efficacy as the non-supplemented mice.
`In humans, the dose of MTA was not increased with folic acid + BIZ
`
`supplementation and the efficacy increased in comparison to the non-
`supplemented group.
`
`However, the in vivo experiment below appears to mimic the clinical data.
`
`1* Scagliorti et al. J Clin Oncol. 2003;21:1556-1561
`
`34
`
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`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`l
`
`To assess the effect of vitamins involved in the folate pathway on the anitumor
`efficacy of LY23 1 514 disodium in a human tumor xenograft model, female nude
`mice bearing human MX-l breast carcinoma were treated with LY231514
`disodiurn (MTA or alimta) alone or along with super physiologic doses of folic
`acid, vitamin B6 (pyridoxine), or vitamin BIZ (cobalamin). The doses used in
`these growth delay experiments were: LY231514 (alimta, 100 or 150 mg/kg)
`administered by intraperitoneal injection on Days 7 through 11 and Days 14
`through 18 post-tumor implantation alone or along with folic acid (6 or 60
`mg/kg), vitamin B6 (100 mg/kg) or vitamin BIZ (165 mg/kg).29
`C
`
`MEDICAL OFFICER NOTE: The schedule of vitamins is different in
`
`JMCIi. In JMCH, the protocol indicated that patients should take
`oral folic acid (350 -'600 ug) daily beginning approximately 1 to 3
`weeks before treatment with MTA plus cisplatin or cisplatin alone
`and continuing daily until 3 weeks after discontinuation from study
`therapy; in the animal study, folic acid was given by intraperitoneal
`injection (the METHODS section suggests IP and the figure indicates
`PO) concurrently with MTA, i.e., d 7-11 and (I 14-18. In JMCH, the
`protocol indicated that a vitamin B12 (1000 ug) injection must be
`administered approximately 1 to 3 weeks before treatment with MTA
`plus cisplatin or cisplatin alone and should be repeated approximately
`every 9 weeks until the patient discontinues from study therapy; in
`the animal study, B12 was given by intraperitoneal injection
`concurrently with MTA, i.e., d 7-11 and d 14-18. In JMCH, patients
`received both folic acid and BIZ; in the animal study, only one of the
`vitamins was given. It is not stated why these doses of vitamins were
`used. For example, the folic acid doses were 6 mg/kg and 60 mg/kg by
`inrraperitoneal injection; in another Lilly Research study, a standard
`mouse diet contained 1-2 mg/kg/day of folate and mice on a low folate
`diet received 15 mg/kg/day of oral folie acid.30 The full dose response
`of these vitamins is not provided; i.e., the dose of the super
`physiological doses of vitamins may be on the inhibitory portion ofa
`bell-shaped dose response curve.
`
`Also, the schedule of MTA was different in another Lilly Research
`study. In this study, nude mice transplanted with MX-l breast cancer
`were treated with MTA 100, 150, and 200 mg/kg/day on a day 7-1]
`schedule.31 In the study described below, the mice were treated with
`MTA on a day 7-11 and day 14-18 schedule or twice the amount of
`MTA. In the other Lilly Research study, the definition of tumor
`growth delay was defined as the time taken by each individual tumor
`
`:9 Lilly Research Laboratories: Nonclinical Pharmacology Report 30, March 2002
`:0 \Vorzalla et al Anticancer Research. 1998; 18:3235-3240
`" Teicher et al Clin Cancer Res. 2000; 6:1016-1023
`
`35
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`

`
`
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`
`lacsEl'lfllSSOcl1339
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`to reach 500 mm3 compared with the time in the untreated controls;
`in study described below, the goal for the tumor size was 1000 mm3.
`
`A figure with the results is below.
`
`RESPONSE OF THE HUMAN MX-‘l BREAST CA
`10 ALIMTA ALONE 5 ALONG WITH VlTA-‘MN SUFF-‘LEMENTS
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`
`35
`
`40
`
`TUMOR GROWTH DELAY. Days
`
`The table below illustrates the same data MTA alone@ 100 mg/kg delayed
`tumor growth by 17 days Although the addition of folate@V6 mg/kg did not
`change tumor growth delay, folate@ 60 mg/kg increased the tumor growth delay
`to 22 days. The addition of B6 did not change tumor growth delay ofMTA. The
`addition ofBIZ increased the tumor growth delay to 22 days. MTA alone @ 150
`mgkg delayed tumor growth by 21 days. Although the addition of folate @ 6
`mg/kg did not change tumor growth delay, folate @ 60 mg/kg increased the tumor
`growth delay to 23 days, The addition of B6 did not change tumor growth delay
`of MTA. The addition of B12 increased the tumor growth delay to 24 days. With
`regard to folate alone, in a dose-response fashion, folate 6 and 60 mg/kg delayed
`tumor growth by 7 and 12 days. respectively. B6 alone delayed tumor growth by
`5.7 days. B12 alone delayed tumor growth by 12 days. It appears that at these
`doses, in this tumor, folate (in a dose-response fashion) and BIZ alone and in
`combination \sith MTA contribute to the delay of tumor growth without an
`increase in MTA dose. This15 in marked contrast to another Lilly Research
`study.32
`
`3: \K’oxzalla et al. Anticancer Research. 1998; 18:3235-3240
`
`36
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`

`I
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`CLINICAL REVIEW
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`Clinical Review Section
`
`}
`
`| REGIMEN, MG/KG
`
`MTA 100 alone
`
`TUMOR GROWTH
`DELAY (DAYS
`17
`
`
`
`17
`22
`17
`
`22
`
`21
`23
`21
`24
`
`'
`
`’
`
`21
`
`'
`
`;
`
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`i
`
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`
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`
`+ 6 folate
`+ 60 folate
`+ 100 B6
`+ 165 B12
`
`MTA 150 alone
`
`;
`
`E
`
`'
`
`+ 6 folate
`+ 60 folate
`+ 100 B6
`+ 165 BIZ
`
`"
`
`Folate agone
`
`100
`
`165
`
`MEDICAL OFFICER NOTE: Although not a mesothelioma cell line,
`these results are consistent with the results in JMCH, i.e., the addition
`
`of folate or BIZ to an antifolate enhances antineoplastic activity. In
`fact, 'high dose folate alone and BIZ alone may have antineoplastic
`activity independent of the antifolate, MTA. These results also run
`counter to the other in vitro and in vivo models presented above.
`
`APPEARS nus WAY
`0N ORIGINAL
`
`37
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`

`

`'
`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`II.
`
`Clinically Relevant Findings From Chemistry, Animal Pharmacology
`and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other
`Consultant Reviews
`
`1. Statistical Review and Evaluation, completed and entered into DFS 12/10/2003
`
`- Yong-Cheng Wang, Primary Reviewer
`Ming Li, Acting Team Leader
`
`2. Clinical Pharmacology and Biopharmaceutics Review, completed and entered into
`DFS, 12/4/2003
`
`0 Brian Booth, Primary Reviewer/Phannacometrics ,
`o Roshni Ramchandani, Atul Bhattram, Pharmacometrics
`
`Joga Gobburu, Pharmacometfics, Team Leader
`N.A.M. Atiqur Rahman, Team Leader
`
`3. Pharmacology/Toxicology Review and Evaluation, completed and entered into DFS
`12/19/2003
`
`0 D00 Y. Lee Ham, Primary Reviewer
`David Morse, Team Leader
`
`___-, and
`‘
`There were three consultations (e.g., medical imaging, _ "\
`pulmonary). The medical imaging consultation is not snown below because the findings
`ofthe consultation were blended into the Medical Officer's evaluation of tumor response.
`
`/
`
`38
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`

`CLINICAL REVIEW
`
`Clinical Review Section
`
`41
`
`Recommendations for labeling:
`
`B ACKGROUND:
`
`The LCSS cannot be interpreted as a general measure of either ‘ \
`__
`” The LCSS15 based on a conceptual modelin which the
`phvsical and functional dimensions are the main determinants ofa patient’ 5 health-related
`quality oflife (HRQL), however, it specifically excludes items that focus on the
`psvchological, social and spiritual domains. 33 The LCSS has been shown to explain only
`half the variabilityin overall HRQL.34 In addition, the LCSS does not directly measure
`symptoms of treatment toxicity except in the situation where the symptoms of the
`condition are similar to the symptoms of treatment toxicity, e.g., fatigue.
`
`_
`
`The LCSS has been documented psychometrically to measure (as demonstrated by
`content, construct and criterion-related validity) the physical symptoms and function
`from the perspective ofthe lung cancer patient 35 Patients with borh NSCLC and SCLC
`haxe been tested. The extent that the same conclusions can be reachedin" malignant
`pleural mesothelioma would depend in part on whether the symptoms measured include
`all
`important symptoms specific to the mesothelioma experience. Symptoms measured
`by the LCSS are fatigue, decreased activity, cough, dyspnea, decreased appetite, pain and
`haemoptysis. The LCSS also includes a general symptom distress item a single-item
`global quality of life item.
`
`Item 9 of the LCSS asks the broad question, “How would you rate the quality of your life.
`today?” This broad question cannot be considered support for a broad claim, i.e.,
`“improved QOL,” since the determinants of that broad concept are not captured and it
`cannot be ascertained what treatment or non-treatment related changes are impacting the
`broad concept.
`
`33 Hollen P, Gralla R, et al. Quality oflife assessment in individuals with lung cancer: Testing the Lung Cancer
`f»mptom Scale (LCSS). Eur J Cancer 29A: 551-,558 1993
`”Hollen P Gralla R, et al. Quality oflife during clinical trials. Conceptual model'for the Lung Cancer Symptom
`fScale (LCSS) Supportive Carein Cancer 2: 213-222, 1994
`”Hollen p, Gralla R, ctal. Measurement ofquality oflifein patients with lung cancer in multicenter trials ofnew
`therapies: Psychometric asse