1038 Vo', 8. 1038- '044. May 2002
`
`Clinical Cancer Research
`
`Phase I and Pharmacokinetic Study of ABI-007, a Cremophor-free,
`Protein-stabilized, Nanoparticle Formulation of Paclitaxel'
`
`Nuhad K. Ibrahim , Neil Desai, Sewa Legha,
`Patr ick SOOiI-Shiong, Richard L. Theriault,
`Edgardo Rivera, Rita Esmaeli, Sigrid E. Ring,
`Agop Bedikian, Gabriel N. Hortobagyi, and
`Julie A. Ell erhorse
`Departments of Breast Medical Oncology [N. K,l, R. L. T .. E. R ..
`G. N. 1'1.1. Melanoma/Sarcoma [So L.. S. E. R .. A. B .. J. A. E.]. and
`OphthalmQlogy [8. E.], The University of Te:<as M D. Anderson
`Cancer Center. Houston, Te:<as 77030. and American Bioscience.
`Inc .. Santa Monica. California 90403 [N. D .. I'. S·S.]
`
`ABSTRACT
`Pllrpose: ABI·OO7 is a nO\'el Cr emophor.free, protein.
`stabilized , nanopartie le formulation of paclitaxel. Th e ab(cid:173)
`sence of C r emophor EL may permit ABI·OO7 to be admin·
`istered w itho ut the premedications used routin ely fo r the
`prevention of h)'penensitivity reactions. Furt hermore, this
`novel formulation permits a higher paelitaxel concentra tion
`in solutio n and, thus, a decreased infusion \'o lume a nd time.
`This Phase I study examines t he toxicity profile, maximum
`tolerated dose (i\1TD), a nd pharmacokin etics of ABI-007.
`Experimemu/ Desigll: AB I'()07 was administered in the
`outpatient selling, as a 30-m in infusion without p r emedica(cid:173)
`tions. Doses of ABI·007 r an ged from 135 ( Ie\'e l 0) to 375
`mg/m 2 (len'l 3). Sixteen patients participated in pharmaco(cid:173)
`kinetic studies.
`RCI>'I1/ts: Nineteen patie nts were treated. No acute hy(cid:173)
`persensitivity reactions were obsen'ed during th e infu sion
`Ileriod. He matological toxicity was mild a nd not cumu lath·e.
`nose-limiti ng toxicity, which occurred in 3 of 6 patients
`treated at level 3 (375 mg/m2), consisted of sensory neuroll'
`athy (3 patients), stom atitis (2 pa tients), a nd superficial
`ke ratopathy (2 patients). The MTD was thus determined to
`bc 300 mg/m 2 (lc"1'1 2). Pharmacukinctic a nalyses r en'alcd
`Il acl it a .~e l C,,"w_, a nd area under the cu n 'eh,r "alues to in·
`cr ease li nearly O\'e r the ABI-{)07 dose range of 135-300
`mg/m 2. C ",,,, and area unde r t he curvelM \'alues for indh'id·
`ual patie nts cor related we ll with toxicity.
`CO/tell/siVilS: A BI·007 offer s se\'er a l fe a tures of clinical
`interest, including rapid infus io n rate, absence of r equire-
`
`Received 9125101: revised 1123102: accepled 211102.
`The COSlS of publication of this article were defrayed in part by lhe
`paymcnt of pagc charges. This article mllSt lherefore be hereby marked
`IlIb'erli;'cIIICIII in aCCOldance with 18 USc. Section 1734 solely lO
`indicate lhis fac\.
`'Supported by American Bioscience. Inc .. Santa Monica. CA
`2 To whom requests for rqrnnts should be addressed. al DepartmClll of
`Molecular and Cellular Oncology. Bo.'!. 79. M. D. AndclSOn Canccr Ccmer.
`1515 Holcombe Boulevard, Houston. TX 77030, Phone: (713)792·8990;
`Fax: (713) 794·0209: E-mail: jaellerl1@maiLmdandcrson.org.
`
`ment for premedication , and a high paelitaxel MTD. Our
`rcsults provide support for Phase II trials to determine the
`antitumor aetivity of th is drug.
`
`INTRODUCTION
`Paclitaxcl is a chemotherapeutic agcnt with a widc spec·
`trum of antitumor activity when used as Illonothcrapy or in
`combination chemotherapy regimens (I). The drug is used ex(cid:173)
`tensively in the treatment of advanced carcinomas of thc breast,
`ovary, head and neck, and lung. Research into its activity in
`prOState cancer and urothelial tumors is ongoing as well. On the
`basis of early reports suggesting a dose·response phenomcnon
`(2.3), and in kecping with standard med ical oncology practice.
`auempts are generally made to maintain paclitaxel doses at or
`near the MTD.3 Several schedules of administration havc been
`studied, each de monstrating a slightly different toxicity profile.
`Short infusions of 1- 3 h result in peripheral neuropathy as a
`longer, continuous infusion
`dose-limiting toxicity, IVhereas
`schedules produce a higher incidence of neutropenia (2. 4 - 6).
`Other common side effects include alopecia. mucositis. arthral·
`gias, myalgias, and mild nausea.
`The paclitaxcl preparation in clinical usc (Taxol; Bristol(cid:173)
`Myers Squibb, Princeton, NJ) is fonnulated in the non ionic
`surfuctun( Cremophor EL (polyoxyclhyluled castor oi l) und eth·
`anolto enhance drug solubility (7). Cremophor EL may add 10
`paclitaxers toxic cffects by producing or contributing to the
`well·described hypersens itivity reactions thut commonly occur
`during infusion, affecting 25- 30% of treated patients (8, 9). To
`minimize the incidence and severity of these reactions, premed(cid:173)
`ication with histamine I and 2 blockers, as well as glucoconi(cid:173)
`coids (usually dexamethasone), has become standard practice
`(l0). The cumulative side effects of dexamethasone used as a
`premedication may add to treatment-related morbidity and, in
`some instances, result in early discontinuation of therapy.
`Cremaphor EL may also contribute to chronic paclitaxel toxic
`effects, such as periphera l neuropathy (II). A n additional prob(cid:173)
`lem arising from the Cremophor and elhanol solvent is the
`leaching of plasticizers from PVC bags and infusion sets in
`routine clinical usc (12). Consequently, Ta.'!.ol must be prepared
`and administered in either glass boules or non-PVC infusion
`systems and with in-line fil tration. These problematic issues
`have spurred interest in t he development of taxanes with im·
`proved solubility in aqueous solutions (13).
`ABl·007 is (I novel Cremophor-frec fOnlw lation o f pacli(cid:173)
`taxel (14). It is prepared by high-pressure homogenization of
`paclitaxel in the presence of human serum albumin, resulting in
`a nanoparticle colloidal suspension. Like Taxol, A BI-007 dos-
`
`J The abbrevi3lions used are: MTD. maximum tolerated dose: ANC.
`absolute neutrophil count: AUC. arca under the curve; CL. clearance:
`PVC. polyvinyl chloride.
`
`Apotex v. Abraxis -IPR201 8-00IS2, Ex. 101 8, p.OI of7
`
`

`

`Clinical Cancer Research 1039
`
`Table I Dose levels
`
`Level
`
`0
`
`2
`3
`
`Dose (mg/m2)
`US
`200
`300
`m
`
`No. patients entered
`
`4
`3
`6
`6
`
`No. cycles
`6
`38
`JS
`
`"
`
`age is determined by the paelitaxel content of the fonnulation,
`making direct comparison of the two drugs possible. AB[-007
`can be reconstituted in normal saline at concentrations of2- [0
`mglml, compared with 0.3- 1.2 mglml for Taxol. Thus, the
`volume and time required for administration is reduced. [n the
`absence of Cremophor EL, the risk of hypersensitivity reactions
`should decrease significantly, and patients receiving AB[-007
`might thus avoid premedication. Moreover, there is no danger of
`[caching plasticizers from infusion bags or tubing, and conven(cid:173)
`tiona[ PVC infusion systems may be safely used.
`To explore the potential clinica[ utility of ABI-007, we
`have conducted a Phasc [ study of this drug for patients with
`advanced solid tumors. The objectives of this trial were to
`dctennine the toxic efTects, MTD, and phannacokinetic profile
`of this unique paelitaxel preparation.
`
`PATIENTS AND METHODS
`I'alient Eligibility and Evaluation on Study, Eligible
`patients inc[ uded those with a diagnosis of an advanced solid
`tumor, having failed standard therapy. Requirements included a
`Zubrod performance status of 0- 3, an expected survival of > 6
`weeks, hemoglobin 2 9 gldJ, ANC 2 1,500/mm 3
`, plate[et
`, serum creatinine < 2 mg/dl, and scrum
`count 2 [00,000/mm3
`bilirubin < 1.5 mg/dl. Patients with prior exposure to taxanes
`were eligible for the study.
`Pretreatment evaluations ineluded a complete blood count
`with difTerentia[ and p[ate[et count, serum chemistry profile,
`chest radiograph, and electrocardiogram. Baseline imaging stud(cid:173)
`ies and serum tumor marker levels were obtained at the discre(cid:173)
`tion of the tTCating physician. Brain imaging by computerized
`tomography or magnetic resonance imaging was required for
`patients with symptoms suggestive of central nervous system
`involvement. Eva[uations perfonned during the study ineluded a
`complete blood count with differential and platelet count at least
`once weekly and a chemistry profile prior to each course.
`Restaging was perfonned after every 2nd or 3rd cycle of ther(cid:173)
`apy. Patients were removed from the study for progression of
`disease, unacceptable toxicity, or at the patient's request.
`Sludy Design. This Phase I study was conducted at The
`University of Texas M. D. Anderson Cancer Center and was
`approvcd by thc M. D. Anderson Instillltional Review Board.
`Infonned consent was obtained from all subjects. Toxicity was
`graded according to Nationa[ Cancer Institute Common Toxicity
`Criteria. Dose [evels of AB [-OO7 are shown in Tab[e l. Dose
`escalation followed the standard "3 + 3" rule. Bricfly, 3 patients
`were accrued at the starting dose level. I f no toxic effects greater
`than grade 2 were observed, ) patients were entered at the next
`dose [evel. If, at any level , one of the first) patients experienced
`a gmde ) or 4 toxic effect, ) additional patients were entered at
`that dose level. The MTD was defined as one dose level below
`
`that at which 2 2 patients experienced grade 3 or 4 toxic efTects.
`Six patients were to be treated at the MTD. Patients were
`permitted to escalate to the next higher dose level if no signif(cid:173)
`icant toxic effects were obselVed after the first 2 cycles of
`therapy. Patients with toxicity greater than grade 2 were per(cid:173)
`milled to reduce dosage by one dose [eve[ and remain on thcrapy
`at the discretion of the treating physician.
`Treatment. A8l-00? was supplied by American Bio(cid:173)
`science, Inc. (Santa Monica, CAl. All therapy was administered
`in the outpatient treatment center of the M. D. Anderson Cancer
`Center, with the exception of patients participating in phanna(cid:173)
`cokinetic studies, which required an overnight hospital stay. The
`prescribed dose of A8[-007 was prepared in [00- [50 ml of
`0.9% saline. The drug was administered i.v. without in-line
`filtration and without premedication. For the first 3 patients on
`study, the total dose of A8[-007 was administered at a rate of
`1.4 mglkglh or roughly over) h. If no acute hypersensitivity
`reactions were noted, the rcmainder of the patients were to
`receive treatment over )0 min. One cycle of therapy was 2 [
`days.
`studies
`Pharmacokinctic Studies. Phannacokinetic
`were perfonned in [6 patients, with at least) patients reprc(cid:173)
`senting each dose level. Whole blood samples of 5 ml each were
`taken to detel1l1ine the phannacokinetics of AI3l-007 at 13 time
`points: 0, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18. 24, and 48 h.
`Paclitaxel was extracted from whole blood samples using pro(cid:173)
`tein precipitation with acetonitrile, followed by solid phase
`extraction. The sample extracts were analyzed for paclitaxel
`using liquid chromatography atmospheric pressure ioni7.ation
`tandem mass spectrometry. The limit of quantilation for pac li(cid:173)
`taxel is 5 ng/ml, and the range of reliable response is 5- 1000
`ng/ml.
`Pharmacokinctic parameters wcre detcnnined from each
`paticnt's whole blood/plasma paclitaxel concentration profile.
`Analysis was pcrformed by thc noncompanmental routine lIsing
`WinNonlin software (Pharsight Corp., Mountain View, CAl.
`The peak or maximum paclitaxcl concentration (Cm"~) and the
`corresponding peak timc (t",a~) were obselVed values. The elim(cid:173)
`ination constant (AI2.) was obtained by log-linear regression
`analysis of thc tcrminal phase of the whole blood/plasma con(cid:173)
`centration l'erSIIS time profilc. The climination half-li fe (Tin)
`was dctcnnined by taking thc ratio of natural log of 2 and A 12z.
`The AUC from timc 0 to time infinity (AUC;",.) was obtained by
`summation of AUC,,, .. (AUC from time 0 to last measurable
`concentration, calculatcd by the linear trapezoidal nile) and
`AUCcx, (extrapo[ated area, estimated by taking the ratio be(cid:173)
`tween the last measurable concentration and A 12). The dosc
`area relationship (i.e .. total ABI-007 dose divided by AUCinf)
`was used to determine total body CL. The volumc of distribution
`(VJ was dctcrmincd by taking thc ratio between CL and A12z.
`Descriptive statistics (mean, median, SD, cocmcient of
`variation, maximum, and minimum) werc computed for peni(cid:173)
`nent phanllacokinetie parameters by ABI-007 dose. Regression
`analysis of mean AUC;"f l'CrSIIS dose was perfomled to gain an
`appreciation of phamlacokinetic linearity, if evident, for the
`dose range evaluated in this trial. DifTerenees in the means of
`Cmax and AUC;nf betwcen groups of paticnts were analyzed for
`significance using a two-tailed, two-sample I test. Pearson's
`
`Apotex v. Abraxis - IPR20I S-00IS2, Ex. lOIS, p.02 of7
`
`

`

`1040 Phase! Trial and Pharmacokinetics of AB! -007
`
`Table 2 Patient characteristics
`
`Enrolled
`Eligible
`Age (yr)
`Median
`Range
`Performance status (Zubrod)
`o
`1
`2
`Gender
`Female
`Male
`Malignancy
`Breast cancer
`Melanoma
`Prior trealmem
`Chemotherapy
`Inununothcrapy
`Radiotherapy
`
`No. (%)
`20
`19
`
`50
`33- 83
`
`2 (10)
`14 (74)
`3 (16)
`
`16 (84)
`3 (16)
`
`13 (68)
`6 (32)
`
`19 (100)
`6 (32)
`15 (79)
`
`correlation coefficient was used to examine the correlation be(cid:173)
`tween degree of myelosuppression and C"",x or AUC;nt'
`
`RES ULTS
`I'aticnts. Twenty patients were enrolled in the trial. One
`of these chose not to be treated after signing an infonned
`consent. Therefore, 19 patients received drug and were evalll(cid:173)
`able for toxic effects. Patient characteristics arc summarized in
`Table 2.
`treatment
`Treatment and MTD Determination. All
`was administered without dexamethasone or histamine I or 2
`blockers. The firs t 3 palients received infusions of AB1-007 over
`2- 3 h. No hypersensitivity reactions wcre observed. Therefore,
`all subsequent infusions were administered over 30 min. Even at
`the faste r infusion rate, there were no instances of acute hyper(cid:173)
`sensitivity to the AB1-OO7 preparation.
`Threc patients were entered initially at level 0, receiving
`135 mg/m2 over 3 h. One of these experienccd progression of
`disease over the next scveral wecks, with rapid elinical deteri(cid:173)
`oration, making it difficult 10 ascertain toxic effects of AB1 -007
`in this individual. To verify toxicity data at this dose level and
`ascenain the safety of administering the drug over a short
`infusion period, a 4th patient was entered at level 0 and was the
`first palient to receivc drugs ovcr 30 min. There were no
`instances of gradc 3 or 4 toxicity observed at dose levels 0 or I
`(200 mg/m2). At dose level 2 (300 mg/m2), I of the first 3
`patients developed gmde 3 sensory neuropathy. Three more
`l1atients werc accrued al this levcl, with no additional observa(cid:173)
`tions of dose-limiting toxicity. At dose level 3 (375 mg/m2),
`during the 1st cycle of treatment, one of the first 3 patients
`experienced grade 3 sensory neuropathy, grade 3 stomatitis, and
`a visual disturbance diagnosed as superficial keratopathy, also
`grade 3. An additional 3 patients were accrued at level 3. One
`patient from this second cohort experienced a similar spectrum
`of grade 3 toxic effects, ineluding sensory neuropathy, stoma(cid:173)
`titis, and superficial keratopathy; this patient developed grade 3
`vomiting and diarrhea and thrombocytopenia as well. An addi-
`
`Tobie J Median absolute neutrophil and platelet nadirs by dose level
`ANC nadir x
`toJ/mm)
`(mngc)
`
`Platelet nadir X
`10)/mm)
`(range)
`
`Dosc level
`o
`1
`2
`3
`
`2.229 (t .850-5.(40)
`1.845 (0.586-3.729)
`0.960 (0.264-3.680)
`0.966 (0.018-1.804)
`
`204 (174- 292)
`197 (118- 270)
`200 (1 05-609)
`173 (25-251)
`
`tional case of sensory neuropathy. this lime as an isolated grade
`3 toxic effect. was obscrved in a 3rd patient at level 3. The study
`was thus tenninated. The MTD for ABI-007 administered as a
`30-min infusion every 21 days, as determined by this study, was
`300 mg/m2
`• The dose-limiting toxic effecl.~ were sensory neu(cid:173)
`ropathy, stomatitis, and superficial kemtop3thy. Specific toxic
`effects are deseribed below.
`Hematological To .~icity. Hematological toxicity was
`dose dependent but remained modest throughout the study (Ta(cid:173)
`ble 3). Of the 96 treatment cycles administered, only 7 (7.3%)
`resulted in an ANC nadir < 500/mm J
`, 6 of which occurred
`above the MTO at dose level 3. There was one hospital admis(cid:173)
`sion for febrile neutropenia. In only one case did the platelet
`count drop below 75,OOO/mmJ • The patient, who was found to
`have 3 platelet nadir of 25.000/mmJ during her 1st eyele of
`therapy at level 3, also developed a constellation of gmde 3
`nonhematological toxic effects. This was the only individual
`who required a platelet transfusion during the study. No patients
`received growth factors for gmnulocyte support.
`Nonhcmatological Toxicity. Table 4 summarizes the
`nonhematological toxic effects obscrved during the first 2 cyeles
`of therapy at each dose level. The majority of these were gmdes
`I and 2; no patient manifested grade 4 toxicity. Nausea, vom(cid:173)
`iting, and muscle and joint aches were common but mild. Skin
`toxicity was also mild, consisting of dry skin or localized
`vesicular or pustular rash. Alopecia was univers;tl. Peripheral
`neuropathy, absent at the lower dose levels, was common with
`higher doses, appearing in II of 12 patients treated at levels 2
`and 3. The neuropathy occurred in a typical stocking/glove
`distribution and was manifested by numbness or pain. Six pa(cid:173)
`tients with peripheml neuropathy developed peri-oml numbness
`as wel l. As described above, the most severe nonhematological
`adverse effects occurred in 2 patients at dose level 3, consisting
`of a complex of peripheral neuropathy. stomatitis. and superfi(cid:173)
`cial keratopathy, all gmde 3.
`A variety of ocular side effects was observed, the severity
`of wh ich appeared to be dose dependent. One patient. entered at
`level 0, complained of dry eyes but noted no visual disturbance.
`No ocular eomplaints wcrc rcgistcred by patients treatcd at lcvel
`I. Four patients developed ocular toxicity at level 2. One noted
`intennillent "smoky" vision, and another experienced blurred
`vision, both occurring with cyele I and both presenting as grade
`1. Two other patients at dose level 2 noted --flashing lights" and
`photosensitivity during their third course of treatment. One went
`on to develop grade 2 superficial keratopathy during course 4.
`The other experienced a reversible decrease in visual acuity
`without specific abnonnalities on ophtha lmologic exam. At
`level 3, 2 patients complained of mild dry eyes throughout
`
`Apotex v. Abraxis -IPR20 IS-00I S2, Ex. lOI S, p.03 of7
`
`

`

`Clinical Cancer Resean::h 1041
`
`Tabl(!4 Nonhematologic toxicity by dose kvclu
`
`Level 0 (n - 4)
`
`Level I (n - 3)
`
`Level 2 (n - 6)
`
`Level 3 (n - 6)
`
`Grade
`1~2
`
`Grade
`Grade
`Grade
`Grn""
`I or 2
`Toxicity
`3
`3
`3
`Sensory neuropathy
`0
`0
`0
`0
`1
`Ocular
`0
`1
`0
`0
`0
`Stomatitis
`0
`0
`0
`0
`1
`Nausea
`0
`0
`0
`1
`1
`Vomiting
`0
`1
`1
`0
`0
`Diarrhea
`2
`0
`0
`0
`1
`Anhralgia/myalgia
`0
`0
`3
`0
`3
`Skin
`0
`0
`0
`0
`0
`Fever (non-neutropenic)
`0
`0
`0
`0
`0
`u Expres5Cd as the number of patients experiencing the toxic effect during the first two cycles of treatment.
`
`Grnd,
`I or 2
`4
`2
`4
`3
`0
`3
`4
`
`Grade
`I or 2
`
`2
`3
`4
`2
`1
`4
`2
`3
`
`Grade
`3
`3
`2
`2
`
`1
`1
`0
`0
`
`1 ~.00 ,-------------------------------------,
`
`I'harmacokinClic profile of ABI -007
`Fig. I
`showing mean whole blood paclitaxel concentra(cid:173)
`tions at increasing doses of ABI-007 ,"{;rSIIS time.
`All infusions were given over 30 min except for
`the first 3 patients who received 135 mglml over
`180 min.
`
`1000.00
`
`100.00
`
`10.00
`
`6 - 135 mQlm2 (11:10 min~ .-.:3
`6 - 135 "'11m2 (30 mln~ ... 1
`+ - 200 moIm2 (30 min~ n" 3
`_ <)_ 300 "'IIIml (30 mi n~ n=5
`- )( 375 "'11m2 (30 mm~ n,,",
`
`_._. __ .-.
`
`1.00 1---__ --__ --__ ----__ --__ --__ --__ --- !
`o
`
`30
`
`36
`
`42
`
`48
`
`6
`
`12
`
`18
`
`24
`
`Time (hr)
`
`therapy but did nOI experience visual disturbances. Two other
`patients at dose level 3 developed grade 3 superficial keratopa(cid:173)
`thy during thcir 1st cycle of treatment, as described above. All
`cases of kcratopathy received fu ll ophthalmologic evaluation,
`and all resol ved with the use of topical lubricating drops and
`oint111ents. No patient developed a permanent loss of vision or
`experienced any other permanent ocular sequeliac.
`Occurrences of new types of toxic effects after the first 2
`cyeles ofthempy were mre. Furthermore, it was uncommon for
`IOxic effects to increase in grade after the first 2 treatment
`cycles. Therefore, cumulative IOxicity did not appear to be a
`significant problem.
`Resllonse. Partial responses were observed in two breast
`Cancer patients, both of whom had prior exposure to Taxol. The
`first paticnt, entcred at dose level 2. experienced a G8% decreaSC"
`in the size of pulmonary metastases. Th is responSC" lasted a total
`of 15 months, ineluding 9 months after diseontinuation ofther(cid:173)
`apy for toxicity. The 2nd patient, who was also treated at dosc
`level 2, had significant improvement in soft tissue disease in(cid:173)
`volving the chest wall. Because of toxic effects, she was taken
`off treatment on Ihe date of her response. Disease progression
`was noted 6 weeks later.
`Pharmacokinetic Stud ies_ Sixteen of the 19 patients en(cid:173)
`tered into the study contributed analyzable phannacokinetic
`
`profiics. Three of these received AI3l-007 as a ISO-min infusion;
`the remaining [3 were treated over 30 min. A scmilog plot of the
`mean values of the whole blood paelitaxel eoneentmtion for
`each dose level ve,.sus time is shown in Fig. 1. The maximum
`paclitaxel concentrations were observed at the tennination of
`ABI-007 infusion; the decline from maximum was biphasic.
`A summary of the pharmacokinetic parameter values de(cid:173)
`rived by noneompanmental methods is shown in Table 5. The
`pharmacokinetics of AB1-OO7 administered oyer 30 min ap(cid:173)
`peared to be linear across the three lower dose levels, which
`included the MTD ( Fig. 2). Calculations from the data in Table
`5 reveal a 2.2-fo[d increase in C",a~ and a 2.7-fold increase in
`AUC;"r oYer the 2.2-fold increase in dose from 135 to 300
`mg/m2. The decline in CL estimates over this range is O.S-fold
`(1(;.[%). [f the highest dose level of 375 mg/m 2 is included,
`nonlinearity becomes evident (Fig. 2). Individual C'n.~ and
`AUC;"r values )"US/IS dose arc shown in Fig. 3, a and b,
`respectively.
`The group of 13 patients who received 3D-min infusions
`and for whom phannaeokine[ie profiles were obtained included
`3 who experienced grade 3 nonhemato[ogical toxic effects (neu(cid:173)
`ropathy with or without stomatitis and kemtopathy). The C,,,,, ..
`and AUC;nf for these 3 patients relative to those of the remaining
`[0 patients arc plotted in Fig . 4. The differences in mean Cm" ..
`
`Apotex v. Abraxis -IPR20IS-00IS2, Ex. lOI S, p.04 of7
`
`

`

`1042 Phase! Trial and Pharmacokinctics of AB! -OO7
`
`T(lhle 5 Summary of noncompartmcnta! pharmacokindic parameters. mean (% coefficient of variation) valucs by dose~
`
`Infusion duration
`AUC;nr
`CL litcrlh/m2
`mm
`V. !iter/m2
`Half-lifc h
`nglhlm!
`C .... , nglm!
`"
`418 (32)
`27.4 (45)
`12.9 (60)
`5654 (42)
`! 392 (30)
`3
`180
`135
`442
`14.6
`21.1
`I
`135
`6427
`6100
`30
`384 (64)
`21.4 (21)
`13.4 (67)
`9613 (20)
`7757 (35)
`3
`200
`30
`370 (23)
`17.7 (22)
`14.6 (14)
`13520(7)
`17610(21)
`30
`300
`5
`236 (54)
`11.9 (42)
`13_2 (12)
`35805 (40)
`19350(15)
`4
`30
`375
`" n. number of patients; C ...... ma:<imum or peak concentration; AUC;nf' area under the whole blood/plasma conccntration -time cur.-e from time
`o to time infinity; CL. total body clearance; V •. volume of distribution.
`
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`Fig 2 Correlation between the mean AUC;nfand
`dose level. The <l.1ta havc becn fit using a linear
`regression and an c:<poncntial regression function
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`and mean AUC;nfbelween the IwO groups werc significant (P =
`0.034 and 0.007, respectively). The effect of A BI ·007 exposure
`on myelosuppression was also examined in t his group of pa(cid:173)
`tients. The pereentage of decrease in ANC from baseline to
`nadir was found to correlate positively with both C,,,,"x (r
`0.610, P = 0.027) and AUC;ndr = 0 .614, P = 0.025).
`
`DI SC USS ION
`This clinical trial was conducted to examine the pharma(cid:173)
`cokinetic properties and spectrum of toxic effects associated
`with AB I-007. Because ABI -007 is not formulated in a Cremo(cid:173)
`phor-containing solvent, we anticipated that hypersensitivity
`reactions would be diminished or abscnt. Our results show that
`A I3I-007 can indeed be administered safely as a short infusion
`without dexamethasone or antihistaminc premedication. Thus.
`when considering the process of drug administration, ABI-007
`appears to offer advantages in terms of safety (avoidance of
`hypersensitivity reactions), morbidity (avoidance of dexametha(cid:173)
`sone premedication), and patient convenience and comfon (less
`time spent in the treatment center). These advantages could
`ultimately tmnslate into an overall decrease in cost of therapy.
`It must be pointed out that, although the absence of Cre(cid:173)
`mophor is clearly desirable wilh respect to toxicity, this same
`compound has been proposed to enhance the efficacy of cyto(cid:173)
`toxic drugs through reversal of the multidrug resistance pheno(cid:173)
`type ( 15). Plasma concentrations of Cremophor attainable dur(cid:173)
`ing Taxol infusions are sufficient to inhibit P-glyeoprotein
`effects ill vitro (16). However, there have been questions raised
`as to whether these Crc mophor concentrations arc relevant to
`
`solid tumors, as phannacokinetic studies demonstrate the com(cid:173)
`pound's distribution to be limited to the central plasma com(cid:173)
`panment (17). This issue should be clarified with the completion
`of ongoing Phase II tria ls of ABI-007. If the response rate o f
`ABI -007 is not less than that of Taxol and if responses arc seen
`in patients who arc previous taxane failufCs, the therapeUlic
`contrib ution ofCremophor to pac1itaxel can be considered neg(cid:173)
`ligible.
`In terms of treatment-related toxicity, a lower incidence o f
`myelosuppression was observed than that which we anticipated
`based on the dose of paclitaxel administered. In this regard,
`hematological toxicity was mild and played vinuaJly no role in
`dose a nd treatment decis ions made in this trial. Although direct
`comparisons to Taxol administered at this dose range and sched(cid:173)
`ule are not possible, the myelosuppression induced by AB I-007
`appeared to be similar to or less severe than that reponed for l-h
`Taxol infusions at lower doses ( 18). Otherw ise, the spectrum o f
`toxic effects produced by ABI-007 resembled that of high-dose
`short-infusion Taxol reported in early Phase I trials, with sen(cid:173)
`sory neuropathy and mucositis becoming dose limiting (19,20).
`A third dose-limiting toxic effect, superficial keratopathy, was
`also observed. We were unable to find any prior repon o f
`superficial keratopathy as a consequence of paclitaxel admi nis(cid:173)
`tration. In our Phase I trial, this side effect appeared to be related
`to dose and presented at the level of grade 3 only above thc
`MTD, at a dose of 375 mg/m2. Superficial keratopathy second(cid:173)
`ary to ABl-007 was similar to that most com monly recognized
`in association with I-f}- D-arabinofuranosylcytosine, although
`any type of ocular surface irri tation, including dry eye syn-
`
`Apotex v. Abraxis - IPR20 IS-00 152, Ex. l OIS, p.05 of7
`
`

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`a -
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`
`Individual values of C ...... (a) and AUC;.r (b) ~WSIIS dose for
`Fig.3
`patients receiving 30-min infusions. of ABl-007.
`
`Clinical Cancer Research 1043
`
`a ,~
`
`~ -E
`5 ' 5000
`~10000
`U
`
`~
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`Grade 3 Toxicity
`
`i
`I
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`o
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`Grade 3 To~ i city
`
`Fig.4 Individual values of C""" (a) and AUC;n' (b) for patients who
`experienced grade 3 nonhematological toxic efT~'{;ts ("yes'') and those
`who did nol r'no··). In Ihe "ycs" category. the solid diamond symbols
`(. ) represenl 2 patients wilh multiple grode 3 toxicities. whereas the
`open circle (0 ) rcprc:scms the patient with only grade 3 neuropathy.
`
`drOIllC, can result in similar cOnical findings (2 1). Other ocular
`complications of taxanc therapy have oc>cn reported. The most
`COlll1110n adverse ocular effects of Taxol arc p hotopsia and
`blurred vision, usually reported by patients during the infusion
`period (22, 23). Cases of oplk nerve disturbances have also
`been documented (24). Cases of grade 2 conjunctivitis necessi(cid:173)
`tating dose reduction and treatment delay have been reponed
`during weekly therapy with docclaxel (25). Similar to our find(cid:173)
`ings, reported ocular effects from paclitaxcl have been noted
`only at higher doses and arc usually transient. Although all cascs
`of keratopathy in this study resolved completely and without
`pemlanent sequellae, in the ensuing Phase II trial, patients will
`be aggressively monitored for the development o f ophthalmo.
`logic abnormalities,
`Pharma<:okinetic analysis of ABJ-007 revealed interesting
`similarities and differences relative to Taxol, based on published
`data. Disappearance from the blood is biphasic for both drugs
`(19). AB1-O07 displays linear pharmacokinetics over the clini·
`cally relcvant dose range of 135-300 mg/m2; over a similar dose
`range, Taxol AUe;nf is nonlinear (26- 28). In comparing thc
`AUC;"rvaluesof ABI-007 infused ovcr 30 min to those reported
`for Taxol infuscd ovcr I or 3 h, AB I-007 in gcncnd showed
`lower AUC;nf values over a similar range of doses (26- 28),
`Although several explanations are possible for the differences in
`AUC;nf> it is reasonable to hypothesize that ABJ·007 may be
`distributed more rapidly out of the vascular compartmcnt, a
`suggestion supported by the diffcrencc in formu lation between
`the two drugs. A substantial a mount of solvent (Crcmophorl
`cthanol) is infused with Taxol, and thc partition o f paclitaxcl
`from thc vascular compartmclll to thc tissucs may thus be
`relatively slow. In contrast, AB I·007 is formulated with human
`
`serum albumin at a conCClltration of 3- 4%. similar to the
`concentration of albumin in the blood. Because paclitaxcl has a
`vel)' limitcd solubility in an aqucous albumin solution «30
`I-lg/ml), it may partition more efficiently into the tissues in the
`case of A BI·007. Furthennore, lipid, macromolecular, and
`nanopanicle drug carriers have been known to preferentially
`accumulate in tumor beds and tissues in what is known as
`enhanced pcnneation and retention effect (29). These factors
`may facilitate the partition of ABJ-007 into tissues.
`The MTO of AB I-007 was found in this study to be 300
`mg/m2 when given as a short infusion on a 21·day cycle.
`Although the usual dose range for Taxol is 135-200 mg/m 2
`,
`doses as high as 250 mg/m2 arc occasionally administered.
`Therefore, the MTD established by this trial represents a mod(cid:173)
`erate increase over that of Ta xoJ. The issue of whether onc can
`achieve unifonn and repeated dosing of ABI·007 at the MT D
`will need to be addressed in Phase I I trials.
`In conelusion, ABI-007 appears to represent an improve.
`ment in paclitaxel fonnulati o n in that it can be administered
`rapidly and safely without the risk of hypersensitivity reactions,
`eliminating the need for stcroid and antihistamine premedica(cid:173)
`tion. FurthertllOre, the increased MTO and favorab le toxicity
`profile of A BI-007 may ultimately prove advantageous in tenns
`of rate and quality of response, Although several interesting
`pharmacokinetic properties were noted for ABI -007, the small
`number of patients in this study renders comparisons with Taxol
`preliminary, and additional swdies will need to be conducted to
`fully appreciate differences in phannacokinetic behavior. The
`partial responses seen in 2 patients with prior exposure to Taxol
`are encouraging and support a continued effort to explore the
`
`Apotex v. Abraxis - IPR201 8-00152, Ex. 1018, p.06 of7
`
`

`

`1(1.14 Phase! Trial and Phann~coki netics of ABI -007
`
`s