CENTER FOR DRUG EVALUATION AND
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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`RESEARCH
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`APPLICA TION NUMBER:
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`APPLICATION NUMBER:
`201023
`201023
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`MEDICAL REVIEW(S)
`MEDICAL REVIEW! S!
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`CLINICAL REVIEW
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`Application Type NDA
`Application Number 201023
`Priority or Standard Priority
`
`Submit Date 03/31/2010
`Received Date 03/31/2010
`PDUFA Goal Date 09/30/2010
`Division / Office DDOP / OODP
`
`Reviewer Names Amy McKee, M.D.
`Ian Waxman, M.D.
`Review Completion Date 06/02/2010
`
`Established Name Cabazitaxel
` Proposed Trade Name Jevtana
`Therapeutic Class Taxane
`Applicant Sanofi-Aventis
`
`Formulation Intravenous
`Dosing Regimen 25 mg/m2 IV over 1 hour every
`21 days
`Indication Hormone-refractory prostate
`cancer
`Intended Population Men with metastatic hormone-
`refractory prostate cancer who
`have previously received a
`docetaxel-containing regimen
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`Template Version: March 6, 2009
`
`

`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`
`Table of Contents
`
`2
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`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 8
`1.1 Recommendation on Regulatory Action ............................................................. 8
`1.2 Risk Benefit Assessment.................................................................................... 8
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 8
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 8
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 9
`2.1 Prostate Cancer.................................................................................................. 9
`2.2 Treatment of Patients with Prostate Cancer ..................................................... 10
`2.3 Product Information .......................................................................................... 12
`2.4 Tables of Currently Available Treatments for Proposed Indications ................. 12
`2.5 Availability of Proposed Active Ingredient in the United States ........................ 12
`2.6 Important Safety Issues With Consideration to Related Drugs ......................... 12
`2.7 Summary of Presubmission Regulatory Activity Related to Submission .......... 13
`2.8 Other Relevant Background Information .......................................................... 17
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 17
`3.1 Submission Quality and Integrity ...................................................................... 17
`3.2 Compliance with Good Clinical Practices ......................................................... 18
`3.3 Financial Disclosures........................................................................................ 18
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 19
`4.1 Chemistry Manufacturing and Controls ............................................................ 19
`4.2 Clinical Microbiology......................................................................................... 19
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 19
`4.4 Clinical Pharmacology...................................................................................... 19
`4.4.1 Mechanism of Action.................................................................................. 19
`4.4.2 Pharmacodynamics.................................................................................... 19
`4.4.3 Pharmacokinetics....................................................................................... 20
`5 SOURCES OF CLINICAL DATA............................................................................ 21
`5.1 Tables of Studies/Clinical Trials ....................................................................... 21
`5.2 Review Strategy ............................................................................................... 22
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 22
`5.3.1 Study design .............................................................................................. 22
`5.3.2 Study drug administration and schedule .................................................... 23
`5.3.3 Study Endpoints ......................................................................................... 23
`5.3.4 Eligibility Criteria......................................................................................... 24
`5.3.5 Duration of Treatment ................................................................................ 26
`5.3.6 Primary Endpoint Evaluation...................................................................... 29
`5.3.7 Secondary Endpoint(s) Evaluation ............................................................. 29
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`

`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`
`5.3.8 Major Protocol Amendments...................................................................... 32
`6 REVIEW OF EFFICACY......................................................................................... 33
`Efficacy Summary...................................................................................................... 33
`6.1
`Indication .......................................................................................................... 33
`6.1.1 Methods ..................................................................................................... 33
`6.1.2 Demographics............................................................................................ 34
`6.1.3 Subject Disposition .................................................................................... 36
`6.1.4 Analysis of Primary Endpoint ..................................................................... 36
`6.1.5 Analysis of Secondary Endpoints............................................................... 39
`6.1.6 Other Endpoints ......................................................................................... 41
`6.1.7 Subpopulations .......................................................................................... 41
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 41
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 42
`6.1.10 Additional Efficacy Issues/Analyses ......................................................... 42
`7 REVIEW OF SAFETY............................................................................................. 43
`Safety Summary ........................................................................................................ 43
`7.1 Methods............................................................................................................ 44
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 44
`7.1.2 Categorization of Adverse Events.............................................................. 45
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 45
`7.2 Adequacy of Safety Assessments .................................................................... 47
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 47
`7.2.2 Explorations for Dose Response................................................................ 50
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 50
`7.2.4 Routine Clinical Testing ............................................................................. 50
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 50
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 50
`7.3 Major Safety Results ........................................................................................ 52
`7.3.1 Deaths........................................................................................................ 52
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 57
`7.3.3 Dropouts and/or Discontinuations .............................................................. 58
`7.3.4 Significant Adverse Events ........................................................................ 60
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 73
`7.4 Supportive Safety Results ................................................................................ 73
`7.4.1 Common Adverse Events .......................................................................... 73
`7.4.2 Laboratory Findings ................................................................................... 77
`7.4.3 Vital Signs.................................................................................................. 78
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 79
`7.4.5 Special Safety Studies/Clinical Trials......................................................... 79
`7.4.6
`Immunogenicity.......................................................................................... 80
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`

`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`
`7.5 Other Safety Explorations................................................................................. 81
`7.5.1 Dose Dependency for Adverse Events ...................................................... 81
`7.5.2 Time Dependency for Adverse Events....................................................... 82
`7.5.3 Drug-Demographic Interactions ................................................................. 83
`7.5.4 Drug-Disease Interactions.......................................................................... 86
`7.5.5 Drug-Drug Interactions............................................................................... 86
`7.6 Additional Safety Evaluations ........................................................................... 86
`7.6.1 Human Carcinogenicity.............................................................................. 86
`7.6.2 Human Reproduction and Pregnancy Data................................................ 86
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 86
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 86
`7.7 Additional Submissions / Safety Issues............................................................ 86
`8 POSTMARKET EXPERIENCE............................................................................... 87
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`9 APPENDICES ........................................................................................................ 87
`9.1 Literature Review/References .......................................................................... 87
`9.2 Labeling Recommendations............................................................................. 87
`9.3 Advisory Committee Meeting............................................................................ 87
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`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`
`Table of Tables
`
`Table 1: Studies in NDA 201023 ................................................................................... 21
`Table 2: Major Protocol Amendments ........................................................................... 32
`Table 3: Patient Characteristics .................................................................................... 34
`Table 4: Prior Treatment ............................................................................................... 35
`Table 5: Prior Docetaxel Exposure................................................................................ 35
`Table 6: Patient Disposition........................................................................................... 36
`Table 7: Overall Survival per Applicant ......................................................................... 36
`Table 8: Progression-Free Survival per Applicant ......................................................... 39
`Table 9: Overall Response Rate per Applicant ............................................................. 40
`Table 10: Major Protocol Violations............................................................................... 43
`Table 11: Incidence of Most Common (>15%) Treatment-Emergent Adverse Events in
`ISS Database................................................................................................. 46
`Table 12: Exposure ....................................................................................................... 48
`Table 13: Dose Modifications........................................................................................ 48
`Table 14: Adverse Events Leading to Dose Modification (≥3 Patients, Either Arm) ...... 49
`Table 15: Safety Population Deaths.............................................................................. 53
`Table 16: Grade 5 Treatment-Emergent Adverse Events Excluding Disease Progression
`and Occurring Within 30 Days of Last Dose on the Cabazitaxel Arm ............ 54
`Table 17: Grade 5 Treatment-Emergent Adverse Events Excluding Disease Progression
`and Occurring Within 30 Days of Last Dose on the Mitoxantrone Arm .......... 56
`Table 18: Summary of Grade 5 Treatment-Emergent Adverse Events Excluding
`Disease Progression and Leading to Death Within 30 Days of Last Dose..... 56
`Table 19: Nonfatal Serious Adverse Events (≥1% on Either Arm) ................................ 57
`Table 20: Reasons for Treatment Discontinuation ........................................................ 58
`Table 21: Discontinuations due to Adverse Events (≥2 Patients on Either Arm) ........... 59
`Table 22: Infection-Related Deaths on EFC6193.......................................................... 60
`Table 23: Neutropenia Adverse Events and Related Discontinuations on EFC6193 .... 61
`Table 24: Neutrophil Count Nadirs (109/L) in Cabazitaxel-Treated Patients Before and
`After First Use of G-CSF................................................................................ 62
`Table 25: Renal Failure Adverse Events in Cabazitaxel-Treated Patients .................... 65
`Table 26: Hematuria Adverse Events1 .......................................................................... 67
`Table 27: Confounding Factors for Hematuria in Safety Population.............................. 68
`Table 28: Confounding Factors in Patients with Grade ≥2 Hematuria1 ......................... 69
`Table 29: Hematuria Dose Delays and Discontinuations1............................................. 70
`Table 30: Cardiac Deaths on the Cabazitaxel Arm (EFC6193)..................................... 70
`Table 31: Cardiac Adverse Events on EFC6193........................................................... 72
`Table 32: Grade 1-4 Adverse Events (≥5% Patients, Either Arm)................................. 74
`Table 33: Grade 3-4 Adverse Events (≥1% Patients, Either Arm)................................. 76
`Table 34: Laboratory Adverse Events ........................................................................... 78
`Table 35: Adverse Events Possibly Related to Immunogenicity.................................... 80
`Table 36: Neutropenia in Cabazitaxel-Treated Patients Receiving <25 mg/m2 q3 Weekly
`Dosing vs. ≥25 mg/m2 q3 Weekly Dosing in ISS Database ........................... 81
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`

`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`Table 37: Neutropenia in Cabazitaxel-Treated Patients Receiving 20 mg/m2 q3 Weekly
`Dosing in ISS Database................................................................................. 81
`Table 38: Time to First Onset of Grade 3-4 Neutropenia .............................................. 82
`Table 39: Time to First Onset of Grade ≥2 Hematuria................................................... 82
`Table 40: Grade 1-4 Adverse Events by Age and Race................................................ 84
`Table 41: Grade 3-4 Adverse Events by Age and Race................................................ 85
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`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`
`Table of Figures
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`Figure 1: Overall Survival for Patients with Metastatic HRPC in the TAX 327 Trial....... 11
`Figure 2: Structural Formula of Cabazitaxel .................................................................. 12
`Figure 3: Study Design Schema.................................................................................... 23
`Figure 4: Schedule of Evaluations................................................................................. 28
`Figure 5: Overall Assessment of Response .................................................................. 30
`Figure 6: Kaplan-Meier Plot of Overall Survival per Applicant....................................... 37
`Figure 7: Overall Survival-Worst-Case Analysis............................................................ 38
`Figure 8: Kaplan-Meier Plot of Progression-Free Survival per Applicant....................... 39
`Figure 9: Effect of G-CSF Use, Dose Reduction, or Combination of Both on Median
`Neutrophil Count Nadirs in Patients Who Received At Least One Dose of G-
`CSF................................................................................................................ 63
`Figure 10: Effect of Dose Reduction on Median Neutrophil Counts in Patients Who Did
`Not Receive Any G-CSF ................................................................................ 64
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`

`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`We recommend approval of cabazitaxel for men with metastatic hormone-refractory
`prostate cancer after a docetaxel-containing regimen.
`
`1.2 Risk Benefit Assessment
`
`The recommendation for approval is based on the single, randomized clinical trial in
`which cabazitaxel in combination with prednisone showed a statistically significant
`survival advantage compared to the combination of mitoxantrone and prednisone in
`patients with metastatic, hormone-refractory prostate cancer (mHRPC).
`
`The single clinical trial enrolled 755 men with mHRPC who had progressed on or after a
`docetaxel-containing regimen. The cabazitaxel arm had a median overall survival of
`15.1 months compared to 12.7 months on the mitoxantrone arm. Although there were
`deaths due to toxicity on the cabazitaxel arm, an overall survival advantage was still
`demonstrated for cabazitaxel-treated patients. Furthermore, as some of the deaths were
`due to infectious complications during a period of neutropenia, infection-related deaths
`may be better prevented in the post-marketing setting with the use of prophylactic G-
`CSF in patients at high risk of neutropenic complications. The proposed patient
`population currently has no treatment options which offer a survival benefit, and the
`robust results in overall survival demonstrated by cabazitaxel would provide a new
`treatment option for these patients.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`
`This drug will be prescribed by physicians familiar with the management of toxicity
`associated with chemotherapeutic agents. Severe toxicities that have led to death in the
`clinical trial will be described in the labeling. Standard post-marketing surveillance
`should be conducted by the applicant.
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`1.4 Recommendations for Postmarket Requirements and Commitments
`
`Four clinical post-marketing requirements (PMRs) have been discussed with the
`applicant:
`1. Conduct a Phase 3 randomized controlled trial in patients with hormone-
`refractory metastatic prostate cancer comparing first-line docetaxel/prednisone
`with cabazitaxel 20 mg/m2/prednisone and cabazitaxel 25 mg/m2/prednisone.
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`

`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`
`The primary endpoint should be overall survival. The trial should be powered to
`detect a realistic difference in overall survival. Submit the protocol for agency
`review prior to commencing the trial.
`2. Conduct a Phase 3 randomized controlled trial in patients with hormone-
`refractory prostate cancer previously treated with docetaxel comparing
`cabazitaxel 20 mg/m2/prednisone and cabazitaxel 25 mg/m2/prednisone powered
`to preserve 50% of the treatment effect of cabazitaxel 25 mg/m2. The primary
`endpoint should be overall survival. Submit the protocol for agency review prior
`to commencing the trial.
`3. Organize a group of renal experts to review and analyze renal toxicity from all
`currently available cabazitaxel trials to identify etiologies and to provide
`recommendations for toxicity mitigation by patient selection or other measures.
`This group’s findings and recommendations should be submitted within nine
`months of the cabazitaxel approval date.
`4. Submit updates on renal toxicity from all active randomized trials every six
`months for three years after the cabazitaxel approval date.
`
`
`Trial designs for the phase 3 randomized trials (PMRs #1 and #2 above) have not yet
`been finalized.
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`Refer to CMC and clinical pharmacology reviews for discipline-specific PMRs.
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`2 Introduction and Regulatory Background
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`2.1 Prostate Cancer
`
`Prostate cancer is the most common cancer diagnosed in men, with an incidence in the
`United States of approximately 192,000 annually, and approximately 27,000 deaths are
`attributed annually to prostate cancer.i Prostate cancer is predominantly a disease of
`older men; the median age at diagnosis is 72 years. As the disease can be indolent in
`many, patients often do not have symptoms of their disease and die of causes other
`than prostate cancer.
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`More recently, the percentage of patients diagnosed with early-stage, low-risk disease
`has increased; 29.8% of newly- diagnosed patients in 1989-1992 compared to 45.3% in
`1999-2001.ii This observation often is attributed to widespread screening of
`asymptomatic patients for the disease by serum prostate-specific antigen (PSA) levels,
`digital rectal examination and ultrasonography. However, there is controversy regarding
`screening of asymptomatic patients, as both false-positive rates with PSA screening
`and discovery of low-risk, indolent disease has led to invasive procedures and treatment
`that have significant morbidity and have not been shown to reduce overall mortality for
`the disease or to reduce it very modestly.iii,iv
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`9
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`

`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`The value of PSA both for screening and measuring response is under question in the
`literature, though its measurement may be reliable for detecting relapse after surgery.
`Doubts have arisen as to whether PSA is sensitive or specific enough to warrant
`screening of asymptomatic men.v,vi Furthermore, the utility of PSA measurements as a
`marker for disease progression in advanced disease is under question. The Prostate
`Cancer Clinical Trials Working Group in its most recent consensus report (PCWG2)
`recommends that changes in PSA levels alone are not used to define progression in
`hormone-refractory disease,vii based on findings in the several recent studies.viii,ix
`
`Patients with metastatic disease often have bone lesions that are not measurable by
`RECIST criteria, and the PCWG2 recognizes that there are no validated criteria for
`response based on radionuclide scans of the bone. For progression, the appearance of
`> two new lesions is recommended by PCGW2 for progression based on radionuclide
`scans. Another measurement frequently used in prostate cancer both for response and
`progression is pain. A recent study on survival in men with metastatic hormone-
`refractory prostate cancer (mHRPC) who have progressed on or after first-line
`chemotherapy revealed that for men with isolated pain progression, continuing
`chemotherapy after documented pain progression was associated with improved OS
`compared with stopping chemotherapy; the authors concluded that if pain scales are to
`be used to define progression in men with CRPC, studies should additionally
`incorporate other measures of progressive disease before withdrawal of a patient from
`therapy.x This study points out the difficulties in using the subjective measurement of
`pain to define progression; the PCGW2 states that “the assessment of pain progression
`is more difficult because of the subjectivity as to what constitutes a ‘clinically significant
`increase’ from baseline or from the point of maximal response to an intervention.”7
`Based on the difficulties noted above for measuring response and progression in the
`metastatic HRPC population, the recommended endpoint in a Phase 3 trial is overall
`survival.
`
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`2.2 Treatment of Patients with Prostate Cancer
`
`First-line therapy for patients with metastatic prostate cancer is medical or surgical
`castration. Approximately 85% of patients will respond to this therapy, which includes
`gonadotropin-releasing hormone antagonists or surgery. However, approximately 15%
`of patients will not respond to hormonal intervention and responders will eventually
`become refractory to hormonal intervention.. For this metastatic HRPC population,
`recommended first-line therapy is the combination of docetaxel and prednisone, which
`showed a survival advantage compared to the combination of mitoxantrone and
`prednisone in the randomized, Phase 3 TAX327 trial.xi
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`10
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`

`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`
`Figure 1: Overall Survival for Patients with Metastatic HRPC in the TAX 327 Trial
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`For patients who have progression on or after docetaxel-based therapy, there are no
`treatments that have shown a survival advantage. Mitoxantrone in combination with
`prednisone is labeled for pain palliation in this setting but has not demonstrated a
`survival advantage. Re-challenging patients who initially responded to docetaxel and
`progressed after completing treatment with a docetaxel-based regimen has brought
`some success with response rates,xii but survival has not been analyzed prospectively
`with this treatment option. Many single agents and combination regimens have been
`investigated in this setting but have shown either unacceptable toxicity or unpromising
`response rates, such as lenalidomide/paclitaxel,xiii the histone deacetylase inhibitor
`romidepsin,xiv pemetrexed,xv multi-kinase inhibitor sunitinib,xvi gefitinib, xvii microtubule
`inhibitor patupilone, xviii and bortezomib,xix among others.
`
`Phase 3 studies are ongoing for the combination of docetaxel and atresentan and for
`the CYP17 inhibitor abiraterone, and promising Phase 2 results were seen with
`docetaxel in combination with bevacizumab and thalidomide.xx However, a recently
`reported large, double-blind, placebo-controlled Phase 3 trial in HRPC patients did not
`show a survival advantage with satraplatin compared to placebo.xxi Thus no treatment
`for metastatic HRPC patients after failure of the docetaxel/prednisone regimen has
`demonstrated a survival advantage.
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`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`2.3 Product Information
`
`Cabazitaxel is a new molecular entity and is a novel taxane, similar to the taxanes
`docetaxel and paclitaxel. It is a semi-synthetic product derived from 10-deacetyl
`Baccatin III, which is extracted from European yew needles. The chemical name of
`cabazitaxel is (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tertbutoxycarbonyl)
`amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-
`epoxytax-11-en-2-yl benzoate – propan-2-one(1:1).
`
`
`Figure 2: Structural Formula of Cabazitaxel
`
`
`
`2.4 Tables of Currently Available Treatments for Proposed Indications
`
`There are no currently available therapies specifically indicated for metastatic hormone-
`refractory prostate cancer patients who have previously received a docetaxel-containing
`regimen. Mitoxantrone in combination with prednisone is indicated for palliation of pain
`in this setting, but not for treatment of prostate cancer.
`
`2.5 Availability of Proposed Active Ingredient in the United States
`
`Please refer to CMC review.
`
`2.6 Important Safety Issues With Consideration to Related Drugs
`
`Both the Taxotere and Taxol labels carry black box warnings for severe hypersensitivity
`and neutropenia. The Taxotere label also carries black box warnings for hepatic
`impairment and severe fluid retention. See section 7.2.6.
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`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`2.7 Summary of Presubmission Regulatory Activity Related to Submission
`
`April 14, 1999: IND 56,999 is activated to study malignant disease under the
`sponsorship of Sanofi-Aventis.
`
`June 29, 2006: An End-of-Phase 2 meeting was held to discuss the indications of
`mHRPC
` At this meeting, FDA emphasized that a Phase 3 trial in
`mHRPC must win on its primary endpoint of overall survival before any analysis of
`secondary endpoints could be undertaken
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`End-of-Phase 2 meeting minutes:
`QUESTIONS for DISCUSSION with FDA RESPONSE and DECISIONS REACHED:
`Sanofi-Aventis: We agree to have overall survival as the single, primary endpoint for both Phase
`3 registration trials, for XRP9881 and for XRP6258. We seek clarification from FDA on the
`following issues:
`1. We appreciate the FDA’s detailed guidance on the pain intensity endpoint measurement in the
`XRP9881 response #3.
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`2. We appreciate the FDA’s comments on the pain endpoint in the XRP6258 response #5.
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`Discussion: See our response to question #1.
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`4. We acknowledge the FDA comments on XRP6258 response #7 and propose to request a
`separate meeting with FDA to discuss the adequacy of the overall planned PK program and
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`

`Clinical Review
`Amy McKee, M.D. (Efficacy) and Ian Waxman, M.D. (Safety)
`NDA 201023
`Jevtana® (cabazitaxel)
`
`address the questions raised by the FDA. However, at this time, we wish to obtain FDA
`agreement with our proposed pharmacokinetic strategy for our Phase III clinical protocol in
`HRPC patients. We propose to implement sparse sampling in as many patients as possible at
`cycle 1 in the Phase III protocol, EFC6193, in order to assess the PK profile in this population,
`assuming no effect of the first dose of prednisone on PK, of XRP6258 and to investigate PK/PD
`relationships for safety and efficacy. In addition, 25 patients will be sampled at cycle 2 in order
`to assess the effect of repeated administrations of prednisone on the PK of XRP6258. Does the
`FDA agree with this proposal for our Phase III HRPC protocol?
`FDA Response: Yes
`
`
`Appendix I XRP9881 End-of-Phase I/II Meeting Questions (regarding HRPC only)
`Questions
`1. Does the FDA agree that the proposed patient population for study EFC6193 is adequately
`defined and suitable for a comparator-controlled Phase III study with marketing approval intent?
`FDA Response: Yes. However, please clarify the following inclusion criteria found on page
`2/11 of the briefing book “Previously irradiated lesions, primary prostate lesion and bone
`lesions are excluded”.
`
`2. Does the FDA agree that mitoxantrone in combination with prednisone is an appropriate
`comparator for this Phase III, randomized, comparator controlled trial?
`FDA Response: Yes. However, M/P therapy can be administered for 12 cy