Phase I and Pharmacokinetic Study of Taxotere (RP 56976)
`Administered as a 24-Hour Infusion
` 
`D. Bissett, A. Setanoians, J. Cassidy, et al.
`Cancer Res  
`
`1993;53:523-527.
`
`Updated version
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`on October 27, 2014. © 1993 American Association for Canceron October 27, 2014. © 1993 American Association for Cancer
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`Research. Research.
`
`IMMUNOGEN 2191, pg. 1
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`ICANCI-R RKSKARC'H 53. 523-527, Febniaiy I. IW|
`
`Phase I and Pharmacokinetic Study of Taxotere (RP 56976) Administered as a
`24-Hour Infusion
`
`D. Bissett,1 A. Setanoians, J. Cassidy, M. A. Graham, G. A. Chadwick, P. Wilson, V. Auzannet, N. Le Bail, S. B. Kaye,
`and D. J. Kerr
`
`6NT, Scotland ¡I).B.. A. S., J. C.. M. A. G., G. A. C.. P. W., S. B. K..
`of Medical Oncology. Beatson Oncology Centre, Western Infirmary, Glasgow Gil
`CRC Department
`I). J. K.¡.ami Rtwne-Ptntlenc Rarer. Recherche-Développement. 92165 Antony Cedex. France ¡V.A.. N. Le B.I
`
`ABSTRACT
`
`(Taxotere, RP
`(axol
`W-Debenzoyl-jV-fert-butoxycarbonyl-lO-deacytyl
`56976)
`is a .semisynthetic analogue of taxol, prepared from a noncytotoxic
`precursor
`extracted from the needles of the European yew tree (Taxus
`boccata L. ). It has a broad spectrum of antitumor
`activity against a variety
`of transplantable
`tumors in mice. In vitro cytotoxicity assays suggest
`that
`it is 2-5-fold more potent
`than taxol. In this phase I study Taxotere was
`administered by 24 h i.v. infusion at 3-week intervals. Thirty patients with
`solid tumors refractory to conventional
`therapy were treated; 70 courses
`of Taxotere were administered
`at doses ranging from IU to 90 mg/m2.
`Grade 4 neutropenia and grade 3 mucositis were dose limiting but revers
`ible at 90 mg/m2. The pattern and grade of toxicity at this dose were
`similar in 3 heavily pretreated patients compared with 7 patients who had
`received a maximum of one previous
`chemotherapy
`regimen. Alopecia
`occurred at 55 mg/m2 and above. Other mild toxicities
`included phlebitis,
`diarrhea, emesis, and sensory peripheral neuropathy, but these were nei
`ther dose-limiting
`nor clearly dose-related. One patient
`treated at 70
`mg/m2 had an anaphylactoid
`reaction following the second dose of Taxo
`tere. No cardiovascular
`toxicity was observed. No partial or complete
`responses were documented. Plasma concentrations
`of Taxotere were de
`termined by high-performance
`liquid chromatography,
`and end-of-fusion
`levels at the maximum tolerated dose exceeded drug concentrations which
`are cytotoxic
`in vitro. The maximum tolerated dose for Taxotere admin
`istered as a 24-h infusion is 90 mg/m2.
`
`INTRODUCTION
`analogue of taxol, which is
`Taxotere2 (Fig. 1) is a semisynthetic
`prepared from 10-deacetyl baccatin III, a noncytotoxic precursor ex
`tracted from the needles of the European yew tree (Taxus baccala L. )
`(1). It is cytotoxic in vitro against murine P388 leukemia cells;
`the
`median inhibiting concentration with 72-h exposure
`to Taxotere is
`0.004 UM compared with 0.01 |UMfor
`taxol
`(2). Under
`the same
`conditions Taxotere is 2.5 and 5 times more potent, as a cytotoxic,
`in
`the mouse macrophage-like
`line J774.2 and its taxol-resistant daughter
`line J7.TAX-50,
`respectively
`(2).
`Its mechanism of cytotoxicity
`is
`similar to that of taxol. Both drugs bind to microtubules, promote their
`assembly, and inhibit
`their depolymerization
`in vitro (2, 3). Initial
`in vivo experiments
`suggested that Taxotere was active against a range
`of transplantable murine tumors and was more active than taxol
`in
`B16 melanoma (4). In vivo studies in the 38 colonie adenocarcinoma
`have examined 4 different
`i.v. bolus schedules: once daily days 1 and
`6; days 1, 5, 9, and 13: and days 1 to 8; and 3 times daily days 1 to
`6 (4). The first two schedules allowed the administration of the largest
`total dose of Taxotere and, at equitoxic doses, had the greatest anti-
`tumor activity. Continuous 24-h i.v. infusions of Taxotere have not
`been evaluated in preclinical models and, given the clinical activity of
`
`Received 7/7/92; accepted 11/11/92.
`The costs of publication of this article were defrayed in part by the payment of page
`charges. This article must
`therefore be hereby marked advertisement
`in accordance with
`18 U.S.C. Section 1734 solely to indicale this fact.
`1To whom requests for reprints should be addressed, at CRC Department of Medical
`Oncology, Beatson Oncology Centre. Western Infirmary, Dumbarton Road. Glasgow Gil
`6NT, Scotland.
`/V-debenzoyl-W-fcri-butoxycartxmyl-IO-deacy-
`- The abbreviations used are: Taxotere,
`area under
`the plasma drug concentration-time
`tyl taxol
`(RP 56976); AUC,
`trapezoidal
`curve; MTD. maximum tolerated dose; HPLC. high-performance
`liquid chromatography.
`
`taxol administered in this way, this schedule was chosen for a phase
`I study of Taxotere.
`The dose which killed 10% of mice with a schedule of 5 consec
`utive daily i.v. doses was 300 mg/m2. One-tenth of this dose (30
`mg/m2) caused toxicity in dogs when administered
`as a single i.v.
`bolus. The dose causing minimal
`toxicity in dogs was 15 mg/m2. The
`major toxicity observed in both mice and dogs was neutropenia. Other
`toxic effects included peripheral neuropathy in mice, and mucositis,
`emesis, diarrhea, and hair
`loss in dogs. Based on these preclinical
`studies,
`the phase I trial program started at a dose of 5 mg/m2,
`one-third of the dose causing minimal
`toxicity in dogs. No toxicity
`was observed in 3 patients who received this dose as a 1-h infusion in
`a tandem study.1 Therefore, we commenced the present
`trial with a
`24-h i.v. infusion at a dose of 10 mg/m2.
`
`MATERIALS AND METHODS
`
`through a
`infusion,
`24-h i.v.
`as a continuous
`Taxotere was administered
`peripheral vein, once every 3 weeks. Patients were hospitalised for each course
`of chemotherapy
`for 24 h after the end of the infusion and closely observed for
`evidence of hypersensitivity
`reactions, hypotension,
`and arrhythmias. Contin
`uous electrocardiogram monitoring was not routinely used. All patients had
`histologically
`proven cancer
`refractory
`lo conventional
`therapy. Written in
`formed consent was obtained from all patients, who were required to have a
`performance
`stalus of <2 on the Eastern Oncology Cooperative Group-Zubrod
`scale;
`life expectancy
`in excess of 12 weeks;
`and normal organ function,
`including WBC >4.(XX)/mm\
`platelets >l(X),(KX)/mml. hilirubin <25 umol/
`
`limit, and
`less than twice the upper normal
`aminotransferase
`liter, aspartate
`serum creatinine <12() umol/liter. No chemotherapy,
`ininiunotherapy,
`or ra
`diotherapy had heen given within 4 weeks of entering the study (6 weeks for
`nitrosoureas, mitomycin C. and wide-field
`irradiation):
`and other exclusion
`criteria included pregnancy,
`lactation,
`sepsis, and cerebral métastases.
`All patients had a baseline history, physical examination,
`full blood count,
`biochemistry
`profile, urinalysis, chest radiograph,
`and electrocardiogram.
`Tu
`mor measurements were made, where possible, using appropriate
`clinical or
`radiological methods. No other investigational
`drugs were administered during
`the study, and all concomitant medication was recorded. Patients on study were
`seen weekly to record toxicity and to monitor hematological
`and biochemical
`indices. Standard response criteria and WHO toxicity grading were used (5):
`neurotoxicity was assessed clinically and was graded according to the National
`Cancer
`Institute criteria; nerve conduction studies were not applied. Patients
`were withdrawn from the study after receiving 6 courses of Taxotere or if there
`was evidence of disease progression
`or
`life-threatening
`toxieity. or at
`the
`request of the patient.
`The drug was supplied by Rhône-Poulenc Rorer. formulated as a concen
`trated sterile solution containing l i mg/ml Taxotere in 509r polysorbate 80 and
`50% dehydrated
`alcohol.
`Immediately
`prior
`to administration
`the drug was
`diluted in KXK)ml 59Ã(cid:141)dextrose, providing a polysorbate
`80 concentration
`of
`<2%. The drug was delivered by continuous
`i.v.
`infusion over 24 h by a
`rate-minder pump (Critikon. Ascot. UK). During the first course of Taxotere,
`blood and urine samples
`for pharmacokinetic
`studies were collected. Blood
`was taken from each patient
`through a heparini/ed
`cannula in the opposite arm
`from the injection site; samples (5 ml) were collected in lithium heparin tubes
`before, during, after the 24-h infusion. The blood was centrifuged immediately,
`and the plasma was collected and stored at -20°C until analysis. Plasma and
`
`1Marty, personal communication.
`
`523
`
`Downloaded from
`
`on October 27, 2014. © 1993 American Association for Cancercancerres.aacrjournals.org
`
`
`Research.
`
`IMMUNOGEN 2191, pg. 2
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`I'HASK I STUDY OF TAXOTI.RI
`
`Leukopenia and mucositis were both dose related and dose limiting.
`The median nadir neutrophil counts at each dose level are summarized
`in Table 5. At 90 mg/m2 neutrophil counts had fallen to their nadir by
`day 7 but
`in general
`recovered by day 14, and no treatments were
`delayed because of persisting neutropenia at day 21. Despite the short
`duration of neutropenia, 3 episodes of pyrexia associated with neu
`tropenia occurred at 90 mg/m2; all 3 also had grade 3 mucositis. These
`patients were hospitalized and given antibiotic therapy, but one patient
`died of an unresolving pneumonia. At 90 mg/m2 one patient had grade
`1 and another
`grade
`2 thrombocytopenia.
`Significant mucositis
`(grades 2 and 3) at
`this dose was characterized
`by painful oral
`erythema progressing to ulcérationin 8 of 21 courses
`(6 of 10 pa
`tients). The oral reactions
`started within 48 h of completion of the
`Taxotere infusion and healed over 3-10 days. Prophylactic mouth-
`washes and the anticandidal
`agent nystatin did not prevent
`this tox
`icity.
`Patients treated at the MTD were subdivided into heavily pretreated
`(2 or more previous
`regimens) and lightly pretreated (only one pre
`vious
`regimen) groups,
`and the pattern of toxicity was compared
`(Table 6). The degree of toxicity was similar in the two groups.
`Other
`toxicities were sporadic and mild. These included anemia,
`emesis, diarrhea,
`sensory peripheral neuropathy, and phlebitis. The
`neuropathy caused digital paresthesiae with no motor deficit. Grade 1
`sensory neuropathy occurred in 2 patients at 55 mg/m2, one patient at
`70 mg/m2. and 2 patients at 90 mg/m2. Three of these 5 patients with
`sensory symptoms had previously received chemotherapy
`including
`either vincristine or cisplatin. Since only 3 patients received more than
`3 courses of taxotere
`at 70 or 90 mg/m2 it
`is uncertain whether
`neurotoxicity is related to the total cumulative dose of drug received.
`The phlebitic reactions were characterized by mild painless erythema
`
`Table 1 Patient characteristic*
`
`No. of patienis
`
`12
`18
`
`10
`16
`4
`
`Sex
`Male
`Female
`
`Performance
`
`status (ECOG)"
`
`0I 2
`
`Age(years)RangeMedianPrior
`
`treatmentNone
`or surgeryaloneChemotherapy
`
`aloneChemotherapy
`radiotherapyTumor
`and
`
`typeRenalOvarianColorectalBreastSarcomaMelanomaOthers22-685391386553227"
`
`OH
`
`OCOC6H5
`
`Taxotcrc : R] = -COOC(CH3>3
`
`; R2 = H
`
`Taxol
`
`: RI = -COC^H;
`
`; R2 = -COCH3
`
`Fig. I. Molecular
`
`structures of Taxotere (RP56976) and taxol.
`
`and
`extraction
`concentrations were measured by solid-phase
`urine Taxotere
`reverse-phase HPLC. The drug was extracted
`from plasma by solid-phase
`extraction using C; ( I ml) Bond Elut cartridges
`(Analytichem). The cartridges
`were solvated prior to use with 1 ml methanol and 1.5 ml water before plasma
`or urine samples
`(0.5 ml) were applied. The plasma and urine contaminants
`were washed to waste with 1 ml water and 1 ml 50% methanol, and Taxotere
`was eluted in 250 ul 90% methanol. One hundred (jl of the isolate were injected
`onto the column. An internal standard,
`taxol. was added to all samples before
`extraction (500 ng in 50 ul methanol/sample).
`The HPLC system consisted of
`a pump
`(Hewlett
`Packard HP1090).
`a variable-wavelength
`UV detector
`(Hewlett Packard 1040). a chromatography
`control module (Hewlett Packard
`85B). and an S5 ODS2 reverse-phase
`column. 25 cm x 4.6 mm, with 5-um
`particle si/.e packing (Spherisorb, Queensferry. UK). The mobile phase com
`prised 67% methanol
`and 0.1% orthophosphoric
`acid, at a flow rate of
`1 ml/min. Peak identity was confirmed
`by diode array detection
`over
`the
`wavelength range 200-500 nm. and quantitation of Taxotere was carried out by
`peak area integration at 225 nm. The HPLC assay for Taxotere demonstrated
`linearity over the range 15-500 ng/ml (r = 0.97);
`the intraassay coefficient of
`variation was between 7 and 13% over
`the range 15-500 ng/ml. The lower
`limit of quantitation
`of Taxotere in both plasma and urine was 15 ng/ml.
`The plasma concentration-time
`data were analyzed by the process of non
`linear
`least-squares
`regression using an in-house computer program based on
`the Marquhardt
`algorithm (STATIS 3; Clydesoft, Glasgow, Scotland), which
`derived the pharmacokinetic
`parameters: elimination half-life (fi/?), volume of
`distribution
`(Vd). AUC. and clearance
`from plasma.
`and tumor
`Thirty patients were entered into the study;
`their characteristics
`types are summarized in Table I. The starting dose was 10 mg/m2. and the dose
`
`scheme (Table 2). A
`followed a modified Fibonacci
`subsequently
`escalation
`minimum of 3 patients were treated at each dose level. When grade 2 or worse
`toxicity was observed, at least 6 patients were entered at the same dose before
`further dose escalation. The MTD was defined as the highest dose which could
`be administered
`to a patient, producing severe but manageable
`and reversible
`toxicity. Nonhematological
`toxicity of grade 3 or worse in more than 50% of
`patients was not acceptable, but grade 3 or 4 neutropenia was deemed tolerable
`if it was not associated with fever and recovered within I week. Dose reduc
`tions were not planned,
`and there was no escalation of dose for individual
`patients. Response was assessed after every 2 courses of Taxotere.
`and in
`patients who had prolonged toxicity but showed evidence of response,
`subse
`quent courses were delayed until
`toxicities had resolved.
`
`RESULTS
`
`Eastern Oncology Cooperative Group.
`
`Toxicity. Thirty patients received a total of 70 courses of Taxotere,
`and all patients were évaluablefor toxicity. The numbers of patients
`treated and courses administered at each dose level are summarized in
`Table 2, and the major toxicities observed after the first and subse
`quent courses are detailed in Tables 3 and 4. Six patients
`received
`more than 3 courses of Taxotere, and there was no evidence of cu
`mulative toxicity within this subgroup.
`Grade 2-3 alopecia occurred at 55 mg/m2 and above, but other
`toxicities were infrequent
`and mild at doses of 10 to 55 mg/m2.
`
`Table 2 Dose escalation scheme
`
`Dose
`of
`(mg/m2)IO2040557090No.
`patients33365IOi2.
`
`of courses
`perpatient2231.
`
`no.
`of courses5710141421
`
`1,4,
`1.5.
`2,2,
`14,
`3, 6,
`1,1,
`
`2a,61.
`1,6,
`2. 1, 2. 2. 3. 1. 1Total
`2,io.
`' Course 2 discontinued after 5 min of infusion because of anaphylactoid
`
`reaction.
`
`524
`
`
`
`Downloaded from on October 27, 2014. © 1993 American Association for Cancercancerres.aacrjournals.org
`
`
`Research.
`
`IMMUNOGEN 2191, pg. 3
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`IMIASi;
`
`I STUDY OF TAXO'l I-.RI-.
`
`Table 3 Toxicity following first course of Taxotere
`
`ToxicityLeukopeniaDose
`
`grade02"
`
`grade10
`
`grade10
`
`and
`vomitingWHO
`
`grade10
`
`grade10
`
`000
`
`1120
`
`00000
`
`20102
`
`30
`
`13547
`
`011131 1
`
`0000
`
`000
`
`1520
`
`22534
`
`Nausea
`
`0000
`
`02
`
`03
`
`AnemiaWHO
`
`(mg/m2)10
`
`20
`40
`5570
`
`22624
`
`00
`
`10303
`
`00002
`
`30
`
`00
`
`10220
`
`MucositisWHO
`
`3453
`
`00002
`
`0101320 1
`
`0022
`
`DiarrheaWHO
`
`30
`
`00
`
`10
`
`00
`
`10030
`
`00200
`
`33252
`
`033
`640
`20
`11
`90WHO
`' No. of patients with specified grade of toxicity.
`
`ToxicityLeukopeniaDose
`
`grade03"
`
`(mg/m2)10
`
`Table 4 Toxicity following all courses of Taxotere
`
`grade10
`
`grade10
`
`and
`vomitingWHO
`
`grade10
`
`grade10
`
`10
`
`01
`
`03
`
`1
`
`66
`
`001340
`
`00000
`
`30103
`
`30
`
`00654
`
`7g
`
`
`
`14AnemiaWHO20
`
`10000
`
`0J4
`
`244
`
`31
`
`11
`1620
`g
`11Nausea
`
`0000
`
`104
`
`20024
`
`30
`
`010
`
`1621
`
`14
`10
`10DiarrheaWHO
`
`59
`
`00
`
`1
`
`03
`
`04
`
`00002
`
`00
`
`1
`
`0130
`
`002
`
`1220
`
`6
`20
`10
`40
`10
`55
`12
`70
`057
`90WHO
`312
`1No. of courses associated with specified grade of toxicily.
`
`00003
`
`00535
`
`10
`g
`1010MucositisWHO
`30
`20
`
`Table 5 Nadir neufmphil counts at each dose level
`
`Dose(mg/m")10
`
`(range)at
`
`nadir neutrophils
`x l()v/liter
`
`20
`40
`SS
`70
`90Table
`
`a family history of coronary artery disease. Another patient developed
`atrial
`flutter, with 2:1 block, 24 h after the completion of his first
`course of Taxotere at 90 mg/m2. The supraventricular
`tachycardia
`
`to therapy, and a subsequent echocardiogram showed
`proved resistant
`evidence of pericardial metastatic involvement.
`One patient with renal carcinoma,
`treated with 90 mg/m2, became
`icteric 8 days after the first course. This occurred in association with
`neutropenia
`and sepsis, but
`there was no evidence of intravascular
`hemolysis. Her pretreatment
`indices were: bilirubin,
`15 umol/liter;
`alkaline phosphatase, 650 IU/liter; aspartate aminotransferase,
`30 IU/
`liter; serum glutamine-pyruvic
`transaminase, 66 IU/liter; and -yGT,83;
`and 7 days after treatment
`these were 270 umol/liter. 445 IU/liter, 25
`IU/liter, 58 IU/liter, and 74 IU/liter, respectively. The patient died of
`an unresolving pneumonia, but autopsy revealed no obvious cause for
`the jaundice. There was no biliary obstruction or hepatic métastases,
`and histológica! examination of the liver was unremarkable, with no
`evidence of intrahepatic
`cholestasis
`or drug-induced
`hepatitis. No
`pharmacokinetic data are available on this patient. No other patients in
`the study had drug-related hyperbilirubinemia
`or elevation of hepatic
`enzymes.
`responses were observed in this study. Of the 28 as
`No clinical
`sessable patients, 25 had disease progression when they were with
`drawn from the study, and 3 had stable disease. One patient with an
`unresected but nonmeasurable peritoneal mesothelioma
`remains well
`and clinically free of disease progression
`11 months after treatment
`with 4 courses of Taxotere at 20 mg/m2.
`The pharmacokinetic data are summarized in Table 7. Both the end
`of infusion plasma drug concentration
`and the AUC showed large
`intersubject variations, although for individuals
`these two parameters
`correlated well (correlation coefficient, 0.90). The AUC was linearly
`related to dose up to 70 mg/m2, but there was evidence of a nonlinear
`increase in AUC at the MTD (Fig. 2). The drug was rapidly cleared
`from plasma at the end of infusion, and the drug disposition in plasma
`was best fitted by a monoexponential model. No Taxotere metabolites
`were detected in plasma or urine, and a mean of 2.3% (range, 1.2-3.
`7%) of the dose received was excreted unchanged in the urine within
`24 h of the completion
`of the infusion. The relationship
`between
`
`5.33(5.18-7.62)
`5.80(5.18-7.62)
`4.91 (2.10-7.19)
`1.79(0.32-7.02)
`0.37«0.05-2.89)to
`
`
`
`prior(iietnotlterapvLeukopenia
`
`MucositisWHO
`
`
`
`gradegrade12340
`
`22361543
`
`WHO
`
`1
`
`
`
`6ToxicityPriorchemotherapy1relationMedian90 ttiK/nr in
`
`
`
`
`
`nadir
`neutrophilsx
`
`109/liter (range)00.48
`
`1"
`«0.05-2.89)
`or 0 regimens
`03.58(1.98-7.91)
`0.34 «0.05-0.67)
`2 or more regimensMedian
`008143032
`" No. of courses associated with specified grade of toxicity.
`
`1
`
`over the course of the vein, lasting 2-3 weeks after the infusion, and
`were often followed by localized desquamation
`at the infusion site.
`This venous toxicity was observed in 9 of 30 patients at all dose levels
`above 20 mg/m2 and did not preclude further treatment
`in any of these
`patients. A desquamating
`skin rash affecting the palms and soles
`occurred in one patient after 3 courses at 90 mg/m2.
`An anaphylactoid reaction occurred in one patient at 70 mg/m2. Her
`first course of Taxotere was interrupted after 15 h because of a pyrexia
`(38°C).It was uncertain whether this was drug or tumor related, and
`
`4 weeks later a second course of Taxotere was commenced. Within 5
`min of the start of the infusion the patient became flushed, developed
`a tachycardia (sinus rhythm, rate 120/min), and complained of severe
`neck and low back pain. All of these phenomena resolved spontane
`ously within 30 min of stopping the infusion. The patient was already
`taking 10 mg/day prednisolone, and it was deemed clinically unsafe to
`administer any further infusions of Taxotere.
`No cardiovascular
`toxicity was observed. One patient suffered an
`uncomplicated
`inferior myocardial
`infarction
`1 week after his first
`course of Taxotere at 70 mg/m2. Although there was no previous
`history of ischemie heart disease,
`this patient was a heavy smoker with
`
`525
`
`Downloaded from
`
`on October 27, 2014. © 1993 American Association for Cancercancerres.aacrjournals.org
`
`
`Research.
`
`IMMUNOGEN 2191, pg. 4
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`l'HASI-:
`
`l STUDY OF TAXOM.Kl
`
`Table 7 Pharmacokinetics
`
`of Taxotere
`
`DoseEnd-of-infusionNo.of patientsconcentration(mg/m2)
`
`(ug/ml)20405570901
`assessed
`
`plasma
`
`t,0.922.19Central
`
`0.093
`0.14"(0.11-0.17)4
`
`0.14(0.06-0.23)3
`
`0.22(0.15-0.33)5
`
`(15.0-28.6)"
`
`Mean(range).10•*>1tJ*=».B
`
`57.029.133.0(2.14-2.24)
`37.9)2.560.6
`(0.4-2.3)
`70.843.3(1.19-3.28)
`(25.0-78.8)3.470.6
`36.033.1(2.90-4.51)
`(29.1-10.3)7.811.2
`
`0.46(0.27-0.57)AUC(ug/ml-h)36.219.5(5.95-9.82)
`
`(0.7-1.5)
`
`(0.5-0.7)
`
`(0.6 2.1)
`
`Clearance4
`
`o (h)(liters/h)0.2
`9.11.2
`
`volumeof
`distribution
`(liters)
`
`(23.4-100.6)
`
`(26.5-167.7)
`
`(29.1-40.3)
`
`(18.2-58.8)
`
`(29.8
`
`every 3 weeks or as a 1-h infusion, days 1-5, every 3 weeks,thepattern
`
`of toxicityis
`very similar to that described here,with
`febrileneutropenia
`associated with oral mucositismucositisappears
`
`(7, 8). Thus
`
`to be schedule dependent, butthecytotoxicity
`there is no evidence that
`of the drug is enhanced with prolonged infusions.
`Sincethe
`
`has been achieved with a 1-2-hinfusionevery
`greatestdoseadministered
`
`3 weeks, phase II studies havebegun
`withthis
`oncentensity
`
`schedule at a dose of 100 mg/m2. This dose is expected tocausea
`
`brief period of grade 4 neutropenia, but in the absence ofmucositisit
`
`is unlikely to lead to a significant number of septic episodes.Fromour
`
`study the dosewhich would be recommended for phase IIstudieswith
`
`a 24-h infusion is 70 mg/m2, although it may be possible tosafelyescalate
`mu-Overall
`90 mg/m2 in patients who do not develop
`the
`dose'0COSltlS.to
`
`arevery
`the patterns of toxicity observed with Taxotere and taxol
`
`similar (9). Neutropenia is the dose-limiting toxicity for both,andperipheral
`neuropathy and mucositis occur at doses around the
`MTD.The
`MTD for taxol administered as a 24-h infusion is 200-275
`(9) a,most 3 ,imes ,he MTD Kponed
`here with Taxotere, and
`,h
`h the prec|injcai data su„gestthat Taxotere is about
`twice
`poten, as the parem compoun(fi
`an inhibitor of tubulin depolymer-
`¡zation ¡t¡suncertain which will be the more active clinical
`
`O O
`
`•¿(cid:3)*^-—•¿(cid:3)C^•f**^
`
`ö
`
`rO
`OjTo
`
`//
`
`£
`
`50
`
`/y^^o
`
`O
`
`„¿(cid:3)_
`
`o0
`
`Plasma AUC(<ig/ml-h)
`
`10
`
`Fig. 3. Relationship between plasma AUC and the percentage relative fall in the
`neutrophil count following the first course of Taxotere.
`
`Table 8 Phase I studies with Taxolere
`
`major
`toxicityMucositisMucositisMucositisSkin
`
`toxicityFebrile
`
`neutropeniaFebrile
`
`neutropeniaFebrile
`
`x5MS55
`
`neutropeniaNeutropeniaNeutropeniaOther
`
`x 2Dose-limiting
`
`toxicityAstheniaReference781012
`
`Schedule24-h
`infusion.q
`3weeks6-h
`infusion.q
`3weeks1-h
`infusion.days
`1-5,q
`3weeks1-2-h
`infusion,q
`3weeks1-h
`infusion.day
`
`1 andday8,
`q 3 weeksMTD(mg/m2)9010016
`
`5§1PI01ôoo0oo
`
`Seo0lili20
`
`8
`
`(mg/m21Fig.
`
`
`
`40liDose
`
`60
`
`80
`
`2. Relationship between Taxotere dose and plasma AUC.once
`
`mg/m2plasma
`the first course of
`after
`in neutrophils
`
`AUC and the fallal-Taxotere
`as£max
`in Fig. 3 and may be approximated by a sigmoid
`isshown
`(maximum fall in neutrophil count) model where C50 (the dose
`
`which results in 50<7rof the maximum effect) = 3.5 ug/ml-h and y =agent.2.3.
`A similar model could be applied to relate the degree of neutro
`penia to theend of infusion plasma drug concentrations, but therewasno
`
`
`apparent correlation between these indices of drug exposure andinnthe
`
`severity ofmucositis.DISCUSSION1-H2
`
`ilEarly
`zin
`clinical studies with taxol have given rise to intense interest
`tubulin-binding
`agents, following the observation of clinical activ
`
`ity in cisplatin-resistant-^advantage
`ovarian cancer
`(6). Taxotere has a major
`over the parent compound:
`it is synthesized from a precur-
`sor derived from the needles rather than the bark of the yew tree, and
`thus the drug source is more plentiful
`and renewable. Preclinical
`studies were generally predictive of the toxicities observed in humans,
`namely leukopenia
`and mucositis. Hypersensitivity
`reactions were
`seen in dogs treated with Taxotere and have been relatively common
`in clinical studies of taxol, but only one such reaction occurred in this
`study. It remains uncertain whether the drug or the injection vehicle is
`the major cause of these reactions.
`The MTD, 90 mg/m2. produced significant but rapidly reversible
`toxicity in most patients.
`In 3 patients the short period of neutropenia
`was complicated by an episode of pyrexia, which required hospital-
`ization for therapy with antibiotics.
`It is likely that coincident oral
`mucosal ulcération(grade 3) provided the portal of entry for these
`infections.
`It has been noted that significant oral mucositis does not
`occur at 85 mg/m2 when Taxotere is infused over 1-2 h once every 3
`weeks, and a dose of 100 mg/m2 produces acceptable toxicity.3 Phase
`I studies with other schedules have recently been completed and are
`summarized in Table 8. When administered either as a 6-h infusion
`
`526
`
`
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`
`
`Research.
`
`IMMUNOGEN 2191, pg. 5
`Phigenix v. Immunogen
`IPR2014-00676
`
`

`

`FHASI-:
`
`I STl'DY OF TAMII
`
`I Kl
`
`reactions will
`the relative frequency of hypersensitivity
`Similarly,
`only be assessable when the phase II studies of Taxotere have been
`completed.
`that Taxotere is rapidly cleared
`data reveal
`The pharmacokinetic
`from plasma, but end-of-infusion
`concentrations
`in plasma are none
`theless greater
`than the median inhibiting concentration
`values for
`some tumor
`lines in vitro (2). Phase I pharmacokinetic
`studies of
`Taxotere administered as a shorter infusion have been less constrained
`by the sensitivity of the HPLC assay, and in these the disposition of
`the drug appears biexponential, with a r,/2a of 5-7 min and a rl/2ßof
`about 3-4 h (7, 8, 10). All studies have found less than 10% of the
`drug excreted in the urine. The corresponding
`pharmacokinetic
`pa
`rameters of taxol are very similar (9). Man appears to be rather more
`sensitive to Taxotere than mice; the plasma AUC in mice at the murine
`MTD was 17 ug/ml-h compared with the AUCs
`in patients at 90
`mg/m2 of 5.9-9.8 pg/ml-h (11).
`It might be expected that the major determinant of cytotoxicity of
`Taxotere and taxol would be the duration of drug exposure above a
`certain threshold concentration,
`and that
`the short half-life of these
`agents would favor the use of prolonged infusions, but the preclinical
`data for Taxotere do not support
`this (4) and as yet there is insufficient
`clinical data for either drug to assess the effect of schedule on anti-
`tumor activity.
`Although no responses were observed in this study, objective re
`sponses have been reported in breast and ovarian cancer
`in the other
`phase I studies of Taxotere (7, 11, 12), and the results of the current
`phase II studies of this agent are awaited with interest.
`
`REFERENCES
`
`F., and Potier, P.
`1. Mangalal. L., Adeline, M. T.. Guenard, D.. Guerette-Voegelein,
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`Application of the vicinal oxyamination
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`3. Gueritte-Voegelein.
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`Polier. P. Relationships between the structure of taxol analogues and their antimitotic
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`F, and Lavelle, F. Experimental
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`Bayassas, M., and Bums, H. Phase I clinical
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`8. Pazdur, R.. Newman. R. A., Newman. B. M.. Bready, B., Bayssas, M., and Raber. M.
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`111, 1992.
`9. Rowinsky, E. K., Cazenave, L. A., and Donehower, R. C. Taxol: a novel
`investiga-
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`10. Rousseau, F.. Extra, J. M., Giacchetti, S., Bruno. R., Le Bail. N.. and Marty, M. Phase
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`study of Taxotere (RP56976). Ann. Oncol..
`.fISuppl. 1): 121.
`1992.
`11. Bissery, M. C., Renard, A.. Montay, G., Bayssas, M., and Lavelle, F. Antitumor
`activity and pharmacokinetics
`in mice. Proc. Am. Assoc. Caner Res., 32: 401. 1991.
`12. Tomiak, E., Piccar!, M. J., Kerger, J., de Valertela, D., Tueni, E., Lossignol. D.,
`Sculier, J. P.. Lips, S., Le Bail, N., and Bayssas, M. A phase I study of Taxotere
`(RP56976 NSC628503) administered as a one hour intravenous
`infusion on a weekly
`basis. Ann. Oncol., J(Suppl.
`1): 122. 1992.
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`Downloaded from
`
`on October 27, 2014. © 1993 American Association for Cancercancerres.aacrjournals.org
`
`
`Research.
`
`527
`
`IMMUNOGEN 2191, pg. 6
`Phigenix v. Immunogen
`IPR2014-00676
`
`