Lilly Research Laboratories
`A Division oi Eli Lilly and Company
`
`Lilly Colporale Center
`Indianapolis. Indiana 46285
`(317) 2762000
`
`July 29, 1998
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Oncologic Drug Products, HFD-150
`i4Si Rockviiie Pike
`Rockville, MD 20852-1448
`
`Subject: IND 40,061, MTA (LY23l5l4) - Serial no. 126
`Briefing document for End-of-Phase [1 Meeting (mesothelioma; -_-on-small
`cell lung cancer and head/neck cancer)
`
`Reference is made to our July 13, 1998 (Serial no. 125) request for an end of Phase 11
`meeting for MTA (LY231514). As stated in that request, please find enclosed 10 copies
`ofthe briefing document to facilitate discussion on the development ofMTA for patients
`with mesothelioma, non-small cell lung cancer and head/neck cancer.
`
`Included in this briefing document is an overview of the development of MTA as well as
`sections on the clinical program, non-clinical pharmacology including toxicology and
`ADME, human pharmacology, clinical statiaics with analysis, and the risk to benefit ratio.
`It is not our intent to discuss the nonclinical issues ofMTA at this requested meeting.
`Section 3 ofthe briefing document contains a summary ofissues and questions; this
`summary was provided as an attachment to the July 13, I998 submission.
`
`.A.ppendices to the briefing docurner are also included. These appendices include more
`extensive data on pharmacokinetics, adverse events, draft clinical study protocols for the
`registration trials ofMTA, a list of completed, ongoing and planned clinical studies, and
`bibliography.
`
`9'' issues
`
`‘ “uested meeting focus on these areas:
`
`0 The dose and dosing schedule to proceed with initial registration trials in patients with
`mesothelioma, patients with NSCLC who have failed prior platin- and taxane-based
`therapy and patients with head or neck cancer who have failed an initial chemotherapy
`regimen for locally recurrent and/or metastatic disease.
`
`TRIAL
`EXHIBIT
`
`2083
`
`CONFIDENTIAL
`
`ELAPO0O07327
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`Lilly Ex. 2098
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`

`
`Food and Drug Administration
`July 29, 1993
`
`®
`
`Page 2
`
`0 Our specific strategy for clinical and non-clinical development and NDA submission
`for treatment of these patients. Specific advice will be requested on the
`appropriateness of the overall study designs (i.e., selection of the MTA regimen for
`phase 111, selected eflicacy endpoints, active control, overall study size, analysis plan
`and confirmation that the overall patient exposure is sufficient for an integrated
`summary of safety). It is our understanding that there is no efiective therapy for these
`patients and thus the studies proposed will satisfy the requirements for accelerated
`approval.
`
`Identification and resolution of any issues that could alter the timing/quality ofthe
`NDA or the review of that application
`
`Since MTA has broad clinical activity in multiple tumor types, our clinical efforts will
`continue to evaluate its safety and efficacy in patients with various tumors, either alone or
`in rational combination with drugs already active in patients with those tumor types.
`It is
`our understanding that the briefing document and subsequent discussion will focus on an
`overview ofthe development ofMTA with specific focus on issues associated with
`adequate and well-controlled studies to support NDAs for treating patients with
`mesothelioma, NSCLC and head/neck cancer. We have undertaken parallel clinical
`development for other patient populations (breast cancer, colo-rectal cancer, first-line
`NSCLC), and propose that fiirther discussions focus on the adequate and we1l~controlled
`studies to support supplemental NDAs for those patient populations.
`
`We request that the FDA provide Eli Lilly and Company with a list of the FDA invitees to
`this meeting.
`In addition, it would be extremely helpful and lead to a more productive
`discussion if the FDA could provide their responses to our questions and any questions or
`issues that the FDA may have prior to the requested meeting.
`
`Please contact Dr. Steven A. Hamburger at (317) 277-8900 concerning proposed meeting
`times. If you require any additional information or clarifications, please contact either Dr.
`Hamburger or me at (317)277-3799.
`
`Sincerely,
`ELI LILLY AND COIVIPANY
`
`ll
`
`M3 8 ‘Em?
`
`Gregory T. Brophy, Ph.D.
`Director
`
`U.S. Regulatory Afi°airs
`
`Enclosure
`
`0
`
`.3.
`
`CONFIDENTIAL
`
`ELAPOOO07328
`
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`
`

`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`INVESTIGATIONAL NEW DRUG APPLICATION (IND)
`LE 21 coDE OF FEDERAL REGUIA nous
`NAME OF SPONSOR
`ELI LILLY AND COMPANY
`3. ADDRESS (Number, street, City, Share and Zip Code)
`
`1.
`
`LiIIy Corporate Center
`Indianapolis, IN 46285
`
`4.
`_
`'
`§3Z7aao»‘~" Date: STQSLDIDQQ
`599 OMB srarememon Reverse-
`
`NOTE: N0 MS may be shipped of cum,
`investigation begun until an N0 form
`invesfeafien is in eIIee1(21 CFR 312.40).
`2. DATE OF SUBMISSION
`‘My 29' 1998
`4. TELEPHONE NUMBER
`(Include Area Cow)
`
`(317) 2762000
`
`5. NAME($) OF DRUG (include all available James; Trade. Genetic, Chemical, Code)
`
`6.
`
`IND NUMBER (lrpteviously assigned
`
`Compound LY231514 Disodium (MTA)
`
`7.
`
`INDICATION(S) (Covered by fink submission)
`Cancer
`
`IND 40,061
`
`8. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: U PHASE I U PHASE 2 U PHASE 3 0 OTHER
`
`NA
`)
`(8 ‘
`9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR ANTIBIOTIC APPLICATIONS
`(21 CFR Part 314), DRUG MASTER FILES (21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Part 601) REFERRED
`TO IN THIS APPUCATION.
`
`NA
`
`10. IND submisdon should be consecutively numbered. The initial IND should be numbered
`"Serial number: 000." The next submission (e.g., amendment, report, or comespondence)
`should be numbered "Serial Number: 001. " Subsequent submission should be
`numbered consecutively in the order in which they are submitted.
`11, THIS SUBMISSION CONTAINS THE FOLLOWING: (Check afl that apply)
`CI INITIAL INVESTIGATIONAL NEW DRUG APPLICATION (IND)
`
`U RESPONSE TO CLINICAL HOLD
`
`SERIAL NUMBER
`
`lg
`
`PROTOCOL AMENDMENT(S):
`U NEW PROTOCOL
`U CHANGE IN PROTOCOL
`U NEW INVESTIGATOR
`
`INFORMATION AMENDMENT(S):
`U CHEMISTRYIMICROBIOLOGY
`D PHARMACOLOGYITOXICOLOGY
`0 CLINICAL
`
`IND SAFETY REPORT(S):
`U INITIAL WRITTEN REPORT
`U FOLLOW~UP TO A WRITTEN REPORT
`
`U ANNUAL REPORT
`U RESPONSE TO FDA REQUEST FOR INFORMATION
`0 REQUEST FOR REINSTATEMENT OF IND THAT IS WITHDRAWN,
`CI OTHER
`INACTIVATED. TERMINATED OR DISCONTINUED
`
`I GENERAL CORRESPONDENCE
`
`CHECK ONLY IF APPLICABLE
`
`CDRIDBIND/DGD RECEIPT STAMP
`
`FOR FDA USE ONLY
`DDR RECEIPT STAMP
`
`IND NUMBER ASSIGNED:
`
`DIVISION ASSIGNMENT:
`
`FORM FDA 1571 (V97)
`
`PREVIOUS ITION IS OBSOLETE.
`
`PAGE 1 OF 2
`
`CONFIDENTIAL
`
`ELAPOOO07329
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`Sandoz v. Lilly IPR2016-00318
`
`

`
`CONTENTS OF APPLICATION
`This application contains the following "terns: (Check all that apply)
`
`1. Form FDA 1571 [21 CFR 312.23(a)(1)]
`2. Table of Contents [21 CFR 312.23(a)(2)]
`3.
`Introductory statement [21 CFR 312.23(a)(3)]
`4. General lnvestigational plan [21 CFR 312.23(a)(3)]
`5.
`Investigators brochure [21 CFR 312.23(a)(5)]
`6. Protocol(s) [21 CFR 312.23(a)(6)]
`D a. Study protocol(s) [21 CFR 312.23(a)(6)]
`D b.
`Investigator data {21CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572
`III e. Facilities data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572
`El d.
`institutional Review Board data [21 CFR 312.23(a)(6)(iii)(b)] or completed Form(s) FDA 1572
`7. Chemistry, manufacturing, and control data [21 CFR 312.23(a)(7)]
`El Environmental assessment or claim for exclusion [21 CFR 312.23(a)(7)(iv)(e)]
`8. Pharmacology and toxicology data ]21 CFR 312.23(a)(8)]
`9. Previous human experience [21 CFR 312.23(a)(9)]
`El 10. Additional information [21 CFR 312.23(a)(10)]
`
`13. IS ANY PART OF THE CLINICAL STUDY TO BE CONDUCTED BYA CONTRACT RESEARCH ORGANIZATION? 0 YES CI NO
`
`NA
`IF YES, WILL ANY SPONSOR OBLIGATIONS BE TRANSFERRED TO THE CONTRACT RESEARCH ORGANIZATION? 0 YES 0 NO
`
`IF YES, ATTACH A STATEMENT CONTAINING THE NAME AND ADDRESS OF THE CONTRACT RESEARCH ORGANIZATION,
`IDENTIFICATION OF THE CLINICAL STUDY, AND A LISTING OF THE OBLIGATIONS TRANSFERRED.
`
`14. NAME AND TITLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT AND PROGRESS OF THE CLINICAL
`INVESTIGATIONS
`
`Steven J. Nicol, M.D.
`
`15. NAME(S) AND T|TLE(S) OF THE PERSON(S) RESPONSIBLE FOR REVIEW AND EVALUATION OF INFORMATION RELEVANT TO THE
`SAFETY OF THE DRUG
`
`Same as #14 Above
`
`I agree not to begin clinical investigations until 30 days after FDA's receipt of the IND unless I receive eartier notification by FDA that the studies
`may begin.
`I also agree not to begin or continue clinical investigations covered by the IND ltthose studies are placed on clinical hold.
`I agree
`that an institutional Review Board (IRS) that complies with the requirements set fourth In 21 CFR Part 56 will be responsible for Initial and
`continuing review and approval of each of the studies In the proposed clinical investigation. I agree to conduct the investigation in accordance
`with all other :
`- vlicable
`vulato
`-
`- ulrernents.
`16. NAME OF SPONSOR OR SPONSOR'S AUTHORIZED
`REPRESENTATIVE
`
`17. SIGNATURE OF SPONSOR OR SPONSOR'S AUTHORIZED
`REPRESENTATIVE
`
`GregoryT. Brophy, Ph.D., Director
`U.S. Regulatory Affairs
`18. ADDRESS (Number, sneer, City, Smteandzip Code)
`
`Eli Lilly and Company
`Lilly Corporate Center
`Indianapolis, IN 46285
`
`W
`19: TELEPH u NE NUMBER
`(include Area Code)
`
`gym
`4/
`
`(317) 277-3799
`
`7/25/93
`
`false statement is a criminal offense. u.s.c. Title 18, Sec. 1001.
`.
`Public reporting burden tor this collection of information is estimated to average 100 hours per response, including the time for reviewing Instructions, searching
`existing data sources, gathering and maintaining the data needed, and completing reviewing the collection of Information. Send comments regarding this burden
`estimate or any other aspect ot this collection of Intonnation. including suggestions for reducing this burden to:
`
`Duns Reports clearance omcer
`Paperwork Reduction Proied 0910-0014
`Hubert H. Humphrey Building, Room 531-I-I
`200 Independence Avenue, S.W.
`Washington, Dc 20201
`
`FORM FDA 1571 (1197)
`
`"An agency may not conduct or sponsor, and a person is not required to respond to. a collection
`of infomiation unless it displays a currently valid OMB control number."
`
`Please DO NOT RETURN this
`
`-
`
`-
`
`PAGE 2OF2
`
`CONFIDENTIAL
`
`ELAPOOO0733O
`
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`Sandoz v. Lilly IPR2016-00318
`
`

`
`This document contains trade secrets, or
`commercial or financial information,
`privileged or confidential delivered
`in confidence and reliance that such
`information will not be made available
`to the public without express written
`consent of Eli Lilly and Company
`
`CONFIDENTIAL
`
`ELAPOOO07331
`
`Lilly Ex. 2098
`Sandoz v. Lilly IPR2016-00318
`
`

`
`28 July 1 998
`MTA (LY231514)
`FDA Briefing Document
`
`Lilly Research Laboratories
`Eli Lilly and Company
`Indianapolis, Indiana 46285
`
`MTA (LY231514)
`Document Page 1
`
`FDA Briefing Document: 28 July 1998
`
`CONFIDENTIAL
`
`ELAPOOO07332
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`
`

`
`Table of Contents
`
`Section
`
`Page
`
`Section 1: Overview of End of Phase 2 Briefing Document ............................................ ..5
`1.1. Scientific Rationale .................................................................................................. ..5
`
`1.2. Summary of Development Program to Date and Integrated
`Timeline for Future Activities .................................................................................. ..5
`
`1.2.1. Development Program to Date ........................................................................... ..8
`
`Section 2: Clinical Program to Date .................................................................................. ..9
`
`2.1. Phase 1 Experience .................................................................................................. ..9
`
`2.1.1. Phase 1 Monotherapy Studies ............................................................................ ..9
`
`2.1.2. Phase 1 Combination Study JMAP (MTA plus cisplatin) ............................... ..l0
`2.2. Phase 2 Experience ................................................................................................ ..ll
`
`2.2.1. Non-Small Cell Lung Cancer........................................................................... .. 11
`2.2.2. Head and Neck Cancer ..................................................................................... ..12
`
`2.2.3. Summary of Other Clinical Experience ........................................................... ..12
`
`Section 3: Summary of Issues and Questions ................................................................. ..l4
`Issue 1. Dose a.nd schedule .......................................................................................... ..l4
`
`Issue 2. MTA in Mesotheliorna ................................................................................... ..15
`
`Issue 3. NSCLC ........................................................................................................... ..16
`
`Issue 4. MTA and NSAIDS ......................................................................................... ..l9
`
`Issue 5. Population Pharmacokinetics ......................................................................... ..2O
`
`Issue 6. Renal Impairment Study ................................................................................. ..2O
`
`Issue 7. Hepatic Impairment Study .............................................................................. ..21
`
`Issue 8. Nonclinical Information ................................................................................. ..21
`
`Issue 9. MTA in Head and Neck Cancer ..................................................................... ..21
`
`Section 4: Pharmacology, Toxicology, and ADME ....................................................... ..23
`
`4.1. Summary of Nonclinical Mechanism of Action Studies ....................................... ..23
`
`4.2. Toxicology ............................................................................................................. ..24
`4.2.1. Overview .......................................................................................................... ..24
`
`4.2.2 Other Completed Studies .................................................................................. ..25
`
`4.2.3. Ongoing Studies ............................................................................................... ..26
`
`4.2.4. Future Studies .................................................................................................. ..26
`
`4.3. ADME.................................................................................................................... ..26
`
`4.3.1. Overall Summary ............................................................................................. ..26
`
`4.3.2. Completed Studies ........................................................................................... ..27
`4.3.3. Future Studies .................................................................................................. ..27
`
`MTA (LY231514)
`Document Page 2
`
`FDA Briefing Document: 28 July 1993
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`
`4.4. Pharmacology ..................................................................................................... ..27
`
`Section 5: Human Pharrnacokinetics and Bioavailability ............................................... ..30
`
`5.1. Clinical Pharmacology ........................................................................................... ..30
`5.1 .1 . Introduction.............................................. ..' ...................................................... ..30
`
`5.1.2. Pharmacokinetic Methods................................................................................ ..3O
`
`5.1.2.1. Phase 1 Studies .......................................................................................... ..30
`
`5.1.2.2. Phase 2 Studies .......................................................................................... ..3O
`
`5.1.3. Pharmacodynamic Methods .................... .; ....................................................... .31
`
`5.1.4. Summary of Human Pharmacokinetics ........................................................... ..3l
`5.1.4.1. Phase 1 Studies .......................................................................................... ..3l
`
`5.1.4.2. Special Populations (Gender, Renal, and NSAID
`Effects) .............................................................................................................. ..32
`5.1.4.3. Phase 2 Studies .......................................................................................... ..33
`
`5.1.5. Summary of Pharmacodynamic Assessments ................................................. ..34
`5.1.6. Conclusions ...................................................................................................... ..34
`
`Section 6: Clinical/Statistical .......................................................................................... ..36
`
`6.1. Table of Studies ..................................................................................................... ..36
`
`6.2. Safety Overview .................................................................................................... ..36
`6.2.1. Studies Included ............................................................................................... ..36
`
`6.2.2. Phase 1 Studies ................................................................................................ ..36
`
`6.2.2.1. JMAA ......................................................................................................... ..37
`
`Demographics ...................................................................................................... ..37
`
`Toxicity ................................................................................................................ ..38
`6.2.2.2. JMAP ......................................................................................................... ..39
`
`Demographics ...................................................................................................... ..39
`
`Toxicity ................................................................................................................ ..39
`6.2.3. Phase 2 Studies ................................................................................................ ..41
`
`6.2.3.1. Lilly Studies JMAC, JMAD, JMAG, JMAH, JMAL ................................ ..4l
`
`Demographics ...................................................................................................... ..42
`
`Toxicity ................................................................................................................ ..42
`6.2.3.2. NCIC Studies JMAN and JMAO ............................................................... ..45
`
`Demographics ...................................................................................................... ..46
`
`6.3. Multivariate Analysis ............................................................................................. ..51
`6.3.1. Introduction ...................................................................................................... ..51
`
`6.3.2. Analysis ............................................................................................................ ..5l
`6.3.3. Results .............................................................................................................. ..52
`
`MTA (LY231514)
`Document Page 3
`
`FDA Briefing Document: 28 July 1998
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`
`6.3.4. Conclusion ....................................................................................................... ..53
`
`Section 7: Risk to Benefit Ratio ..................................................................................... ..54
`
`Section 8: Measurement of Unidimensional Disease is
`
`Appropriate in Mesothelioma
`
`List of Appendices
`
`Appendix 1 ................................................................ .. Pharmacokinetic Figures and Tables
`
`Appendix 2 .................................................................. ..Phase 1 Studies BP—O0l and JMAB
`
`Appendix 3 ........................................................................................... ..Surnmary of Deaths
`
`Appendix 4 ......................................................................... ..List of Serious Adverse Events
`
`Appendix 5 ............................................. .. Detailed Methodology for Multivariate Analysis
`
`Appendix 6 ............................................................................. ..Protocol I-I3E—MC-JMBQ(a)
`
`Appendix 7 ................................................................................. .. Protocol H3 E-MC-JMCH
`
`Appendix 8 ........................................... .. List of Completed, Ongoing, and Plaxmed Studies
`
`Appendix 9 ..................................................................................................... .. Bibliography
`
`19
`
`MTA (LY231514)
`Document Page 4
`
`FDA Briefing Document: 28 July 1998
`
`CONFIDENTIAL
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`

`
`Section 1: Overview of End of Phase 2 Briefing
`Document
`
`1.1. Scientific Rationale
`
`Background information is provided below on the preclinical profile, clinical
`pharmacology, clinical data to date (Phase 1 and 2 studies), and the safety profile of MTA
`(LY23 1514). MTA inhibits multiple enzymes in the folate pathway including
`thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinarnide
`ribonucleotide formyl transferase (GARFT) (Shih et al 1997). Initial clinical studies have
`shown that, as a single agent given once every 21 days at either 500 or 600 mg/m3, MTA
`appears to have broad spectmm antitumor activity. Responses have been observed in
`patients treated in Phase 2 clinical trials of non—small cell lung cancer, colorectal cancer,
`pancreas cancer, locally advanced/metastatic breast cancer, head and neck cancer, renal
`cell cancer, bladder cancer, and cervical cancer. A Phase 1 trial (JMAP) has shown that
`MTA can be successfully combined with cisplatin, and that full doses of both compounds
`may be given. In this trial, partial responses were noted in 5 of 13 mesothelioma patients
`treated with MTA plus cisplatin.
`
`1.2. Summary of Development Program to Date and Integrated
`Timeline for Future Activities
`
`This document focuses on the efficacy of MTA in the tumor types in which we are
`seeking initial registration, ie, mesothelioma, second-line non-small cell lung cancer, and
`second-line head and neck cancer. Validated safety data (cutoff date of 11 December
`1997) from Phase 2 trials in NSCLC (JMAL and JMAN), colorectal cancer (JMAC and
`JMAO), pancreatic cancer (JMAD), esophageal cancer (JMAH), and locally advanced or
`metastatic breast cancer (JMAG) are presented. The safety profile in these 250 patients
`(with 1,020 cycles of treatment) appears typical of an antifolate; this is discussed in
`greater detail in Section 6.2.
`
`Phase 2 studies have shown that MTA has broad activity (see Tables 1.1 and 1.2). This
`presents a challenge in drug development, ie, to define the appropriate role for MTA in
`the treatment of cancer patients. Our overall clinical development snategy has two
`components. The first involves initial registration in “refractory” tumor types or settings,
`such as mesothelioma, second line NSCLC, and second line head and neck cancer. The
`second component involves the continued clinical development in a parallel fashion in
`breast cancer and front line NSCLC.
`
`MTA (LY231514)
`Document Page 5
`
`FDA Briefing Document: 28 July 1998
`
`CONFIDENTIAL
`
`ELAPOOO07336
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`Sandoz v. Lilly IPR2016-00318
`
`

`
`
`
`
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`CONFIDENTIAL
`
`ELAPOOO07337
`
`Lilly Ex. 2098
`Sandoz v. Lilly IPR2016-00318
`
`

`
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`ELAPOOO07338
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`.o3m__~>«8:m_:o:.:E8=_m_£E5m2S.6EI
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`Lilly Ex. 2098
`Sandoz v. Lilly IPR2016-00318
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`

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`‘.
`
`1.2.1. Development Program to Date
`A total of 748 patients have received MTA worldwide as of 21 April 1998. Table 1.3
`shows the number of patients treated in Phase 1 and Phase 2 studies.
`
`Table 1.3.
`
`Patients Treated with MTA in Phase 1 and 2 Studies
`
`Phase 1 Single Agent
`Phase 1 Combination
`Phase 2 Single Agent
`Phase 2 Combination
`
`Number of Patients
`
`100
`[09
`504
`35
`
`During the course of clinical development of MTA we decided to perform a multivariate
`analysis to test the hypothesis that patients at risk of developing serious toxicity could be
`predicted from a knowledge of potential prognostic factors. Early pre-clinical and
`clinical studies of other antifolates had suggested that a patient’s folate status might play
`a role in the likelihood of experiencing severe toxicity. A key part of this multivariate
`analysis was to examine the role of a patient’s functional folate status as assessed by
`homocysteine, cystathionine, methyl citrate I and H, and methylmalonic acid levels in
`determining the risk for developing toxicity. The rationale for looking at these vitamin
`metabolites as potential indicators is described in more detail in Appendix 5. Thus,
`vitamin metabolite data were prospectively obtained from patients in studies JMAC,
`JMAD, JMAG, and JMAH. Results from the multivariate analysis are based on a total of
`139 patients. However, this is a dynamic process and additional analyses will be
`undenaken as data becomes available from studies (including NSCLC) which will start
`shortly. Toxicities resulting from therapy with MTA appear to be predictable from
`pretherapy homocysteine levels. Elevated baseline homocysteine levels (21 0pM) highly
`correlate with severe hematologic and nonhematologic toxicities following therapy with
`MTA. The results of this multivariate analysis are discussed in Section 6.3.3.
`
`In summary, MTA has shown broad activity in multiple tumor types including
`mesothelioma, NSCLC, and head and neck cancer, and the toxicity profile is consistent
`with that of other antifolates. Work is underway to identify patients at risk of developing
`serious toxicity. A knowledge of potential risk factors may allow better management of
`individual patients, the use of appropriate prophylactic measures, or potentially the
`identification of those patients for whom MTA might be an appropriate therapy. The
`efficacy data (response and survival) from the completed Phase 2 MTA studies in
`NSCLC compares favorably with historical data on other single agents in chemotherapy
`naive patients. In addition, the emerging data from the ongoing Phase 2 study in head
`and neck cancer and the responses observed in mesothelioma in the Phase 1 study of
`MTA and cisplatin are encouraging. We therefore believe that registration efforts in
`these tumor types are warranted.
`
`MTA (LY231514)
`Document Page 8
`
`FDA Briefing Document: 28 July 1998
`
`CONFIDENTIAL
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`ELAPOOO07339
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`

`
`Section 2:
`
`Clinical Program to Date
`
`2.1. Phase 1 Experience
`
`2.1.1. Phase 1 Monotherapy Studies
`Three monotherapy dosing schedules have been investigated in Phase 1 studies.
`
`0
`
`In Study JMAA: 37 patients were treated on a schedule of once every 21
`days.
`
`Study JMAB: 24 patients received drug once weekly for 4 weeks every 6
`weeks.
`
`Study BP-001: 38 patients were treated using a schedule of daily times
`five every 21 days.
`
`The once every 21 day schedule has been carried forward into Phase 2 trials. In the
`Phase 1 trial investigating this dose, 37 patients were administered drug at doses ranging
`from 50 to 700 mgrnl 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 (Rinaldi et al 1996). Toxicity experienced in this
`study is described in Section 6.2.2.1.
`
`The weekly times four, every 6 weeks schedule is not currently being pursued in Phase 2
`trials. Dose-limiting toxicity (DLT) on this schedule was myelosuppression, particularly
`leukopenia and granulocytopenia. Inability to maintain the weekly treatment schedule
`due to neutropenia limited dose escalation on this schedule.
`
`The daily times five every 3 weeks schedule resulted in an MTD of 4 mg/m2/day. DLTs
`on this schedule were reversible neutropenia and elevated liver enzymes.
`Nonhernatologic toxicities were mild and included mucositis, diarrhea, rash, fatigue, and
`elevated transatninases. Minor responses were observed using this schedule in 1 patient
`with colorectal cancer and 1 patient with NSCLC. This schedule is being evaluated in a
`single Phase 2 trial in colorectal cancer in order to further assess its feasibility.
`
`The Phase 1 experience is summarized in Table 2.1.
`
`MTA (LY231514)
`Document Page 9
`
`FDA Briefing Document: 28 July 1998
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`CONFIDENTIAL
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`

`
`Phase 1 Experience
`
`Schedule*
`
`Once every 21 days
`
`No. of patients treated
`
`37
`
`Weekly x 4, every 6
`weeks
`24
`
`Daily X 5, every 21
`days
`38
`
`Dose range
`
`50 to 700 mg/m2
`
`10 to 40 mg/m2
`
`0.2 to 5.2 mg/m1
`
`Recommended Phase 2
`dose
`
`600 mg/m2
`
`30 mg/m3
`
`4 mg/m2
`
`DLT
`
`Responses
`
`Neutropenia, mucositis, Myelosuppression,
`fatigue
`particularly
`granulocytopenia
`Minor responses in
`colorectal (2)
`
`Partial responses in
`pancreas (2), and
`colorectal (2)
`
`Neutropenia
`
`Minor responses in
`colorectal (1) and
`NSCLC (1)
`
`“ all doses administered as a 10-minute infusion
`
`Details ofthe pharmacokinetic determinations from Study JMAA are given in Section
`5.1.
`
`A more complete description of the JMAB (weekly times four every 6 weeks) and BP-
`001 (daily times five every 21 days) studies can be found in Appendix 2 (McDonald et al
`1998; Rinaldi et al 1995).
`
`2.1.2. Phase 1 Combination Study JMAP (MTA plus cisplatin)
`In a Phase 1 trial of MTA in combination with cisplatin, patients with solid tumors were
`enrolled into one of two cohorts. The first cohort received MTA followed 30 minutes
`
`later by cisplatin on Day 1 of a 21-day cycle, and the second cohort received MTA on
`Day 1 and cisplatin on Day 2 of a 21-day cycle. Forty patients were enrolled into the first
`cohort; the MTD was reached at 600 mg/m2 MTA and 100 mg/m2 cisplatin, with dose-
`limiting toxicities of thrombocytopenia and febrile neutropenia. Eleven patients were
`enrolled into the second cohort. The degree of toxicity seen using this split schedule,
`which has included two therapy-related deaths, has led to the conclusion that the second
`schedule is clinically inferior. Partial responses were seen in 1 of 6 patients with non-
`small cell lung cancer, 2 of 4 patients with colorectal cancer (one of these on the split
`schedule), 3 of 9 patients with head and neck cancer, 1 of 2 patients with melanoma, 1
`patient with cancer of unknown primary, and in particular, 5 of 13 patients with
`mesothelioma (12 of the 13 had pleural mesothelioma). All responses with the exception
`of one response in colorectal cancer and one response in mesothelioma were seen in the
`first cohort (MTA and cisplatin on Day I). Table 2.2 includes information regarding
`
`MTA (LY231514)
`Document Page 10
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`FDA Briefing Document: 28 July 1998
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`CONFIDENTIAL
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