2592
`
`Intraarterial Chemotherapy with Polyoxyethylated
`Castor Oil Free Paclitaxel, Incorporated in Albumin
`Nanoparticles (ABI-007)
`Phase I Study of Patients with Squamous Cell Carcinoma of the Head and Neck and
`Anal Canal: Preliminary Evidence of Clinical Activity
`
`Bruno Damascelli, M.D.'
`Giulio Cantu, M.O?
`Franco Mattavelli, M.o?
`Paolo Tamplenizza, M.D.3
`4
`Paolo Bidoli, ",.0.
`Ennanno Leo, M.O.5
`Franco Dosia, M.D.6
`Anna M. Cerrotta, M.D?
`Giuseppe Di Tolla, M.D.'
`Laura F. Frigerio, M.Il.'
`Francesco Garbagnati, M.D.'
`Rodolla lanoeita, M.D.'
`Alfonso Marchiano, N .D.'
`Gianluigi Patelli, M.D.'
`Carlo Spreafico, M.D.'
`I
`Vladimira TicM, M.D.
`Valentina Vespro, M.D.'
`8
`Franco Zunino, M.D.
`
`, Departmool of Radiology, IstrtlIlo Naziooale Tu·
`moO, Milano, Italy
`
`2 Departmeot 01 Head and Neck Surgery, lstrtuto
`Naziooale Tumoti, Milano, Itary.
`
`l Departmoo! of Head and Neck SurgeI)'. Uni'ler·
`siUJ degli studi di Milano, Milano, Italy
`
`• Department 01 Medical Oncology. lsIiMo Nalio(cid:173)
`nate Tumor!, Mitaoo, Hal)'.
`
`5 Departme.1t of GastrOintesbnal Surgery. lstitulo
`Nalionale Tumofi, Milano, ltaty
`
`• Department 01 GIlemical, Food. Pharmaceuncal
`and Pharmacological Scieoces, University of Pi·
`emonte East. NO'iara, ltaty
`
`1 Departme11t of Radiotherapv, IsUtuto N;uionale
`Tumori. Milano, ltaty
`
`'Departme11t of Experimental Or.cology, lst~uto
`Nalionale Tumofi, Milano, ltaty
`
`C 2001 American Cancel" SocietY
`
`BACKGROUND. This slUdy was designed 10 detennine the feasibili ty, maximum
`tolerated dose, and toxicities of i1llraanerial administration of paclitaxel-albumin
`nanoparticlcs in patients with advanced head and neck and recu rren t anal canal
`squamous cell carcino m a. A1llitulllor activity also was assessed.
`METHODS. I'ony-th ree patients (31 with advanced he~d and neck and 12 with
`recurre1ll anal canal squamous cell ca rcinoma) were treated intraarterially with
`AB I-007 every 4 weeks for 3 cycles. In 101(11, 120 treatment cycles were completed,
`86 in patients with head and necl: careinoma [median. 3 cyclts; rilnge, 1~4) and 34
`in patients with anal canal ca rcinoma (med ian, 3 cycles; range, 1-4). ABI-007 was
`compared preliminarily \vith Taxol'- for in vitro cytostatic activity. Increasing dose
`levels from 120 to 300 m g/m2 we re slud ied in 18 patients. l'harmacokinet ic profiles
`after int raa rteria l administration were obtained in a restricted n u mber of pa tients.
`RESULTS. The dose-limiting tox icity of ABI-007 was myelosuppression consisting of
`Grade 4 neutropenia in 3 patients. Nonhematologic toxicities i ncluded total alo(cid:173)
`pecia (30 patients), gastrointestinal toxici ty (3 patients, Grade 2), skin toxicity (S
`patients, Grade 2), neurologic toxicity (4 patients, Grade 2) ocula r toxicity (I
`patient, Grade 2), nu-li ke syndrome (7 patients, Grade 2: 1 plllient, Grade 3). In
`tota!, 120 transfemora l, percutaneous catheterization procedure-related compli(cid:173)
`cations occurred only during catheterization of the neck vessels in 3 patients (2
`TIA, I hemi paresis) and resolved spontaneously.
`CONCLUSIOKS, Intraarterial ad m inistration of ABI·OO7 by perc u taneous cat heter·
`i1~l t i on docs not require premedication, is easy and reproducible, and has accept(cid:173)
`able toxicity. The ma:<imum tolerated dose in a single administration was 270
`mg/m2. Most dose levels showed considerable antitumor activity (42 assessable
`p~tients with 80.9% complete response and partial responsc), The recommended
`Phase II dose is 230 mg/m2 cvery 3 weeks. Ctlllcer 2001 ;92: 259 2-602,
`(:) 2001 AmeriCllII Cancer Sociery-
`
`KEYWORDS: laxanes, paclilaxel, in1raarterial chemotherapy, squamous cell carcinoma.
`
`Supported in part by AC:3 Dobfar, Mitano, ttaly, as
`licensee fO( ABHXl7 and in part by a grant from
`lega ltaliana per ta Lotta contro i Tumofi, Milano
`
`The authors are iooebled to Marco Falciani. Pabick
`Soon Shloog, and Neil Desai, without whose sup·
`port this stl.ll1y WOltId not have been possible, and
`to Flora Stivan. Mary Trotter, and Sauro Ceccali ni
`for assistance in preparation of lt1e article
`
`Address lor reprints: Bruno Damascelli. M.D .• De (cid:173)
`partment of Radiology, Isli1ulo Nazionale per 10
`Studio e ta Cura dei Tu mori di Milano, V~ Ven·
`ezian. I , 20133 Milano, ltaty: Fax: 390-2239-
`0398:
`E·rna il: damascelliCistitutoiumon .mi, ~
`
`Received February 5. 2001: accepted July 16.
`2001 . Pre<:is
`
`Apotex v. Abraxis - IPR20 18-00 15 I, Ex. 1017, p.O 1 of 11
`
`

`

`Intraarterial Polyoxyethyla1ed Castor Oil Free PaclitaxellDamascelli et at
`
`2593
`
`Paclitaxel was the first taxane to be introduced into
`
`clinical practice, but because of its poor solu bility
`in water it must be formulate d with polyoxyethylated
`castor oil and ethanol [faxol®). Polyoxyethylated cas(cid:173)
`tor oil can cause allergic reactions; therefore, patients
`must receive premedication with dexamethazone, di (cid:173)
`phenhydramine, and cimetidine before paclitaxel ad(cid:173)
`ministration. In addition, special precautions fo r the
`imravenous administration set a re necessary, and it is
`advisable for infusion to be given over 3-24 hours.1. 2
`Despite these measures, severe hyperse nsitivity reac(cid:173)
`tions are reported in 1.5-3% of patien ts, and more
`modest reactions are observed in almost half of pa(cid:173)
`tients. 3 A recently published article highligh ts this
`problem and suggests changing patients with allergic
`reactions to another taxane, docetaxel.4
`Intraarterial administration of taxanes has been
`considered only sporadically up to now. 5 •6 The pres(cid:173)
`ence of a lcohol in the commerci al fo rmulat ion and the
`problem of hypersensit ivity reactions represent an ob(cid:173)
`stacle to administrat ion by this route, unless the drug
`is dilu ted considerably. A new polyoxyeth ylated castor
`oil free form ulation of pacl itaxel provided the oppor(cid:173)
`tunity to assess intraarterial chemotherapy with this
`cytostatic agent in squamous cell carcinomas of the
`head and neck and of the anal canal.
`Few studies have been conducted to date on the
`activity of systemically admin istered taxanes in ad (cid:173)
`vanced head and neck carcinoma . In these studies,
`in travenous paclitaxel as a single agent has shown
`superior activity to that of the standard combined
`chemotherapy (cisplatin, 5-fluorou racil) in recu r(cid:173)
`rences of these cancers, but the improvement was not
`very great. Overall , when more recent taxanes such as
`docetaxe l are included, objective response rates (com(cid:173)
`plete and partial cli nical-radiologic) ran ge from 30%
`to 42% in recurrences. 7
`9
`-
`less than 30% of patients with locally advanced
`disease (American loint Committee on Cancer [AlCC]
`TNM Stage III /IV) can be cured with surgery and/or
`radiotherapy. The chemotherapy regimen that achieves
`a complete clinical response of 30-50% and greater is
`the combination of cisplatin and fluorourac il given at
`initial presentation of the disease. Combination with
`radiotherapy improves the results but at the cost of
`greater toxicity. IO-12 Despite this result. neoadjuvant
`chemotherapy has not bro ught an improvement in sur(cid:173)
`vival, which depends more on locoregional recurrence
`than on distant metastases. A high T classificat ion makes
`local recurrence more likely and is less amenable to
`clinical response and even less to complete pathologic
`response. Efforts to improve the results of neoadju(cid:173)
`vant chemotherapy in advanced carcinoma of the oral
`cavity and hypopharynx are justified by the possibility
`
`((X"iginal magnification
`FIGURE 1, Electron microscope enlargement
`x 34,OOO) of paclitaxel-albumin nanoparticles (ABI-007).
`
`of achieving definitive local treatme nt by surgery or
`radiotherapy while maintaining an acceptable q uality
`of life, including organ preservation.
`Cystostatic drugs have been given by intraarterial
`admin istration in the pas!. particularly since the in (cid:173)
`troduction of cisplatin . The responses repo rted (clin(cid:173)
`ical-radiologic, complete, and partial) range from 47%
`to 94% in patients with miscellaneous advanced dis(cid:173)
`ease at presentation or with recurrence. The rate o f
`catheter-related complications was greater
`than
`30%.13-16
`The expansion of interventional neuroradiology
`techniques, which now have high reproducibility and
`an acceptable complication rate, has led to the avail(cid:173)
`ability of new materials for superselective catheteriza(cid:173)
`tion, prompting renewed interest in intraarterial che(cid:173)
`motherapy of the cervicofacial d istrict. 11- 19 However,
`in this reappraisal of intraarterial chemotherapy, the
`drugs used thus far have been the same as in the past,
`and in no case have taxanes been used.
`AliI -007 is a new formu lation of paclitaxel. l(s
`novelly lies in the use of human album in as a stabilizer
`in place of the usual excipients, polyoxyethylated cas(cid:173)
`tor oil and alcohol. The particles of the paclitaxel(cid:173)
`human albumin complex have a dimension of 150-
`200 nm (Fig. ll. and the product takes the form of a
`colloid when suspended in sali ne solution. Animal
`swdies have shown that the pharmacokinetic profile
`of ABI-007 differs from that of the commercial formu (cid:173)
`lation (Taxo!) in Ihal it shows lower plasma levels and
`higher tissue levels with wider, more rapid distribu(cid:173)
`tion a nd slower meta bolism. ABI-007 is 59-fold less
`toxic than Taxol and 29-fold less toxic than the excipi(cid:173)
`ems of Taxol.20 Preliminary results of clinical intrave(cid:173)
`nous and intraarterial use were presented recent(cid:173)
`l y.2 1,22
`The decision to study intraarterial chemotherapy
`
`Apotex v. Abraxis - IPR20 18-00 15 I, Ex. 10 17, p.02 of 11
`
`

`

`- " -- . M
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`.-
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`-- .-
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`....... - .~
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`
`.~
`
`-"
`~-
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`
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`
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`
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`
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`
`,.
`
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`
`IGROV -11Pt1
`
`-,
`
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`~
`j
`•
`U
`•
`~
`~
`~ •
`•
`
`• ._,
`,.
`
`•
`
`2594
`
`GANGER Novembe r 15, 2001 I Volume 92 I Number 10
`
`with paclitaxel in albu min nanoparticles in patients
`with squamous cell carcinoma of the head and neck
`and of the anal canal was based on consideration of
`the mechanism of action of th is drug and of the par(cid:173)
`ticu lar problems posed by these two carcinomas. The
`antitumor efficacy of paclitaxel is related to its ability
`to stabilize microtubules. Alte ratio ns of microtubule
`dynamics may be of relevance not only in the mitotic
`spindle. but also in cyto skeleton functions. Because
`cytoskeleton is involved in signaling pathways med i(cid:173)
`ated by growth factor receptors. the pharmacologic
`effects of taxanes could be at least in part caused by
`their interference with signal transd uction. Because
`squamous cell carcinomas of different tissue origin
`(lung. head/neck. cervix) are characterized by overex(cid:173)
`pression of epide rmal growth factor (EGF) receptors.
`the efficacy of paclitaxel in the treatment of these
`tumor types could reflect an interfe rence of this tax(cid:173)
`ane in specific processes mediated by growth factor
`receptors. This hypothes is should be addressed by
`specific approaches of modulat ion of receptor func(cid:173)
`tion. A better documentation of this additional molec(cid:173)
`ular effect could allow a more rational design of clin(cid:173)
`ical studies with taxanes. 23
`Squamous cell carcinoma of the anal canal has a
`high curabili ty rate at presentat ion when treated by a
`combination of chemotherapy. radiotherapy, and sur(cid:173)
`gery. but no furt her systemic therapeut ic regimen is
`available for effective management of recu rrence. 24
`2S
`•
`The rationale of intraarterial adm inist ra tion is rein(cid:173)
`forced in this pathology by the critical nature of pelvic
`vascularization due to the previous treatments, which
`might make it difficult to achieve an effective local
`concentration of systemically administered cytostatic
`agents.
`The principal goals of the current study were l) to
`determine the feasi bility of intraarterial administra(cid:173)
`tion of ABl-007. 2) to determine the maximum toler(cid:173)
`ated dose (MTD). 3) to determine the dose-limiting
`toxicity. 4) to establish the recommended dose for a
`Phase " study. and 5) to seek preliminary evidence of
`anti tumor activity.
`
`MATERIALS AND METHODS
`Comparative In Vitro CytotoxiC Evaluation of ABH)!)7
`and Taxal
`A comparative study of the cytotoxic effects ofTaxol
`and ABl-007 was perform ed in tw o human ovari an
`carcinoma cell lines, includ ing a cell line sensi tive 10
`cisplatin (lGROV-l) and a su bl ine selected fo r resis(cid:173)
`tance to cisplatin (lGHQV-I/ Ptlj, exhi biting a col(cid:173)
`latera l sensitivity to taxane and in a sq uamous cell
`carcinoma of the cervix (A431) exh ibiti ng overex(cid:173)
`pression of the EGF receptor. The cytotoxic activit y
`
`FIGURE 2. ClXlIPi:llisull of Lytotoxk; aGlivily uf IJilGlilaxt:J (TX) an~ ABI-007 ill
`ovarian cell carcinoma IGROV-I , in a su~ine selected for resistance to cisplatin
`IGROV-l/Pt 1 and in cervical squamous cell carcinoma cells. Cells were
`exposed to the drug II)" 24, 48, or 72 hoors as indicated. The antiproliferative
`effect was determined by the growth inhibHion assay (cell counting 72 hours
`alter the start of exposure). 1C5(I values refer to drug concentratiO!ls required for
`50% inhibition of cell growth.
`
`was eval uated using an antipro li ferative assay (de(cid:173)
`termination of the n umber of surviving cells 72
`hou rs after drug exposure) and variable exposu re
`times (24. 48, and 72 hours). The cell systems were
`chosen because the cyto toxic effect of paclitaxel was
`p redicti ve of antitumor efficacy afte r in vivo treat(cid:173)
`ment o f tu mor xenografts in athymic mice.
`Because the drug formulation could interfere
`wit h cellular up take of the drug. a compa rat ive cel(cid:173)
`lu lar pharmacology s tudy was performed to exam(cid:173)
`ine the cytotoxic potential of the drug in variou s
`formu Jations lIsing a panel of hu man tumor cell
`lines. The resu lt s are shown in Figure 2 as dose(cid:173)
`respunse cu rves. It is eviuent thilt the cytutuxic ac(cid:173)
`tivity o f paclitaxei is retained completely in it s fo r(cid:173)
`mulati on wit h a lbu min. Althou gh
`the observed
`diffe rence in cellul ar response should be regarded
`as ma rginal. an increased cytotoxicity of ADI -OO?
`was consistently found in all expe rim ents. A si milar
`result was found in t he A431cell line, wh ich exh ib(cid:173)
`ited an increased sensitivity \0 taxanes.
`
`Apotex v. Abraxis - IPR20 18-00 15 I, Ex. 1017, p.03 of 11
`
`

`

`Intraarterial Polyoxyethylated Castor Oil Free PaclitaxellOamascelii et at
`
`2595
`
`Group performance status of less than 2; previous
`chemotherapy, with exclusion of taxanes, completed
`at leas t 4 weeks before study enrollment ; life expect(cid:173)
`ancy longer than 3 months; and adequate bone mar(cid:173)
`row (platelet count > 75,000 X 109 cells/L, absolute
`neutroph il count > 1.5 X 109 cells/L), hepatic function
`(total bilirubin within normal limits, transaminases
`< 2 times normal), and renal function (creatinine
`< 1.5 times the upper limit of norma l). Patients with
`fo rmal contraindications or in whom transfemoral
`catheterization/angiography was not possible and
`those with severe cardiopathy were excluded.
`Before enrollment in the trial, patients were re(cid:173)
`quired to sign the informed consent document to be
`enrolled in the trial, which was approved by the Eth (cid:173)
`ical and Scientific Committee of the iJlStitutio n.
`
`Dosage and Administration of ABI-007
`ABI -OO? was supplied by American BioScience, Inc.
`(Los Angeles, CA) in vials containing a lyophil equal to
`30 mg ofpaclitaxellalbumin. The solution obtain ed by
`diluting each vial with 10 mL of 0.9% sodium chloride
`solution was administered over 30 minutes by selec(cid:173)
`tive percu taneous catheterization of the neck vessels
`in patients with head and neck carcinoma, with access
`from the femoral artery under local anesthesia, with(cid:173)
`out premedication. A guiding catheter (Envoy HI SF;
`CordislJohnson & Johnson, Miami, FL) first was posi(cid:173)
`tioned in the common carotid artery for digital an(cid:173)
`giography. Bilateral catheterization was performed fo r
`tumors that exceeded the median line. Intraa rterial
`chemotherapy was performed by selectively or super(cid:173)
`selectively catheterizing the external carotid artery or
`its branches with coaxial microcatheters in a gu iding
`catheter (Transit Infusion Catheter; Cordis/Johnson &
`Johnson).
`In patients with recurrence of allal canal carci(cid:173)
`noma, unilateral or bi lateral transfemoral percutane(cid:173)
`ous catheterization of the internal iUac arteries was
`performed [rem po 4 C3. 4F; CordislJohnson & John(cid:173)
`son) after pelvic aortography, with placement of a
`coaxial microcatheter (Rapid Transit; CordislJohnson
`& Johnson) distal to the gluteal artery. To prevent
`clottin g within the catheter. we used a co ntinuous
`washin g set of our own design produced by SIDAM
`(M irandola,
`italy). Three
`treatment cycles were
`planned for both groups of patients. with a 4-week
`interval between cycles (in 2 patients 4 cycles were
`performed). The hospital stay was 3 days for each
`cycle.
`The MTD was defined in this study as the dose
`level below that inducing dose-limit ing toxicity in
`greater than a third of cycles at the sam e dose level (at
`least three cycles of a group of six).
`
`FIGURE 3. carcinoma ollell margin 01 tongue. M presentation (top left), after
`one cycle of ABI-007 into the lingual artery ~~ right), after two cycles (bottom
`left), after thref! cycles (bottom right). This patient received a fourth cycle of
`intraarterial chemotherapy, and no tumor was found at surgery. The patient
`also underwent totallaterocervical lymph node resection with negative histol·
`ogv. The patient was disease free at last follow-up (10 months)
`
`FIGURE 4. carcinoma of the tongue. Computed tomography with contrast
`medium (top left); the arrows indicate the tumlX margins. Result after three
`cycles of intraarterial chemotherapy (t~ right). Angiogram of right common
`carotid artery (oollom left). catheterization and angiography oIlingll3l artery
`(bottom right).
`
`PATIENTS
`Patient Selection
`Patients considered eligi ble for this study were I)
`those wi[h histologic diagnosis of locally advanced
`sq uamous cell carcinoma of the head and neck with or
`without previous treatment; and 2} patients with re(cid:173)
`current squamous cell carcinoma of the anal canal.
`Inclusion criteria were age older than ]8 years and
`younger than 75 years; Eas tern Cooperative Oncology
`
`Apotex v. Abraxis - IPR20 18-00 15 I, Ex. 101 7, p.04 of 11
`
`

`

`2596
`
`CANCER November 15, 2001 I Volume 92 I Number 10
`
`The dose increase scheme was empiric and arbi(cid:173)
`trarily designed by us.
`The starting dose of 120 mg/m2 was increased by
`30 mg/m 2 at each subsequent level. Each level con(cid:173)
`sisted of a group of six cycles. In the first 4 cycles,
`Grade 4 hematologic toxici ty occurred in 3 cases in the
`group receiving 300 mg/m 2
`• The MTD therefore was
`defined as 270 mg/m 2
`• The total number of cycles
`"necessary" to define the dose- lim iting toxicity and
`the MTD was 40 (29 cycles for 12 patients with head
`and neck carcino ma and 11 cycles for 6 patients wit h
`carcinoma of the anal canal).
`Of the 18 patients part icipating in dose escalation
`(5 of whom completed treatment after determination
`of the MTD, receiving 250 mg/m 2 fo r the remaining
`cycles), l) 8 patients rece ived 3 cycles; 2) 6 patients
`received 2 cycles (1 discont inued treatment because of
`progression, I withdrew despite evidence of complete
`clinical response, and 4 received the thi rd cycle at the
`dose 250 mg /m2
`), 3) 4 patients received only I cycle (\
`completed the treatm ent at 250 mg/m2
`, 2 discontin(cid:173)
`ued it because of progression, \ patient died after
`rupture of esophageal varices complicating concomi(cid:173)
`tant cirrhosis).
`To better define the importance of [he intraarte(cid:173)
`rial chemotherapy procedure and make a prelim inary
`evaluation of the tolerability of the ABI -007 dose to be
`recommended for Phase II study, we enrolled an ad (cid:173)
`di tional 19 patients with head and neck carcinoma
`and 6 with recurrence of anal canal carcin oma. Treat(cid:173)
`men t with 250 mg/ m2 every 4 weeks for 3 cycles was
`planned for this additional group.
`
`Dose-Limiting Toxicities
`All toxicities were graded according to World Health
`Organization (WHO) toxicity criteria. 111e MTD, as
`already stated , was defined as the dose level below
`that which induced a limHing toxicity in at least three
`of six cycles. Grade 4 neutropenia lasti ng 5 days or
`longer, Grade 4 thrombocytopen ia or anem ia of any
`duration, and Grade 3 or 4 nonhematologic toxicities
`were considered as dose- lim iting.
`
`Pretreatment and Follow-Up Studies
`Complete clinical h istory, physical exami nation, he(cid:173)
`malOlogic examination, serum electrolytes, and chem(cid:173)
`istries were performed at the time of enrollment and
`before each cycle. Complete blood cell counts were
`taken weekly while patients were on study. Radiologic
`studies (computed tomographic scans or magnetic
`resonance imaging) were pe rformed at baseline and
`before each treatment cycle to assess tumor response,
`which was graded accord ing to WHO criteria.
`
`Pharmacokinetic Analyses
`To study the pharmacoki netics of ABI-007. extensive
`blood sam ples were drawn in 11 patients, from the
`superior vena cava (5 patients with head and neck
`carcinoma), from the inferior vena cava (6 patients
`with anal canal carcinoma), and from peripheral veins
`(I I patients) at multiple times during each infusion (at
`0,5, 15, and 30 minutes) and up to 18 hours (at 35, 45.
`60.90, 150,270, 510, 750, and 1080 minutes).
`Wh ole blood paclitaxel concentrations were de(cid:173)
`termined by high -performance liquid chromatogra(cid:173)
`phy after solid phase extraction, as described by Willey
`et al.26 with some modifications. Stan dard curves were
`obtained using paclitaxel C (in dena, Milan, Italy) as
`interna l standard. The drug quantitation limit was
`0.06 ~ mollL and the linearity up to 30 ~m ollL with a
`preciSion range between 8.1 % and 18% and an accu(cid:173)
`racy that exceeded 85%. The recovery of paditaxel was
`95%. The same method was used to check the pad i(cid:173)
`taxel contents in administered ABJ-007 solutions.
`Pharmacoki netic mod eli ng and parameters were
`performed using the nonli near regression program
`Kinetica 2000 version 3.0 (Innaphase Co., Philadel(cid:173)
`phia, PAl. The concentration versus time curves were
`fi tted using a three-compartment open pharmacoki(cid:173)
`netic model.
`The data were co mpared with pharmacokinet ic
`profiles with intravenous infusion of ABl-007 (Ibrahim
`NK, Ellehorst JA, Theriault HL, et al. Phase I and phar(cid:173)
`macokinetic study of ABI-007, a cremophor-free, pro(cid:173)
`tein -stabi lized, nanoparticle formulation of pacl itaxel,
`unpub lished).
`
`RESULTS
`Thi rty-one patients with head and neck carcinoma
`received a total of 86 cycles (median, 3). Twelve pa(cid:173)
`tien ts with recurren t anal canal carcinoma received 34
`cycles (median, 3).
`Patient characteristics are summarized in Table 1.
`
`Toxicity
`Tables 2 and 3 summarize the hematologic and nOI1-
`hematologic toxicities of all grades observed in 12
`patients with squamous cell carcinoma of the head
`and neck and in 6 patients with squamous cell carci(cid:173)
`noma of the anal canal who participated in dose es(cid:173)
`calation to define the MTO of intraarterial chemother(cid:173)
`apy with ABI -007.
`Neutropenia was the main dose- li miting toxicity
`for intraarterial administration of paclitaxel. Of the
`three episodes recorded, two we re sh ort-lasting and
`did not require hospitalization. These episodes oc(cid:173)
`curred in two patients with recurrent anal canal car-
`
`Apotex v. Abraxis - IPR20 18-00 15 I, Ex. 101 7, p.05 of 11
`
`

`

`Intraarterial Polyoxyethyla1ed Castor Oil Free PaclitaxellDamascelii et at
`
`2597
`
`TABLE 1
`Patient Characteristics
`
`Chara(len.lic
`
`No. of patients
`Gender
`Male
`Female
`Age. median (range]
`I're\iou~ treat ment
`Surgery + CHI + RT
`CHT + RT
`Surgery + RT
`Surgery
`CHT
`RT
`None
`Surgery + CHI
`Tumor site
`Tongue
`Maxillary sinus
`Floor of mouth
`Soft tissues of the necl
`Laf)llgopharyfU
`Overlapping lesion of orol
`h)'POphaf)1lX
`~om
`Piriform sinus
`Retromolar trigone
`Orophal'jll(
`Overlapping lesion of
`tonsil and palate
`Lower pellis
`
`T,""
`
`Head and nl'(k
`ClII'tinoma
`
`Anal canal
`can:inoma
`
`Jl
`
`25
`
`63 [36-75]
`
`27
`16
`58 (36-75]
`
`12
`
`10
`56 [4t-75]
`
`"
`
`10
`
`12
`
`00: ch€motheraj1)~ RT: l3diation tbtrap)'_
`
`TABLE 2
`Hematologic Toxlclty
`
`Cycles with neutropenia/grade
`
`Head and nl'(k (grade]
`
`Anal canal (grade]
`
`2
`
`4
`
`"'~
`[mg/m~
`
`IW
`I~
`180
`110
`1~
`1m
`300
`
`Total no.
`ofq'des
`
`,
`,
`,
`,
`,
`,
`
`cinoma who previously had been treated with rad ia(cid:173)
`tion
`thera py (IlT) and chemotherapy and with
`chemotherapy plus IlT plus surgery, respectively. The
`third case was a patient with metastatic carcinoma of
`the head and neck from an unknown primary site,
`previously treated with RT and surgery and who also
`
`had cirrhosis wi th esophageal varices. The patient was
`admitted to the hospital because of nlpture of the
`varices 6 days alter intraarterial chemotherapy and
`died o f esophageal bl eeding.
`Neutropenia never was associated with infection,
`occurred approximately 8 days after the chemother(cid:173)
`apy, and resolved wi thin a week in the 2 assessable
`cases. At a dose of 270 mg/m 2
`, Grade 4 neutropeni a
`occurred in I previously untreated patient with carci(cid:173)
`noma of the head and neck. Grade 2 neutropeni a
`occurred in 15. 7% of patients in the series with tumo rs
`of the head and neck treated with 250 mg/ m2
`, and in
`33.3% in the much smaller series of patients with
`recurrent anal canal carcinoma.
`The most important non hematologic toxicities
`fro m the point of vie \V of their impact on the quality of
`life were neuropathy lasting approximately 2 weeks,
`flu-like syndrome (of shorter durat ion), and ocular
`toxici ty (keratitis). All these toxicities. which were in
`any case of low grade, occurred in few patients treated
`at the dose of 250 mg/m2 (Table 4).
`
`Procedural Complications
`Of 120 percutaneous catheterizat io ns , 3 complications
`(2.5%) were observed in 3 patients during catheteriza·
`tion of the neck vessels for infusion of ABl-007. These
`complications were l'.\IO transient ischemic attacks
`and one hemiparesis, the latter resolving within a few
`days. The patiem \Vho had the hemiparesis previously
`had undergone surgery, including radical bilateral
`neck dissection, chemotherapy, and RT. The two ce(cid:173)
`rebral transient ischemic attacks occu rred in two pa(cid:173)
`tients who had received previous treatment , one RT
`and one chemotherapy. In all three cases, the external
`carotid an ery was selectively catheterized by the
`method descri bed. The accidents occu rred at the time
`of removal of the catheter, most likely due to detach(cid:173)
`ment of debris at the carotid bifurcation, which
`showed atheromatous plaque in all three cases, par(cid:173)
`ticularly in the patient with hemiparesis.
`No complicat ions related to the catheterizat ion
`procedure occurred in the population treated for re(cid:173)
`current anal canal carcinoma.
`
`Antitumor Activity
`Forty of 43 patients were assessable for antitumor
`aclivily of intraaflerial chemotherapy with ABJ -OO?
`Three patients (all previously treated with combined
`regimens) received only one cycle and were not as(cid:173)
`sessable: one died after rupture of esophageal varices
`comp licating cirrhosis and the other two discontinued
`treatment because of disease progressio n. The latter
`two patients were treated with alternative chemother(cid:173)
`apy regimens wit hout success.
`
`Apotex v. Abraxis - IPR20 18-00 15 I, Ex. 1017 , p.06 of 11
`
`

`

`2598
`
`GANGER November 15, 2001 I Volume 92 I Number 10
`
`TABLE 3
`Nonhematologic Toxicity for Head and Neck Carcinoma and Anal Canal Carcinoma
`
`Total
`no. of ",,,
`
`Neuropathy
`",",,'I
`
`Gastrointestinal
`(grade)
`
`Flu syndrome
`""dol
`
`Ocular (grade)
`
`CutanooU'; (grade)
`
`Alopecia (grade)
`
`2
`
`2
`
`3
`
`4
`
`4
`
`4
`
`2
`
`Dose (mgJm~
`
`Head and ned
`carcinoma
`120
`150
`ISO
`210
`2<0
`270
`300
`
`Total No.
`ofCytles
`
`Neurop;lIhy
`
`Gastrointestinal
`
`Flu syndrome
`
`3
`
`4
`
`Alopecia
`
`3
`
`Anal canal carcinoma
`120
`150
`ISO
`210
`240
`270
`300
`
`4
`3
`
`TABLE 4
`Hemato)ogic and Nonhemato)ogic Toxicity in 2!'i Patien t~ Treated Intraarterially with ARI-007 at a J)o~ of 2.',0 mg/m2
`(Total of 80 Cycles, Median 3)
`
`Charocteristlc
`
`Total
`
`Head and neck cancer
`
`Anal canal cancer
`
`I (,,)
`
`2 (,,)
`
`3 (,,)
`
`4 (,,)
`
`1(")
`
`2 (,,)
`
`3 (,,)
`
`4 ('lb)
`
`Gmd,
`
`Gmd,
`
`25
`
`19
`
`16
`64 (36-n)
`
`57(41~)
`
`No. of patients
`Gender
`Female
`Male
`Age. median ( ran~)
`Hematologic toxicity
`Nonhematologic toxicity
`Alopecia
`Ga:;trointeslinal
`Flu·like syndrome
`Cutaneous
`Ocular
`Neurologic
`
`41.3
`
`15.7
`
`11
`I
`3
`2
`
`50.0
`
`1<6
`
`33.3
`
`833
`
`Of the 40 assessable patients, 29 belonged to the
`head and neck carcinoma group in which there were 3
`com plete responses (2 pathologic and I clinical). The
`three patients had recei ved no previolls treatment and
`were treated with radical surgery (1 patient with car(cid:173)
`cinoma of the tongue wh o had received 4 cycles), with
`radical neck dissection and radiotherapy (1 patient
`
`with carcinoma of the piriform sin us), and with sur(cid:173)
`gery and radiotherapy (I case of carcinoma of the
`retromolar trigone).
`Nineteen panial responses were observed in head
`and neck carcinomas (6 previously treated patients
`and 13 not previously treated). The sum of complete
`and partial responses was 75.85% {complete response,
`
`Apotex v. Abrax is - IPR20 18-00 15 I, Ex. 101 7, p.07 of II
`
`

`

`Intraarterial Polyoxyethylated Castor Oil Free PaclitaKellOamascelii et al.
`
`2599
`
`A
`
`I I
`
`•
`"
`"
`"
`
`" i: - .. . ..
`
`I :~
`
`0. ___ I
`
`6
`
`- -
`.. __ .. ...,..,.
`
`I
`
`,
`
`..
`
`."
`
`•
`
`"""'( ...... 1
`
`.. '---'---------;:;::::;:::::==;1
`"j •
`"
`• --
`I
`~"--""-
`
`,.
`
`n
`
`." ~ .. - " . ..
`I :; vn
`
`0
`
`............... _
`
`FIGURE 5. carcinoma 01 right pirilOfm sl1us. Computed tomography (Cl) of
`pharyn)(,/larynx wHh arrows indicating the tumOf margins (top left). CT with
`arrows indicating adenopathy (top right). CT after third cycle of intraarterial
`chemotherapy (bottom left); arrow I1dicates the primary tumor site no k:lIlger
`evident at histologic examination. CT of neck also shows a partial response for
`adenopathy (bottom right).
`
`FIGURE 6. Recurrent anal canal carcinoma. Computed tomography (eT) with
`contrast medium at presentatkln ~op left). CT after first cycle of chemotherapy
`via the internal iliac arteries (top right). CT after second cycle (bottom left). CT
`after third cycle (bottom right). It is not possible with
`imaging alone to
`determine whether tumor is still present. No tumor was found at surgery. The
`patient was disease free at last follow-up (4 months).
`
`10.34%; partial response, 65.51 %; Figs. 3-5). The six
`previously treated patients we re offered alternative
`chemotherapy. Of the 13 not previously treated, 9
`received surgery after intraa rterial chemotherapy, 1
`chemotherapy, I RT, and 2 RT and chemotherapy. Six
`
`!
`
`I
`
`..
`
`..
`
`1 .... (ri'Ij
`
`..
`
`• •
`
`FIGURE 7. (A and 8) Mean paclilaxel concentration versus lime profiles in
`patients with head and neck (A) or anal canal (8) carcinomas during and after
`30·minute constant infusion of ABHI07 (250 mg/m2 of paclitaxel). The dotted
`line ill tla~h panel repr~nts Hltl proliltl 01 an 'llravenuu~ '1jtl(:ltld dootl. iv:
`intravenous; ia: intraarterial; svc: superior vena cava; ivc: inferior vena cava.
`
`of the remaining seven assessable patients had re(cid:173)
`ceived previous lreatment. and of these one pro(cid:173)
`gressed, four had stable disease, and one developed a
`massive tumor necrosis with fistu lization after the sec(cid:173)
`ond cycle of intraarterial chemotherapy, and therefore
`treatment was discontinued. The last patient, not pre(cid:173)
`viously treated, showed stable disease.
`In the 22 responding patients. the median dura(cid:173)
`tion of follow- up for patients who had not received
`previous treatment was 12 month s (range. 3- 13
`months); for previous ly treated patients, the median
`was 5 months (range, 3- 13 months).
`Twelve previously treated patients belo