CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-462
`
`Medical Review(s)
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0001
`
`

`
`Division Director's ~Iemorandum
`
`Date:
`NDA:
`Sponsor:
`Proprietary Name:
`
`February 4, 2004
`21-462
`Eli Lilly and Company
`Alimta® (pemetrexed for injection)
`
`Administrative Histon'
`On July 8, 1992, the initial IND was submitted. The product received Orphan designation on
`August 28, 2001. On June 10,2002, this application received Fast Track designation for
`malignant pleural mesothelioma and the Division accepted Lilly's plan for a rolling
`submission. The first parts ofthe NDA,were submitted October 24,2002 and the last
`reviewable unit (CMC) was received on September 30,2003. The PDUF A goal date for this
`priority review is March 30, 2004.
`
`Proposed Indication
`ALlMTA in combination with cisplatin is indicated for the treatment of patients with
`malignant pleural mesothelioma whose disease is either unresectable or who are otherwise
`not candidates for curative surgery.
`
`Ayailable Therapies
`No drug treatment has been shown to prolong survival in this setting.
`
`Clinical Reyiew (see reviews by Dr. White, Dr. Hazarika, and Dr. Jor.nson)
`A single randomized clinical trial was conducted, entitled, "A Single-blind Randomized
`Phase 3 Trial of Alimta plus Cisplatin versus Cisplatin Alone in Patients with Malignant
`Pleural Mesothelioma."
`
`This multi-center study included 88 principal investigators at a total of 88 study centers
`located in 20 countries. The primary objective was to compare survival in chemonaive
`patients with malignant pleural mesothelioma treated with Alimta plus cisplatin combination
`therapy !o survival in the same patient population treated with cisplatin alone.
`
`A total of 574 patients were entered into the study (signed the informed consent document).
`F our hundred fifty-six of these patients were randomized to a treatment arm and 448 were
`treated and constitute the randomized and treated (RT) population.
`
`During this study, after about 25% of the randomized population had been treated, vitamin
`B12 and folic acid supplementation was found to reduce Alimta toxicities. At that time all
`patients in both treatment groups in the randomized trial were supplemented with vitamins.
`This resulted in three subgroups in each treatment arm regarding vitamin supplementation.
`These groups are never supplemented (NS), partially supplemented (PS) and fully
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0002
`
`

`
`Division Director's Memo
`
`NDA 21-462: Alimta
`Page 2
`
`supplemented (FS). Patient totals for the Alimtalcisplatin group are RT 226, FS 168, PS or
`never supplemented 58, and for the cisplatin alone group are RT 222, FS 163 arid PS or NS
`59. The FDA review focuses on all RT patients (the primary analysis) and the FS patients
`(the proposed labeled administration.)
`
`The primary efficacy analysis was comparison of survival between the study amlS in the RT
`population. Differences were assessed using a two-sided log rank test. Because an interim
`analysis v.·as conducted (resulting in a decision to continue the trial to planned completion),
`the comparison of sun:ival was tested at the p=0.0476 level.
`
`In the RT patient analysis, the combination of Alimta and cisplatin demonstrated a
`statistically significant improvement in survival with median survivals of 12.l versus 9.3
`rr;onths, respectiyely (p=O.020). This superiority in the combination ann was also
`demoristrated in the fully supplemented subgroup with median survivals of 13.3 and 10.0
`months in the coinbination and cisplatin alone groups, respectively (p=O.051). In an
`exploratory analysis, the effect on survival was larger in females (n=83, 15.7 vs. 7.5 months
`median survival) than in males (n=305, 11 months vs. 9.4 months).
`
`Pathologic diagnosis of malignant pleural mesothelioma may be difficult. Because of
`concern that some patients may have other kinds of cancer, a subgroup survival analysis was
`performed, including only the 303 patients with a histologic diagnosis of malignant pleural
`mesothelioma confirmed by a central independent pathology review. This subgroup analysis
`corroborates the primary survival analysis. The median survival times were 13 and 10.2
`months in the RT combination and cisplatin alone groups, respectively (p=0.06). The median
`survival times were 14.4 and 10.3 months in the RT fully supplemented combination and
`.cisplatin alone groups, respectively (p=0.058).
`
`Prior to the trial's initiation, the FDA indicated to the Applicant that tumor response in this
`disease car.not be reliably assessed and that the FDA would not fonn primary efficacy
`decisions based (In tumor response or time· to-tumor progression. Tumor response and time(cid:173)
`to-progression were assessed, but the results were not interpretable. Tumor response criteria
`are not well established in pleural malignant mesothelioma. The tumor often grows in sheets
`rather than well demarcated spherical configurations. The tumor response assessments were
`inconsistent between the study investigators and the two independent reviewers. The FDA
`review of the submitted films could confirm tumor response in only 47 of the 94 patients in
`the combination group for whom the Applicant claimed responses. Patients in the
`combination group did appear to have a better response rate and longer time-to-progression;
`however, numerical results for tumor response and time-to-progression are not included in
`the product label.
`
`Patients were assessed with the Lung Cancer Symptom Scale (LCSS). Although there were
`statistically significant changes favoring the combination group in some components and in
`the overall score, none of the changes was judged to be clirticaJly important. No claims
`regarding the LCSS w.ere included in the label.
`
`Patients were also assessed during the study for pulmonary function by measuring slow vital
`capacity, forced vital capacity and forced expiratory volume in one second. There were
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0003
`
`

`
`Diyision Director's Memo
`
`NDA 21-462: AJimta
`Page 3
`
`statistically significant changes in the pulmonary function tests favoring the combination
`group. However, consultation from the FDA's Division of Pulmonary Drug Products
`indicated that the reported mean changes were within the range of nonnal variation of the
`tests and are not considered clinically important.
`
`The Division of Pulmonary Drugs recommended forced vital capacity (FYC) as the most
`appropriate pulmonary function test in these patients because the disease effect is constrictive
`rather than obstructive. To further assess the effect of treatment on pulmonary function, the
`Oncology Drug Products Division perfonned the following two analyses intended to consider
`meaningful changes in pulmonary function using the electronic database.
`
`In the first analysis 337/448 (75%) ofRT patients who had a baseline and at least one follow(cid:173)
`up FYC, 26.6% and 21.3% of combination group patients had an increase over baseline FYC
`of~ 400 mL and ~ 500 mL, respectively, on at least one follow-up yisit. The differences
`between the combination and cisplatin alone groups are statistically significant. However,
`the increases in FYC were maintained for at least 6 weeks in only about half of the
`combination group patients. The difference between treatment groups was no longer
`statistically significant.
`
`In the second analysis 28.4% and 17.2% of combination group patients had an increase from
`baseline FYC of ~ 20% and ~ 30% on at least one foHow-up visit, respectively. The
`differences ben.veen the combination and cisplatin alone treatment groups are statistically
`significant. The increases in Fye were maintained for at least 6 weeks in only about half of
`the combination group patients. But the difference between treatment groups remains
`statistically significant.
`
`Based on these two analyses, together with the overall mean increase, a labeling claim for a
`modest beneficial effect on pulmonary function can be made.
`
`The adverse effects of the combination regimen are acceptable for chemotherapy drug
`products. The principal adverse effects that are greater with the combination than with
`cisplatin alone are myelosuppression, severe nausea and vomiting, and rash/desquamation.
`Patients in both groups were fatigued and had dyspnea and chest pain, probably related to the
`underlying disease. Severe hematologic and gastrointestinal adverse effects are significantly
`reduced by supplementation with vitamin B)2 and folic acid without any decrement in
`efficacy.
`
`Alimta is eliminated primarily by the renal route. In clinical studies, patients with creatinine
`clearance ~ 45 mL/min required no dose adjustments other than those recommended for all
`patients, although AUC's were increased by about 50-60% in patients with CLcr of 45-50
`mL/min. Insufficient patient numbers with creatinine clearance below 45 mL/min have been
`treated to make dosage recommendations for this patient group. Alimta should not be
`administered to patients whose creatinine clearance is < 45 mL/min using the Cockcroft and
`Gault fonnula or GFR measured by Tc99m-DPTA serum clearance method .
`
`.. -----
`
`. -
`
`. ,
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0004
`
`

`
`Division Director's Memo
`
`NDA 21-462: Alimta
`Page 4
`
`Biostatistical Review (see Dr. Wang's review)
`The results of the biostatistical review are presented in the table below and have been
`previously discussed in the clirucal section.
`
`Primary Endpoint: Sun'ival for RT Population (FDA Analysis)
`RT Population
`FS Population
`PS+NS Population
`(N=448)
`(N=ll7)
`(N=33J)
`Combo
`Combo
`Combo
`Cis
`(N=226)
`(N=168)
`(N=58)
`(N=59)
`n (%)
`n (%)
`n (%)
`n (%)
`145 (64)
`50 (86)
`56 (95)
`95 ~57)
`
`Patients dead·
`
`Cis
`(N=222)
`n (%)
`159 (72)
`
`Cis
`(N=163)
`n (%)
`103(63)
`
`Survival time (months)
`Median
`(95% Cl)
`p-\'alueb
`Long-rank
`Wilcoxon
`
`12.1
`(10.0,14.4)
`
`9.3
`(7.8,10.7)
`
`13.3
`(11.4,14.9)
`
`10.0
`(8.4, 11.9)
`
`9.5
`(8.1,10.8)
`
`7.2
`(6.5,9.9)
`
`0.021
`0.028
`
`0.051
`0.039
`
`0.253
`0.440
`
`0.766
`Hazard Ratio'
`95% CI for Hazard Ratio'
`(0.61. 096)
`Results based on the analysis of data sets provided by the sponsor.
`Combo = combination of cisplatin plus Alimta; Cis = single-agent cisplatin
`• Patients were died for different reasons: study disease related, study toxicity, and other causes.
`b P-\alue is based on the test results for the two treatment groups.
`C Hazard Ratio is based on the proponional-hazards.model with the treatment as single independent variable.
`
`0.758
`(0.57. 1.0)
`
`0.798
`(0.54, 1.17)
`
`Chemistrv/Manufacturing and Controls Review (see Dr. Liang's review for details)
`. ALIMTA, pemetrexed (L-Glutarruc acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-IH(cid:173)
`pyrrolo[2,3-dJpyrimidin-5-yl)ethyIJbenzoyl]-,disodium salt heptahydrate) drug substance,
`contains one chiral center and is a disodium salt containing seven \",ater molecules of
`hydration (heptahydrate) in the solid state ofthe drug product. The molecular formula is
`C2oHI9N506Na2'.7H20, and the molecular weight is 597.49 daltons.
`
`_ . and its structure is well
`Pemetrexed drug substance is
`characterized. During the review process, several discrepancies related to stereoisomer
`control and correct USAN nomenclature were resolved.
`
`Alimta drug product is supplied in glass vials as a single-use sterile lyophilized powder for
`of Alimta contains
`.....-- pemetrexed disodium
`intravenous infusion. Each
`heptahydrate (equivalent to 500 mg pemetrexed free acid) and 500 mg of mannitol. Sodium
`hydroxide and, if necessary, hydrochloric acid are added to adjust the pH. Eli Lilly
`manufactures the drug product in F egersheim, France.
`
`Each vial of Alimta is reconstituted with 20 rnL of commercially available 0.9% Sodium
`Chloride Injection without preservatives to a concentration of 25 mg/rnL of pemetrexed as
`free acid. This reconstituted pemetrexed solution must be further diluted to 100 rnL with
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0005
`
`

`
`Division Director's Memo
`
`NDA 21-462: Alimta
`Page 5
`
`0.9% Sodium Chloride Injection prior to intravenous infusion. The final concentration of
`drug product solution to be admiillstrated is 0.25 mg./mL pemetrexed as free acid.
`
`During the review process, deficiencies related to the control of drug product total impurities
`were resolved. The applicant agreed to restrict the limit for total impurities from NMT - %
`to l\'MT - % as an interim specification and to reevaluate the limit for total impurities
`within 24 months (or after ten commercial batches of drug product have been manufactured) .
`
`./'
`
`/ /"
`
`-
`-
`-
`_ .
`raise clinical concern; Any impurity profile
`, -
`. range will be within current impurity limits.
`
`-
`within the specified
`
`The drug substance, drug product, and the reconstituted drug product solution have adequate
`stability characteristics to support a 24-month shelf life for the drug product based on primary
`and supportive stability data.
`
`l\'onclinical Review (see Dr. Lee Ham's review and Dr. Morse's team leader memo)
`Alimta® (pemetrexed disodium) is a pyrrolopyrintidine antifolate. Although it's mechanism
`of action is not fully understood, multiple non-clinical studies suggest pemetrexed exerts
`antineoplastic activity by interfering with folate-dependent metabolic processes essential for
`cell replication. After entrance into the cell (via reduced folate carrier [RFC] and membrane
`folate-binding protein [fBP]), pemetrexed is rapidly po)yg!utamated by folypolyglutamate
`s)111hetase. Both parent and polyglutamated pemetrexed act as competitive inhibitors of
`several folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate
`reductase (DHFR), and glycinamide ribonucleotide transferase (GARFT), which are key
`enzymes for de novo nucleotide biosynthesis. These actions are similar to methotrexate,
`which has inhibitory effects on thymidylate synthase (TS) and dihydrofolate reductase
`(DHfR).
`
`When tested in a series of in vitro and in vivo (xenograft) models of cancer, pemetrexed
`demonstrated activity against a variety of tumor types, including leukemia (CCRF-CEM,
`Ll210), lung (A549), mesothelioma (NCI-H2052 and MSTO-211H), breast (MCF7), colon
`(GC3 and HeTB), and ovarian cancer (SKOVl).
`
`Non-clinical toxicity studies were conducted to determine the acute and repeat-dose effects
`when administered to mice, rats, and dogs. Toxicity studies included: single and repeat dose
`studies of2- and 6-weeks intraperitoneal (ip) dosing in mice, and 4- and 6-weeks, and 6-
`months intravenous (iv) dosing in dogs. In single dose studies, pemetrexed demonstrated
`limited acute toxicity in mice and rats, but more extensive toxicity in dogs. Six week repeat
`dose studies were conducted using daily, twice weekly or weekly ip doses in mice and iv
`doses in dogs. Mice tolerated weekly ip doses of up to 944 mg/m2 (twice the c1iillcal dose)
`without death or toxicity, whereas weekly iv dosing at 2099 mg/m2 (four times the clinical
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0006
`
`

`
`Division Director's Memo
`
`NDA 21-462: Alimta
`Page 6
`
`dose) resulted in the early termination of several dogs. Repeat-dose adverse effects at higher
`doses caused decreased food consumption, emesis, diarrhea, mucositis, decreased red cell
`parameters, leukopenia, neutropenia, and increased hepatic enzymes in dogs. In mice,
`weight loss and leukopenia were the predominant drug toxicities. Histopathologic indices
`generally occurred in the thymus, lymph nodes, GI tract, testis, bone marrow, and skin.
`
`Pemetrexed (intravenous) doses of;:: 0.3 mg/m2 caused testicular atrophy and reduced
`fertility. further, pemetrexed was embryotoxic and teratogenic in mice when administered at
`0.6 mg/m2. Pemetrexed caused no genetic damage in a standard battery of in vitro tests,
`mutation and clastogenicity assays, although, pemetrexed was clastogenic in the
`lnicronucleus assay. Carcinogenicity studies ofpeIlJftrexed disodium have not been
`conducted.
`
`'
`
`Limited non-clinical investigations of "rescuing agents" (leucovorin and thymidine) were
`conducted with pemetrexed administration. Results suggest that the co-administration of
`leucovorin (20 mg/kg im days 5-10; 25 mg/kg im days 4, & 5, and 50 mg/kg iv day 4)
`reduced or reversed the toxicity ofpemetrexed (50 mg/kg iv days 1 & 4) in dogs. Dogs
`given pemetrexed (50 mg/kg, iv days 0 & 3) with thymidine (8 mg/kg, days 4-7,
`administration as a continuous infusion) had no toxic alterations associated with pemetrexed
`compared to the saline-treated controls.
`
`Aue values for pemetrexed were approximately dose proportional following single ip or iv
`administration to mice, and iv administration to dogs and humans. Elimination half-life was
`sign.ificantly shorter in dogs and man when compared to mice. The PK profile was biphasic
`following radiocarbon tracer administration, with rapid tissue distribution following an iv
`dose and subsequent elimination (tissue levels generally did not persist beyond 3 hrs post(cid:173)
`dose).
`
`Clinical Pharmacology and Biopharmaceutic Review (see Dr. Booth's review)
`The pharmacokinetics of Alimta follow a 2-compartment model, and excretion is
`predominantly renal. Alimta was not metabolized by any cytochrome P-450, nor did it
`inhibit any C}10cbrome P-450 isozyme. Total systemic clearance is 91.8 mL/min and is
`correlated with glomerular filtration rate and creatinine clearance (CLcr) (Cockcroft-Gault
`formula). The elimination half-life is 3.5 hours; accumulation v.'as not noted. The
`pharmacokinetics were unaffected by sex, age or ethnicity.
`
`Cisplatin co-administration did not alter the Alimta's pharmacokinetics or vice versa. Co(cid:173)
`administration of carboplatin did not alter the pharmacokinetics of Alimta, but the
`pham:acokinetics of carboplatin may have been affected. Neither folic acid/vitamin BJ2 nor
`aspiri!1 (1.3 mg/day) altered Alimta pharmacokinetics. However, ibuprofen increased Alimta
`AUe by approximately 20% at a moderate dose of 1.6 gmlday. Renal impairment studies of
`Alimta as a single agent indicated that the Alimta AVe increased by 130% in patients with
`moderate renal impairment (CLcr 30-50 mL/rnin; n=6), suggesting that neutropenia might be
`exacerbated in these patients. These studies were not considered sufficient to provide dosing
`recommendations for patients with CLcf < 45 mL/min.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0007
`
`

`
`Division Director's Memo
`
`NDA 21-462: Alimta
`Page 7
`
`Labeling (see DMETS review)
`DMETS reviewed the draft container labels, carton, and insert labeling for Alimta and
`focused on safety i~sues relating to possible medication errors. DMETS recommended the
`following changes to minimize potential user errors.
`
`• Carton labeling (500 mg Single-Use Vial): Increase the prominence of the route of
`administration on the principal display panel by bolding or other means. Repeat the
`statement, "Caution: Cytotoxic Agent" on the principal display panel.
`
`•
`
`/
`
`Data Integrity Issues (see Dr. Gan's Clinical Inspection Summary)
`The Division of Scientific Investigation investigated four sites (University of Chicago
`Hospital, Chicago, IL; Texas Oncology, Dallas, TX; and sites in Milano, Italy and Hamburg,
`Germany) and found the data adequate for safety and efficacy evaluation.
`
`Tradename consultation
`The tradename, Alimta, is acceptable to DDMAC and DMETS (see DMETS review).
`
`Pediatric Considerations
`Malignant pleural mesothelioma does not occur in children.
`
`Conclusions and Recommendations: Approval
`The trial contained in this application demonstrates a survival advantage in patients with
`malignant pleural mesothelioma treated with Alimta plus cisplatin compared to those treated
`with single-agent cisplatin. These patients were either unresectable or were otherwise not
`candidates for curative surgery. No other drug, including cisplatin, has demonstrated a
`survival advantage in this life-threatening disease setting associated with a short survival.
`The Division has consistently accepted a survival improvement to demonstrate clinical
`benefit. Hence, this application was not presented to the Oncologic Drugs Advisory
`Committee (ODAC). The trial's design allows demonstration of Alimta's effect on the
`primary study endpoint (survival).
`
`Although a single randomized trial supports this NDA, this trial was multi-institutional with
`over 88 study centers enrol1ing over 574 patients and is the largest randomized study ever
`conducted in this disease. The primary efficacy analysis was confirmed in the randomized
`and treated (RT) popUlation as we]] as in a subset population--the fully vitamin supplemented
`group (FS). Although the Division did not allow specific numbers to be included in response
`rate and time-to-progression analyses because of the inaccuracies and difficulties in
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0008
`
`

`
`Division Director's Memo
`
`NDA 21-462: AJimta
`Page 8
`
`measuring disease in mesothelioma patients, the Division acknowledges that the combination
`treatment group did appear to show an improvement in these secondary endpoints. An
`~
`additional secondary endpoint of improvement in pulmonary function (forced vital capacity)
`was also included in the product label.
`
`The safety profile Of the proposed combination of Alimta plus cisplatin with vitamin
`supplement (and corticosteroids for skin rash prophylaxis) is consistent \vith other cytotoxic
`chemotherapy agents approved by the Division. The primary toxicities include
`myelosuppression, fatigue, nausea, vomiting, and dyspnea. The product label clearly advises
`physicians of specific vitamin use to reduce the toxicity. Hence, an acceptable risk-benefit
`relationship is noted with the combination. The recommended regulatoI)' action is approval
`ofNDA 21-462.
`
`Richard Pazdur, MD
`Director, Division of Oncology Drug Products
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0009
`
`

`
`This is a representation of an electronic record that was signed electronically and
`this page is .the manifestation of the electronic signature.
`
`lsi
`
`Dianne Spillman:
`2/4/04 12:26:54 PM
`CSO
`
`Richard Pazdur
`2/4/04 12:31:55 PM
`r':EDICAL OFFICER
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0010
`
`

`
`O~COLOGY DRUGS CLINICAL TEA]\'1 LEADER
`REVIE\V OF NDA
`
`]\'DA 21462
`
`NAME OF DRUG
`
`Alimta (pemetrexed)
`
`APPLICANT
`
`Eli Lilly
`
`CLINICAL TEA]\I LEADER
`
`•
`John R. JohnsonM. D.
`
`DATE REVIEW CO\IPLETED December 10,2003
`
`AD\lI)\ISTRA TI\'E
`
`8-28-01 Orphan Drug Designation
`6-10-02 Fast Track Designation
`10-24-02 Initial Rolling Submission
`9-30-03 Final Rolling Submission
`
`PROPOSED INDICATION
`
`ALIMT A in combi..'lation with cisplatin is indicated for the treatment of patients with
`malignant pleural mesothelioma whose disease is either unresectable or who are not
`otherwise candidates for curative surgery.
`
`PRESEl"T AR\lA\IEl"T ARJUM
`
`No t;-eatment has been shown to prolong survival in this setting.
`
`CLINICAL TRIAL
`
`. One randomized clinical trial was conducted.
`
`Title:
`
`A Single-blind Randomized Phase 3 Trial of Alimta plus Cisplatin versus Cisplatin
`Alone in Patients with Malignant Pleural Mesothelioma
`
`This multicenter study included 88 principal investigators who entered patients at a total
`of 88 study centers located in 20 countries.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0011
`
`

`
`Primary Objective:
`
`To compare survival in chemonaive patients with malignant pleural mesothelioma
`whose disease is either unresectable or who are otherwise not candidates for curative
`surgery when treated with Alimta plus cisplatin combination therapy to survival in the
`same patient population when treated with cisplatin alone.
`
`Secondary Objectives:
`
`To compare between the tv.'o treatment arms: (1) time-to-event efficacy measures,
`including: a) duration of response for responding patients, b) time to progressive disease,
`c) time to treatment failure; (2) tumor response rate; (3) clinical benefit response rate;
`(4) Lung Cancer S)mptom Scale (LCSS) patient and observer scores; (5) pulmonary
`function tests; (6) lung density; (7) relative toxiCities; (8) to assess the impact of folic
`acid and vitamin B 12 supplementation on toxicity; (9) pharmacokinetic effects;
`(10) infom1ation regarding vitamin metabolite status in this patient population.
`
`Treatment:
`
`Alimta plus cisplatin treatment arm: Alimta was administered at a dose of 500 mg/m2
`diluted in approximately 100 mL normal salin~ as a lO-minute intravenous infusion.
`Approximately 30 minutes after the administration of Alimta, cisplatin was administered
`at a dose of75 mg/m2 over 2 hours. Both drugs were administered on Day I ofa 2 I-day
`period. This 21-day period defined one cycle of therapy.
`
`Cisplatir: alone treatment arm: Approximately 100 mL normal saline was given as an
`intravenous infusion over approximately 10 minutes. Approximately 30 minutes after
`the administration of 1101111al saline, cisplatin was administered at 75 mg/m2 over 2 hours
`on Day 1 of a 21-day period. This 21-day period defined one cycJe of therapy.
`
`Both treatment arms:
`
`~ Dexamethasone 4 mg (or an equivalent corticosteroid) was taken by all patients orally
`twice a day 1 day before, on the day of, and 1 day after each dose of Alimta for primary
`prophylaxis against rash.
`
`~ Folic acid and vitamin B12 for supplementation were standard components of therapy for
`all patients participating in the study from December 2,1999 onwards. Folic acid 350
`to I 000 ~g was administered orally daily, beginning approximately 1 to 3 weeks before
`the first dose of therapy and continued daily for I to 3 weeks after the patient
`discontinued treatment. A vitamin B 12 injection 1000 ~g was administered
`intramuscularly approximately I to 3 weeks before the first dose of therapy and was
`repeated approximately every 9 weeks until the patient discontinued study therapy.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0012
`
`

`
`Patient Population:
`
`A total of 574 patients were entered into the study (that is,signed the lnfonned Consent
`Document). Four ~undred fifty six of these patients were randomized to a treatment ann
`and 448 of these patients were treated and constitute the randomized and treated (RT)
`population.
`.
`
`In.itially no vitarr.in supplementation was given. Part way through the study it became
`apparent from other Alimta studies that vitamin supplementation was beneficial from a
`safety standpoint. At that time all patients in both treatment groups in the randomized
`trial were supplemented with vitamins. This resulted in three subgroups in each
`treatment ann regarding vitamin supplementation. These groups are never supplemented
`(NS), partially supplemented (PS) and fully supplemented (FS). Results are reported for
`each group. This review will focus on all RT patients (the primary analysis) and the FS
`patients (the proposed labeled administration.)
`
`Alirhta plus cisplatin: Total RT 226, Male 184, Female 42,
`Fully Supplemented (FS) 168, Partially Supplemented (PS) or
`Never Supplemented (NS) 58.
`
`Cisplatin alone: Total RT 222, Male 181, Female 41,
`Fully Supplemented (FS) 163, Partially Supplemented (PS) or
`Never Supplemented (NS) 59.
`
`Statistics:
`
`The primary efficacy analysis was comparison of survival time between the study arms in
`the RT population. Differences were assessed using a two-sided log rank test. Because
`an interim analysis was conducted (resulting in a decision to continue the trial to planned
`compietion), the comparison of survival was tested at the p=O.0476 level.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0013
`
`

`
`Patient Characteristics:
`
`The following Tables compiled by the Applicant show the disease and demographic
`factors for the study patients. These are well balanced between the treatment groups.
`
`Table JMCH.11.3.
`
`Summary of Patlsnt Charnctsrlstlcs
`RT Population by Suppl9msntatlon Status
`H3E·MC..JMCH
`
`LYI1:ia
`
`136(81:0%). ··48(12.8%). ·134 (8:z:2%) . 41 (79:7%)
`:32(19.0}
`Iii (17.2)·
`29(11.8)
`li(2II.3}
`
`153 (93.9)
`7 (4.3)
`J (I.I!)
`0
`
`53 (89.8)
`5 (8.5)
`1(0.7)
`0
`
`60
`19
`82
`
`61
`35
`84
`
`.......... SR .. ··
`·· .•. ·.·•· ....• ··.··Miihi
`. ···.Fuiotde
`orilla
`Cllu::asiso
`His}lauic
`Asianl
`Africm
`AI:i/
`Median
`62
`00
`12
`29
`Minimmn
`Mamnum
`77
`85
`I WB!it1!iii and E8BWouIhilBBl Amn haw bilitl cmnbinlld
`
`150 (89.3)
`10 (6.0)
`7(4.2)
`1(0.6)
`
`S4 (93.1)
`1(1.7)
`J (~.2)
`0
`
`APP£P,RS nBS WAY
`ON OR~G\N~.l
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0014
`
`

`
`Table JMCH.11.S.
`
`Basellno Stratification FactorS Usodfor Randomization
`RT PopulatIOn by Supplomontatlon Status
`H3E-MC-JMCH
`
`LYfrlI
`
`FS
`
`KPS
`Low (S8D)
`High (290)
`
`OqrH or MllBlIrabilityl
`Unidinumoiwal
`Bidirmlll5ional
`
`HiltUJitk Swbtnw
`lipithelial
`MiDd
`, "<smciiiriirliiid''''·
`0Ifuir
`
`WBe
`Low «8.3 GIil..)
`High (28.3 Gl/l..)
`
`Pat. I at n!ily2
`Low «20 mm)
`High (220 mm)
`
`Anal2fsk cOli.nn.,tioa
`Low (<60 rug mlTp eqfday)
`High (2tiO rug iilap eq/daj')
`
`O),lIpaeaJ
`Low «20 mID)
`.HigJ:J (220mm)
`
`Jlou.ry.§td.i?
`Low «12 umoJ/l..)
`High (~1211moIi1.,J
`
`83(49.4%)
`8S (SO.6)
`
`26 (44.11)
`32 (55.2)
`
`W (423%)
`94 (57.7)
`
`28 (475)
`31 (525)
`
`61 (36.5)
`106 (63.5)
`
`12 (20.7)
`46n9.3)
`
`62 (38.0)
`101 (62.0)
`
`J\ (IS.6)
`48 (SI.4)
`
`117 (W.6)
`. 2S (14.9)
`... '14(8.1)
`12 (7:1)
`
`37 (63:11)
`12(20.7j
`4(6.9)
`5(11.6)
`
`111 (69.3)
`.. 2S (153) ..
`., .. 11 (1D.4) ..
`8 (4.9)
`
`39 (66.1)
`11(18.6) .
`. 8 (13.6>
`1(1.7)
`
`72 (42.9)
`96 (57.1)
`
`25 (43.1)
`33 (56.9)
`
`68 (41.7)
`95 (58.3)
`
`23 (39.0)
`36 (61.0)
`
`82 (49.4)
`It4 (50.6)
`
`30 (51.7)
`28 (48.3)
`
`&) (49.1)
`83 (50.9)
`
`33 (55.9)
`26 (44.1)
`
`129 (16.8)
`39 (23.2)
`
`44 (75.9)
`14 (24.1)
`
`124 (76.1)
`39(23.9)
`
`46 (7s.0)
`13 (22.0)
`
`titi (39.11)
`100 (00.2)
`
`25 (4J.I)
`33 (56.9)
`
`68 (41.7)
`95 (58.3)
`
`24 (40.7)
`35 (59:3)
`
`119 (10.8)
`49 (29.2)
`
`36 (62.1)
`22 (37.9)
`
`118 (72.4)
`45 (27.6)
`
`38 (64.4)
`21 (35.6)
`
`Su
`Male
`Female
`) A. singJe pBIient was miMing their evaJuahIe diaoll!iilmllal!UTllmlJlt Blbue1iUI!.
`2 P!msIiIs 3cQ"302SBrui no-7209 a:uipJstsd the Pmmt LCSS at basiJioe, bot ontsida oftbe prttaXll
`dillined lliD.dOW; 1hi:lsir.dala are not inclUded in IbIi I'Ilpcrting dalBbase.
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0015
`
`

`
`Tablet JMCH.11.7.
`
`Summary of Baseline OIsoase Characteristics
`RT Population by Supplomontatlon Status
`H3E·MC-JMCH
`
`LY/cis
`
`FS
`(N~I68)
`
`PS-INS
`_(N=S8)
`
`ctliJlalio
`PStNS
`tN=59}
`
`FS
`(N=16J)
`
`I I7 (OJ.6%)
`2S (14.9)
`14(83)
`12 (7.1)
`
`37(63.8%) 113(69.3%)
`25 (IS.3)
`12 (20.7)
`4 (6.9)
`17(10.4)
`5 (11:6)
`8(4.9)
`
`39(66.1%)
`1 I (18.6)
`8(B.6)
`1 (1.7)
`
`8 (4.8)
`7 (4.2)
`27 (16.2)
`Sl (30.5)
`74 (44.3)
`_ I (0.6) -_
`
`25 (14.9)
`58 (34.5)
`67 (39.9)
`18(10.7)
`
`1(1.7)
`0
`8 (13.8)
`22 (37.9)
`27 (46.6)
`0
`
`12 (20.7)
`14 (24.1)
`26 (44.8)
`6 (10.3)
`
`7(43)
`5 (3.1)
`27 (16.8)
`49 (30.4)
`73 (453)
`2 (12)
`
`i2 (liS)
`47 (28.8)
`OJ (423)
`25 (IS.3)
`
`I (I. 7)
`J (1.7)
`6 (10.2)
`19 (32.2)
`32(54.2)
`-"--,-,0
`
`9 (lS.3)
`19 (32.2)
`25 (42.4)
`6(JO.2)
`
`Dial •• m IHhtdarY
`Epithelial
`Mixed
`Sarcanatoid
`01Iwr
`S~atEDIry
`la
`Ib
`IT
`m
`_
`_. IV
`.
`... "'
`<:,' l.1n.pacifiBd_' -.. > -,-- -
`PmliiiUliuea.dm
`70
`80
`90
`100
`
`Efficacy Results:
`
`Survival
`
`In the all RT patients analysis the combination of Alimta and cisplatin demonstrates a
`statistically significant improvement in survival compared to cisplatin alone with median
`survivals of 12.1 versus 9.3 months, respectively (p=0.020). An ITT analysis on all
`randomized patients, including 8 patients not in the R T analysis, yields nearly identical
`results to the RT analysis. This superiority in the Alimtalcisplatin arm is also
`demonstrated in the fully supplemented subgroup with median survivals of 13.3 and 10.0
`months in the Alimta/cisplatin and cisplatin alone treatment groups, respectively
`(p=O.051).
`
`APPEARS nus WAY
`ON ORIGINAL
`
`Sandoz Inc. IPR2016-00318
`Sandoz v. Eli Lilly, Exhibit 1119-0016
`
`

`
`All Randomized Treated Patients (448)
`
`Product-Limit Survival Fit
`Survival Plot
`
`1",
`
`0.8
`0.7
`0.6
`g> 0.5
`.:~ 0.4
`~ 0.3
`0.2
`0.1
`0.0
`-0.1~~--~~--~~~--~~--~~--~~
`25
`30
`10
`5
`20
`15
`SURVIVAL TIME
`
`-1....._
`
`Time intervals are in months.
`
`M2 =