British Journal of Cancer 2008 98 16081613
`0 2008 Cancer Research UK
`$3000
`rights reserved 0007092008
`
`All
`
`wwwbjcancercom
`
`Phase III
`
`trial comparing paclitaxel poliglumex vs docetaxel
`second line treatment of non smallcell
`lung cancer
`
`in the
`
`I
`
`L Paz Ares H Ross2 M OBrien3 A Riviere4 U Gatzemeiers J Von Pawel6 E KaukeI7 L Freitags W DigeI9
`H Bischoff R GarciaCampelol I N lannottiI2 P ReitererI3 I Boyer J Prendivillels AJ Eisenfeld
`FB Oldham B Bandstra JW Singer and P Bonomi7
`Hospital Universitario 2 de Octubre Servicio de Oncologid Medica Madrid 28041 Spain 2Earle A Chiles Research Institute Portland OR 97213 USA
`3Royal Marsden Hospital London 5W3 611 UK 4Centre Francois Baciesse Centre de Lutte Contre le Cancer de Caen Caen 14076 France
`Munchen Gauting Gauting 82131 Germany 7Allgemeines
`5Krankenhaus Grosshansdorf Grosshansdorf 22927 Germany 6AsklepiosFachkliniken
`Krankenhaus Harburg Hamburg 21075 Germany 8Lungenklinik Hemer Hemer 58675 Germany 9Universitatsklinikum
`Freiburg Freiburg 79106
`Thoraxklinik Heidelberg GmbH Heidelberg
`69126 Germany
`Germany °Department of Radiology
`Juan Canalejo University Hospital Servicio de
`1 2HemOnc Associates of The Treasure Coast Port St Lucie FL 34952 USA I3Masarykova
`Oncologla Medico La Corutra 15006 Spain
`Nemocnice
`UstInad Labem 4013 Czech Republic
`I4Hospital San Llatzer Palma de Mallorca 07198 Spain I5Guys Hospital Medical Oncology and Breast Unit
`London SE 9RT UK 6Cell Therapeutics
`Inc Seattle WA 981 19 USA I 7Rush University Medical Center 1725 West Harrison Street Chicago
`IL 60612 USA
`
`disease Median
`
`different
`
`results but had
`
`Paclitaxel poliglumex PPX a macromolecule drug conjugate linking paclitaxel
`acid reduces systemic exposure to
`to polyglutamic
`of free paclitaxel Patients with non smallcell lung cancer NSCLC who had received one prior platinum based
`peak concentrations
`175 or 210 mg m2 PPX or 75 mg m2 docetaxel The study enrolled
`treated NSCLC
`849 previously
`received
`chemotherapy
`arms hazard ratio = 109 P = 0257 I year survival
`survival 69 months in both
`patients with advanced
`PPX = 25 docetaxel = 29 P = 0134 and time to progression PPX = 2 months docetaxel =26 months P = 0075 were
`similar between treatment arms Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia P <0001 and
`febrile neutropenia P = 0006 Grade 3 or 4 neuropathy P <0001 was more common in the PPX arm Patients receiving PPX had
`in the PPX arm
`receive routine premedications More patients discontinued
`due to adverse events
`less alopecia and did not
`compared to the docetaxel arm 34 vs 16 P < 0001 Paclitaxel poliglumex and docetaxel
`produced similar survival
`toxicity profiles Compared with docetaxel PPX had less febrile neutropenia
`and less alopecia shorter infusion times and
`reactions Paclitaxel poliglumex at a dose of 2 I 0 mg m2 resulted
`elimination of routine use of medications
`to prevent hypersensitivity
`in increased neurotoxicity compared with docetaxel
`British Journal of Cancer 2008 98 16081613 do i101038sjbjc6604372
`13 May 2008
`Published online
`D 2008 Cancer Research UK
`
`wwwbjcancencom
`
`Keywords lung cancer poliglumex docetaxel
`
`is the most common cancer and one of the most lethal
`Lung cancer
`In the United States an estimated 213 380 new lung cancer
`cancers
`cases and 160 390 lung cancer deaths were expected in 2007 Jemal
`et al 2007 For patients who present with advanced stage disease
`IIIb or IV platinum based multi agent chemotherapy modestly
`improves survival compared with best supportive care or single
`therapy Pfister et al 2004 However nearly all patients
`agent
`relapse and only 1020 survive 2 years Three
`are
`agents
`for second line therapy in advanced non
`approved
`lung cancer NSCLC Docetaxel
`and erlotinib were
`on the basis of improved survival compared with best
`approved
`supportive care Shepherd et al 2000 2005 Pemetrexed
`received
`approval as second line therapy due to its similarity in survival
`
`small cell
`
`currently
`
`Correspondence Dr P Bonomi Email PhilipBonorniarushedu
`17 September 2007 revised 27 February 2008 accepted
`Received
`March 2008 published online 13 May 2008
`
`3
`
`toxicity than that of docetaxel
`rates with lower
`and response
`although statistical noninferiority was not achieved Hanna et al
`2004 Despite response rates of approximately 10 second line
`treatment improves survival by approximately 2 months compared
`with best supportive care
`Owing to the palliative nature of second line therapy in NSCLC
`and its relatively modest effect on survival minimising the toxicity
`consideration Additional
`therapy is an important
`of
`effective
`therapies that achieve that goal are needed
`Paclitaxel poliglumex PPX is a macromolecular polymer drug
`to a biodegradable polymeric
`links paclitaxel
`conjugate
`backbone
`acid residues Because the
`consisting of Lglutamic
`conjugation site is through the 2 hydroxyl of paclitaxel
`a site
`crucial for tubulin binding conjugated paclitaxel does not interact
`et al 2005
`with fltubulin and is biologically
`inactive Singer
`Paclitaxel poliglumex is relatively stable in circulation
`the area
`is 12 of the
`under the curve AUC of unconjugated paclitaxel
`AUG of conjugated paclitaxel Clinical plasma pharmacokinetics of
`PPX show a biphasic decline with a prolonged distribution phase
`
`that
`
`Abraxis EX2007
`Actavis LLC v Abraxis Bioscience LLC
`1PR201701101 1PR201701103 1PR201701104
`
`

`

`PPX and docetaxel
`L Paz Ares et al
`
`in NSCLC
`
`I 609
`
`docetaxel
`
`reaction HSR
`arm received
`routine hypersensitivity
`prophylaxis including corticosteroids eg dexamethasone
`20 mg
`iv histamine 2 receptor blockers eg cimetidine 300 mg iv
`50 mg iv These
`antihistamines eg diphenhydramine
`and
`agents were administered just before chemotherapy Patients
`the PPX arm received no standard HSR prophylaxis Patients were
`treated until
`intolerable
`disease progression
`toxicity patient
`withdrawal of consent or investigator decision to stop treatment
`All concurrent medications were recorded Anti emetic prophy
`laxis was permitted Granulocyte
`colony stimulating factor
`GCSF and granulocyte macrophage
`colony stimulating factor
`were administered according to American Society
`Oncology guidelines
`Patients were stratified based on stage IV vs other PS 0 or 1 vs
`2 start of frontline platinum based chemotherapy <16 weeks
`from randomisation vs
`16 weeks from randomisation gender
`and prior taxane therapy yes vs no
`
`in
`
`of Clinical
`
`and an elimination phase with a long terminal halflife Bernareggi
`et al 2005 The total systemic exposure to unconjugated
`paclitaxel
`of equivalent doses of PPX and
`is similar after administration
`standard paclitaxel however
`the Cmax values
`for paclitaxel are
`significantly lower in patients treated with PPX Bernareggi et al
`2005 The single cycle maximum tolerated dose of PPX in phase
`Ia study was 233 mg 1112 every 3 weeks with neutropenia being the
`dose limiting toxicity Boddy et al 2005 In the phase Ib portion
`in which CT 2103 was administered every 2 weeks
`the
`of the trial
`maximum tolerated dose was 177 mg m2 with neuropathy being
`the dose limiting side effect Neither study was able to address
`multi cycle toxicities A dose of 210 mg m2 was chosen for the
`that most patients will
`current study in view of the expectation
`have had prior paclitaxel
`therapy and a potential
`for cumulative
`neuropathy with prolonged administration of CT 2103
`Macromolecules such as PPX passively accumulate
`in tumour
`the hyperpermeable tumour
`by taking advantage
`tissues
`of
`and reduced
`lymphatic clearance
`This phenomenon
`vasculature
`is known as the enhanced permeation and retention EPR effect
`which results in a 10 to 100 fold increase in intratumoral drug
`concentrations when
`dose of
`compared with an equivalent
`the
`drug given conventionally Matsumura and Maeda 1986 Greish
`et al 2003 To take advantage of the EPR effect macromolecules
`least 6 h Matsumura
`have to remain in circulation for at
`and
`Maeda 1986 The prolonged circulation time of PPX facilitates
`accumulation through the EPR effect
`tumour
`as has been
`demonstrated in animal models Li et al 2000 The release of
`paclitaxel from the polymeric backbone is dependent
`on lysosomal
`et al 2007 In
`B Shaffer
`cathepsin
`proteases particularly
`tumours and premalignant
`lesions increased cathepsin
`malignant
`B mRNA expression is associated with elevated cathepsin
`B protein
`levels and activity and correlates with tumour invasion Podgorski
`and Sloane 2003
`trial of 28 patients who were either elderly had
`In a phase II
`performance status PS 2 or both with treatment naïve advanced
`NSCLC PPX at a dose of 175 mg m2 every
`3 weeks yielded a
`median survival of 81 months in a PS 01 population and 54
`months in a PS 2 cohort Richards et al 2005 This dose was well
`tolerated with a median of three cycles administered The disease
`rate was 71 2 partial
`remissions and 15 patients with
`control
`stable disease
`Given the enhanced
`
`efficacy of PPX in preclinical models its
`and its tolerability the present
`trial was
`activity in phase
`II
`in NSCLC patients treated with PPX
`initiated to compare survival
`as second line therapy in patients who had
`to that of docetaxel
`previously received a platinate combination
`
`MATERIALS AND METHODS
`
`The study was approved by the local research ethics committees
`All patients gave written informed consent
`
`Study design
`
`III
`
`STELLAR
`an open label
`2 was
`study comparing
`phase
`docetaxel with PPX Paclitaxel poliglumex was administered as a
`10 to 20mM infusion at 210 mg 1112 for advanced disease NSCLC
`patients with Eastern Cooperative Oncology Group PS 0 or 1 and at
`175 mg 1112 for patients with PS 2 The dose was reduced for PS 2
`the trial had started based on the results from an
`patients after
`ongoing study in PS 2 patients In that study the data monitoring
`incidence
`committee noted an increased
`of death resulting from
`neutropenia in 96 patients treated with 235 mg m2 PPX As a
`result of these observations the dose was reduced to 175 mg m2
`PPX OBrien et al in press Docetaxel was administered as a 1h
`75 mg m2 In both study arms
`intravenous iv infusion at
`iv treatment every
`3 weeks Patients
`patients received
`
`in the
`
`End points
`
`objectives
`
`evaluation
`
`criteria
`
`The primary end point of this study was the comparison of overall
`survival of patients treated with PPX to that of docetaxel No
`patients were censored regardless of the apparent cause of death
`included response rate time to progression
`Secondary
`TTP safety and quality of life Response status was established
`in solid tumours RECIST
`by response
`Therasse et al 2000 Computed tomography CT or other
`imaging techniques were used to assess patients during the third
`week of every other cycle For patients who completed therapy and
`had no evidence of disease progression reevaluation of indicator
`lesions was obtained every 8 weeks until documentation of disease
`progression or alternative therapy
`Safety data were collected
`on all patients In addition disease
`related symptoms were measured by the functional assessment of
`therapy lung cancer symptom FACTLCS scale at baseline
`cancer
`treatment administration
`and within 3 days of each
`
`Eligibility
`
`All patients enrolled in this study had histologically or cytologi
`cally confirmed advanced NSCLC and had been treated with a
`single platinum based systemic therapy Patients who
`received
`radiation sensitising doses of platinum based chemotherapy with
`concurrent chest radiation were not eligible Patients who received
`full doses of adjuvant
`chemotherapy were eligible Patients were
`18 years with adequate
`end organ indices including baseline
`count ANC
`1500 µ11 platelet
`count
`absolute
`neutrophil
`100 000 µ11 adequate
`function
`defined as creatinine
`renal
`limit of normal bilirubin > 10 times the
`15 times the upper
`upper limit of normal transaminases <25 times the upper limit of
`<5 times the upper
`normal
`if hepatic metastases were
`limit
`25 times the upper limit
`documented
`and alkaline phosphatase
`unless documented bone metastases were present Patients with
`known brain metastases were required to have stable disease after
`treatment eg whole brain
`standard antitumour
`radiation
`and be either off
`radiation or surgical
`resection
`treatment or on tapering doses Those who had
`recovered
`Patients with
`to be fully
`undergone surgery had
`commit
`potential were
`reproductive
`
`required to
`
`to
`
`adequate
`
`stereotactic
`
`corticosteroid
`
`contraception
`Exclusion criteria included evidence of small cell carcinoid or
`mixed small cellNSCLC histologies no previous treatment with a
`platinum regimen for NSCLC other concurrent
`active primary
`malignancies requiring treatment with the exception
`of carcinoma
`the uterine cervix or nonmelanomatous
`in situ of
`skin cancer
`2 neuropathy
`grade
`infection
`clinically
`significant
`agents within 4 weeks
`to other
`exposure
`investigational
`study entry unstable medical conditions
`including myocardial
`
`baseline
`
`of
`
`© 2008 Cancer Research UK
`
`British Journal of Cancer 2008 9810 1608 I 6 I 3
`
`

`

`I
`
`1610
`
`PPX and docetaxel
`
`in NSCLC
`L Paz Ares et at
`
`infarction within the prior 6 months inadequately treated chronic
`obstructive pulmonary disease or significant arrhythmias All
`patients were required to sign informed consents
`
`Criteria for removal
`
`from study
`
`for
`
`Patients were treated until documentation of disease progression
`clinically or on CT imaging or in the event of intolerable toxicities
`3 nonhaematologic toxicities grade 4
`including persistent grade
`HSR grade 3 HSR despite adequate prophylaxis or other toxicities
`continuation
`Other criteria
`treatment
`precluding
`study
`discontinuation
`
`of
`
`individual
`
`included withdrawal
`consent
`unrelated to toxicities and
`
`physician discretion for
`violation of study protocol
`
`reasons
`
`including patient noncompliance
`
`Dosing and dose modifications
`
`The
`
`reduced
`
`for
`
`the
`
`following
`
`doses of study agents were
`conditions 1 febrile neutropenia at any time 2 grade
`4
`neutropenia lasting >7 days 3 failure to recover
`to ANC of
`1500 µ11 by day 22 4 platelet count >20 000 or <50000 with
`bleeding 5 grade
`2 neuropathy 6 any other
`toxicity with the
`or HSR and
`vomiting
`
`associated
`
`attributable
`
`grade
`
`3 or
`
`exception
`
`of manageable
`
`4 nonhaematologic
`nausea
`and
`
`7 dose delays due to drug related toxicity
`For PPX the first onset of dose limiting toxicity mandated a
`dose reduction to 175 mg m2 for patients whose initial
`dose was
`doses of 175 mgm2 second dose
`210 and to 135 mg M2 for initial
`reductions mandated a decrease to 135 or 90 mg m2 respectively
`
`performed using Cox regression models with covariates
`analysis of survival
`the secondary
`Safety variables were summarised by descriptive statistics for
`patients who received
`toxicities were
`any study treatment All
`Institutes Common
`to the National Cancer
`graded
`according
`Toxicity Criteria version 2 Toxicities were compared between the
`treatment arms using Fishers exact
`
`used in
`
`test
`
`Quality of life
`Disease related symptoms were measured by the FACTLCS scale
`a validated 5 point Likerttype scale ranging from 0 not at all
`to
`4 very much The total LCS score ranged
`from 0 to 28 with
`higher scores indicative of fewer symptoms Fishers exact
`test for
`equal proportion of patients achieving
`at least a 2point increase in
`FACTLCS score from baseline
`to week 3 was performed in the
`overall sample and by each baseline covariate strata Patients with
`a missing FACTLCS score at week 3 were classified as having a
`<2 point increase in the primary analysis data but classified as
`missing and excluded
`from the supplemental analysis
`
`RESULTS
`
`Disposition of patients
`
`A total of 849 patients were randomised to receive either PPX
`n = 427 or docetaxel n = 422 Five patients two patients had
`one patient
`progressive disease one patient requested withdrawal
`did not comply with the protocol and no reason was given for one
`patient in the PPX treatment arm and six patients one patient
`receiving study drug two
`died of pulmonary embolism before
`patients had progressive disease one patient requested withdrawal
`the physician requested withdrawal not related to toxicity for one
`patient and one patient did not comply with the protocol
`in the
`docetaxel arm were randomised but did not
`receive study drug
`The first patient was randomised on 18 October 2002 and the last
`patient was enrolled on 13 August 2004
`Demographic breakdown is included in Table 1 Both arms were
`characteristics 72 of
`well balanced with regard to baseline
`patients were male 92 were Caucasian 81 had
`stage IV disease
`and 29 of patients had received prior taxanes The median
`age
`in the PPX arm and 62 in the docetaxel arm The
`was 61 years
`majority of patients 57 came from western Europe and Canada
`34 came from the United States
`The most
`reasons
`progressive disease 57 in the PPX arm compared with 63 in
`the docetaxel arm P = 0107 and adverse events 34 in the PPX
`arm compared with 16 in the
`arm P < 0001
`Additionally 4 of patients in the PPX arm withdrew consent
`compared with 8 in the docetaxel
`arm P = 0011
`
`frequent
`
`for
`
`stopping
`
`treatment were
`
`docetaxel
`
`Efficacy
`
`summary Median overall survival was 69 months in
`both arms of the study P = 026 Table 3 Oneyear survival rates
`were 25 in the PPX arm and 29 in the
`arm
`docetaxel
`P = 0134 The 2year survival
`rates were higher in the docetaxel
`
`arm 12 compared with the PPX arm9 These differences were
`
`not statistically significant P = 0195 Survival curves are shown
`in Figure 1
`Noninferiority defined as retention of 90 of docetaxel effect
`was not observed between the two arms hazard ratio HR = 109
`interval CI = 094 127 In
`95 confidence
`analyses a method that uses historic
`placebo controlled trials to adjust the HR observed when working
`The results from
`with a nonplacebo
`control was implemented
`this method yielded an HR of 061 95 CI = 038 098 indicating
`that PPX is an active
`agent when
`indirectly compared with
`
`subsequent
`size estimates
`of
`
`effect
`
`placebo
`
`following
`
`Once a dose reduction was instituted doses were not re escalated
`experienced grade 3 HSR during or
`Patients who
`treatment were allowed
`to continue treatment at
`investigators
`discretion but were required to receive standard premedication in
`accordance with institutional guidelines
`the first onset of dose limiting toxicity mandated
`For docetaxel
`a dose reduction to 75 mg 1112 second dose reductions mandated a
`decrease to 55 mg m2 Once a dose reduction was instituted doses
`re escalated Patients who experienced grade 3 HSR
`were not
`during or following treatment were allowed to continue treatment
`investigators discretion but were required to receive standard
`at
`premedication in accordance with institutional guidelines
`
`Efficacy parameters and statistical considerations
`
`Overall survival was defined as the interval between randomisation
`and death from any cause Patients
`remaining alive including
`the date of last contact
`those lost to followup were censored at
`Nonstratified log rank testing was used for the formal primary
`840
`This study targeted
`accrual
`of
`comparison of survival
`evaluable patients which guaranteed 80 power and 005 type I
`error to show a 15 month improvement 30 increase in median
`survival from baseline of 6 to 75 months The study was slated to
`accrue over 18 months with an additional 6 months of followup A
`secondary noninferiority analysis of overall survival was also
`performed using the fraction retention method described by
`Rothmann et al 2003 In addition secondary analyses comparing
`treatment arm were conducted
`using Cox regression models
`each
`which
`included
`covariates
`reflected
`factors
`that
`prognostic
`in patients with NSCLC
`associated with survival
`Response was assessed according to RECIST criteria Disease
`control was determined by the percentage of patients alive without
`disease progression for at least 12 weeks All randomised patients
`were included in these comparisons using Fishers exact
`test
`Time to progression was defined as the time interval between
`randomisation and the first observation of disease progression due
`to any cause Primary analysis of TTP was made using an
`analyses of TTP were
`log rank
`unstratified
`test Secondary
`
`British Journal of Cancer 2008 981 0 I 608 I 6 I 3
`
`© 2008 Cancer Research UK
`
`

`

`PPX and docetaxel
`L Paz Ares et at
`
`in NSCLC
`
`PPX
`
`Docetaxel
`
`Median
`
`427
`
`422
`
`20 months
`26 months
`
`PPX
`Docetaxel
`
`HR=1 13
`Log rank P=075
`
`1 0 f
`
`09 H
`
`Tz 08 H
`>
`
`07
`
`cn
`
`45 06
`= 05 H
`
`r5 04
`2
`
`03 H
`
`02
`
`01 H
`
`0
`
`100
`
`200
`
`300
`
`400
`
`500
`
`600
`
`700
`
`Time from randomisation days
`Kaplan Meier plot of time to disease progression intent to
`Figure 2
`treat data set HR hazard ratio PPX paclitaxel
`poliglumex
`
`in
`
`1611
`
`Ir
`
`Mr
`
`el
`
`Table I
`
`Demographic and baseline characteristics
`
`PPX n=427
`
`Docetaxel n=422
`
`302 716
`120 284
`
`381 903
`21 50
`5 12
`11 26
`4 09
`0 0
`
`422
`621 972
`630 3485
`
`140 332
`245 581
`37 88
`
`80 19
`280 66
`62 15
`
`308 721
`119 279
`
`397 930
`19 44
`5 12
`4 09
`1 02
`1 02
`
`427
`613 981
`620 3087
`
`150 351
`240 562
`37 87
`
`93 22
`277 65
`57 13
`
`Gender
`
`Male
`
`Female
`
`Race
`
`Caucasian
`
`Black
`
`Asian
`
`Hispanic
`Other
`Unknown
`
`Age at
`
`randomisation
`
`Mean sd
`Median range
`
`Geographic location
`
`United States
`
`Western Europe and
`Other
`
`Canada
`
`ECOG performance rating
`
`0 1 2
`
`12 weeks
`occurred
`as absence of progression during the first
`40 in the PPX arm compared with 45 in the docetaxel arm
`There was no significant difference in median TTP 20 months
`in the PPX arm compared with 26 months in the docetaxel arm
`HR= 113 log rank P=0075 Time to progression curves are
`in Figure 2 There was
`shown
`no difference in subsequent
`therapies 11 of
`those enrolled in the PPX arm went
`on to
`radiation therapy compared with 13 in the docetaxel arm In
`both arms 57 received additional chemotherapy but no specific
`agents predominated
`
`Quality of life
`
`The primary FACTLCS analysis consisted of 767 patients PPX
`n= 379 docetaxel n= 388 There was no difference between the
`two treatment groups in the proportion
`of subjects achieving
`at
`least a 2 point increase in FACTLCS score from baseline to cycle 3
`P=0329 Both treatment groups reported similar proportions of
`FACTLCS scale score and item score changes from baseline
`over
`time During the study period 41 of patients treated with
`in FACTLCS
`achieved
`least a 2point improvement
`score from baseline compared with 34 of patients treated with
`PPX
`
`docetaxel
`
`at
`
`Toxicity profile
`
`The median number of cycles received was two in
`Drug delivery
`arm More patients
`the PPX arm and three
`in the docetaxel
`6 cycles in the docetaxel arm P<0001 In aggregate
`patients received >90 of mean expected dose during the second
`and subsequent
`
`received
`
`cycles
`
`Relative toxicities
`
`Patients
`
`enrolled in the docetaxel
`
`arm were significantly more
`likely to experience grade 3 or 4 neutropenia 37 vs 14 P < 0001
`and febrile neutropenia 6 vs 2 P= 0006 Table 2 Alopecia
`arm 43 vs 14
`also occurred more frequently in the docetaxel
`P<0001 Patients enrolled in the PPX arm were significantly
`more likely to experience grade 3 or 4 HSR 3 vs <1 P=0007
`and neuropathy 19 vs 3 P<0001 Neuropathy of all grades
`occurred in 50 of patients in the PPX arm and 30 of patients in
`the docetaxel arm Severe neuropathy common toxicity criteria
`grade 3 or 4 was observed in 19 of patients in the PPX arm and
`3 of patients in the docetaxel arm Of note only grade 3 events
`were seen in the docetaxel arm There was a general
`
`trend towards
`
`Disease
`
`stage
`
`IV
`
`Other
`Unknown
`
`342 80
`84 20
`1 <1
`
`Time since start of first
`<16 weeks
`
`16 weeks
`
`line chemotherapy
`13231
`295 69
`
`Prior taxane use
`
`Yes
`No
`Unknown
`
`127 30
`286 67
`14 3
`
`343 81
`75 18
`4<l
`
`133 32
`289 68
`
`123 29
`287 68
`12 3
`
`ECOG = Eastern Cooperative Oncology Group PPX= paclitaxel poliglumex
`
`PPX
`
`Docetaxel
`
`Median
`
`1 year
`
`2 years
`
`69 months 25 9
`69 months 29
`12
`
`N
`
`427
`
`422
`
`PPX
`Docetaxel
`
`HR=109
`Log rank P=026
`
`10 I
`
`09 I
`
`7 08
`>
`07H
`
`cn
`
`HE 06
`t 05 I
`
`43
`
`4H
`
`2 C
`
`L 03H
`
`02 H
`
`01 H
`
`100
`
`200
`
`300
`400
`500
`600
`Time from randomisation days
`
`700
`
`800
`
`Figure I
`
`Kaplan Meier plot of overall survival
`
`intent to treat data set
`
`Response and progression data
`
`The overall
`
`response
`
`rate for the PPX arm was 8 with no
`complete responses CRs Table 3 The overall response rate for
`the docetaxel arm was 12 with two CRs Disease control defined
`
`0 2008 Cancer Research UK
`
`British Journal of Cancer 2008 981 0 I 608 I 6 I 3
`
`

`

`PPX and docetaxel
`
`in NSCLC
`L Paz Ares et at
`
`1612
`
`Table 2 Number
`
`of patients with select adverse events
`
`PPX n = 422
`
`Docetaxel n = 416
`
`Toxicity
`
`All
`
`Grade 3 or 4
`
`All
`
`Grade 3 or 4
`
`Anaemia NOS
`
`Neutropenia
`Leukopenia NOS
`Thrombocytopaenia
`
`Febrile neutropenia
`
`Anorexia
`
`Dehydration
`Neuropathy NOS
`Dyspnoea NOS
`Nausea
`Vomiting NOS
`Diarrhoea NOS
`Stomatitismucositis
`
`Arthralgia
`
`Fatigue
`Asthenia
`
`Weight
`
`loss
`
`Alopecia
`
`19 5
`58 14
`28 7
`10 2
`8 2
`12 3
`10 2
`8119
`50 12
`14 4
`9 2
`6 1
`2 <1
`2<I
`24 6
`215
`3 <1
`NA
`
`109 26
`73 17
`183 44
`87 21
`26 6
`48 II
`18 4
`31 7
`25 6
`8 2
`72 17
`96 23
`23 6
`24 6
`123 30
`21150
`105 25
`99 23
`139 33
`140 33
`72 17
`82 19
`108 26
`67 16
`32 8
`93 22
`4310
`5112
`148 36
`115 27
`95 23
`68 16
`4110
`63 13
`38 9
`134 32
`NA= not applicable NOS = not otherwise specified PPXpaclitaxel
`
`17 4
`152 37
`8 2
`3 <1
`23 6
`27 6
`8 2
`14 3
`5112
`8 2
`17 4
`11 3
`10 2
`4<I
`35 8
`24 6
`11 3
`NA
`
`0002
`<0001
`0004
`0077
`0002
`0057
`
`1000
`<0001
`0574
`
`1000
`0476
`<0001
`<0001
`
`0445
`0011
`0015
`0230
`<0001
`
`poliglumex
`
`second line chemotherapy in NSCLC The TTP and
`date evaluating
`survival results in the current
`trial are similar to results reported
`observed
`for docetaxel pemetrexed and erlotinib
`in smaller
`randomised studies Fossella et al 2000 Shepherd
`et al 2000
`Hanna et al 2004 Table 3 Collectively these data suggest
`that
`second line therapy with an active agent has a modest survival
`over
`and that
`the effects of
`supportive care alone
`advantage
`docetaxel PPX pemetrexed and erlotinib are similar
`treated with PPX received
`a median of two cycles of
`Patients
`arm with more patients
`therapy vs three cycles in the docetaxel
`withdrawing from PPX for adverse events and more patients in the
`arm withdrawing for progressive disease The dose of
`docetaxel
`210 mg m2 PPX used in this study may have been higher than
`optimal and may have been responsible for the relatively high
`rate Nevertheless patients treated with PPX had
`withdrawal
`significantly less neutropenia and febrile neutropenia and required
`less growth factor and transfusion support However
`they did
`
`experience more grade 3 neuropathy 19 vs 3 a common cause
`
`for discontinuation A general
`trend towards increasing incidence
`by cycle was seen in the PPX arm Additional
`experience
`in
`patients with other diseases
`the optimal dose for
`that
`suggests
`repeated cycles of PPX is 175 mg 1112 with early dose reduction for
`In this study the dose
`development of even grade 1 neuropathy
`only when
`reduced
`2 neuropathy had
`was
`grade
`persistent
`developed Studies with paclitaxel have consistently failed to
`demonstrate a dose response relationship
`In contrast
`in a phase
`III study of single agent PPX at 175 mg m2 grade 3 neuropathy
`occurred in 4 of patients despite administration
`
`of a median of
`four cycles of therapy OBrien et al in press In that study in PS 2
`patients PPX was not inferior to single agent
`therapy with either
`gemcitabine or vinorelbine median survival = 220 vs 198 days
`respectively HR = 095 and produced fewer grade 3 or 4 toxicities
`over docetaxel
`Paclitaxel poliglumex has advantages
`in ease of
`administration requiring a 10 to 20 min peripheral vein infusion
`without
`of neutro
`routine premedications and a low incidence
`penic fever or infections An additional advantage is the decreased
`rate of alopecia 43 vs 14 due to reduced systemic exposure to
`high levels of free paclitaxel Despite prior taxane exposure in 30
`of HSR was only 5
`3 grade 3 or 4 compared with 3 <1 grade 3 or 4 for
`of patients treated with PPX the incidence
`
`docetaxel
`
`Preclinical and clinical studies
`suggest an interaction between
`PPX and oestrogen Ross et al 2006 A clinical
`in women
`levels > 30 pg ml is being conducted
`with oestradiol
`to test
`the
`hypothesis that women with normal oestradiol
`levels who
`are
`treated with PPX and carboplatin will have improved survival
`compared to women treated with paclitaxel and carboplatin
`
`trial
`
`Final conclusions
`
`Paclitaxel poliglumex produces
`similar survival
`to docetaxel
`as
`in NSCLC with less febrile neutropenia and
`second line treatment
`alopecia and greater ease of administration The higher incidence
`of neuropathy can likely be reduced by lowering the starting dose
`to 175 mg 1112 and using early dose reduction for development of
`in patients under
`even grade 1 neuropathy Additional
`studies
`going second line therapy are needed to validate this
`
`Conflict of interest
`Amy J Eisenfeld Jack Singer Bruce Bandstra and Fred B Oldham
`Inc
`are employees of Cell Therapeutics
`
`at The 11th World Congress on Lung
`exposure to paclitaxel Presented
`Cancer July 36 Barcelona Spain
`
`Table 3 Outcomes of second line single agent
`
`treatment of NSCLC
`
`Reference
`
`Drug
`
`Fosse Ila et al
`Hanna et al
`PGT302
`
`Docetaxel
`
`Docetaxel
`
`Docetaxel
`
`Hanna et al
`
`Pemetrexed
`
`Shepherd et al Erlotinib
`PCT302
`PPX
`
`N
`
`125
`
`288
`
`422
`
`283
`
`41
`
`427
`
`Median survival
`months
`
`I year
`survival
`
`TTP
`months
`
`57
`79
`69
`83
`67
`69
`
`32
`
`30
`
`29
`
`30
`NA
`25
`
`20
`35
`26
`34
`22
`20
`
`NA= not applicable NSCLC= non small cell
`mex HP= time to progression
`
`lung cancer PPX= paclitaxel poliglu
`
`observed in the docetaxel arm
`The incidence
`
`of severe neuropathy by cycle in the PPX
`an increasing incidence
`arm through cycle 4 The mean cumulative dose of PPX at the first
`event of neuropathy was 5329 mg m2 A similar pattern was not
`of febrile neutropenia was 2 in the PPX arm
`compared with 6 in the docetaxel arm P=0002 The use of
`erythropoietin and
`transfusions
`care
`including
`supportive
`GCSF was lower
`in the PPX treatment arm Grade
`3 or 4
`than in the PPX arm 7
`arm 11
`infections occurred more frequently in the docetaxel
`Twelve per cent of patients in the PPX arm and 16 of patients
`in the docetaxel arm died within 30 days of treatment but only 2
`of these deaths were attributable to study drugs 9 appeared to be
`disease related and 3 were due to comorbidities
`The incidence of HSR was 5 for the PPX arm without
`HSR prophylaxis compared with 3 for the docetaxel arm with
`HSR prophylaxis
`
`routine
`
`DISCUSSION
`
`poliglumex and docetaxel produced similar results for
`Paclitaxel
`TTP and overall survival
`in one of the largest phase III
`studies to
`
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`
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`
`prolonged
`
`paclitaxel
`
`British Journal of Cancer 2008 98 I 0 I 608 I 6 I 3
`
`© 2008 Cancer Research UK
`
`

`

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