VOLUME 23
`
`NUMBER
`
`31
`
`NOVEMBER
`
`1 2005
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`ORIGINAL REPORT
`
`OilBased
`
`Phase III Trial of Nanoparticle AlbuminBound
`Paclitaxel Compared With Polyethylated Castor
`Paclitaxel in Women With Breast Cancer
`William J Gradishar Sergei Tjulandin Neville Davidson Heather Shaw Neil Desai Paul Bhar
`
`Michael Hawkins and Joyce OShaughnessyABSTRACT
`
`Purpose
`albumin bound paclitaxel
`ABI007 the first biologically interactive
`in a nanameter particle
`castor oilbased standard paclitaxel
`free of solvents was compared with polyethylated
`patients with metastatic breast cancer M BC This phase III study was performed to confirm
`preclinical studies demonstrating superior efficacy and reduced toxicity of ABI007 compared
`with standard paclitaxel
`
`in
`
`Patients and Methods
`Patients were randomly assigned to 3 week cycles of either ABI007 260 mgm2 intrave
`nously without premedication n = 229 or standard paclitaxel 175 mgm2 intravenously with
`premedication n = 225
`
`Results
`ABI007 demonstrated
`
`significantly higher
`
`response rates compared with standard paclitaxel
`
`33 v 19 respectively P = 001 and significantly longer time to tumor progression 230 v
`was significantly lower for ABI007 compared with standard paclitaxel 9 v22 respectively
`hazard ratio = 075 P = 006 The incidence of grade 4 neutropenia
`169 weeks respectively
`P < 001 despite a 49 higher paclitaxel dose Febrile neutropenia was uncommon < 2
`and the incidence did not differ between the two study arms Grade 3 sensory neuropathy was
`more common in the ABI007 arm than in the standard paclitaxel arm 10 v2 respectively
`P< 001 but was easily managed and improved rapidly median 22 days No hypersensitivity
`reactions occurred with ABI007 despite the absence of premedication and shorter administra
`tion time
`
`Conclusion
`ABI007 demonstrated greater
`compared with
`and
`favorable
`safety profile
`efficacy
`a
`in this patient population The improved therapeutic
`index and elimination
`standard paclitaxel
`required for solvent based taxanes make the novel albumin
`of corticosteroid
`premedication
`in the treatment of MBC
`bound paclitaxel ABI007 an important advance
`
`J Clin Oncol 237794780310
`
`2005 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`The currently available taxanes paclitaxel
`Taxol BristolMyers Squibb Co Prince
`ton NJ and docetaxel Taxotere Aventis
`Inc Bridgewater NJ play
`Pharmaceuticals
`role in the treatment of breast
`a central
`cancer Because the taxanes are highly hy
`drophobic commercially available formula
`
`tions include
`
`solvents to enable
`synthetic
`parenteral administration paclitaxel con
`tains a combination of polyethylated castor
`oil Cremophor EL BASF Ludwigshafen
`and ethanol
`Germany
`the vehicle
`and polysorbate
`
`as
`
`80 and an ethanol diluent
`
`are the vehicles for docetaxe12
`
`Although
`paclitaxel
`proved to have significant activity against
`
`docetaxel
`
`and
`
`From Northwestern University
`
`BioScience
`
`IL Duke University Medical
`Chicago
`Center Durham NC American
`Inc Santa Monica CA
`Baylor Charles A Sammons Cancer
`Center US Oncology Dallas TX
`Russian Cancer Research Center
`Moscow Russia and Broomfield
`
`Hospital Essex United Kingdom
`
`Submitted November 9 2004 accepted
`April 28 2005
`
`by American
`Supported
`Inc Santa Monica CA
`
`BioScience
`
`Presented
`
`in part at
`
`the 26th Annual
`
`San Antonio Breast Cancer Symposium
`San Antonio TX December 36 2003
`
`Authors
`
`disclosures
`
`of potential
`
`con
`
`flicts of
`
`interest are found at
`
`the end of
`
`this article
`
`reprint requests
`
`Address
`to William J
`Gradishar MD Director Breast Oncol
`ogy Division of HematologyOncology
`Robert H
`Department
`of Medicine
`
`Cancer Center
`
`Northwestern
`
`Lurie Comprehensive
`University 676 N St
`Clair Ste 850 Chicago IL 60611
`email wgradisharnorthwesternedu
`
`0 2005 by American
`Oncology
`
`Society
`
`of Clinical
`
`0732183X0523317794$2000
`
`DOI 101200JC0200504937
`
`7794
`
`Abraxis EX2017
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`

`

`ABI007 Versus Paclitaxel
`
`in MBC
`
`breast cancer and other solid tumors emerging data indi
`cate that the solvents polyethylated castor oil and polysorbate
`80 directly contribute to the severe toxicities observed in pa
`tients treated with paclitaxel or docetaxel Among the well
`solvent related toxicities
`characterized
`are hypersensitivity
`reactions which can rarely be fatal even with corticosteroid
`premedication and prolonged sometimes irreversible pe
`ripheral neuropathy associated with demyelination and ax
`onal degeneration 5 More recently it has been recognized
`that these solvents may adversely affect efficacy because of
`entrapment of active drug in micelles formed in the plasma
`compartment67 leading to increased systemic drug expo
`sure decreased drug clearance nonlinear pharmacokinetics
`Drug en
`and lack of dose dependent antitumor activity6
`trapment affects not only the taxanes but also the coadminis
`tered drugs eg anthracyclines
`and thus is an important
`consideration in the design of combination therapies6
`ABI007 Abraxane American BioScience Inc Santa
`Monica CA is a novel biologically interactive nanometer
`sized albumin bound paclitaxel particle initially
`developed
`to avoid the toxicities associated with polyethylated castor
`is the first of a new class of anticancer
`oil
`agents that
`incorporate albumin particle technology
`and exploit
`the
`unique properties of albumin a natural carrier of lipophilic
`molecules in humans Administered as a colloidal suspen
`sion of 130 nanometer particles ABI007 allows the safe infu
`than the doses
`sion of significantly higher doses of paclitaxel
`
`It
`
`9
`
`conventional
`
`infusion
`therapy with shorter
`used with standard paclitaxel
`schedules 30 minutes v 3 hours respectively and no pre
`medication In addition the albumin bound nanoparticle
`was designed to preferentially deliver paclitaxel
`to tumors by
`biologically interacting with albumin receptors that mediate
`in vitro studies have demonstrated a 45 fold
`drug transport
`increase in paclitaxel transport across endothelial cells for ABI
`007 compared with standard paclitaxe11°
`A phase I trial of ABI007 in 19 patients with advanced
`solid tumors determined the maximumtolerated dose to
`be 300 mgm2 which is approximately 70 higher than the
`paclitaxel 175 mgm212 No severe hyper
`occurred with ABI007 despite the
`sensitivity reactions
`absence of premedication and administration over 30 min
`utes Dose limiting toxicities included sensory neuropathy
`stomatitis and superficial keratopathy which occurred at a
`dose of 375 mgm2 Pharmacokinetic analysis revealed lin
`increases in paclitaxel maximum concentration
`and
`ear
`time curve over the ABI007
`area under the concentration
`dose range of 135 to 300 mgm2
`A phase II
`Ibrahim et al submitted for publica
`trial
`tion evaluating ABI007 at 300 mgm2 in patients with
`metastatic breast cancer MBC demonstrated an overall
`response rate ORR of48 with a response rate of 64 for
`patients who received ABI007 as first line therapy Time to
`tumor progression TTP was 266 weeks
`for all patients
`and 481 weeks for patients with confirmed tumor respons
`
`es median overall survival was 636 weeks The observed
`adverse events AEs of myelosuppression and peripheral
`than what
`neuropathy were less frequent and less severe
`would be expected with comparable doses of standard pac
`litaxe112 No severe ocular events occurred and no hyper
`sensitivity reactions were reported despite the absence of
`premedication These findings suggested that ABI007 may
`offer important advantages over standard paclitaxel and
`supported the conduct of this phase III
`trial
`The present study was designed to directly compare the
`efficacy and safety of ABI007 with standard paclitaxel
`in
`patients with MBC in a randomized trial The dose of ABI
`007 was reduced from the maximumtolerated dose used in
`the phase II study to 260 mgm2 with the expectation that
`the ABI007 regimen would not be more toxic than the
`standard dose of standard paclitaxel 175 mgm2
`
`PATIENTS AND METHODS
`
`conducted
`
`randomized open label phase III study was
`This international
`at 70 sites 28 RussiaUkraine sites 350 patients 22
`United StatesCanada
`sites 37 patients and 20 United Kingdom
`sites 67 patients The protocol and related materials were ap
`proved by the appropriate institutional review boards and in
`The study was conducted in
`dependent ethics committees
`compliance with Good Clinical Practice Guidelines of the In
`ternational Conference on Harmonization and the Declara
`tion of Helsinki Written informed consent was required from
`
`all patients
`
`Patient Population
`
`Nonpregnant nonlactating females at least 18 years of age
`with histologically or cytologically confirmed measurable MBC
`and an expected survival of more than 12 weeks were eligible for
`participation Patients were included if
`they were candidates
`for
`single agent paclitaxel therapy had not received paclitaxel or do
`cetaxel for metastatic carcinoma had not relapsed with metastatic
`disease within 1 year of adjuvant paclitaxel or docetaxel
`treatment
`had no other malignancy within the previous 5 years except non
`melanoma skin cancer cervical
`intraepithelial neoplasia or in situ
`cervical cancer and had acceptable clinical
`laboratory test results
`at baseline
`Patients were excluded from participation if they had clinical
`evidence of active brain metastasis or a clinically serious concur
`illness an Eastern Cooperative Oncology Group ECOG
`rent
`performance status of more than 2 received hormone therapy for
`2 weeks or chemotherapy immunotherapy or another investiga
`tional drug for 4 weeks before administration of the first study
`dose preexisting peripheral neuropathy of grade 1 according to
`Institute Common Toxicity Criteria or a history
`National Cancer
`of allergic or hypersensitivity reactions to the study drug or any of
`its excipients
`
`Treatment
`Eligible patients were randomly assigned 11 to receive treat
`ment every 3 weeks with either ABI007 260 mgm2 intravenously
`over 30 minutes without corticosteroid or antihistamine premedica
`tion or special infusion sets or standard paclitaxel 175 mgm2 intra
`venously over 3 hours with premedication and special infusion sets as
`
`wwwjcoorg
`
`7795
`
`

`

`Gradishar et al
`
`taxel n = 225 were considered the intent to treat ITT
`population Almost all > 99 of the ABI007 infusions
`were administered in 50 minutes or less and 815 were
`infused over 30 minutes 229 of the standard paclitaxel
`infusions were longer than the planned infusion time of 180
`minutes Actual delivered paclitaxel dose intensity was 49
`higher in the ABI007 group than in the standard paclitaxel
`group mean ± standard deviation 8513 ± 3118 mgm2 v
`5702 ± 3008 mgm2 per week respectively At least six
`cycles were administered
`129 patients
`treatment
`56 in the ABI007 group and 112 patients 50 in
`
`the standard paclitaxel group The last patient came off
`study in April 2004
`
`to
`
`indicated in the prescribing information Within country balance
`for anthracycline exposure was ensured by within country stratifica
`and naive groups Up to two dose
`tion into anthracyclineexposed
`reductions 40 mgm2 each were allowed from the initial 260 mgm2
`dose of ABI007 Reductions
`doses were al
`in standard paclitaxel
`insert for each country
`
`lowed according to the package
`
`Assessments
`Imaging studies were performed at baseline at weeks 5 9
`and 15 and at
`the end of treatment Responses were assessed
`according to Response Evaluation Criteria in Solid Tumor guide
`lines13 Complete and partial responses required subsequent con
`firmation of response > 4 weeks later
`The primary efficacy measure was ORR secondary efficacy
`measures were TTP and overall survival Quality of life QOL
`assessment data ECOG performance status scores from the Eu
`ropean Organisation for Research and Treatment of Cancer Qual
`ity of Life Questionnaire C30 and body weight were collected
`
`Statistical Analysis
`The statistical power of this study was based on a noninferi
`ority design proving that ABI007 was at least 75 as active as
`standard paclitaxel assuming an ORR 20 greater
`than the ORR
`of standard paclitaxel The design had 80 power with a one
`sided type I error of 0025 twosided a = 050 All statistical
`analyses were performed with SAS Version 82 SAS Institute Inc
`Cary NC The primary efficacy analysis consisted of three nested
`tests which were conducted
`sequentially and contingent on the
`these tests were noninferiority with
`prior tests being successful
`all patients superiority with all patients and superiority with
`receiving study drug as first line therapy Treatment dif
`patients
`ferences in TTP and survival were analyzed
`using the Kaplan
`Meier method QOL which was measured using the European
`Organisation for Research and Treatment of Cancer Quality of
`Life Questionnaire C30 was analyzed as change from baseline at
`each cycle ECOG performance status was analyzed by cycle and as
`the worst score at any time during the study The influence of
`prognostic factors on ORR was assessed using a logistic regression
`model with effects for country treatment group prognostic fac
`tor and treatment group byprognostic
`factor interaction AEs
`and laboratory toxicities were classified and graded according
`to National Cancer Institute Common Toxicity Criteria and
`by maximum grade
`using the Cochran Mantel
`analyzed
`H aenszel test
`
`Patient Population
`From November 2001 to November 2002 460 patients
`were enrolled onto the study and randomly assigned to
`treatment groups All patients were female 97 were white
`and 83 were postmenopausal The study population typ
`ically had more than three metastatic lesions 76 visceral
`lung abdominal or liver disease 79 prior chemo
`therapy 86 and progression after first line therapy for
`disease 59 No important between group
`metastatic
`differences were noted in demographic or other baseline
`Six patients 1 did not
`characteristics Table 1
`
`receive study drug the re
`maining 454 patients ABI007 n = 229 standard pacli
`
`therapy
`
`paclitaxel
`
`Efficacy
`Efficacy analyses were based on the ITT population
`The ORR was significantly greater
`for ABI007 than for
`for all patients 33 v 19 respectively
`standard paclitaxel
`P = 001 patients who received first line therapy 42 v
`27 respectively P = 029 patients who received second
`line or greater therapy 27 v 13 respectively P = 006
`and patients who had received prior anthracycline
`in either the adjuvantmetastatic setting 34 v 18 re
`spectively P = 002 or the metastatic setting only 27 v
`14 respectively P = 010 Table 2 Tumor response rate
`was also significantly higher for ABI007 than for standard
`in patients with visceral dominant lesions 34 v
`19 respectively P = 002 and in patients aged younger
`than 65 years 34 v 19 respectively P < 001 Table 2
`ORR also was greater for ABI007 compared with standard
`dominant
`in patients with nonvisceral
`34 v 19 respectively and in patients
`65 years old
`27 v 19 respectively but the results did not
`reach
`because of the small number of
`
`paclitaxel
`
`lesions
`
`statistical significance
`patients in these subsets
`Maximum responses occurred by cycle 3 in 91 of
`responders in the ABI007 group and in 81 of responders
`in the standard paclitaxel group For ORR no significant
`interaction with treatment effect was observed for the prog
`nostic factors assessed indicating that the treatment effect
`of ABI007 versus standard paclitaxel was consistent be
`tween the strata of these factors
`Median TTP was significantly longer with ABI007
`than with standard paclitaxel for all patients 230 v 169
`weeks respectively hazard ratio HR = 075 P = 006
`log rank test Fig 1 TTP was longer for patients who
`received first line therapy compared with other patients
`240 v 197 weeks respectively although the difference
`was not statistically significant TTP also was signifi
`cantly longer with ABI007 than with standard pacli
`taxel for patients who received study drug as second line
`therapy 209 v 161 weeks
`or greater
`respectively
`HR = 073 P = 020
`
`7796
`
`JOURNAL
`
`OF CLINICAL ONCOLOGY
`
`

`

`ABI007 Versus Paclitaxel
`
`in MBC
`
`Table 1 Demographic
`
`and Other Baseline Characteristics
`
`ABI007 n = 229
`
`Standard Paclitaxel n = 225
`
`No of
`Patients
`
`229
`
`199
`
`30
`
`221
`
`1
`
`3
`
`2
`
`1
`
`1
`
`225
`
`134
`
`81
`
`14
`
`189
`
`40
`
`531
`
`1018
`
`2679
`
`706
`
`1409
`
`42125
`
`100
`
`87
`
`13
`
`97
`<1
`
`1
`
`< 1
`<1
`<1
`
`59
`
`35
`
`6
`
`83
`
`17
`
`533
`
`1005
`
`3083
`
`694
`
`1238
`
`40105
`
`No of
`Patients
`
`225
`
`193
`
`32
`
`218
`
`5
`
`2
`
`0
`
`0
`
`0
`
`223
`
`138
`
`82
`
`5
`
`187
`
`38
`
`100
`
`86
`
`14
`
`97
`
`2
`< 1
`
`0
`
`0
`
`0
`
`61
`
`36
`
`2
`
`83
`
`17
`
`72
`
`Characteristic
`
`Sex female
`Age years
`Mean
`
`SD
`
`Range
`<65
`
`65
`
`Ethnicity
`
`White
`
`Black
`
`Hispanic
`
`South Asian
`
`Asian
`
`Other
`
`Body weight
`kg
`No of patients
`Mean
`
`SD
`
`Range
`ECOG status
`
`1
`
`0
`
`23
`
`Menopausal
`
`status
`
`Postmenopausal
`
`lesions
`
`Premenopausal
`No of
`>3
`23
`
`1
`
`Dominant metastatic organ site
`
`Liver
`
`Lung
`
`Only lymph nodes soft tissue andor breast
`
`Bone
`
`Abdominal
`
`Unknown
`
`Prior metastatic chemotherapy
`regimens
`0 study drug administered as first line therapy
`
`1
`
`2
`
`> 3
`
`Prior therapy
`
`Chemotherapy
`No
`
`Yes
`
`Anthracycline
`No
`
`Yes
`
`therapy
`
`Metastatic
`
`only
`
`180
`
`42
`
`7
`
`92
`
`74
`
`37
`
`13
`
`10
`
`3
`
`97
`
`94
`
`23
`
`15
`
`28
`
`201
`
`53
`
`176
`
`115
`
`79
`
`18
`
`3
`
`40
`
`32
`
`16
`
`6
`
`4
`
`1
`
`42
`
`41
`
`10
`
`7
`
`12
`
`88
`
`23
`
`77
`
`50
`
`163
`
`53
`
`9
`
`97
`
`79
`
`30
`
`13
`
`6
`
`0
`
`89
`
`96
`
`35
`
`5
`
`34
`
`191
`
`50
`
`175
`
`130
`
`24
`
`4
`
`43
`
`35
`
`13
`
`6
`
`3
`
`0
`
`40
`
`43
`
`16
`
`2
`
`15
`
`85
`
`22
`
`78
`
`58
`
`Abbreviations ECOG Eastern Cooperative Oncology Group SD standard deviation
`total 100 because of rounding
`Percentages may not
`
`At the time of these analyses October 2004 the me
`dian censoring time for overall patient survival was 103
`weeks for the ABI007 group and 101 weeks for the standard
`
`paclitaxel group There was a trend for greater median
`survival for all patients treated with ABI007 than with
`standard paclitaxel 650 v 557 weeks respectively
`
`wwwjcoorg
`
`7797
`
`

`

`Gradishar et al
`
`Table 2 Response Rates
`ABI007 260 mgm2
`
`No of
`PatientsTotal
`No of
`
`Patients
`
`76229
`
`4197
`
`35132
`
`60176
`
`31115
`
`59176
`
`95 Cl
`
`2709 to 3929
`
`3244 to 5210
`
`1898 to 3405
`
`2709 to 4109
`1885 to 3507
`
`2655 to 4050
`
`33
`
`42
`
`27
`
`34
`
`27
`
`34
`
`34
`
`Response
`
`Complete and partial
`
`response
`
`All patients
`
`First line therapy
`
`Second line or greater
`
`therapy
`
`Prior anthracycline
`therapy
`Adjuvant andor metastatic
`
`Metastatic
`
`only
`
`Dominant metastatic organ site
`
`Visceral
`
`Patients
`
`42225
`
`2489
`
`18136
`
`32175
`
`18130
`
`34182
`
`Standard Paclitaxel 175 mgm2
`No of
`PatientsTotal
`No of
`
`95 Cl
`
`P
`
`001
`
`029
`
`006
`
`002
`
`010
`
`002
`
`1358 to 2376
`
`1775 to 3619
`
`754 to 1893
`
`1256 to 2401
`791 to 1978
`
`1302 to 2434
`
`19
`
`27
`
`13
`
`18
`
`14
`
`19
`
`19
`
`Nonvisceral
`Age years
`<65
`
`65
`
`1750
`
`68199
`
`830
`
`Abbreviation NS not significant
`
`statistically
`
`2087 to 4713
`
`843
`
`697 to 3024
`
`NS
`
`34
`
`27
`
`2758 to 4076
`
`1084 to 4249
`
`36193
`
`632
`
`19
`
`19
`
`1316 to 2415
`
`523 to 3227
`
`< 001
`NS
`
`dose intensity 49
`group received an average paclitaxel
`greater than that received by patients in the standard pacli
`taxel group treatment compliance was high with 96 of
`receiving 90 of
`in the ABI007 group
`the
`patients
`protocol specified dose Similarly of the patients who re
`ceived standard paclitaxel at 175 mgm2 94 received 90
`the protocol specified dose Furthermore AE related
`infrequent 3 to 7 in both treatment arms with no
`dose reductions and dose delays were
`discontinuations
`
`noted
`
`between
`
`the
`
`of
`
`statistically
`
`significant
`
`differences
`
`P = 374 Fig 2A Although no difference in survival was
`observed in first line patients the difference was statisti
`in patients who received ABI007 com
`cally significant
`as second line or greater
`pared with standard paclitaxel
`therapy 564 v 467 weeks respectively HR = 073
`P = 024 Fig 2B
`
`Safety
`A11454 patients in the ITT population were included in
`the safety analysis Although the patients in the ABI007
`
`a61007 n=229
`224
`
`Paclitaxeln
`P 006
`
`100
`
`075
`
`050
`
`a6
`
`z Sta2
`
`025
`
`°
`
`0
`
`8
`
`16
`
`24
`
`32
`
`40
`
`48
`
`56
`
`64
`
`72
`
`80
`
`88
`
`96 104
`
`112
`
`120
`
`Week
`
`Fig 1 Median time to disease progression
`
`groups Consistent with the safety data no differences in
`QOL were noted between the two treatment groups despite
`the higher dose administered to the ABI007 group Fig 3
`The incidence of hypersensitivity reactions any grade
`was low for both arms < 1 for ABI007 and 2 for
`standard paclitaxel No severe grade 3 or 4 treatment
`the
`related hypersensitivity reactions occurred in any of
`patients in the ABI007 group despite the absence of pre
`medication In contrast grade 3 hypersensitivity reactions
`occurred in the standard paclitaxel group despite standard
`premedication chest pain two patients allergic reaction
`three patients Per protocol corticosteroids and antihista
`mines were not administered routinely to patients in the
`ABI007 group however premedication was administered
`for emesis myalgiaarthralgia or anorexia in 18 patients
`
`8 in the ABI007 group in 2 of the treatment cycles
`whereas 224 patients > 99 in the standard paclitaxel
`group received premedication in 95 of the cycles
`The most frequently reported AEs all grades are pre
`sented in Figure 4A and treatment related grade 3 and 4
`AEs are presented in Figure 4B Despite the higher dose of
`paclitaxel administered to patients in the ABT007 group
`the incidence of
`treatment related grade 4 neutropenia
`
`1198
`
`JOURNAL
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`OF CLINICAL ONCOLOGY
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`

`

`ABI007 Versus Paclitaxel
`
`in MBC
`
`ABI007 n = 229
`Pactitaxel n = 225 B
`p= 374
`
`ABI007 = 131
`Paclitaxel n = 136
`P 024
`
`I CO
`
`A
`
`075
`
`cf
`
`5 050
`
`2
`
`026
`
`8
`
`16
`
`24
`
`32
`
`40 48
`
`56 64 72
`
`80 88 N 104
`
`20 128 136
`
`144
`
`16
`
`24
`
`32
`
`40 48
`
`56
`
`64
`
`72
`
`80 88
`
`96
`
`104
`
`112 120 128 136 144
`
`Week
`
`Week
`
`Fig 2 A Patient survival over time B Patient survival over
`time from first dose of study drug to date of death
`
`indicates
`
`time in patients who received second line or greater
`
`therapy P values from log rank test Survival
`
`laboratory test values was signifi
`based on the central
`cantly lower in the ABI007 group than in the standard
`paclitaxel group 20 of 226 patients 9 v48 of 222 patients
`22 respectively P < 001 with a higher mean neutrophil
`nadir 167 v 131 X 1091L respectively P = 046 suggest
`ing that polyethylated castor oil may have contributed to
`this toxicity in patients who received standard paclitaxel
`
`Final
`
`Evaluation
`
`Follow Up
`
`Fig 3 Quality of life measurements European Organisation
`for Research
`of Cancer Quality of Life Questionnaire C30 for patients
`and Treatment
`receiving ABI007 or standard paclitaxel SD standard deviation
`
`Febrile neutropenia was uncommon < 2 in both study
`arms and no septic deaths occurred Eight patients 3 in
`the ABI007 group and 14 patients 6 in the standard
`
`treatment for neu
`
`paclitaxel group received growth factor
`tropenia or leukopenia during the study
`As expected with a higher dose of paclitaxel treatment
`related grade 3 sensory neuropathy occurred more fre
`quently in the ABI007 arm than in the standard paclitaxel
`
`arm 24 patients 10 v five patients 2 respectively
`P < 001 Fig 4B however these episodes improved with
`in a median 22
`interruption of treatment to grade 2 or 1
`days and were easily managed with treatment interruption
`and dose reduction Fig 5 By day 28 after its first occur
`rence the number of patients with persistent grade 3 sen
`sory neuropathy was the same n = 4 in both study arms
`No episodes of motor neuropathy or grade 4 sensory neu
`ropathywere reported in either group and no differences in
`physician or patient grading of peripheral neuropathy were
`observed between the two groups when these parameters
`were analyzed on the basis of total paclitaxel dose adminis
`tered The only clinical chemistry value that was notably
`different between the two treatment arms was higher serum
`glucose levels in the standard paclitaxeltreated patients
`who also had a higher incidence of hyperglycemia reported
`as an AE compared with ABI007treated patients 15 pa
`
`tients 7 v three patients 1 respectively P = 003
`
`wwwjcoorg
`
`7799
`
`

`

`Gradishar et al
`
`100
`
`A so
`
`o
`
`60
`
`40
`
`20
`
`0
`
`50
`
`40
`
`7 30
`
`20a
`
`10
`
`ii
`
`III
`
`c1
`
`<43
`
`1 A8I007 260 mom2
`175 m0irn2
`
`Paclitaxel
`
`I I
`
`cr
`
`I
`
`V
`
`sts
`
`ABI007 Grade 3
`A6I007 Grade 4
`
`JFaciitaxei Grade 3
`
`EPactItaxel Grade 4
`
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`Ng
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`s
`CP
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`0
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`ri
`IL
`0 A
`0
`
`64
`
`in either
`
`treatment
`
`neutrophil
`
`Fig 4 A Adverse events all grades reported in more than 20 of patients
`count B Treatment
`group ANC absolute
`related grade 3 and 4 adverse events reported in 5 of
`patients in either
`P< 05 CochranMantel
`
`group Data are based on adverse event reporting
`test GGT gamma glutamyl
`Haenszel
`transferase
`
`Subgroup analyses revealed that the safety profiles of
`in patients who received
`ABI007 and standard paclitaxel
`the drugs as first line therapy were similar to those in the
`
`1 00
`
`075 I
`
`0 50
`
`0
`
`25
`
`g
`
`z
`
`2o
`
`Median = 22 days 95 CI 17 to 22
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90
`
`100
`
`Days From Grade 3 to Improvement
`
`to Grade 1 or 2
`
`Fig 5 Time to improvement in ABI007treated
`Censored
`grade 3 peripheral neuropathy
`
`patients who developed
`
`overall study population In subgroup analyses by age the
`reported AEs were similar in patients less than 65 years old
`65 years old in both groups Of the patients
`and patients
`65 years old the incidences of the following AEs were
`notably lower in the ABI007 group than in the standard
`paclitaxel group neutropenia 23 v 59 respectively
`leukopenia 10 v31 respectively nausea 20 v38
`respectively hyperglycemia 0 v 19 respectively and
`flushing 0 v 16 respectively These data indicate no
`Six patients 3 in the ABI007 group and eight pa
`tients 4 in the standard paclitaxel group died during the
`< 1 in the standard paclitaxel group died of multiorgan
`
`study all as a result of disease progression No treatment
`related deaths occurred in the ABI007 group one patient
`
`failure which was considered by the investigator to be pos
`sibly related to treatment but may also have been a result of
`sepsis andor progressive disease
`
`additional safety concerns for ABI007 in patients
`years old compared with younger patients
`
`65
`
`DISCUSSION
`
`In this large international phase III study ABI007 a novel
`130 nanometer albumin bound paclitaxel particle was su
`for both ORR and TTP in all
`perior to standard paclitaxel
`patients with MBC The ABI007 dose used in this study
`50 higher than the dose delivered with solvent based
`
`could be administered safely over 30 minutes
`paclitaxel
`without premedication Paclitaxel particles were well toler
`ated requiring minimal dose modification for AEs and no
`severe hypersensitivity reactions to ABI007 occurred de
`spite the absence of corticosteroid premedication
`The robustness of the efficacy data is underscored by
`finding of greater tumor response to ABI007
`the consistent
`in subgroup analyses The ORR
`than to standard paclitaxel
`of ABI007 was superior
`for all patients patients who
`received study drug as first line therapy patients who re
`ceived study drug as second line or greater therapy patients
`exposure elderly patients and
`with prior anthracycline
`patients with poor prognostic factors including visceral
`tumor involvement Median TTP for all patients was
`in the ABI007 group than in the
`standard paclitaxel group P = 006 Patients receiving
`ABI007 as second line or greater therapy whose clinical
`course would be less affected by subsequent
`therapies
`had significantly prolonged survival with the risk for
`death being reduced by 28
`
`significantly longer
`
`Preclinical models demonstrated increased antitumor
`
`activity and higher intratumor paclitaxel concentrations
`for
`ABI007 compared with equal doses of standard paclitax
`e116 In addition ABI007 was less toxic than standard pac
`of 50 higher
`litaxel permitting the administration
`doses These two factors of higher intratumor paclitaxel
`
`1800
`
`JOURNAL
`
`OF CLINICAL ONCOLOGY
`
`

`

`ABI007 Versus Paclitaxel
`
`in MBC
`
`concentrations and higher dose administered may ex
`plain the increased antitumor activity demonstrated for
`in this ran
`ABI007 compared with standard paclitaxel
`domized study
`The findings of improved efficacy with high doses of
`albumin bound paclitaxel ABI007 in patients with MBC
`to the recently reported failure of high doses
`are in contrast
`of polyethylated castor oilbased paclitaxel standard pac
`to improve outcome in similar patients In a large
`litaxel
`study conducted by the Cancer and Leukemia Group B
`CALGB8 the response rates for first or second line pa
`tients treated with standard paclitaxel
`175 210 or 250
`mgm2 administered as a 3 hour infusion every 3 weeks
`were 23 26 and 21 respectively By contrast
`tumor
`response with ABI007 260 mgm2 was significantly greater
`than that achieved with standard paclitaxel 175 mgm2
`33 v 19 respectively P = 001 Similarly TTP
`which was comparable for standard paclitaxel 175 mgm2
`in both the CALGB trial and the present study 170 and
`161 weeks respectively improved significantly with
`ABI007 P = 03 but not with standard paclitaxel 250
`mgm2 P = 12
`The failure of higher doses of solvent based paclitaxel
`to improve outcome may not reflect on paclitaxel per se but
`rather on the increasing concentrations of the polyethylated
`castor oil vehicle which is known to entrap paclitaxel
`in
`micelles thereby limiting bioavailability and antitumor
`2° Results of the present study indicate that
`activity3617
`such limitations may be overcome by the use of albumin
`bound paclitaxel
`There may also be a fundamental difference between
`ABI007 and standard paclitaxel with respect
`to albumin
`drug transport and binding of
`the
`receptormediated
`albumin drug complex to proteins expressed in tumor
`tissue Albuminbound macromolecules
`can leave the cir
`and accu
`culation through leaky tumor microvasculature
`the enhanced
`mulate in the interstitium because
`of
`
`permeation and retention effects characteristic of neopla
`sia21 In addition albumin is actively transported across
`microvessel
`endothelial
`cells via
`a unique receptor
`mediated transport mechanism using the gp60 receptor22
`Binding of albumin to its gp60 receptor on endothelial cells
`activates caveolin1 which leads to the formation of vesicles
`the albumin drug complex and
`caveolae that transport
`other
`across the endothelial cells
`fluid phase components
`and into the tumor interstitium1022 25 We have
`demonstrated in vitro that polyethylated castor oil
`SPARC secreted protein
`this transport mechanism26
`acidic and rich in cysteine another albumin binding pro
`tein expressed by tumor cells and secreted into the tumor
`interstitium is known to be overexpressed in breast can
`cer27 and has been implicated in tumor progression and
`angiogenesis28 SPARC overexpression may account
`
`for
`
`recently
`
`inhibits
`
`preferential accumulation of the albumin drug complex at
`sites of tumor29
`Despite a 50 increase in the dose of paclitaxel pa
`tients treated with ABI007 experienced significantly less
`neutropenia P < 001 Polyethylated castor oil
`is believed
`to contribute to taxaneassociated myelosuppression by in
`hibiting MDR1 Pglycoprotein in hematopoietic progeni
`low volume of distribution
`of
`tor cells3° Because
`
`its
`
`remains within the vasculature
`
`polyethylated castor oil
`compartment in continuous contact with bone marrow and
`may enhance myelosuppression while having less effect on
`MDR1 in tumor tissues3°
`In the CALGB tria18 the incidence and severity of my
`elosuppression were markedly increased with the higher
`In contrast with ABI007 260
`doses of standard paclitaxel
`mgm2 the incidence of grade 4 neutropenia was markedly
`
`lower than that expected with high dose paclitaxel 9 for
`ABI007 v 53 for standard paclitaxel
`250 mgm2 in the
`CALGB trial ABI007induced neutropenia also was sub
`stantially less frequent and less severe than that reported for
`In one study31 more than 90
`solvent based docetaxe1231
`of patients treated with docetaxel 100 mgm2 experienced
`severe neutropenia clinical consequences included febrile
`neutropenia 12°0 of patients and septic death 15 of
`it seems that ABI007 causes
`patients2 Taken together
`substantially less myelosuppression than the solvent
`based taxanes
`Sensory and motor neuropathy are wellrecognized
`34 The incidence of grade 3
`AEs of solvent based taxanes332
`sensory neuropathy was higher with ABI007 260 mgm2
`than with standard paclitaxel
`spectively However this incidence was substantially lower
`250 mgm2 in
`than that reported with standard paclitaxel
`the CALGB trial 32 grade 3 sensory neuropathy8
`
`175 mgm2 10 v 2 re
`
`castor oil has been shown to cause axonal
`Polyethylated
`degeneration and demyelination that can lead to prolonged
`37 As a
`sometimes irreversible sensory neuropathy3235
`class effect peripheral neuropathy would be expected to
`occur with solvent free paclitaxel however without
`the
`damage induced by polyethylated castor oil neuropathy
`might resolve more rapidly Indeed with ABI007 sensory
`neuropathy improved rapidly median 22 days from grade
`3 to lower grades with treatment interruption
`Other well recognized taxaneassociated AEs eg myal
`gia and arthralgia typically were selflimited treated with
`and resolved without dose modification or
`acetaminophen
`interruption Similar to the experience with ABI007 in phase
`trials1338 nail changes excessive fluid retentio