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`Lilly Research Laboratories
`A Division ol Eli Lilly arcS Company
`
`Lilly Corporale Center
`Indianapolis. lndiena 46285
`1317) 276-2000
`
`November 24, 1999
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Oricologic Drug Products, HFD-1 50
`Attn: Mr. Avis Dunson
`1451 Rockville Pike
`Rockville, MD 20852-1448
`
`INI) Safety Report
`
`Subject: IND 40,061, MIA (LY231514) Serial no. 194
`Letter to Investigators Regarding Patients with High Baseline
`Homocysteine Levels
`
`An updated multivariate analysis has been recently conducted for patients in the
`clinical trials with LY23 1514 (NITA) in an attempt to better understand patterns of
`toxicity and to identify factors that may predict patients at increased risk for
`serious toxicity. A preliminary report of this analysis was included as part of the
`LYZ3I 514 annual report (submission serial no. 191 submitted on November 8,
`1999; Summary pages 1-5). As mentioned in the covering letter that
`accompanied the annual report. Lilly at that time decided to continue to collect
`baseline homocysteine levels and strongly recommended that investigators on
`LY231 514 trials increase their vigilance following patients with high
`homocysteirte levels.
`
`Further analysis of baseline homocysteine levels for patfents enrolled in trials
`with LY231 514 has led to the following conclusions:
`
`Elevated baseline homocysteine levels significantly correlate with increased
`risk of both hematologic and non-hematologic toxicity
`
`As a result of these observations and after communicating with several external
`consultants, Lilly has taken the following action to provide for improved safety for
`patients in LY231514 trials:
`
`EXHIBIT
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`'fz/iz.
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`LC
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`CONFIDENTIAL
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`AVOO 995705
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`L
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`L
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`TX 394
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`Lilly Ex. 2102
`Sandoz v. Lilly IPR2016-00318
`
`

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`Page
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`2
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`A global mailing to all investigators (excluding investigators in the two trials
`mentioned below) was sent out today (see attachment 1) informing
`investigators of the following:
`
`At this time patients with baseline homocysteine levels greater to (or equal to)
`12 pM must be excluded from participation in LY231514 clinical trials (unless
`folio acid supplementation is being administered in a trial)
`
`There are two clinical trials H3E-MC-JMAF (A Phase 2 Trial of LY23 1514
`Administered Intravenously Every 21 Days in Patients with Gastric Cancer) arid
`H3E-MC-JMAS (Phase 1 Trial of LY231514 with Folic Acid Supplementation in
`Patients with Locally Advanced or Metastatic Cancer) where folio acid is being
`administered. The first study is being conducted to determine if folate
`supplementation can improve toxicity. The second trial is testing whether the
`dose of LY231514 can be increased safely when folio acid is added. Patients
`with high bas&ine homocysteine levels wi4l not be excluded from participation in
`these two trials.
`
`As pera previous telephone conversation with Alvis Dunson, further
`communications to the FDA will be forthcoming shortly with more details of the
`actions to lessen the serious
`updated safety analysis and proposals for futui
`toxic effects in patients with high homocysteine levels.
`
`Please call Mr. John Worzalla at (317) 276-5052 or myself at (317) 277-3799 if
`there are any questions.
`
`Sincerely,
`
`ELI LILLY AND COMPANY
`
`Gregory T. Brophy, PhD.
`Director
`U.S. Regulatory Affairs
`
`Enclosure: Attachment
`
`copy
`
`CONFIDENTIAL
`
`AV00995706
`
`Lilly Ex. 2102
`Sandoz v. Lilly IPR2016-00318
`
`

`
`r
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`L
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`aEli Lilly and Company
`
`Lilly Corncrate Corner
`Indianapolis. Indlara 46285
`a i 7.276. 2O
`
`Page 1
`
`November 24. 1999
`
`Dear Investigator,
`
`As part of ongoing endeavors to improve the safety of patierns receiving LY231514
`(MTA), we have been conducting an evaluation of toxicity resulting from the
`administration of MTA. You are aware that in each of our clinical trials, the protocol
`calls for the measurement of the vitamin metabolites homocysteine, cystathionine,
`methylmalonic acid, and methylcitrates. Our analysis of the correlation between
`nutritional status (as measured by these metabolites) and taticity has shàwn that the
`homocysteine level of a patient directly correlates to the risk of both hematologic and
`non-hematoogic toxicity. For example, it has been shown that homocysteine levels
`12 tM are associated with a 59% probability of developing CTC Grade 4 hematologic
`toxicity or CTC Grade 3 or 4 non-hematologic toxicity while levels below 12 pM are
`associated with a 27% probability of developing this toxicity.
`
`We have data which shows thatmultivitainin (including folic acid, B6 and B12)
`supplementation can be used to lower homocysteine levels and potentially decrease the
`degree of toxicity associated with MTA, and we will be discussing with the FDA
`appropriate actions to take based on this infonnation. These actions may take the form of
`supplementing patients with multivitamins to lower homocysteine levels 12 liM before
`treatment, or excluding those patients with homocysteine levels
`l2 pM from MTA
`trials. You will receive additional infomiation concerning final deciions on this issue,
`
`In the interim, please take the following actions immediately:
`Do not administer therapy with MTA until the patient's homocysteine vaLue is
`reported to you.
`Until you receive additional information, do not treat any patient with a
`hoanocysteine level 12 pM.
`If a patient with a homocysteine level 12 pM has already been receiving
`treatment with MTA, the patient must sign a new informed consent form, based
`on the information contained in the first paragraph above, if they choose to
`remain on study after consultation with you. In light of the information
`presented here, we would recommend a fall discussion between you and each
`patient
`
`copy
`
`CONFIDENTIAL
`
`AVOO 995707
`
`Lilly Ex. 2102
`Sandoz v. Lilly IPR2016-00318
`
`

`
`As is the case with alt cytotoxics, please continue to carefully monitor patients currently
`undergoing treatment with MTA for the following events:
`
`Paga 2
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`Febrile neutropenia
`crc Grade 4 neutropenia >5 days
`CTC Grade 3 cr4 neutropenia
`crc Grade 4 thrombocytopenia
`Diarrhea or vomiting
`Mucositis
`
`More detailed information on appropriateinterventions is contained in the existing
`protocol.
`
`Please forward this letter to your respective Ethics Committee(s). As soon as all the
`protocols are amended, they will be forwarded for implementation. The Informed
`consent Documents will also require modification, and patients may need to be
`reconsented.
`
`We realize this step is inconvenient for you and your patients, but it is of the greatest
`importance to protect the safety of every individual who participates in our thals. Thank
`you for your cooperation in this matter.
`
`Yours Sincerely
`
`ELI LILLY AND COMPANY
`
`Paolo Pacletti, MD
`Product Team Leader
`Oncology New Product Development Team
`
`copy
`
`CONFIDENTIAL
`
`AVOO 995708
`
`Lilly Ex. 2102
`Sandoz v. Lilly IPR2016-00318