orip
`
`Phase II Study of Weekly Albumin Bound
`Paclitaxel for Patients with Metastatic Breast
`Cancer Heavily Pretreated with Taxanes
`Joanne L Blum13 Michael A Savin23 Gerald Ede1man23
`John E Pippen13 Nicholas J Robert3 Brian V Geister3
`Robert L Kirby23 Alicia Clawson4 Joyce A OShaughnessy13
`
`Abstract
`Purpose Nanoparticle albumin bound paclitaxel
`a solvent free albumin bound paclitaxel demonstrated
`antitumor activity in patients with taxanenaive metastatic breast cancer MBC We examined albumin bound
`paclitaxel 100 mgm2 or 125 mgm2 administered weekly to determine the antitumor activity
`in patients
`with MBC whose disease progressed despite conventional
`taxane therapy Patients and Methods Women with
`MBC that was previously treated with taxanes were eligible for participation
`Taxane failure was defined as
`metastatic disease progression during taxane therapy or relapse within 12 months of adjuvant
`taxane therapy
`Primary objectives were response rates RRs and the safetytolerability of albumin bound paclitaxel Results
`Women were treated with albumin bound paclitaxel 100 mgm2 n = 106 or 125 mgm2 n = 75 on days
`1 8 and 15 of a 28 day cycle Response rates were 14 and 16 for the 100mgm2 and 125mgm2
`cohorts respectively an additional 12 and 21 of patients respectively had stable disease SD 16 weeks
`times were 3 months at 100 mgm2 and 35 months at 125 mgm2 median
`Median progression free survival
`times were 92 months and 91 months respectively Survival was similar for responding patients and
`those with SD No severe hypersensitivity reactions were reported Patients who developed treatment limiting
`dose of albumin bound paclitaxel after a
`peripheral neuropathy typically could be restarted on a reduced
`in < 5 of patients Conclusion Albumin bound paclitaxel
`12week delay Grade 4 neutropenia occurred
`100 mgm2 given weekly demonstrated the same antitumor activity as albumin bound paclitaxel 125 mgm2
`weekly and a more favorable safety profile in patients with MBC that had progressed with previous
`taxane
`therapy Survival of patients with SD
`16 weeks was similar to that of responders
`
`survival
`
`Clinical Breast Cancer Vol 7 No 11 850856 2007
`Key words Absolute neutrophil count Dose reduction
`Peripheral neuropathy Progressive disease Stable disease
`
`Introduction
`
`albuminbound paclitaxel
`Nanoparticle
`vent free 130nanometer
`
`particle formulation of paclitaxel
`
`is a novel sol
`
`1Baylor Charles A Sammons Cancer Center Dallas
`2Texas Oncology PA Dallas
`3US Oncology Houston
`Texas
`
`Inc Los Angeles CA
`4Abraxis BioScience
`Current affiliation Cancer Care Associates Oklahoma City OK
`
`Submitted Aug 3 2007 Revised Oct 10 2007 Accepted Oct 22 2007
`Joanne L Blum MD PhD Texas Oncology
`Address for correspondence
`PA 3535 Worth St Dallas TX 75246
`Fax 2143701060 email joanneblumusoncologycom
`
`is
`
`Results of animal human xenograft studies of albuminbound
`indicate that the active ingredient paclitaxel
`paclitaxell
`distributed into tumor tissue more rapidly and at higher
`concentrations with this new formulation than with conven
`tional solvent based paclitaxe12 In a phase II clinical study
`albumin bound paclitaxel was tolerated at a higher dose
`300 mgm2 every 3 weeks than that approved for the sol
`vent based formulation 175 mgm2 every 3 weeks and was
`tolerated3 In addition the infusion time is shorter
`well
`for
`albumin bound paclitaxel
`than for solvent based paclitaxel
`30 minutes vs 3 hours and the nab formulation can be
`given without steroid or antihistamine premedication
`spe
`infusion sets or in line filters
`
`cial
`
`forwarding or copying is a violation of US and International Copyright Laws
`Electronic
`Authorization to photocopy items for internal or personal use or the internal or personal use of specific clients is granted by CIG Media Group LP
`ISSN 15268209 provided the appropriate fee is paid directly to Copyright Clearance Center 222 Rosewood Drive Danvers MA 01923 USA 9787508400
`
`850
`
`Clinical Breast Cancer December 2007
`
`Abraxis EX2016
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`

`

`naive metastatic
`
`breast
`
`response
`
`rate
`
`In a phase III study albuminbound paclitaxel was com
`pared with solvent based paclitaxel
`in patients with taxane
`cancer MBC4 Albumin bound
`paclitaxel demonstrated a significantly higher
`RR 33 vs 19 P = 001 and significantly
`time
`longer
`to tumor progression 23 weeks vs 169 weeks hazard ratio
`075 P = 006 than the solvent based formulation
`of solvent based paclitaxel have
`schedules
`been
`Weekly
`compared with every 3week schedules in patients with breast
`in 2 phase III studies56 Weekly paclitaxel demonstrat
`cancer
`ed greater antitumor activity than the every 3week regimen
`but was associated with increased rates of neurotoxicity
`The current study was designed to explore albuminbound
`whether albumin bound paclitaxel 100 mgm2 or 125 mgm2
`administered weekly for 3 weeks followed by 1 week of rest
`has antitumor activity in patients with MBC that had pro
`gressed with conventional
`taxane therapy
`
`Patients and Methods
`The protocol was approved by the US Oncology
`Review Board and the study was conducted
`in compliance
`with Good Clinical Practice guidelines of the International
`on Harmonization Each patient provided written
`Conference
`informed consent before the study drug was administered
`
`Institutional
`
`Patients
`Women
`
`18 years had histologically or cytologically
`aged
`confirmed breast cancer with evidence of recurrence or metas
`tasis that was measurable according
`to Response Evaluation
`Criteria in Solid Tumors RECIST7 Patients must have devel
`oped progressive disease PD while receiving a taxane for their
`metastatic disease or relapsed within 12 months of taxanecon
`therapy Patients with HER2positive MBC
`taining adjuvant
`must have been treated previously with trastuzumab Patients
`had to have adequate hematologic hepatic and renal function
`and expected survival of > 12 weeks
`they had
`Patients were excluded from participation if
`serious con
`evidence
`of active brain metastases
`current illness a Southwest Oncology Group performance
`score of > 2 or peripheral neuropathy of grade > 1 based on
`National Cancer Institute Common Toxicity Criteria NCI
`CTC Version 20 No restriction was placed on enrollment
`based on the number of previous chemotherapy regimens
`
`clinical
`
`125 mgm2 weekly on days 1 8 and
`of patients to receive
`15 followed by 1 week of rest Separate analyses were con
`ducted for each cohort
`to determine whether
`the higher dose
`was associated with greater antitumor activity
`
`Treatment
`Patients received albumin bound paclitaxel 100 mgm2 or
`125 mgm2 IN over 30 minutes without steroid or antihista
`mine premedication recombinant human granulocyte colony
`
`stimulating factor support specialized infusion sets or in line
`filters Doses were administered on days 1 8 and 15 and fol
`lowed by 1 week of rest every 28 days 4 week cycle Patients
`continued on treatment until disease progression or unac
`
`required dose
`ceptable toxicity occurred If an adverse event
`interruption albumin bound paclitaxel dosing was reinitiated
`
`the patients absolute
`
`1500 cellsµL platelet count was
`
`at the start of a treatment cycle only if
`neutrophil count ANC was
`100000 cellsµL or any other toxicity had resolved to grade
`1 For each subsequent albumin bound paclitaxel dose within a
`treatment cycle days 8 and 15 patients had to have an ANC
`1000 cellsA and a platelet count
`75000 cellspct
`Up to 2 dose reductions were permitted for patients who
`sepsis grade 34 thrombocytopenia
`had febrile neutropenia
`neurotoxicity or any other grade 34 nonhematologic
`toxic
`ity Dose reductions were from 100 mgm2 to 80 mgm2 to
`60 mgm2 or from 125 mgm2 to 100 mgm2 to 75 mgm2
`
`target
`
`Assessments
`Tumor lesions were measured using RECIST at baseline
`and at
`the end of every other
`treatment cycle7 Response
`analyses were based on investigator evaluation of radiologi
`cally and clinically detected
`lesions and were catego
`rized according to RECIST Responses
`to treatment were
`4 weeks after the initial documen
`confirmed by restaging
`tation of response An early stopping rule was incorporated
`into the study design which mandated that
`the study be
`stopped if no objective responses were observed in the first 30
`patients thereby ruling out at the P = 05 level that the RR
`to albuminbound paclitaxel
`in this patient population was
`10 Stable disease SD was evaluated after a minimum
`16 weeks
`of 4 cycles ie at
`
`Adverse events were coded using the Medical Dictionary
`for Regulatory Activities and then mapped to appropriate
`NCI CTC terms
`
`II study was designed to evalu
`
`Study Design
`This open label phase
`ate the antitumor activity overall RR ORM safety and
`tolerability of weekly albumin bound paclitaxel
`in patients
`with MBC that had previously been treated with taxanes
`objectives were to evaluate progression free sur
`
`Secondary
`
`vival PFS and overall survival OS
`Initially patients were planned to receive albuminbound
`IV over 30 minutes
`paclitaxel 100 mgm2 intravenously
`on days 1 8 and 15 followed by 1 week of rest Because
`minimal toxicity was observed with this dose and schedule
`the protocol was amended to include an additional
`
`cohort
`
`endpoint was
`
`Statistical Methods
`The primary efficacy
`the percentage
`patients who achieved
`a confirmed objective complete or
`partial response PR ie ORR Secondary
`efficacy endpoints
`of patients who achieved SD after
`were the percentage
`weeks PFS and OS Disease control
`rate was defined as the
`a complete or PR plus
`of patients who achieved
`percentage
`those who had SD for
`16 weeks Safety and tolerability
`
`of
`
`16
`
`endpoints were the incidences of adverse events hematologic
`nadir and the percentages of patients who discontinued study
`
`treatment or had their doses reduced or treatment delayed
`
`Clinical Breast Cancer December 2007
`
`851
`
`

`

`Albumin Bound Paclitaxel
`
`for TaxanePretreated MBC
`
`Table IA Patient Demographics and Other Baseline
`Characteristics N = 181
`
`Table IB Patient Demographics and Other Baseline
`Characteristics N = 181
`
`Albumin Bound Paclitaxel
`
`100 mgm2
`n = 106
`
`125 mgm2
`n = 75
`
`106
`
`75
`
`53 3476
`8681
`
`53 3374
`56 75
`
`2019
`
`19 25
`
`90 85
`7 7
`4 4
`3 3
`2 2
`
`105
`
`48 46
`
`5149
`5 5
`1 <1
`
`58 77
`6 8
`11 15
`
`75
`
`34 45
`
`32 43
`
`9 12
`
`0
`
`Characteristic
`
`Previous Taxane Therapy on a
`Weekly Schedule for Metastatic
`Disease
`
`Number of patients
`
`Paclitaxel
`
`Docetaxel
`
`Paclitaxeldocetaxel
`
`Previous Adjuvant
`
`Chemotherapy
`
`Any
`
`Anthracyclinecontaining
`
`Taxa necontaining
`
`Patients with Metastatic Breast
`Cancer
`that Progressed with
`Previous Taxane Therapy
`
`Tumor progression while on
`taxane
`therapy for metastatic
`
`disease
`
`Paclitaxel
`
`Albumin Bound Paclitaxel
`
`100 mgm2
`n = 106
`
`125 mgm2
`n = 75
`
`58
`
`23 40
`
`20 34
`
`1526
`
`85 80
`
`80 75
`
`3129
`
`41
`
`1844
`
`1537
`
`8 20
`
`59 79
`
`42 56
`
`20 27
`
`93 88
`
`67 89
`
`20 27
`
`Characteristic
`
`No of Patients
`
`Median Age Years Range
`<65
`
`> 65
`
`Ethnicity
`
`White
`
`Black
`
`HispanicLatino
`
`Asian
`
`Unknown
`
`SWOG Performance Score
`
`Number of patients
`
`0
`
`1 2 3
`
`30 28
`
`34 32
`29 27
`
`1312
`
`28 37
`1925
`
`811
`
`3 07
`
`3114
`
`59 56
`
`4341
`1 < 1
`33
`
`49 65
`
`2635
`
`0
`
`0
`
`Docetaxel
`
`Paclitaxeldocetaxel
`
`sequential
`
`Relapse within 12 months of
`adjuvant taxane therapy
`
`Median Number of Previous
`Chemotherapy Regimens for
`Metastatic Disease Range
`
`Preexisting Peripheral
`Neuropathy by Grade
`
`0
`
`1 2 U
`
`nknown
`
`Patients
`
`can appear
`
`in > 1 dosing regimen category
`
`Results
`
`Between May 31 2002 and December 29 2003 181
`patients were enrolled at 43 sites in the United States
`Table 1 106 patients
`received albumin bound paclit
`axel 100 mgm2 under
`the original protocol 75 additional
`the protocol amendment and
`patients were enrolled under
`received albuminbound paclitaxel 125 mgm2
`
`Efficacy
`The early stopping rule was not activated
`because
`responses to albumin bound paclitaxel occurred in some of
`the 30 initial patients Thus the stopping rule had no effect
`on the conduct
`of the study
`Complete or PRs were reported for 15 patients 14 in the
`100 mgm2 cohort and 12 patients 16 in the 125mgm2
`
`99 93
`7 7
`
`1 <1
`2 2
`34 32
`
`69 65
`
`105
`
`99 94
`6 6
`23 22
`
`6158
`
`73 69
`5 5
`3129
`
`7195
`4 5
`
`0
`
`4 5
`19 25
`
`52 69
`
`75
`
`67 89
`811
`26 35
`
`4155
`
`43 57
`811
`19 25
`
`Menopause Status
`
`Postmenopausal
`
`Premenopausal
`
`Total Number of
`Metastatic Organ Sites
`
`0
`
`1 2
`
`3
`
`>3
`
`Dominant Lesion Site
`
`Number of patients
`
`Visceral
`
`Nonvisceral
`
`Previous Trastuzumab Therapy
`
`Previous Taxane
`by Schedule
`
`Therapy
`
`Weekly
`
`Every 3 weeks
`
`Some other schedule
`
`Multiple schedules
`
`Baseline
`
`evaluation was
`
`not available for
`
`1 patient who was
`
`considered a
`
`non responder
`Abbreviation SWOG = Southwest Oncology Group
`
`The following were presented for each dose cohort for the
`primary efficacy analysis sample size number and percent
`age of patients with a confirmed complete or PR and 95
`interval for the RR All patients who
`binomial confidence
`1 dose of albumin bound paclitaxel were included
`received
`in the response and toxicity analyses
`
`852
`
`Clinical Breast Cancer December 2007
`
`

`

`Joanne L Blum et al
`
`Table 2 Overall Response and Disease Control Rates N = 181
`
`Number of Patients
`95 Cl
`P Value
`
`Response
`
`Complete response
`
`Partial
`
`response
`
`Stable disease
`
`16 weeks
`
`Number of Patients by Previous Taxane Therapy for
`Metastatic Disease
`
`By drug
`
`Paclitaxel
`
`Docetaxel
`
`Paclitaxeldocetaxel
`
`By schedule any taxanet
`
`Weekly
`
`Every 3 weeks
`
`Number of Patients by Previous Weekly Taxane Therapy for
`Metastatic Disease
`
`Paclitaxel
`
`Docetaxel
`
`Paclitaxeldocetaxel
`
`Albumin Bound Paclitaxel
`
`Overall Response Rate
`
`Disease Control Rate
`
`100 mgm2
`n = 106
`
`15 of 106 14
`7522079
`
`125 mgm2
`n = 75
`
`12 of 75 16
`77243
`
`100 mgm2
`n = 106
`
`28 of 106 26
`18023481
`
`125 mgm2
`n = 75
`
`28 of 75 37
`
`26394828
`
`7309
`
`1175
`
`0
`
`15 of 106 14
`
`1 of 75 1
`11 of 75 15
`
`0
`
`15 of 106 14
`
`1 of 75 1
`11 of 75 15
`
`13 of 106 12
`
`16 of 75 21
`
`4 of 30 13
`
`7 of 34 21
`2 of 29 7
`
`4 of 20 20
`
`6 of 28 21
`
`0
`
`9 of 30 30
`
`9 of 20 45
`
`11 of 34 32
`
`13 of 28 46
`
`6 of 29 21
`
`4 of 19 21
`
`7 of 58 12
`
`6 of 48 13
`
`7 of 41 17
`
`4 of 29 14
`
`14 of 58 24
`
`13 of 48 27
`
`16 of 41 39
`
`9 of 29 31
`
`0
`
`6 of 20 30
`1 of 15 7
`
`3 of 18 17
`4 of 15 27
`
`0
`
`3 of 23 13
`8 of 20 40
`
`3 of 15 20
`
`6 of 18 33
`7 of 15 47
`
`3 of 8 38
`
`rate is the completePRs plus SD
`16 weeks
`Disease control
`tFive additional patients in the 125mgm2 cohort received
`
`taxanes as adjuvant therapy
`
`an additional
`
`16 weeks was observed in
`
`cohort Table 2 Stable disease for
`13 patients 12 in the 100mgm2 cohort and
`16 patients 21 in the 125mgm2 cohort Median PFS was 3
`months for 100 mgm2 and 35 months for 125 mgm2 Median
`OS was 92 months and 91 months respectively Overall sur
`vival was similar for patients with confirmed responses and
`16 weeks P = 7106 logrank
`for nonresponders with SD
`Figure 1 Based on Kaplan Meier curves for patient survival
`the probability of surviving 1 year was 39 and 32 for the
`100mgm2 and 125mgm2 cohorts respectively No statistical
`ly significant differences in ORR disease control rate or PFS
`were observed between the 100mgm2 and 125mgm2 cohorts
`or between patients who achieved
`response and
`an objective
`16 weeks Table 2 Figure 1
`Four patients 4 in the 100mgm2 cohort and 7 patients
`nonresponders who had SD
`9 in the 125 mgm2 cohort had SD for
`
`24 weeks
`Of the patients who received previous taxane therapy on
`a weekly schedule the percentage of objective responders
`was greater at both dose levels for those who had received
`alone 30 with albumin bound paclitaxel
`docetaxel
`100 mgm2 27 with 125 mgm2 than for those who had
`received paclitaxel alone 0 for 100 mgm2 17 for 125 mgm2
`
`Table 2 No significant differences in objective response or
`rates according to hormone receptor status
`or site of metastatic disease were seen with albuminbound
`
`disease control
`
`paclitaxel
`
`treatment Table 3
`
`cohort
`
`in the
`
`Safety
`Treatment was well tolerated 87 of patients
`100mgm2 cohort and 68 of patients in the 125mgm2
`received albuminbound
`the protocol
`paclitaxel at
`the study Patients received a mean
`specified dose throughout
`of 53 and 47 cycles of albuminbound paclitaxel
`treatment
`in the 100mgm2 and 125mgm2 dose groups respectively
`a mean of 152 doses in the 100mgm2
`Patients received
`cohort and 131 doses in the 125mgm2 cohort median cumu
`lative doses were 9005 mgm2 and 1125 mgm2 respectively
`The median delivered dose intensity was 98 mgm2 range 36
`103 mgm2 per week in the 100mgm2 cohort and 114 mgm2
`range 77131 mgm2 per week in the 125mgm2 cohort
`Treatment related adverse
`events all grades resulted in
`
`of therapy for 6 patients 6 in the 100
`mgm2 cohort and 7 patients 9 in the 125 mgm2 cohort
`
`discontinuation
`
`primarily for sensory neuropathy dose reductions for 13
`
`Clinical Breast Cancer December 2007
`
`853
`
`

`

`Albumin Bound Paclitaxel
`
`for TaxanePretreated MBC
`
`cohorts Table 4 Grade 4 febrile neutropenia occurred in 1
`< 1 in the 100mgm2 cohort
`
`in either
`
`9 patients 8 developed treat
`
`loss
`
`patient
`No treatment related grade 4 nonhematologic
`adverse
`in either group No
`events were reported for > 1 patient
`reactions were observed
`severe hypersensitivity
`group despite the absence of steroid premedication
`In the 100mgm2 cohort
`ment related grade
`3 sensory neuropathy ie sensory
`or paresthesia interfering with activities of daily living 3 of
`whom had preexisting grade
`onset occurred
`1 neuropathy
`after a median of 5 treatment cycles range 123 cycles In the
`14 patients 19 developed grade 3 sen
`125mgm2 cohort
`sory neuropathy 3 of whom had preexisting grade 1 peripheral
`onset occurred after a median of 3 cycles range
`neuropathy
`26 cycles Of the 23 patients with grade 3 sensory neuropathy
`both cohorts combined 15 patients restarted albumin bound
`treatment at a reduced dosage 4 patients continued
`
`paclitaxel
`
`treatment
`
`on schedule with no treatment modification
`
`3
`
`patients discontinued treatment and 1 patient discontinued
`treatment because of PD at the time grade 3 sensory neuropa
`thy occurred Patients who continued treatment were able to
`resume dosing typically in 12 weeks
`Treatment related alopecia was reported in both groups In
`16 patients 15 had grade 1 mild
`the 100mgm2 cohort
`alopecia and 37 patients 35 had grade 2 pronounced alo
`pecia in the 125mgm2 cohort 3 patients 4 and 36 patients
`48 reported grade 12 alopecia respectively However many
`of the patients in this heavily pretreated study population 31
`in the 100mgm2 cohort 41 in the 125mgm2 cohort had
`the toxicity profile
`alopecia at time of enrollment In general
`65 years was similar to that for patients
`aged < 65 years in both cohorts Figure 2
`
`for patients aged
`
`Figure 1
`
`Survival Curves for the 100mgm2 and 125mgm2
`Cohorts Combined N = 181
`
`Confirmed Responders
`Stable Disease
`16 weeks
`
`Nonresponders
`
`100
`
`751
`
`501
`
`251
`
`fSurvival
`
`Probabilityo
`
`P= 7106
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`27
`
`30
`
`Months
`
`responders n = 27 patients with SD
`Confirmed
`16 weeks
`confirmed responders n = 29 and nonresponders n = 125 Survival was
`similar for patients with confirmed responses and nonresponders with SD
`16
`weeks P = 7106 log rank
`
`excluding
`
`patients 12 and 24 patients 32 in the 100mgm2
`and 125mgm2 cohorts respectively primarily for sensory
`neuropathy and dose delays for 19 patients 18 and 32
`patients 43 in the 100mgm2 and 125mgm2 cohorts
`
`respectively primarily for neutropenia
`
`Despite the high degree of pretreatment grade 4 neutro
`
`penia and leukopenia occurred in < 5 of patients in both
`
`Table 3
`
`Response Rates by Hormone Receptor Status and Site of Metastatic Disease N = 181
`
`Number of Patients by Hormone Receptor Status
`ER PgR+
`ER
`PgRHER2+
`ER PgR
`HER2Number
`of Patients by Site of Metastatic Disease
`
`Bone
`
`Lungs
`
`Liver
`
`Lymph nodes
`
`Abdoment
`
`Skin
`
`Albumin Bound Paclitaxel
`
`Overall Response Rate
`
`Disease Co ntrol Rate
`
`100 mgm2
`n = 106
`
`125 mgm2
`n = 75
`
`100 mgm2
`n = 106
`
`125 mgm2
`n = 75
`
`5 of 39 13
`1 of 13 8
`4 of 35 11
`
`3 of 21 14
`
`10 of 44 23
`
`8 of 7511
`
`7 of 66 11
`
`4 of 22 18
`
`4 of 14 24
`
`0
`
`5 of 31 16
`
`2 of 11 18
`
`6 of 37 16
`1 of 714
`
`4 of 31 13
`4 of 46 9
`5 of 48 10
`
`3 of 1323
`
`2 of 1414
`
`3 of 1030
`
`11 of 39 28
`1 of 138
`10 of 35 29
`
`5 of 21 24
`
`17 of 44 39
`
`16 of 7521
`
`13 of 66 20
`
`5 of 22 23
`
`5 of 1436
`
`3 of 1030
`
`15 of 31 48
`
`3 of 11 27
`
`14 of 3738
`
`1 of 7 14
`
`11 of 31 35
`
`14 of 46 30
`
`16 of 48 33
`
`6 of 1346
`
`5 of 1436
`
`5 of 1050
`
`Disease control
`
`16 weeks
`
`rate is completePRs plus SD
`tPeritoneal carcinomatosis
`ER = estrogen receptor
`
`Abbreviations
`
`PgR = progesterone receptor
`
`854
`
`Clinical Breast Cancer December 2007
`
`

`

`Joanne L Blum et al
`
`Table 4
`
`Treatment Related ToxicitiesAdverse Events by Grade N = 181
`Albumin Bound Paclitaxel
`
`Adverse Event
`
`100 mgm2 n = 106
`
`125 mgm2 n = 7
`
`5
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Grade 2
`
`Grade 3
`
`Grade 4
`
`Hematologict
`
`Leukopenia
`
`Neutropenia
`
`Non hematologic
`
`Fatigue
`
`Sensory neuropathy
`
`Nausea
`
`Diarrhea
`
`Vomiting
`
`Alopecia
`
`46 45
`
`3231
`
`34 32
`
`18 17
`
`11 10
`8 8
`77
`37 35
`
`2 3
`2 3
`
`1919
`
`1414
`
`5 5
`9 8
`4 4
`1 <1
`3 3
`
`1 <1
`4 4
`
`0
`
`2130
`
`2130
`
`25 33
`
`24 32
`
`11 15
`
`9 12
`811
`36 48
`
`23 33
`
`2231
`
`9 12
`
`1419
`2 3
`4 5
`1 1
`
`If a patient reported the same toxicity more than once that patient was counted only once
`to National Cancer Institute Common Toxicity Criteria version 20
`According
`tBased on laboratory values 100 mgm2 n = 102 125 mgm2 n = 70
`Based on adverse
`
`event
`
`reports
`
`for that toxicity using the highest grade
`
`Figure 2A
`
`Treatment Related Toxicities
`
`by Age
`
`Figure 2B
`
`Treatment Related Toxicities
`
`by Age
`
`80
`
`60
`
`0
`
`201
`
`<65 Years n =86
`65 Years n = 20
`
`IT
`
`Fatigue
`
`Nausea
`
`Sensory
`
`Vomiting
`
`Diarrhea
`
`Neuropathy
`
`Grade 34
`Neutropenia
`
`80
`
`60
`
`2 40
`0
`
`20
`
`0
`
`<65 Years n = 56
`65 Years n = 19
`
`111011
`11111
`111111EN
`1111111111
`111111111111
`IL1LJLILJLJLJ
`
`Fa
`
`fig ue
`
`Na use
`
`Sensory
`
`Vomiting
`
`Diarrhea
`
`Neuropathy
`
`Grade 34
`NeJtropenia
`
`Albumin bound paclitaxel 100 mgm2 n = 106
`
`Albumin bound paclitaxel 125 mgm2 n = 75
`
`Discussion
`Results of the present study demonstrate that weekly albu
`minbound paclitaxel resulted in an objective response or SD for
`16 weeks in 31 of patients with MBC that had been previ
`ously treated with taxanes Women with SD maintained at 16
`to those who achieved an objec
`weeks had survival equivalent
`tive response P = 71 and therefore likely derived benefit
`the OS in the
`from albumin bound paclitaxel We evaluated
`patients with SD because it has been previously demonstrated
`that among patients with heavily capecitabinepretreated
`MBC survival rates are similar between responders and those
`patients who had SD that was a median of 4 months in dura
`tion8 Although the antitumor activity of weekly albumin
`
`bound paclitaxel at 100 mgm2 in patients who had received
`weekly paclitaxel was limited a substantial number of women
`up to 35 had benefit after progressing on weekly docetaxel
`and a few patients even had benefit after progressing despite
`weekly paclitaxel and weekly docetaxel as shown in Table 2
`Therefore albuminbound paclitaxel does not demonstrate
`cross resistance with solvent based paclitaxel and docetaxel
`even in heavily pretreated patients
`Treatment with weekly albumin bound paclitaxel had
`a favorable safety profile with an anticipated dose related
`The most
`increase in peripheral
`neuropathy
`events
`reported treatment related adverse
`in this study
`fatigue nausea and alopecia were
`
`sensory neuropathy
`
`frequently
`
`Clinical Breast Cancer December 2007
`
`855
`
`

`

`Albumin Bound Paclitaxel
`
`for TaxanePretreated MBC
`
`generally mild and readily managed Febrile neutropenia
`nail changes and fluid retention were uncommon
`and no
`reactions occurred In contrast
`to another
`hypersensitivity
`
`study which demonstrated a 23 incidence of grade 3 sen
`sory neuropathy with solvent based paclitaxel at 80 mgm2
`weekly the incidence rate in the present study using a
`higher dose 100 mgm2 weekly was only 8 in patients
`
`with taxanepretreated
`The
`use of albumin as the vehicle in albuminbound
`
`disease5
`
`castor oil
`
`the vehicle
`
`instead of polyoxyethylated
`paclitaxel
`in solvent based paclitaxel avoids
`the solvent associated
`the paclitaxel dose that can be adminis
`toxicities that limit
`tered safely In a randomized phase III study albuminbound
`paclitaxel was given at a paclitaxel
`dose approximately
`49 higher
`than solvent based paclitaxel and did not cause
`toxicity4 Consistent with these
`findings the
`significant
`maximum tolerated doses of albumin bound paclitaxel were
`100 mgm2 and 150 mgm2 administered weekly for 3 weeks
`followed by a week off treatment for heavily and minimally
`
`pretreated patients respectively9
`The decision
`to include an additional cohort of patients at
`a higher dosage ie 125 mgm2was based on the observation
`of minimal toxicity at the 100 mgm2 dose coupled with the
`principle that administration of a higher dosage should be
`
`explored safely in the interest of possible added antitumor
`
`activity In this interest a posthoc comparison of these cohorts
`in terms of response PFS and survival was warranted and
`between these
`differences were observed
`no meaningful
`cohorts in terms of demographics or other baseline character
`istics However an inherent
`limitation in this analysis stems
`from the lack of a prospective randomized design
`The ORRs
`for patients with disease heavily pretreated
`with albumin bound paclitaxel at 100 mgm2 and 125 mgm2
`weekly in this study were 14 and 16 respectively showing
`dose response relationship with weekly albumin
`no obvious
`bound paclitaxel
`in taxanepretreated disease These rates are
`comparable with the reported RRs for weekly paclitaxel
`in
`patients who received previous treatment with paclitaxel every
`3 weeks 16 7 of 45 patients10 and for docetaxel given every
`3 weeks 18 8 of 44 patients11 to patients with MBC that
`was resistant to paclitaxel However in patients with MBC that
`solvent based
`through previous taxane
`progressed
`therapy
`paclitaxel administered at 80 mgm2 was associated with a
`15 incidence of grade 34 neutropenia grade 3 10 grade 4
`510 and docetaxel administered at 100 mgm2 caused febrile
`neutropenia in 24 of patients11 The finding of a higher RR
`of albumin bound paclitaxel
`in patients whose disease was
`pretreated with docetaxel
`compared with those whose disease
`was pretreated with paclitaxel could be based in the differing
`mechanisms of actions between these 2 taxanes
`A recent phase II study compared albuminbound paclit
`axel 300 mgm2 administered every 3 weeks albuminbound
`paclitaxel 100 mgm2 and 150 mgm2 administered weekly and
`100 mgm2 administered every 3 weeks
`solvent based docetaxel
`as first line therapy in patients with MBC12 Weekly albumin
`
`856
`
`Clinical Breast Cancer December 2007
`
`bound paclitaxel demonstrated greater antitumor activity than
`docetaxel or albuminbound paclitaxel administered every 3
`weeks with no dose response relationship
`
`Conclusion
`In conclusion weekly administration of albumin bound
`paclitaxel 100 mgm2 has approximately the same antitumor
`activity as 125 mgm2 and a better safety profile in women
`with MBC that had progressed on previous taxane therapy In
`addition albumin bound paclitaxel 100 mgm2 weekly is well
`tolerated in pretreated patients with no hypersensitivity reac
`
`tions minimal myelosuppression and a low rate of treatment
`for peripheral neuropathy Weekly albumin bound
`cessation
`paclitaxel 100 mgm2 is a well tolerated regimen for women
`with MBC previously treated with taxanes In this setting
`obtaining prolonged SD for
`16 weeks appeared to provide the
`same clinical benefit as exhibiting an objective response This
`observation warrants further evaluation in larger trials
`
`Acknowledgements
`The authors acknowledge
`Sharyn Carrasco who served
`for this study and Susan A Thomas
`as the project manager
`ELS for writing assistance This study was sponsored by
`Abraxis BioScience Inc Los Angeles CA
`
`References
`1 Desai N Trieu V Yao Z et al Increased antitumor activity intra
`tumor paclitaxel concentrations
`and endothelial cell
`transport of
`albumin bound paclitaxel ABI007 compared with
`Cremophorfree
`Cremophorbased paclitaxel Clin Cancer Res 2006 12131724
`2 Taxol paclitaxel Injection prescribing information Princeton NJ
`BristolMyers Squibb 2003
`3 Ibrahim NK Samuels B Page R et al Multicenter phase II
`trial of
`ABI007 an albumin bound paclitaxel
`in women with metastatic
`breast cancer J Clin Oncol 2005 23601926
`4 Gradishar WJ Tjulandin S Davidson N et al Phase III
`of
`trial
`nanoparticle albumin bound paclitaxel compared with polyethylated
`in women with breast cancer J Clin
`castor oilbased paclitaxel
`Oncol 2005 237794803
`5 Seidman AD Berry D Cirrincione C et al CALGB 9840 phase III
`study of weekly W paclitaxel P via 1 hour h infusion versus stan
`dard S 3h infusion every third week in the treatment of metastatic
`breast cancer MBC with trastuzumab T for HER2 positive MBC
`and randomized for Tin HER2 normal MBC Proc Am Soc Clin Oncol
`2004 2214 suppl6s Abstract 512
`6 Green MC Buzdar AU Smith T et al Weekly paclitaxel
`improves patho
`logic complete remission in operable breast cancer when compared with
`once every 3 weeks J Clin Oncol 2005 23598392
`1 Arbuck SG Eisenhauer EA et al New guidelines to
`7 Therasse
`in solid tumors J Nati Cancer
`the response to treatment
`evaluate
`Inst 2000 9220516
`8 Blum JL Jones SE Buzdar AU et al Multicenter phase II study of
`in paclitaxelrefractory metastatic breast cancer J Clin
`capecitabine
`Oncol 1999 1748593
`9 Nyman DW Campbell KJ Hersh E et al Phase I and pharmaco
`kinetics trial of ABI007 a novel nanoparticle formulation of pacli
`in patients with advanced nonhematologic malignancies J Clin
`taxel
`Oncol 2005 23778593
`10 Perez EA Vogel CL Irwin DH et al Multicenter
`trial of
`phase II
`in women with metastatic breast cancer J Clin
`weekly paclitaxel
`Oncol 2001 19421623
`11 Valero V Jones SE Von Hoff DD et al A phase II study of docetaxel
`in patients with paclitaxelresistant metastatic breast cancer J Clin
`Oncol 1998 1633628
`12 Gradishar W Krasnojon D Cheporov
`S et al A randomized
`phase 2 trial of qw or q3w ABI007 ABX vs q3w solvent based
`docetaxel TXT as first
`line therapy in metastatic breast cancer
`MBC Presented at the 29th Annual San Antonio Breast Cancer
`Symposium December 17 2006 San Antonio TX Abstract 46
`
`paclitaxel
`
`