These results are supplied for informational purposes only.
`Prescribing decisions should be made based on the approved package insert in the country of prescription.
`
`
`01 April 2004
`30 September 2006 (data cut-off date)
`
`Study Identifier: NCT00081796
`Sponsor / Company: sanofi-aventis
`Study code: EFC6089 [XRP9881B-3001]
`Drug substance(s): Larotaxel (XRP9881; RPR109881)
`Title of the study: A randomized, open-label, Phase 3 study of larotaxel IV every 3 weeks versus capecitabine (Xeloda®) tablets
`twice daily for 2 weeks in 3-week cycles in patients with metastatic breast cancer (MBC) progressing after
`taxanes and anthracycline therapy (EFC6089)
`Study center(s): 240 centers activated worldwide; patients were enrolled at 142 centers
`Study period:
`Date first patient enrolled:
`Date last patient completed:
`Phase of development: 3
`Objectives:
`
`Primary: The primary objective of this study was to compare progression free survival (PFS) in patients with MBC, progressing
`after taxanes and anthracycline therapy, when treated with larotaxel versus capecitabine.
`
`Secondary: The secondary objectives were to compare survival and other measures of anti-tumor efficacy (response rate [RR],
`time to tumor response [TTR], duration of response [DR], single time progression rate [STPR], and time to treatment failure [TTF])
`in patients treated with larotaxel versus capecitabine; to compare the safety and tolerability of larotaxel versus capecitabine; and to
`compare the quality of life and other clinical benefit measures in patients treated with larotaxel versus capecitabine
`Methodology: Global multi-center, open-label, two-arm randomized, Phase 3 clinical trial
`Number of patients: Planned: 800; Randomized: 438; Treated: 433
` Evaluated: Efficacy: 438; Safety: 433
`Diagnosis and criteria for inclusion: Histologically or cytologically proven diagnosis of breast adenocarcinoma that was
`metastatic or locally recurrent and inoperable. Patients must have had measurable disease as defined by RECIST at study entry.
`Patients must have received prior treatment for the breast cancer including anthracyclines, and taxanes.
`Investigational product: Larotaxel (XRP9881; RPR109881)
`Dose: 90 mg/m² IV larotaxel on Day 1 over 1 hour (75 mg/m² IV in patients with known bone marrow involvement). Treatment
`was repeated every 3 weeks
`Administration: Intravenous (IV)
`Duration of treatment: Patients continued to receive treatment until disease progression, patient intolerance, withdrawal of
`consent, or Investigator decision.
`Duration of observation: Patients were followed every 3 months to document subsequent anticancer therapy and survival status.
`Reference therapy: Capecitabine
`Dose: 1250 mg/m² (2500 mg/m²/day) capecitabine tablets administered orally twice daily (morning and evening) for 2 weeks
`followed by a 1-week rest period, to form a 3-week cycle.
`Administration: Oral
`
`According to template: WW-CLIN-ER-102-SD-02 VERSION N°02 (05-OCT-2007)
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`Page 1/5
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`AVENTIS EXHIBIT 2003
`Mylan v. Aventis, IPR2016-00712
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`

`
`Criteria for evaluation:
`Efficacy: The primary efficacy variable was progression free survival (PFS), based on Independent Review Committee (IRC)
`analysis, which was defined as the time from randomization to first documentation of RECIST-defined objective tumor
`progression or death due to any cause.
`The secondary efficacy variables included overall survival (OS), single time progression rate (STPR), and response rate (RR).
`Other efficacy variables were time to tumor response (TTR), time to treatment failure (TTF), and duration of response (DR).
`Safety: Safety parameters were adverse events, hematology, blood chemistry, vital signs, physical examinations, and ECOG
`performance status.
`Special safety parameters included febrile neutropenia, infection with neutropenia, septic death, sensory neuropathy, diarrhea,
`hand-foot syndrome, and fluid retention.
`Pharmacokinetics:
`Statistical methods:
`The primary efficacy variable was median PFS, based on IRC evaluation. The PFS was compared between the two treatment
`groups using a 2-sided log rank test stratified by the randomization factors “treatment setting of prior taxanes administration” and
`“prior taxane responsiveness” as specified at the time of randomization. The rate of PFS events was also estimated using the
`Kaplan-Meier method. The analyses were performed on the ITT population.
`
`As secondary efficacy variables, OS and TTF were compared between the two treatments by the 2-sided log-rank test stratified by
`the stratification factors at randomization. The survival curves were estimated using Kaplan-Meier estimates. Response Rate was
`compared between the two treatment groups using 2-sided CMH test stratified by the same stratification factors. The other
`secondary efficacy variables STPR, TTR, and DR were summarized by treatment using mean, standard error, and range. The
`analyses were performed on the ITT population.
`
`The study was terminated based on the recommendation of the IDMC. All safety analyses followed the sanofi-aventis safety
`analysis Guideline. The comprehensive analysis of safety was based on “treatment-emergent” principle. Descriptive statistics were
`provided for TEAE, SAE, major labs, and death.
`
`The changes in the statistical analyses compared to the original SAP are documented in the main body of this report.
`
`Page 2/5
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`

`
`
`Summary: In general, patient characteristics were well balanced between arms; however, there were a higher proportion of black
`patients and younger patients (<50 years old) in the larotaxel arm. A slightly higher proportion of patients in the larotaxel group
`had liver metastases.
`A pre-specified futility analysis that was performed after the first 200 patients was reviewed by the IRC and resulted in the early
`termination of the study since the study did not reach its primary endpoint of superiority of larotaxel over capecitabine.
`Efficacy results: The primary efficacy variable, median PFS, was longer in the capecitabine group (18.4 weeks) than in the
`larotaxel group (14.1 weeks) according to IRC analyses; patients in the larotaxel arm responded later (median TTR: 11.1 weeks
`vs. 7.0 weeks) in the course of treatment but had a similar duration of response (DR) as compared with capecitabine. Median OS
`was 65.4 weeks in each arm.
`
`
`
`
`Progression free survival – ITT population – number (%) of patients
`Investigator
`IRC [a]
`LAROTAXE
`Capecitabin
`LAROTAXE
`L
`e
`L
`(N=219)
`(N=219)
`(N=164)
`12.57
`15.43
`14.14
`(11.00,16.86)
`(13.14,18.14)
`(11.86,17.86)
`
`Capecitabine
`(N=168)
`18.43
`(17.43,24.14)
`
`
`Median PFS (weeks)
`95% CI
`Log-rank test (p-
`value)[b]
`0.0482
`0.1710
`1.3306
`1.1603
`Hazard Ratio
`(1.0032,1.7647)
`(0.9394,1.4330)
`95% CI
`Note: [a] ITT for IRC is defined as randomized patients who had tumor assessment data reviewed.
`Note: [b] P-value was based on 2-sided log-rank test after adjusting for prior taxane setting and prior taxane
`responsiveness
`
`
`
`Overall survival – ITT population – number (%) of patients
`LAROTAXEL
`Capecitabine
`(N=219)
`(N=219)
`
`
`Number of Deaths,
`108 (49.3%)
`111 (50.7%)
`n(%)[a]
`65.43
`65.43
`Median OS (weeks)
`(54.429,78.429)
`(60.571,75.286)
`95% Confidence Interval
`0.7740
`Log-rank test (p-value)
`1.0400
`Hazard Ratio
`(0.7960,1.3587)
`95% Confidence Interval
`Note: [a] 2 LAROTAXEL patients censored due to partial death dates
`
`
`
`
`Best overall response rates – ITT population – number (%) of patients
`IRCb
`Investigator
`LAROTAXE
`LAROTAXE
`Capecitabin
`Capecitabine
`L
`L
`e
`(N=219)
`(N=219)
`(N=164)
`(N=168)
`
`54 ( 24.7)
`38 ( 17.4)
`15 ( 9.1)
`28 (16.7)
`RR (CR + PR)
`(19.1,30.9)
`(12.6,23.0)
`( 5.2,14.6)
`(11.4, 23.2)
`95% Exact CI
`P-valuea
` 0.0560
`0.0408
`Note: [a] P-value was based on 2-sided CMH test stratified by prior taxane setting and prior taxane
`responsiveness. P-value was analyzed at an overall two-sided alpha level of 0.05.
`Note: [b] ITT for IRC is defined as randomized patients and had tumor assessment data reviewed.
`
`
`Page 3/5
`
`
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`
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`

`
`Safety results: Over 95% of patients in each treatment group experienced a TEAE. The percentage of patients with SAEs or
`who died during the study was similar in each group. The proportion of patients withdrawing from study treatment was slightly
`higher for larotaxel patients.
`
`
`
`Any treatment emergent AE
`Any treatment emergent SAE
`Permanent withdrawals from treatment due to
`AEa
`Total number of patients who died (all causes)
` Deaths within 30 days of last dose
` Deaths within 60 days of first dose
`[a] data derived from CRF “AE” page
`
`LAROTAXEL
`(N=218)
`214 (98.2)
`75(34.4)
`34 (15.6)
`
`Capecitabine
`(N=215)
`206 (95.8)
`69(32.1)
`23 (10.7)
`
`113 ( 51.8)
`9 ( 4.1)
`8 ( 3.7)
`
`108 ( 50.2)
`13 ( 6.0)
`9 ( 4.2)
`
`The main nonhematologic and hematologic toxicities for larotaxel and capecitabine are summarized in the following tables.
`Safety results were as expected with gastrointestinal events and neutropenia/febrile neutropenia predominating in the larotaxel
`group and gastrointestinal events and palmar-plantar erythrodysesthesia syndrome predominating in the capecitabine group.
`
`
`
`
`
`
`
`
`Main Nonhematologic AEs
`Diarrhoea
`Nausea
`Alopecia
`Fatigue
`Vomiting
`
`
`
`Febrile neutropenia
`
`
`Hematology laboratory results
`Leukocytes
`Neutrophils
`Hemoglobin
`Platelets
`
`
` LAROTAXEL (N=218)
`n(%)
`
`All
`
`137(62.8)
`122(56.0)
`105(48.2)
`88(40.4)
`78(35.8)
`
`24(11.0)
`
`
`202 ( 92.7)
`195 ( 89.4)
`180 ( 82.6)
`75 ( 34.4)
`
`
`Grade 3/4
`
`18( 8.3)
`9( 4.1)
`7( 3.2)
`14( 6.4)
`7( 3.2)
`
`24(11.0)
`
`
`122 ( 56.0)
`155 ( 71.1)
`15 ( 6.9)
`23 ( 10.6)
`
`
`Page 4/5
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`

`
`
`
`
`
`Main Nonhematologic AEs
`Palmar-plantar erythrodysaesthesia
`syndrome
`Diarrhoea
`Nausea
`Fatigue
`Vomiting
`
`
`
`Febrile neutropenia
`
`
`Hematology laboratory results
`Leukocytes
`Neutrophils
`Hemoglobin
`Platelets
`
`
`Date of issue: 10-July-2012
`
`
`
`Capecitabine (N=215)
`n(%)
`Grade 3/4
`
`
`All
`
`
`138(64.2)
`118(54.9)
`111(51.6)
`77(35.8)
`69(32.1)
`
`1( 0.5)
`
`
`126 ( 58.6)
`97 ( 45.1)
`161 ( 74.9)
`78 ( 36.3)
`
`36(16.7)
`27(12.6)
`8( 3.7)
`8( 3.7)
`10( 4.7)
`
`1( 0.5)
`
`
`16 ( 7.4)
`34 ( 15.8)
`8 ( 3.7)
`16 ( 7.4)
`
`Page 5/5