8027.4
`
`Lilly Research Laboratories
`A Division of Eli Lilly and Company
`
`Lilly Corpo,ale Center
`Indianapolis. Indiana 46285
`(317) 276-2C00
`
`November 18, 1998
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Oncologic Drug Products, HF])- 150
`Ann: Ms. Linda McCollum, CSO
`1451 Rockville Pike
`Rockville, Maryland 20852-1448
`
`INID # 40,061 - LY231514
`End-of-Phase 2 Meeting Minutes
`Compound LY231514 (MTA, Multitargeted Antifolate)
`
`Serial No.: 137
`
`Enclosed are Lilly's minutes for the End-of-Phase 2 meetings held on September 23
`(Biopharmaceutics) and September 25 (Clinical) 1998 to discuss LY23 1514 with members
`of the Division of Oncologic Drug Products. We sincerely appreciate the willingness of
`the Division members to meet with us and to offer advice regarding the development of
`this investigational drug.
`
`We respectfUlly request a copy of the Division's meeting minutes when they are available.
`
`Please call Mr. John Worzalla at (317) 276-5052 or me at (317) 277-3799 if there are any
`questions. Thank you for your continued cooperation and assistance.
`
`Sincerely,
`
`ELI LILLY AN) COMPANY
`
`Gregory It Brophy, Ph.D.
`Director
`U.S. Regulatory Affairs
`
`CONFIDENTIAL
`ELAP00008700
`
`TX 392
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`INVESTIGATIONAL NEW DRUG APPLICATION (IND)
`(7171.5 21, CODE OFFEDER4L REeL/LA 77CN$ (GAF) PART 312)
`I. NAME OF SPONSOR
`
`ELI LILLY AND COMPANY
`a ADDRESS (Nimter. Sbor, Cl,. Ste and Zip code)
`Lilly Corporate Center
`Indianapolis, IN 46285
`
`8027.5
`
`Eçka
`SeeOMBsc,watonps.is,se.
`
`TZtthat
`invegaSn is in elIect (21 Cm 12.4Q).
`2. DATE OF SuBMISSION
`November18, 1998
`
`4. TELEPHONE NUMBER
`(&tia%,e Code)
`
`(317) 276-2000
`
`5. NAME(S) OF DRUG (ir,cludeallavnllablonames made, Gened Chen*al, code)
`
`6. IND NUMBER (YusOaSSfl&
`
`Compound LY231 514 Disodiuni (MTA)
`
`IND 40,061
`
`7. INDICATION(S) (Cowmdbythissuzwm'sskn)
`
`Cancer
`
`8. PHASE(S) OF CLINICAL INVESTIGATION TO BE CONDUCTED: U PHASE I U PHASE 2 U PHASES U OTHER
`
`(Specif)
`9. LIST NUMBERS OF ALL INVESTIGATIONAL NEW DRUG APPLICATIONS (21 CFR Part 312), NEW DRUG OR AN11BIO11C APPLICATIONS
`(21 CRR Part 314), DRUG MASTER FILES I21 CFR Part 314.420), AND PRODUCT LICENSE APPLICATIONS (21 CFR Pair 601) REFERRED
`TO IN THIS APPLICATION.
`
`-
`
`NA
`
`10. MiD submission should be consecutively numbered. The Initial IND should be numbered
`"Serial number 000. The next submission (e.g., amendmen4 repor4 or con'espondence)
`should be numbered seziai Number OO1. Subiequent submission should be
`numbered consecutively in the order in which they are submitted.
`
`SERL NUMBER
`
`II. THIS SUBMISSION CONTAINS THE FOLLOtMNG:
`U INrTIAL INVES11GATIONAL NEW DRUG
`
`that apply)
`(Check
`APPLICATION (IND)
`
`U RESPONSE TO CLiNICAL HOLD
`
`PROTOCOL AMENDMENT(S):
`U NEW PROTOCOL
`U CHANGE IN PROTOCOL
`U NEW INVESTIGATOR
`
`AMENDMENT(S):
`INFORMATION
`U CHEMISTRYIMICROBIOLOGY
`U PHARMACOLOGWrO)OCOLOGY
`U CUNICAL
`
`ND SAFETY REPORT(S):
`U INITiAL WRITTEN REPORT
`U FOLLOW-UP TO A WRITTEN REPORT
`
`U ANNUAL REPORT
`U RESPONSE TO FDA REQUEST FOR INFORMATION
`U OTHER
`U REQUEST FOR REINSTATEMENT OF ND THAT
`IS WITHDRAWN,
`INACTIVATED, TERMINATED OR DISCONTINUED
`
`s=t-rr-
`
`..
`
`-c.;..?jr.Lesr t*e'U*
`
`rr::-',S,t'-rto7t.,.,..
`
`CHECK ONLY IF APPUCAE&E
`
`.---r-1%...
`
`.'*ta
`
`.
`
`GENERAL CORRESPONDENCE
`
`t''-
`
`(Spociv)
`
`z:: to
`
`.
`
`_%tt:2t?..
`-
`-
`- ---- fl_s
`
`_-
`
`.
`
`CDRJDBINDa'OGD RECEIPT STAMP
`
`FORFDAUSEONL'Y
`DDR RECEIPT STAMP
`
`.
`
`IND NUMBER ASSIGNED:
`
`DIViSION ASSIGNMENT:
`
`FORM FDA 1671 (1297)
`
`PREVIOUS EDmON IS OBSOLETE.
`
`CONFIDENTIAL
`ELAP000087O1
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`iz
`
`CONTENTS OF APPLICATION
`This application ccntuins the following items: (Check all that apply)
`
`O 1. Form FDA 1571(21 CFR 312.23(a)(1)J
`0 2. Table of Contents (21 CFR 312.23(a)(2)1
`O 3.
`Introductory statement (21 CFR 312.23(a)(3fl
`O 4. General Investigational plan £21 CFR 31223(a)(3))
`U 5. Investigators brochure [21 CFR 312.23(aX5)]
`O 6. Protocol(s) [21 CFR 312.23(a)(6)]
`O a. Study protocol(s) 121 CFR 312.23(a)(6fl
`O b.
`Investigator data (2ICFR 312.23(aX6)(iii)(b)J or completed Form(s) FDA 1572
`0 c. Facilities data [21 CER S12.23(a)(5)(iii)çb)3 or completed Form(s) FDA 1572
`C d.
`Institutional Review Board data £21 CFR 312.23(a)(exiii)(b)J or completed Form(s). FDA 1572
`U 7. Chemistry, manufacturing, and control data (21 CFR 3l2.23(aX7)]
`O
`Ci Environmental assessment or claim for exclusion (21 CER 312.23(a)(7)(W)(e)1
`O 8. Pharmacology and toxicology data 121 CFR 312.23(a)(8fl
`o 9. Previous human experIence [21 CFR 312.23(a)(9)J
`U 10. Additional information (21 CFR 312.23(a)(1O)1
`
`13, IS ANY PART OF THE CLINICAL STUDY TO BE CONDUCTED BYA CONTRACT RESEARCH ORGANIZATION? U YES Ci NO
`
`IF YES, WILL ANY SPONSOR OBLIGATIONS BE TRANSFERRED TO THE CONTRACT RESEARCH ORGANIZATION? U YES U NO
`
`NA
`
`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 OBUGATIONS TRANSFERRED.
`
`14 NAME AND TITLE OF THE PERSON RESPONSIBLE FOR MONITORING THE CONDUCT AND PROGRESS OF THE CLINICAL
`INVESTIGATIONS
`
`Steven J. Nicol, M.D.
`
`IS. NAME(S) AND TITLE(S) OF THE PERSON(S) RESPONSIBLE FOR REVIEW AND EVALUATION OF INFORMATION RELEVANT TO THE
`SAFETY OFTHE DRUG
`
`Same as #14 Above
`
`I agree not to begIn clinIcal Investigations untIl 30 days alter FDA's receIpt of the (ND unless I receIve earlier notificatIon by FDA that the studies
`may begin. I also agree not to begin er continue clinical Investigations covered by the l?W Itthose studies are placed on clinIcal 1mM. I agree.
`that an InstItutional Review Board (IRS) that compiles with the requIrements act fourth in 21 CFR Putt 68 wIll be responalbie 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 applicable regulatory requirements,
`16. NAME OF SPONSOR OR SPONSORS AUThORIZED
`REPRESENTATIVE
`
`17. SIGNATURE OF SPONSOR OR SPONSOR'S AUTHORIZED
`REPRESENTATIVE
`
`Gregory tBroph Ph.D., Director
`
`IS. ADDRESS(NuntoçSeoor,ClçSeteancJZipCoW)
`
`Eli Lilly and Company
`Lilly Corporate Center
`Indianapolis, IN 48285
`
`UMBE
`. TELEPHON
`Ame COC)
`
`20. DATE
`
`(317) 277-3799
`
`11/18198
`
`ARNlNG; A wIflMIy false statement Is a criminal offense. U.S.C. TItle IS, Sec. 1001.)
`Public repoding burden tot this collection of information is estimated to average 100 hours per response, InCOJdIng the thne for reviewing Inatluctions, searching
`existIng data sources, gathering and maintaining the data needs, and completing reviewing the collection of Information. Send comments regardIng ttIs burden
`estimate or any other aspect of th1 collection of Intormatlon, Including suggestions ton reducing tilts burden to:
`
`01*15 Repoits Clearance Officer
`Papeiwotic Reduction Project 091 O'at4
`Hubert H. Humphrey BuIldIng, Room 53141
`ZO Independence Avenue, S.W.
`I
`Washington, DC
`
`FORM FDA 1511(1197)
`
`"Ass agency may not conduct or Sponsor, and a person Is not required to respond to. a collection
`of Information unless It dIsplays a currently valid 0MB control number."
`
`Please DO NOT REmUIN thIs applIcation to this address.
`
`PAGE 2 OF 2
`
`CONFIDENTIAL
`ELAP000087O2
`
`Lilly Ex. 2101
`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
`
`8028
`
`CONFIDENTIAL
`ELAP00008T03
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8029
`
`LY231614 (MTA} End of Phase 2 Meeting with the FDA
`Biopharmaceutics Issues Wed. Sept. 23, 1998 at FDA
`
`FDA Participants: Division of Oncoloay Druci Products
`Robert White, M.D., Medical Reviewer
`Atiq Rahman, Ph.D., Biopharm Team Leader
`Liang Zhou, Ph.D., Chemistry Team Leader
`Linda McColluni, Consumer Safety Officer
`Lilly Participants:
`Steven Hamburger, Ph.D., U.S. Regulatory Affairs
`Robert D Johnson, Ph.D., Pharmacokineticist
`Mary Pat Knadler, Ph.D., Drug Disposition
`Clet Niyikiza, Ph.D., Statistician
`David Seitz, M.D., Ph.D., Medical Advisor
`Jackie Walling, Ph.D., Director of Science, MTA Team
`John Worzalla, U.S. Regulatory Affairs
`Lilly Consultant:
`Sharyn Baker, PharrmD., Cancer Therapy and Research Center, San Antonio
`Cancer Institute
`
`Meeting Request Submission Date: July 13, 1998
`Briefing Document Submission Date: July 29, 1998
`Additional Submission Dates: Sept. 8, 1998
`
`Meeting Minutes:
`
`Issue 4: MTA and NSAIDS
`
`The FDA showed the following acetate:
`'MTA and NSAIDS - Currently the Phase 2 studies and all registration directed
`studies have excluded those patients who have a need for chronic administration
`of NSAIDS or aspirin. Do you agree that if this study shows no pharmacokinetic
`interaction that this will be sufficient evidence to take the course of action
`outlined, i.e., remove the exclusion criterion, and to prevent this exclusion from
`being part of the label?"
`
`4A NO. The decision to remove exclusion criterion for Ibuprofen will
`depend on the outcome of the study. Depending on the P1< parameter
`variability, sample size of the proposed interactions study may be
`inadequate to rule out absence of interaction between MTA and Ibuprofen.
`Please submit a detailed protocol for Agency Review.
`
`CONFIDENTIAL
`ELAP0000S7O4
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8030
`
`Acetate #1
`
`Evaluation of response in solid tumors
`
`"Important note:
`Data from the NCI US support simplifying
`response evaluation through the use of
`unidimensional measurements and the sum of the
`longest diameters instead of the conventional
`method using two measurements and the sum of
`the products. This new approach is implemented
`in the present document."
`
`WHO criteria for Response Evaluation in solid Tumors
`August 1998
`
`CONFIDENTIAL
`ELAP000087O5
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8031
`
`Acetate #2
`
`Comparison of nnidimensional (New) and WHO
`response criteria in the same patients
`
`CR
`
`Pit
`
`SI)
`
`PU
`
`KR
`
`Brst (n=48)
`WHO
`New
`Uzstr 572)
`WHO
`New
`8.3211 (n3I)
`WHO
`New
`McIanana(nI9O)
`WHO
`New
`NSCLC (r24>
`WHO
`Ncw
`I_elan (n3 I)
`WHO
`New
`Sarnm(n2)
`WHO
`New
`hary (n4)
`
`New
`
`4
`4
`
`4
`4
`
`12
`12
`
`9
`9
`
`0
`0
`
`I
`
`I
`
`I
`
`I
`
`0
`0
`
`22
`22
`
`36
`40
`
`10
`0
`
`37
`34
`
`4
`
`4
`
`6
`
`5
`
`4
`
`5
`
`7
`
`6
`
`54%
`54%
`
`23%
`26%
`
`71%
`71%
`
`24%
`23%
`
`27%
`17%
`
`23%
`21%
`
`18%
`21%
`
`16%
`13%
`
`16
`9
`
`IS
`17
`
`13
`58
`
`9
`25
`
`4
`I
`
`9
`8
`
`10
`4
`
`9
`4
`
`James, tEat 1998
`
`CONFIDENTIAL
`ELAP000087O6
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8032
`
`Acetate #3
`
`Folic Acid reduces toxicity of MTA but
`does not diminish antitumor activity in
`L5178/TK-/Hx- Lymphoma
`
`Dose mg/kg ip dailyx 10
`
`95%-100% Tumor
`Inhibition (fl)
`03
`
`30
`
`30
`
`Lethality
`
`100% Lethality
`
`3
`
`300
`
`1000
`
`none at 1000
`
`Low Folate Diet
`
`Standard Diet
`(1.5mg/kg/day folk ach
`
`Low Folate Diet + Folk Acid
`(15mg/kg day -2 to +2)
`
`Mice are more sensitive to MM when folate deprived
`Folate supplementation reduces toxicity but does not reduce anti-tumor activity
`
`CONFIDENTIAL
`ELAP000087O7
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8033
`
`4B The information that will be part of the labeling will be restricted to the
`population and the drug studied.
`4C Pharmacodynamic data (e.g., toxicity) should also be provided.
`
`Dr. White began the discussion asking why studies should not be done with
`aspirin. He mentioned the non-analgesic uses of aspirin for preventing coronary
`artery disease. Dr. Walling explained that one patient showed an apparent
`interaction between MTA and aspirin, and how this might be explained by renal
`impairment in this patient rather than due to drug interaction. Dr. Knadler
`explained that there is data from dogs to suggest a lack of interaction between
`MTA and aspirin. Dr. White asked whether methotrexate was studied in the
`same animal model - he said it would be hard to interpret our animal data
`without having data for methotrexate in the same model. Dr. Rahman asked if
`Lilly wouldn't be interested in having a label not excluding aspirin? There was
`further discussion on MTA interactions with aspirin and ibuprofen. Dr. Rahman
`stated that human data is needed for labeling. Lilly has a chance to present
`MTA with an improved label as compared to methotrexate.
`If Lilly can show a
`lack of interaction with ibuprofen clinically (under study in JMAW) then Dr. White
`felt that it would be important to show if methotrexate acts as a positive control in
`the animal studies Assuming this was shown to be the case, then Dr. White
`would be more comfortable with animal data showing a lack of interaction for
`MTA. Ibuprofen should serve as an example of its class, and the Agency
`recommended that Lilly pick the most frequently used drug in each class.
`
`The following was agreed to as an addition to 4A (shown above):
`4A Ibuprofen as example of class? This requires further discussion in
`the oncologic division of the FDA pertaining to the present rationale, plan
`and data, etc. (make a case)
`
`Next the discussion turned to the cross-over study design using 6 patients per
`arm. Dr. Rahman thought that the sample size was small, but this was
`dependent on the variability of the data. Dr. Johnson said that in Phase I studies
`the intra-patient variability in drug clearance observed was approximately 20%.
`Lilly stated a sample size of 16 to 20 patients would be adequate to secure an
`80% power to detect a difference of 33%. The agency requested a detailed
`protocol including sampling times, statistical analyses, justffication for the
`number of patients, etc.
`
`A discussion on the measurement of MTA in third space fluids was highlighted
`with Dr. Walling informing the FDA that the sponsor has 17 samples from three
`patients (acetates #1 and #2). Lilly does not have a validated assay for samples
`from this source, and there are questions on stability since the samples were
`over one year old. Dr. White suggested that he would be very interested in
`patient data on MTA levels in third space fluids, and that such data might help
`the label by differentiating MTA from methotrexate.
`
`CONFIDENTIAL
`ELAP0000S7O8
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8034
`
`Final resolution of the other issues for point number 4.
`4B and 4C - Final agreement as shown above.
`
`4D Division is particularly concerned with the similarity of MTA with
`methotrexate and this will likely be considered during review.
`
`4E Additional drug interaction information from animal data will be
`considered for review re: classes of NSAIDS - e.g. one from each class
`(supportive information).
`
`Issue 5: Population Pharmacokinetics
`
`The following was agreed:
`5. POPULATION PHARMACOKINETICS - The pharmacokinetic analysis of
`MIA has been completed in all Phase I and many Phase 2 patients. The
`pharmacokinetics of MTA determined from an interim analysis of
`approximately 100 patients after three cycles was highly predictable between
`and within patients. The clinical study reports (CSR's) for the Phase 1
`studies will contain complete pharmacokinetic analyses appropriate for the
`amount of available data. Do you agree with this strategy?
`
`If population pharmacokinetic analysis is intended to provide
`supportive P1< information, the strategy appears to be acceptable.
`However this issue should be revisited at the pre-NDA meeting with the
`Agency.
`Please submit any PK population data and analysis as soon as possible
`for Agency review.
`
`There was a very short discussion on this issue. Dr. Rahman said that anything
`in the labeling needs to be submitted at the time of NDA submission
`
`Issue 6: Renal Impairment
`
`6. RENAL IMPAIRMENT STUDY - Do you agree that the information from the
`mild renal impairment from the JMAW study will be sufficient as not to delay the
`review and approval of the NDA?
`A. No The NDA application review will not be delayed, but approval is data
`driven.
`
`Dr. Rahman made reference to their guideline on renal impairment. Dr. Johnson
`said that we will comply and the data will be analyzed according to these
`guidelines, and that he will look at the data as a continuous variable. The
`
`CONFIDENTIAL
`ELAP000087O9
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8035
`
`question was asked if this study is unfinished at the time of NDA submission, will
`this delay approval. The Agency answered no; this would not automatically
`delay approval as long as data is submitted for a sufficient number of patients,
`then approval can be granted based on the submitted data. Dr. Hamburger
`asked if a request for additional information would be treated as a formal
`amendment; the FDA responded, no. The amount of data from this study will be
`revisited at the pre-NDA meeting.
`
`Dr. Rahman suggested that the effect of MTA on cisplatin be studied as well as
`the effects of cisplatin on MTA.
`
`For Issue 6, the following was added:
`A. Clarification - if study analyses are unfinished at time of NDA
`submission will this delay the review? The application will be reviewed
`on basis of data provided at time of submission. Formal completion of
`this study after submission is a pre-requirement. We'll revisit this issue
`at pre-NDA meeting.
`
`Issue 7: Fleoatic Impairment
`
`The next issue was hepatic impairment and the Agency presented the following
`acetate:
`
`7. REPATIC IMPAIRMENT STUDY - Do you agree that a separate study in
`patients with hepatic dysfunction does not appear to be warranted?
`A. Since the markers of hepatic dysfunction will be assessed in the
`population pharmacokinetic analyses as well as in the multivariate
`analysis, a separate study in patients with hepatic dysfunction does not
`appear to be warranted at this time. However, the long-term effect on
`MTA on patients with liver dysfunction is unknown and may require study.
`
`Dr. White expressed concern that because of polyglutamation, the MTA
`metabolites will be retained for a long time. Dr. Walling showed acetate #3; this
`acetate presented the grade 3 and 4 toxicities observed for patient #806
`(advanced breast cancer) in study JMAG. Dr. White asked about animal data for
`hepatic toxicity - he suggested that the liver be observed in animals dosed
`chronically or alternatively giving MTA and then waiting 6 months. Further
`discussion on the relevance of preclinical data and the relative short half life of
`MTA (2 to 3 hours) led to Dr. White stating that he was 'becoming more
`comfortable" with the data.
`
`It was stated that a hepatic function study might be a requirement for Phase 4,
`but that would depend on data supplied in the NDA. The final agreement as to
`the hepatic impairment reads as follows:
`
`CONFIDENTIAL
`ELAP0000871 0
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8036
`
`A. Lilly has no data to indicate there are long term effects, but as standard
`procedure, patients will be followed for liver function.
`
`Dr. White asked why Lilly is not pursuing colorectal cancer for MTA, and Dr.
`Walling responded that while we have seen activity for MTA in chemonaive
`patients with colorectal cancer, MTA was not active as second line therapy in
`patients with colorectal cancer, and thus colorectal cancer has a lower priority.
`
`Issue 8: Nonclinical Information
`
`The final slide on Nonclinical Information was presented without discussion.
`
`8. NONCLINICAL INFORMATION - The toxicology, ADME nonclinical
`pharmacology plans for the MTA NDA are provided in the briefing
`document. Are these plans sufficient?
`Preclinical studies are in order in regards to toxicity and PK studies.
`Under the future studies on page 26, the segment II reproductive
`studies are planned in mice and rabbits. If one of the segment II
`studies is positive in one species, the same study in the second
`species is waived.
`
`Issues 10 and 11: CMC Issues; Multivitamins
`
`Before the meeting was adjourned, the acetates for the CMC issues were
`shown:
`
`Redacted
`
`CONFIDENTIAL
`ELAP0000871 1
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8037
`
`For the questions on multivitamins (Questions 1 Ia and 1 Ib) the agency did not
`wish to discuss these at the biopharrnaceutics meeting.
`
`The meeting was adjourned.
`
`CONFIDENTiAL
`ELAP0000871 2
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8038
`
`Acetate #1
`
`Does MTA accumulate in pleural effusions and cause excess toxicity?
`
`Phase I study of MTA and cisplatin
`
`PN 3lThe patient had a mesothelioma primary who received
`MTA 600mg/m2and cisplatin 100mg/rn2 on 11 March 97.
`The patient then had S taps before receiving the second
`dose of M TA/cisplatin:
`
`14 March97
`21 March97
`27 March 97
`8 April 97
`8 April 97
`TOTAL
`
`2100 ml
`2000 ml
`2700 ml
`1000 ml
`120 ml
`/92U ml
`
`This patient had only moderate toxicity in course 1 maximum. CTC 02 hem,
`ALT/AST 01, Cutaneous 02.
`
`The patient was noted to be responding after cycle 2. After cycle 3 there was
`increased clinical benefits and the effusions no longer needed to be tapped.
`cycle 4 the patient experienced CTC 03 & 4 neutropenia and came off study
`
`Thus response correlated with a decrease in the volume of pleural effusions
`excess toxicity was not observed in course 1.
`
`CONFIDENTIAL
`ELAP000087I 3
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8039
`
`Acetate #2
`
`Does MTA accumulate in pleural effusions and
`cause excess toxicity?
`
`Data from three patients in phase I study of MTA + cisplatin
`
`PN 2 Patient with a NSCLC primary treated with 60 mg/rn2
`cisplatin and 300 mg/rn2 MTA. 1300 ml of pleural efthsate
`was tapped 48 hours afier first dose. Patient did not experience
`significant toxicity (no neutropenia) Withdrew from study due
`to PD after course 1.
`
`PN 35 Patient with a colorectal primary with metastatic disease to the
`liver who received 1 cycle of MTA at 600mg/rn2 and cisplatin
`at 75 mg/rn2. On day 17, the patient had 1000 ml of ascites
`tapped. Toxicity in course 1= wbc CTC 03, FIb 02, ANC 04,
`platelets G4. Withdrew from study due to PD after course 1.
`
`CONFIDENTIAL
`ELAP0000871 4
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8040
`
`Acetate #3
`
`Vis
`
`0
`
`1
`
`1
`
`1
`2
`2
`2
`3
`
`3
`3
`3
`4
`4
`4
`5
`5
`
`5
`6
`6
`6
`
`Day
`0
`
`7
`
`14
`
`18
`30
`
`37
`
`41
`
`50
`57
`61
`64
`71
`78
`
`82
`
`92
`99
`
`103
`119
`126
`130
`
`ALT
`139
`533
`429
`360
`246
`156
`lOB
`117
`76
`74
`
`71
`114
`86
`75
`119
`107
`74
`120
`174
`
`141
`
`AST
`133
`298
`169
`200
`155
`132
`109
`177
`83
`94
`102
`128
`77
`80
`142
`121
`137
`168
`184
`178
`
`WA
`600
`
`Day
`0
`
`600
`
`600
`
`600
`
`600
`
`21
`
`44
`
`64
`
`85
`
`600
`
`113
`
`Proj
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`JMAG
`
`mv
`801
`801
`
`831
`
`801
`
`801
`801
`
`801
`801
`
`801
`801
`
`Pt
`806
`806
`806
`806
`806
`806
`806
`806
`806
`806
`808
`801
`801 806
`806
`801
`806
`801
`806
`806
`805
`801
`806
`801
`801 806
`806
`801
`
`801
`801
`
`JMAG - patient 806
`
`600 .-..U-
`
`-
`
`. U.
`
`a
`
`500-.
`
`a 400- I S
`0
`aooja -.\
`
`I-
`
`I
`:-V
`
`0
`
`o
`
`.
`
`..--
`A-.; -...
`
`-
`
`I-,
`N-
`
`Co
`
`Study Day
`
`-
`
`-
`
`.
`
`e.J
`0
`
`600
`
`-600
`
`-400
`5
`-soot
`
`;.:
`
`__-a,,n
`
`2
`
`E-y-i00
`iiri 0
`a
`
`en
`
`Co
`
`0--ALT
`
`.
`
`MTA
`
`CONFIDENTIAL
`ELAP0000871 5
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8041
`
`LY231 514 (MTA) End of Phase 2 Meeting with the FDA
`Clinical Issues - Friday, September 25, 1998 at FDA
`
`FDA Participants: Division of Oncology Drua Products
`Rachel Behrman, M.D., Deputy Office Director, ODEI
`Julie Beitz, M.D., Deputy Division Director
`Gang Chen, Ph.D., Statistics Team Leader
`John Johnson, M.D., Medical Team Leader
`Robert Justice, M.D., Oncology Division Director
`Robert White, M.D., Medical Reviewer
`Liang Zhou, Ph.D., Chemistry Team Leader
`Linda McCollum, Consumer Safety Officer
`Lilly Participants:
`Greg Brophy, Ph.D., U.S. Regulatory Affairs
`Steven Hamburger, Ph.D., U.S. Regulatory Affairs
`Robert D Johnson, Ph.D., Pharmacokineticist
`Astra Liepa, Health Outcomes
`Clet Niyikiza, Ph.D., Statistician
`David Seitz, M.D., Ph.D., Medical Advisor
`Gerald Thompson, Ph.D., MTA Product Team Leader
`Jackie Walling, Ph.D., Director of Science, MTA Team
`John Worzalla, U.S. Regulatory Affairs
`Lilly Consultants:
`Ned Patz, M.D., Duke University
`Nicholas Vogelzang, M.D., University of Chicago
`
`Meeting Request Submission Date: July 13, 1998
`Briefing Document Submission Date: July 29, 1998
`Additional Submission Dates: Sept. 8, 1998
`
`Meeting Minutes:
`
`Schedule and Dose: The FDA showed the following acetate:
`
`1. DOSE and SCHEDULE - Do you agree with the proposed dosing schedule
`for single agent MTA studies - specifically the registration studies involving
`NSCLC?
`A. Our agreement is limited to the proposed dosing schedule for single
`agent MTA. There does not appear to be sufficient efficacy advantage
`with the 600 mg/rn2 dose of MTA over the 500 mg/rn2 dose. Also there
`is a trend for hematologic toxicity to be greater for the 600 mg/rn2 dose
`of MTA than for the 500 mg/rn2 dose. Therefore, the 500 mg/m2 dose is
`
`CONFIDENTIAL
`ELAP0000871 6
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8042
`
`recommended unless a dose response for overall response has been
`shown. Alternatively, patients can start at 500 mg/rn2 and the dose can
`be escalated to 600 mgfm2 if tolerated.
`
`The FDA agreed with the proposed 21 day dosing cycle. There was a
`discussion on the safety profile of the 500 mg/rn2 and 600 mg/m2 MTA doses
`between Dr. Walling, Dr. White, Dr. Johnson and Dr. Vogelzang. The FDA
`recommended an MTA starting dose of 500 mg/rn2 for single agent studies with
`dose escalation to 600 mg/rn2 allowed. Dr. Walling pointed out that there was no
`significant increase in Grades 3 and 4 neutropenia seen at the 600 mg/rn2 dose
`(45% versus 41% at the 500 mg/rn2 dose, but the increase was not statistically
`significant). Also no excess of toxic deaths has been seen with the 600 mg/rn2
`dose. There is not enough data yet to examine the dose response with respect
`to efficacy, but Lilly agreed to the 500 mg/rn2 staffing dose.
`
`The following addition to 1A was provided.
`
`FDA recommendation to use 500 mg/rn2 is advice and not a requirement.
`
`Mesotheliorna: The FDA showed the following acetate:
`
`1. MTA in Mesothelioma - The indication being pursued is "MTA Injection is
`indicated for the treatment of pleural mesothelioma."
`
`FDA Preliminary comment: Usually, lead indications are approved with two
`studies. Mesothelioma is a rare disease. Depending on the quality of the
`mesothelioma trial design and data, further discussions may convince the
`Agency to accept one mesothelioma study and confirmatory evidence from a
`closely related disease.
`
`2a Do you agree this is an acceptable registration strategy (i.e., patient
`population, patient nurnbers endpoints) for accelerated approval for this
`indication?
`NO. Serial measurement of disease are difficult and inaccurate in
`mesothelioma. Confirmation of responses by FDA is likely to be
`impossible and the clinical benefit of response in rnesothelioma is
`uncertain.
`In order to
`Accelerated approval based on response rate is unlikely.
`gain accelerated approval with the combination of MTA + cisplatin,
`you would have to provide evidence that MTA + cisplatin is better
`than any other combination in response and response duration.
`Survival should be the primary endpoint. Since survival is short in
`this population, it should not take long to reach the endpoint.
`Tumor related symptoms could also be addressed in a blinded trial.
`
`CONFIDENTIAL
`ELAP0000871 7
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8043
`
`A lengthy discussion took place on the issues of response rate and
`unidimensional measurements for mesothelioma. These discussions were led
`by Drs. Vogeizang and Patz. Dr. Vogelzang explained that unidimensional
`measurements can be easily obtained, the number of responders is always low
`and a high correlation was shown in a recent paper between clinical benefit and
`response. Dr. Patz explained how the CT scans can have resolution down to I
`mm, and that the scans would be digitized and blinded and then read only by Dr.
`Patz and a colleague in France. Dr. Patz showed an acetate (#1) with W.H.O.
`guidance on the use of unidimensional measurements and another acetate (#2)
`with a table showing good concordance between uni and bi-dimensional tumor
`measurements. Dr. White noted that there were no mesothelioma studies which
`correlated these measurements. A number of slides with several mesothelioma
`scans were shown and the technique for using unidimensional measurements
`was discussed. A discussion suggesting several ways in which unidimensional
`measurements could be taken at different locations and what changes in these
`measurements would qualify for a response did not sway the FDA concerning
`response rate as the primary endpoint. It was restated by the FDA that survival
`should be the primary endpoint, but response rate might be considered for
`inclusion in the label.
`
`The FDA recommended using Study JMCH as designed except using survival as
`the primary endpoint with clinical benefit (reduction in pain or dyspnea) as a
`secondary endpoint to qualify for full approval. Thus, if survival was improved,
`but fell short of statistical significance, then response rate plus clinical benefit
`(reduction in pain or dyspnea) might provide additional evidence for approval.
`
`Dr. Walling asked about the censoring rate for the survival study, and the FDA
`responded that 50% or less censoring rate (50% patients alive in the control arm)
`is the minimum, but that 25% censoring rate (25% of patients alive) would be
`better.
`
`The final agreement to points 2a. A and 2a. B above were listed as shown
`below:
`
`2a A. Lilly has access to the technology (Spiral Hi-Res CT scans),
`protocol, and dedicated assessment team in place to adequately
`assess response in mesothelioma
`2a B. We recommend that appropriately designed trials demonstrating
`clinical benefit, i.e., pain reduction breath shortness, etc., (see C & D)
`be the strategy for gaining full approval if survival benefit can't be
`shown instead of response rate for accelerated approval. (See
`previous FDA comments)
`The FDA also agreed that evidence of activity against NSCLC might also
`serve as confirmatory evidence (see FDA preliminary comment above).
`
`CONFIDENTIAL
`ELAP0000871 8
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8044
`
`A discussion was held on the suggestion of blinding for study JMCH. Dr. Justice
`said that approval could be given for an unblinded study. However, the FDA
`also pointed out that it would be easier to get approval with a blinded trial, since
`improved clinical benefit would be considered more robust in context of a blinded
`trial. Again, this was advice from the FDA, and it is Lilly's decision as to whether
`or not to do a blinded study.
`
`The following FDA acetate for issue 2b was shown:
`
`2b
`
`Is the design of study (JMCH) adequate and well controlled?
`Yes, with reservations. This would be a better study if it were blinded.
`A randomized trial of MTA + cisplatin vs. cisplatin alone is an adequate
`trial. However the addition of the vitamins to the MTA arm without data
`that efficacy is not reduced is risky. We would like to know the basis for
`your determination that the addition of vitamins will not affect efficacy.
`
`Dr. Walling answered this with an acetate (#3) with preclinical data from a murine
`L517BYITK-/Hx- lymphoma tumor model showing that folic acid at 15 mg/kg (45
`mg/rn2) ameliorates the toxicity of MTA, but it does not affect the efficacy. There
`still was concern from the FDA that folic acid might reduce efficacy. Dr. Walling
`again responded that we are using low doses of folic acid that are in a range
`(350 to 600 gg/day which is similar to the 100% RDA of 400 igIday) that would
`give physiologic levels that might be expected from dietary exposure to folate.
`Thus, if MTA efficacy was negatively impacted by these low levels of folic acid in
`the muftivitamins, then the activity of MTA would be compromised by similar
`levels of folate that could be ingested with food in a normal diet. The FDA
`responded that it was Lilly's decision whether or not to use folate.
`
`The following FDA acetates for issues 2c through 2e were shown, but agreement
`as to these had been reached in the discussions noted above:
`
`2c. Do you agree that the choice of primary and secondary endpoints, and the
`analysis plan in study JMCH is acceptable?
`NO. Response rate is not an acceptable primary endpoint in this
`disease. Survival should be the primary endpoint and superior survival
`in the patients on the MTA arm should be the basis for approval.
`Secondary endpoints of response rate, duration of response and time
`to progression could be supportive of the primary endpoint.
`
`2d. Do you agree that allowing the measurement of unidimensional disease will
`provide sufficient information for determining response rate?
`
`CONFIDENTIAL
`ELAP000087I 9
`
`Lilly Ex. 2101
`Sandoz v. Lilly IPR2016-00318
`
`

`
`8045
`
`A. NO. It is uncertain that unidimensional disease measurements in
`mesothelioma will provide sufficient information for determining
`response rate.
`
`2e. Do you agree that there will be sufficient safety data to support registration,
`