CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-660
`
`MEDICAL REVIEWgSg
`
`
`
`

`

`
`
`Division NDA Review Summary
`
`NDA:
`
`21-660
`
`Applicant:
`Proprietary Name:
`
`American BioScience, Inc. (AB1)
`AbraxaneTM (paclitaxel protein-bound particles for injectable suspension)
`
`Regulatog History
`Regulatory Landmarks
`
`May 12, [998: original IND 55,974 was submitted.
`
`January 16, 2003: Product received Fast Track designation for metastatic breast cancer.
`
`June 30, 2003: ABl submitted first piece of rolling NDA (CMC'and non-clinical).
`
`March 8, 2004: Division received the last piece of the rolling NDA (clinical).
`
`January 8, 2005: PDUFA goal date for this standard review.
`
`FDA met with the sponsor on several occasions to discuss trial designs that could serve as the
`basis for approval. The sponsor was developing a new formulation of paclitaxel that was
`cremophore-free and promised to be less toxic. FDA agreed that ABI could be compared to
`paclitaxel under the 505 b2 regulations, however, clinical studies would be necessary. FDA
`stated that objective response rate could be used as a comparative measure of paclitaxel activity.
`ABI was to be compared to Taxol
`in a non-inferiority analysis which would assure statistically
`at least 75% retention of the paclitaxel activity in the Taxol control arm. (Although the Agency
`often allows a standard of 50% retention of control effect, a more stringent standard was required
`because 1) response rate is a surrogate rather than a ultimate end point, and 2) the sponsor was
`relying on results from only a single study). Breast cancer was chosen as the disease for study
`because of the high response rate of breast cancer to single—agent Taxol. As discussed below, the
`sponsor exceeded the goal of demonstrating non‘inferiority by demonstrating clearly superior
`response rates with ABI.
`
`Indication
`
`For the treatment of breast cancer after failure of combination chemotherapy for metastatic
`disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have
`included an anthracycline unless clinically contraindicated.
`
`Clinical/Statistical (See revieWS by Drs. Scher, Dagher’s, Drs. Yang & Sridhara’s )
`
`The clinical database supporting efficacy and safety in this setting includes two single-arm .
`studies and one randomized, multi-center, international study enrolling 460 patients (Study
`CA012-0).
`
`Study CAOIZ-O was arandomized, multi-center, open—label, phase 3 trial in breast cancer
`patients. It was conducted at 70 sites located in Russia/Ukraine, Canada= the US. and the United
`Kingdom. Patients were randomized to receive Abraxane (233 patients), 260 mg/mz, as a 30—
`minute infusion, or 175 mg/m2 paclitaxel injection (227 patients) as a 3—hour infusion. Fifty-nine
`
`

`

`NDA 21—660: Abraxane
`Division Summary
`
`Page 2 Indication: Breast Cancer, metastatic
`
`percent of patients received study drug as second-line or greater than second-line therapy.
`Seventy-seven percent of the patients had previous exposure to anthracyclines.
`
`The primary efficacy endpoint was response rate based on reconciled (investigators and
`independent radiology experts) assessment of target lesions through cycle 6. The primary
`analysis was a sequential test with the following pro-specified testing order: non-inferiority test
`in the whole study population, superiority test in the whole study population, and superiority test
`in the subgroup of patients who received study treatment as the lSt line therapy. Based on the
`FDA clinical reviewer’s adjudication of response status, there were 50 and 25 responders in the
`ABI~OO7 arm and Taxol arm, respectively. The observed response rates were 21.5% and 11.1%,
`respectively and the estimated ratio of response rates (ABI-007/Taxol) was 1.899 with a 95%
`confidence interval (CI) of 1.223 — 2.937. This suggests the superiority of ABI—OO'I‘ with respect
`to the primary endpoint in the whole study population.
`
`Table 1: Reviewer's Results of FDA-Confirmed recTLRR All Randomized Patients
`
`Reconciled Target Lesion Response Assessment
`Dataset
`
`ARI-007
`[N F 233]
`
`Taxnl
`[N = 227]
`
`Response Rate
`95% Binomial CI
`Ratio of Response Rates (ABI-UO7/Taxol)
`95% Cl “
`
`21.5%
`16.19%726.73%
`1.899
`1.228 — 2.937
`
`11.1%
`6.94%“- l5.09%
`
`
`
`
`
`
`‘ 95% CI of the ratio in superiority analysis based on the stratified Cochran-Mantel-Haenszel (CMH) test, stratified
`by lSt line vs. > lSt line therapy.
`b P-value from the stratified CMI-I test.
`
`
`
`
`
`
`Time to progression data also appeared favorable, but evaluation of this secondary endpoint was
`neither rigorous enough, nor mature enough, for definitive conclusions to be reached. Central
`review of the radiologic findings was only conducted for the first six cycles of therapy. The
`FDA statistical team evaluated TTP by two methods: I) analyzing only the reconciled
`progression dates through cycle 6, and 2) analyzing all investigator-specified progression dates
`which were available beyond cycle 6. By both analyses the hazard ratio was about 0.75 and the
`p value was about 0.04.
`-'—:
`/
`
`Survival data was not mature enough for evaluation. The applicant will be required to submit
`survival data for review as a phase 1V post—marketing commitment.
`
`Abraxane has an acceptable safety profile compared to paclitaxel as evaluated in study CA012-0.
`Hypersensitivity reactions were fewer in the Abraxane arm compared with paclitaxel (4% vs.
`12%), with no severe hypersensitivity reactions observed for Abraxane. The incidence of
`neutropenia was lower for patients in the Abraxane arm compared to paclitaxel (9% vs. 22%),
`despite a 49% higher dose of ABI—007. The incidence of Sensory neuropathy was greater in the
`Abraxane treatment arm (71% vs. 56% for all grades and 10% vs. 2% for grade 3). However, it
`
`
`
`
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`

`

`Division Summary
`Page 3
`
`NDA 21-660: Abraxane
`Indication: Breast Cancer, metastatic
`
`appears that of the 24 patients with grade 3 neuropathy, [4 improved at a median of 22 days, 10
`resumed treatment at a reduced dose, and 2 discontinued due to peripheral neuropathy.
`
`Outside Consultation: This application was not presented at the Oncologic Drugs Advisory
`Committee. The review team discussed this application with three outside SGE consultants (two
`oncologists and a radiologist).
`
`Chemistry, Manufacturing and Controls (see Dr. Y. Hsieh’s review)
`Abraxane is a formulation of microparticles of paclitaxel coated with human albumin. The mean
`particle size of albumin bound paclitaxel particles is between
`__
`nm. The drug product is
`provided as a sterile, lyophilized cake of 100 mg of paclitaxel and approximately 900 mg of
`human albumin in a 50 mL ——- glass vial. Currently marketed paclitaxei drug products use a
`Cremophor-EL formulation. Abraxane can be stored at 25 °C/60% RH. An expiration dating
`period of 24 months under the recommended storage conditions has been granted. For
`administration, each vial of Abraxane is reconstituted with 20 mL 0.9% Sodium Chloride
`
`Injection, USP to give a suspension of microparticles containing 5 mg paclitaxel per mL.
`Reconstituted drug product solution should be used immediately, but may be refrigerated at 2“-
`8°C (361461?) for a maximum of 8 hours if necessary. Adequate information on the drug product
`has been provided to assure its identity, strength, purity and quality.
`
`The active ingredient, paclitaxel, is an antitubulin agent, exhibiting a unique anti-mitotic activity.
`The drug product is manufactured from paclitaxel obtained
`'—
`Taxus
`media (commonly known as Anglojap Yew).
`it is a white to off-white powder with poor water
`solubility. Complete information on the drug substance is provided in DMF No
`.__
`Adequate information and data have been provided to support the use of the
`-—'
`.naterial in
`the manufacturing of the Abraxane drug product.
`
`Nonclinical (see Drs. Brower & Leighton’s reviews)
`Abraxane is a cytotoxic agent that functions as a microtubule inhibitor, promoting the assembly
`of microtubules and preventing depolymerization. To support the NDA, the applicant submitted
`nonclinical studies reports that evaluated the efficacy of paclitaxel protein-bound particles;
`general toxicology and reproductive toxicity studies; and pharmacokinetic and biodistribution
`studies. A study to justify an increased level of an impurity was also provided. ABI conducted
`these studies. Information on the mechanism of action and genetic toxicology of paclitaxel was
`obtained from product labels from previously reviewed NDA applications.
`
`Single dose toxicology studies of paclitaxel formulated as protein-bound particles compared to
`cremophor-formulated paclitaxel did not raise any new concerns that were not addressed in
`clinical development. Developmental toxicity of paclitaxel protein—bound particles was assessed
`in a fertility and early embryonic toxicity study in which male rats were mated with untreated
`females. An embryo-fetal developmental toxicology study (Segment II) was also conducted in
`female rats. Results from both these studies indicated that paclitaxel protein—bound particles are
`a developmental toxicant. Pregnancy Category D is recommended.
`
`ABI conducted a comparative toxicology to justify an increase in shelf-life specification of
`/
`primary
`./
`impurity of ABl-007, from
`-’
`
`’
`
`
`
`

`

`NDA 21-660: Abraxane
`Division Summary
`
`Page 4 Indication: Breast Cancer, metastatic
`
`Clinical Pharmacology and Biopharmaceutics (see Dr. Men’s review)
`Pharmacokinetic parameters of total paclitaxel were determined in Phase 1, 2 and 3 studies afier
`intravenous infusion of Abraxane over 30- and 180- minutes in cancer patients at doses of 80—
`375 mgfmz. The maximal tolerated dose (MTD) of Abraxane was determined to be 300 mg/ml,
`which was about 50% higher than the MTD for Taxol. Linear pharmacokinetics (PK) of
`Abraxane were observed between 80 to 375 mg/rnz. The total clearance of Abraxane was 15
`L/hr/m2 and the volume of distribution was 632 L/m2. The total clearance and volume of
`
`distribution of paclitaxel were higher when administered as Abraxane compared to Taxol. The
`terminal half-life of 21-hour was the same as Taxol. Urinary excretion of Abraxane accounted
`for <6% of paclitaxel and the renal clearance was 0.16 to 1.08 L/hrfm2 which indicates that extra-
`renal elimination was extensive. Fecal excretion accounted for 22% of totai dose. Paclitaxel
`
`accounted for 3% and its metabolite, 60t-hydroxypaclitaxel, 18%. The applicant did not study
`the safety and pharmacokinetics of Abraxane in hepatically-impaired patients.
`
`Tradename and Labeling Consultation (see DMETS & DDMAC reviews)
`The Division of Medication Errors and Tech Support (DMETS) had no objection to the use of
`the proprietary name, Abraxane. Additionally, DMETS provided label & labeling
`recommendations in their reviews.
`
`The Division of Drug Marketing, Advertising and Communications (DDMAC) found the
`proprietary name acceptable from a promotional perspective. DDMAC reviewers Joseph Grillo
`and Iris Masucci reviewed and commented on the draft labeling submitted in the application.
`
`Data Integrity Issues (see Dr. Gan’s Clinical Inspection Summary)
`The Division requested that the Division of Scientific Investigation (DSI) inspect 5 sites in
`Russia (2 in Moscow, 3 in St. Petersburg).
`
`Dr. Gan concluded that the clinical investigators at the five Russian sites “did not always adhere
`to good clinical practices governing the conduct of clinical investigations”. However, Dr. Gan
`found the data from the sites adequate for efficacy evaluation. He noted that adverse events are
`underreported in Russia compared to the U.S., Canada and the UK. for 4 of the 5 sites.
`Therefore, Dr. Gan recommended, for assessing adverse events, the Division consider using data
`reported by study subjects (patient) on the study questionnaire instead of physician’s report.
`
`Pediatric Considerations
`
`Metastatic breast cancer does not exist in children so the Division granted a full waiver to the
`applicant regarding conduct of pediatric studies.
`
`Conclusions
`
`The study results from the randomized, multi-center, open—label, Study CA012—O support the
`breast cancer efficacy claim based on the primary endpoint, reconciled target lesion response
`rate. Response rate served as a surrogate for the antitumor effects of the active ingredient,
`paclitaxel, in breast cancer patients. Comparing the effects of Abraxane and Taxol on this
`surrogate in breast cancer'patients, the sponsor was able to reference the proven efficacy of
`
`
`
`

`

`NDA 21-660: Abraxane
`Division Summary
`-——————.__—_____—___________
`Page 5
`Indication: Breast Cancer, metastatic
`_
`
`Taxol in breast cancer through the 505(b)(2) process. Through this process Abraxane is granted
`the same breast cancer indication as found in the Taxol label.
`
`Although the regulatory goal was for Abraxane to demonstrate at least 75% preservation of the
`Taxol response rate, the Abraxane study exceeded this goal by showing a superior response rate
`to Taxol. The study also suggested that Abraxane might be superior with respect to a secondary
`endpoint, time to progression.
`"--“
`
`/
`
`The applicant agreed to the following phase 4 commitments:
`
`1. Submit survival data and analysis results from the randomized study CA012-0 when 80%
`of the patients have died. Data should be available for submission approximately June
`2005.
`
`2. Evaluate Abraxane safety and pharmacokinetics in subjects with hepatic impairment, to
`allow the determination of dosing adjustment for this population. The final report should
`be available for submission by December 2006
`
`Grant Williams, MD
`Deputy Director, Division of Oncology Drug Products
`
`
`
`

`

`--—---—-—-———-u—-m----u-——-—--—-———m---.---n-—-um.----nu-—_---u---———----nu-_-—------——------
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`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`u-M—n-—-"-n—_-—_-_—-----——--——-u.--..__-—-__-_--“-—-—---——-----—_—-—-n--u__---------—--—-n----—--—_-—---
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`/s/
`
`Grant Williams
`
`2/7/05 04:53:11 PM
`MEDICAL OFFICER
`
`
`
`
`
`

`

`
`
`Clinical Review of a
`
`New Drug Application
`
`NDA Number:
`
`21—660
`
`Submission Number:
`
`N-OOO
`
`Drug Trade Name:
`Established Name:
`
`Therapeutic Class:
`Applicant:
`
`ABRAXANETM for Injectable Suspension
`Paclitaxel protein-bound particles for injectable
`suspension
`Cytotoxic antineoplastic (taxane)
`American Biosciences, Inc.
`
`Review Priority:
`Submission Date:
`
`Standard
`
`March 8, 2004
`
`PDUFA Goal Date:
`
`January 8, 2005
`
`Primary Reviewer:
`Nancy S. Scher, M.D.
`Medical Team Leader: Ramzi Dagher, M.D.
`Project Manager:
`Sheila Ryan, PharmD.
`
`
`
`

`

`
`
`Table of Contents
`
`The Executive Summary of the Primary Clinical Review ............................................................. l
`1 Recommendations ................................................................................................................ 1
`
`2
`
`Recommendations on Approvability .............................................................................. l
`1.1
`1.2 Recommendations on Postmarketing Studies and/or Risk Management Steps as
`Appropriate. ............................................................................................................................ l
`Summary of Clinical Findings .............................................................................................. l
`2.1
`Brief Overview of Clinical Program ............................................................................... 1
`2.2
`Efficacy ......................................................................................................................... l
`2.3
`Safety............................................................................................................................. 2
`2.4 Dosing, Regimen, and Administration ............................................................................ 3
`2.5 Drug-Drug Interactions ..........................................~. ....................................................... 3
`2.6
`Special Populations ........................................................................................................ 3
`Clinical Review ........................................................................................................................... 6
`
`1
`
`Introduction and Background................................................................................................ 6
`1.]
`Established and Proposed Trade Name of Drug, Drug Class, Sponsor's Proposed
`Indications(s), Dose, Regimens, Age Groups ........................................................................... 6
`1.2
`State of Armamentarium for the Indication .................................................................... 7
`
`Important Milestones in Product Development ............................................................... 8
`1.3
`1.4 Other Relevant Information ............................................................................................ 9
`
`Important Issues with Pharmacologically Related Agents ............................................... 9
`1.5
`Significant Findings from Chemistry, Animal Pharmacology and Toxicology, andfor
`2
`Microbiology ............................................................................................................................ 10
`2.1
`Chemistry .................................................................................................................... 10
`2.2 Animal Pharmacology and Toxicology ........................................................................ l 1
`2.3 Microbiology ............................................................................................................... 11
`3 Human Pharmacokinetics and Pharmacodynamics .............................................................. 11
`3.1
`Pharmacokinetics ......................................................................................................... l2
`
`Pharmacodynamics ...................................................................................................... 12
`3 .2
`4 Description of Clinical Data and Sources ............................................................................ 12
`4.1
`Sources of Clinical Data ............................................................................................... 12
`
`4.2 Overview of Clinical Trials .......................................................................................... 13
`
`4.3
`4.4
`
`Postmarketing Experience ............................................................................................ 13
`Literature Review ......................................................................................................... 13
`
`5 Clinical Review Methods .................................................................................................... 14
`5.1 Describe How Review was Conducted ......................................................................... 14
`5.2 Overview of Materials Consulted in Review ................................................................ 14
`
`5.3 Overview of Methods Used to Evaluate Data Quality and Integrity .............................. 14
`5.4 Were Trials Conducted in Accordance with Accepted Ethical Standards? .................... 15
`5.5
`Evaluation of Financial Disclosure ............................................................................... 16
`
`6
`
`Integrated Review of Efficacy ............................................................................................ 16
`6.1
`Brief Statement of Conclusions .................................................................................... 16
`
`6.2 General Approach to Review of the Efficacy of the Drug ............................................. 17
`6.3 Detailed Review of Randomized Trial CAOl2—0 ......................................................... 17
`
`6.4
`
`Summary of Single Arm Trials ..................................................................................... 58
`
`ii
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`
`

`

` CLINICAL REVIEW
`
`7
`
`Efficacy Conclusions ................................................................................................... 59
`65
`Integrated Review of Safety ................................................................................................ 60
`7.1
`Brief Statement of Findings .......................................................................................... 60
`7.2 Materials Utilized in the Review .................................................................................. 61
`
`7.3 Description of Patient Exposure ................................................................................... 61
`7.4
`Safety Findings from Clinical Studies .......................................................................... 65
`7.5 Miscellaneous Studies .................................................................................................. 76
`
`Literature Review for Safety ........................................................................................ 77
`7.6
`Postmarketing Surveillance .......................................................................................... 77
`7.7
`Safety Update 120 Day ................................................................................................ 77
`7.8
`7.9 Drug Withdrawal, Abuse, and Overdose Experience .................................................... 77
`7.10
`Adequacy of Safety Testing ...................................................................................... 77
`7.11
`Labeling Safety Issues and Postmarketing Commitments .......................................... 78
`8 Dosing, Regimen, and Administration Issues ...................................................................... 78
`9 Use in Special Populations .................................................................................................. 79
`9.1
`Evaluation of Applicant's Efficacy and Safety Analyses of Effects of Gender, Age, Race,
`or Ethnicity ............................................................................................................................ 79
`9.2
`Pediatric Program......................................................................................................... 80
`9.3 Data Available or Needed in Other Populations Such as Renal or Hepatic Compromised
`Patients, or Use in Pregnancy ................................................................................................. 80
`10
`Conclusions, Recommendations, and Labeling ................................................................ 81
`10.1
`Conclusions Regarding Safety and Efficacy .............................................................. 81
`10.2
`Recommendations on Approvability ......................................................................... 82
`10.3
`Labeling .................................................................................................................... 82
`Appendix ................................................................................................................................... 85
`
`Individual More Detailed Study Reviews, if Performed ...................................................... 85
`1
`2 Detailed Labeling Changes or Revised Drug Label ............................................................. 85
`3 Bibliography ....................................................................................................................... 85
`
`iii
`
`

`

` CLINICAL REVIEW
`
`
`Table of Tables
`
`Table leilestones in Drug Deve10pment (Reviewer Table) ....................................................... 8
`Table 2: Clinical Trials Submitted to NDA (Reviewer Table) ................................................... 13
`Table 3: D81 Audit Sites (Reviewer Table) ............................................................................... 15
`Table 4: Milestones for Study CA012—0 (Reviewer Table) ........................................................ 17
`Table 5: Schedule of Assessments (Applicant Table) ................................................................ 23
`Table 6: Cycles of Therapy by Region and Treatment Arm ....................................................... 26
`Table 7: Treatment Exposure by Treatment Arm (Reviewer Table) ........................................... 27
`Table 8: Reasons for Withdrawal from Therapy (Applicant Table) ............................................ 28
`Table 9. Patient Populations for Analysis (Applicant Table) ..................................................... 29
`Table 10: Baseline Demographics (Applicant Table) ................................................................. 31
`Table 11: Patient Characteristics at Diagnosis (Applicant Table) ............................................... 32
`Table 12: Initial Treatment of Breast Cancer (Applicant Table) ................................................ 33
`Table 13: ECOG Performance Status at Baseline (Applicant Table) .......................................... 33
`Table 14: Baseline Number of Lesions and Dominant Sites (Applicant Table) .......................... 34
`Table 15: Prior Therapies at Baseline (Applicant Table) ........................................................... 35
`Table 16: Pn'or Treatment for Metastatic Breast Cancer (Applicant Table) ................................ 35
`Table 17: Use of Corticosteroids and Antihistamines (Applicant Table) .................................... 36
`Table 18: "Predosing" Use of Corticosteroids and Antihistamines (Applicant Table) ................ 37
`Table 19: Cumulative Dose & Mean Dose Intensity (Safety Population) (Applicant Table) ...... 39
`Table 20: Target Lesion ReSponse Rates and Superiority Test (Applicant Table) ...................... 41
`Table 21: RecTLRR for Patients Who Met Taxol Indication .................................................... 42
`Table 22: invORR by Line of Therapy (Applicant Table) .......................................................... 43
`Table 23: InvORR by Prior Anthracycline Therapy (Applicant Table) ...................................... 45
`Table 24: InvORR by Country and Treatment arm .................................................................... 46
`Table 25: Applicant's Summary of invORR by Line of Therapy and Prior Anthracycline .......... 46
`Table 26: Time to Disease Progression (Applicant Table) ......................................................... 48
`Table 27: TTP by Line of Therapy (Applicant Table)................................................................ 49
`Table 28: Patient Survival (Applicant Table)............................................................................. 50
`Table 29: ABI~007 Treatment Arm Patients with Discrepancy in Response Status between FDA
`and Applicant (Reviewer Table) ......................................................................................... 52
`Table 30: Line of Therapy Data for Disputed Patients (Reviewer Table) ................................... 52
`Table 31: Applicant's Response Regarding FDA-Adjudicated Patients ...................................... 53
`Table 32: List of Patients Designated as Reconciled Complete Target Lesion Response by
`Applicant (Reviewer Table) ................................................................................................ 54
`Table 33: FDA Evaluation of Response and TTP (All Randomized Patients) (Reviewer Table) 55
`Table 34: FDA Evaluation of Response for First-Line Therapy Patients (All Randomized)
`(Statistical Reviewer Table) ................................................................................................ 56
`Table 35: Duration of Response on FDA-Confirmed Responders (Based on Reconciled
`Assessment through Cycle 6) (Statistical Reviewer Table) .................................................. 56
`Table 36: FDA Results for Overall Survival (All Randomized) (Statistical Reviewer Table) ..... 57
`Table 3?: Cumulative Dose, Dose Intensity, Cycles Administered in phase 2 and 3 Studies
`(Applicant Table) ............................................................................................................... 62
`Table 38: Treatment Exposure by Cycle (Applicant Table) ....................................................... 63
`Table 39: Treatment Exposure by Cycle and Dose (Applicant Table) ........................................ 64
`
`iv
`
`
`
`

`

`
`
`Table 40: Most Commonly Reported (>= 10% Patients per either Arm) Treatment-Emergent
`Adverse Events for All Cycles (Applicant Table) ............................................................... 66
`Table 41: Number (%) of Patients with Treatment-Emergent Grade 3 and 4 Adverse Events (2
`5% Either Treatment Arm) ................................................................................................. 67
`Table 42: Incidence of Grade 3 or 4 Neutropenia and Time to Recovery (Applicant Table) ....... 68
`Table 43: Incidence of Grade 3 Sensory Neuropathy and Time to Improvement to Grade] or 2
`(Applicant Table) ............................................................................................................... 70
`Table 44: Tolerability in Patients Receiving First-Line Therapy (Applicant Table) ................... 73
`Table 45: Toxicities with Significant Differences between Treatment Arms .............................. 74
`Table 46: GI Adverse Events by Subcategory and Severity (Reviewer Table) ........................... 74
`Table 47:Most Frequent Treatment-Emergent Grade 3—4 Adverse Events (Reviewer Table) ..... 75
`Table 48: Liver Function Test Elevations by Severity and Treatment (Reviewer Table) ............ 76
`Table 49: Response Rate by Age Category and Treatment Arm ................................................ 80
`
`

`

` CLINICAL REVIEW
`
`Table of Figures
`
`Figure l: InvORR for All Treated Patients and by Line of Therapy (Applicant Figure) ............. 44
`
`
`
`vi
`
`

`

`
`
`The Executive Summary ofthe Primary Clinical Review
`
`1 Recommendations
`
`1.1 Recommendations 0n Approvability
`
`The NDA for ABI-OO7 is filed under Section 505 (b)(2), referencing the label, efficacy and
`safety of Taxol (paclitaxel) Injection. We recommend approval of ARI-007 for the
`indication in the paclitaxei injection label based on clinical data from 460 patients in a
`randomized controlled comparative trial that provide evidence of safety and efficacy of ABI—
`007 compared to Taxol in metastatic breast cancer- The efficacy claim is supported by
`superiority for ABI-007 compared with Taxol for the primary response rate endpoint. Data
`from 106 patients accrued in two single arm open label studies provide additional support.
`ABI—007 is indicated for the treatment of breast cancer after failure of combination
`
`chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.
`Prior therapy should have included an anthracycline unless clinically contraindicated.
`
`1.2 Recommendations on Postmarketing Studies andlor Risk Management Steps as
`Appropriate.
`
`The appropriate dose of ABI—007 for patients with bilirubin greater than 1.5 mgldL is not
`known. The effect of hepatic dysfunction on the disposition of ABI-OO? has not been
`investigated. Since paclitaxel is metabolized by the liver, the applicant should study safety
`and pharmacokinetics in patients with hepatic impairment, in order to guide dosing.
`
`The applicant has also agreed to fulfill a phase 4 commitment to provide survival data and
`analysis results from randomized study CA012-0 after 80% of patients have died.
`
`2 Summary of Clinical Findings
`
`2.] Brief Overview of Clinical Program
`
`A single randomized controlled, multi—center, phase 3 trial in 460 women with metastatic
`breast cancer demonstrated that ABI—007 260 mg/mZ IV over 30 minutes every 3 weeks was
`superior to Taxol 175 mg/mZ IV over 3 hours every 3 weeks for the primary re3ponse rate
`endpoint, with a similar safety profile. Data in two single arm trials from 103 patients with
`metastatic breast cancer were supportive of the efficacy and safety of ABI-007.
`
`2.2 Efficacy
`
`As a 505 (b)(2) application, referencing the label, efficacy and safety of Taxol (paclitaxel)
`Injection, the applicant was required to demonstrate non-inferiority (in response rate) to
`Taxol for the indication in metastatic breast cancer in a single, randomized, controlled, multi-
`center, open—label trial, with supportive data from single arm trials. In one single arm trial,
`63 patients were treated with ABI—007 at a dose of 175 mg/m2 over 30 minutes every 3
`
`
`
`
`
`

`

`
`
`weeks. The second trial treated 43 patients with ABI—007 at a dose of 300 mgi’m2 as a 30
`minute infusion. Patients were treated without steroid premedication for ABI-OO7. Objective
`responses were observed in both studies.
`
`The randomized controlied trial was conducted at 70 sites, located in Russiankraine, Canada
`
`and the U.S., and the United Kingdom. A total of 460 patients were randomized in
`comparative trial