2592
`
`Intraarterial Chemotherapy with Polyoxyethylated
`Castor Oil Free Paclitaxel, Incorporated in Albumin
`Nanoparticles (ABI-007)
`PhaseIStudyofPatientswithSquamousCellCarcinomaoftheHeadandNeckand
`AnalCanal:PreliminaryEvidenceofClinicalActivity
`
`Bruno Damascelli, M.D.1
`Giulio Cantu` , M.D.2
`Franco Mattavelli, M.D.2
`Paolo Tamplenizza, M.D.3
`Paolo Bidoli, M.D.4
`Ermanno Leo, M.D.5
`Franco Dosio, M.D.6
`Anna M. Cerrotta, M.D.7
`Giuseppe Di Tolla, M.D.1
`Laura F. Frigerio, M.D.1
`Francesco Garbagnati, M.D.1
`Rodolfo Lanocita, M.D.1
`Alfonso Marchiano` , M.D.1
`Gianluigi Patelli, M.D.1
`Carlo Spreafico, M.D.1
`Vladimira Ticha` , M.D.1
`Valentina Vespro, M.D.1
`Franco Zunino, M.D.8
`
`1 Department of Radiology, Istituto Nazionale Tu-
`mori, Milano, Italy.
`
`2 Department of Head and Neck Surgery, Istituto
`Nazionale Tumori, Milano, Italy.
`
`3 Department of Head and Neck Surgery, Univer-
`sita` degli studi di Milano, Milano, Italy.
`
`4 Department of Medical Oncology, Istituto Nazio-
`nale Tumori, Milano, Italy.
`
`5 Department of Gastrointestinal Surgery, Istituto
`Nazionale Tumori, Milano, Italy.
`
`6 Department of Chemical, Food, Pharmaceutical
`and Pharmacological Sciences, University of Pi-
`emonte East, Novara, Italy.
`
`7 Department of Radiotherapy,
`Tumori, Milano, Italy.
`
`Istituto Nazionale
`
`8 Department of Experimental Oncology,
`Nazionale Tumori, Milano, Italy.
`
`Istituto
`
`© 2001 American Cancer Society
`
`BACKGROUND. This study was designed to determine the feasibility, maximum
`tolerated dose, and toxicities of intraarterial administration of paclitaxel-albumin
`nanoparticles in patients with advanced head and neck and recurrent anal canal
`squamous cell carcinoma. Antitumor activity also was assessed.
`METHODS. Forty-three patients (31 with advanced head and neck and 12 with
`recurrent anal canal squamous cell carcinoma) were treated intraarterially with
`ABI-007 every 4 weeks for 3 cycles. In total, 120 treatment cycles were completed,
`86 in patients with head and neck carcinoma (median, 3 cycles; range, 1– 4) and 34
`in patients with anal canal carcinoma (median, 3 cycles; range, 1– 4). ABI-007 was
`compared preliminarily with Taxolt for in vitro cytostatic activity. Increasing dose
`levels from 120 to 300 mg/m2 were studied in 18 patients. Pharmacokinetic profiles
`after intraarterial administration were obtained in a restricted number of patients.
`RESULTS. The dose-limiting toxicity of ABI-007 was myelosuppression consisting of
`Grade 4 neutropenia in 3 patients. Nonhematologic toxicities included total alo-
`pecia (30 patients), gastrointestinal toxicity (3 patients, Grade 2), skin toxicity (5
`patients, Grade 2), neurologic toxicity (4 patients, Grade 2) ocular toxicity (1
`patient, Grade 2), flu-like syndrome (7 patients, Grade 2; 1 patient, Grade 3). In
`total, 120 transfemoral, percutaneous catheterization procedure–related compli-
`cations occurred only during catheterization of the neck vessels in 3 patients (2
`TIA, 1 hemiparesis) and resolved spontaneously.
`CONCLUSIONS. Intraarterial administration of ABI-007 by percutaneous catheter-
`ization does not require premedication, is easy and reproducible, and has accept-
`able toxicity. The maximum tolerated dose in a single administration was 270
`mg/m2. Most dose levels showed considerable antitumor activity (42 assessable
`patients with 80.9% complete response and partial response). The recommended
`Phase II dose is 230 mg/m2 every 3 weeks. Cancer 2001;92:2592– 602.
`© 2001 American Cancer Society.
`
`KEYWORDS: taxanes, paclitaxel, intraarterial chemotherapy, squamous cell carcinoma.
`
`Supported in part by ACS Dobfar, Milano, Italy, as
`licensee for ABI-007 and in part by a grant from
`Lega Italiana per la Lotta contro i Tumori, Milano.
`
`The authors are indebted to Marco Falciani, Patrick
`Soon Shiong, and Neil Desai, without whose sup-
`port this study would not have been possible, and
`to Flora Stivan, Mary Trotter, and Sauro Ceccarini
`for assistance in preparation of the article.
`
`Address for reprints: Bruno Damascelli, M.D., De-
`partment of Radiology,
`Istituto Nazionale per lo
`Studio e la Cura dei Tumori di Milano, Via Ven-
`ezian, 1, 20133 Milano,
`Italy; Fax: 390-2239-
`0398;
`E-mail: damascelli@istitutotumori.mi.it
`
`Received February 5, 2001; accepted July 16,
`2001. Precis
`
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`Intraarterial Polyoxyethylated Castor Oil Free Paclitaxel/Damascelli et al.
`
`2593
`
`Paclitaxel was the first taxane to be introduced into
`
`clinical practice, but because of its poor solubility
`in water it must be formulated with polyoxyethylated
`castor oil and ethanol (Taxolt). Polyoxyethylated cas-
`tor oil can cause allergic reactions; therefore, patients
`must receive premedication with dexamethazone, di-
`phenhydramine, and cimetidine before paclitaxel ad-
`ministration. In addition, special precautions for the
`intravenous administration set are necessary, and it is
`advisable for infusion to be given over 3–24 hours.1,2
`Despite these measures, severe hypersensitivity reac-
`tions are reported in 1.5–3% of patients, and more
`modest reactions are observed in almost half of pa-
`tients.3 A recently published article highlights 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-
`ence of alcohol in the commercial formulation and the
`problem of hypersensitivity reactions represent an ob-
`stacle to administration by this route, unless the drug
`is diluted considerably. A new polyoxyethylated castor
`oil free formulation of paclitaxel provided the oppor-
`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 administered taxanes in ad-
`vanced head and neck carcinoma. In these studies,
`intravenous paclitaxel as a single agent has shown
`superior activity to that of the standard combined
`chemotherapy (cisplatin, 5-fluorouracil)
`in recur-
`rences of these cancers, but the improvement was not
`very great. Overall, when more recent taxanes such as
`docetaxel are included, objective response rates (com-
`plete and partial clinical-radiologic) range from 30%
`to 42% in recurrences.7–9
`Less than 30% of patients with locally advanced
`disease (American Joint Committee on Cancer [AJCC]
`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 fluorouracil given at
`initial presentation of the disease. Combination with
`radiotherapy improves the results but at the cost of
`greater toxicity.10 –12 Despite this result, neoadjuvant
`chemotherapy has not brought an improvement in sur-
`vival, which depends more on locoregional recurrence
`than on distant metastases. A high T classification 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-
`vant chemotherapy in advanced carcinoma of the oral
`cavity and hypopharynx are justified by the possibility
`
`FIGURE 1. Electron microscope enlargement
`(original magnification
`334,000) of paclitaxel-albumin nanoparticles (ABI-007).
`
`of achieving definitive local treatment by surgery or
`radiotherapy while maintaining an acceptable quality
`of life, including organ preservation.
`Cystostatic drugs have been given by intraarterial
`administration in the past, particularly since the in-
`troduction of cisplatin. The responses reported (clin-
`ical-radiologic, complete, and partial) range from 47%
`to 94% in patients with miscellaneous advanced dis-
`ease at presentation or with recurrence. The rate of
`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-
`ability of new materials for superselective catheteriza-
`tion, prompting renewed interest in intraarterial che-
`motherapy of the cervicofacial district.17–19 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.
`ABI-007 is a new formulation of paclitaxel. Its
`novelty lies in the use of human albumin as a stabilizer
`in place of the usual excipients, polyoxyethylated cas-
`tor oil and alcohol. The particles of the paclitaxel-
`human albumin complex have a dimension of 150 –
`200 nm (Fig. 1), and the product takes the form of a
`colloid when suspended in saline solution. Animal
`studies have shown that the pharmacokinetic profile
`of ABI-007 differs from that of the commercial formu-
`lation (Taxol) in that it shows lower plasma levels and
`higher tissue levels with wider, more rapid distribu-
`tion and slower metabolism. ABI-007 is 59-fold less
`toxic than Taxol and 29-fold less toxic than the excipi-
`ents of Taxol.20 Preliminary results of clinical intrave-
`nous and intraarterial use were presented recent-
`ly.21,22
`The decision to study intraarterial chemotherapy
`
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`2594
`
`CANCER November 15, 2001 / Volume 92 / Number 10
`
`with paclitaxel in albumin 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 this drug and of the par-
`ticular problems posed by these two carcinomas. The
`antitumor efficacy of paclitaxel is related to its ability
`to stabilize microtubules. Alterations of microtubule
`dynamics may be of relevance not only in the mitotic
`spindle, but also in cytoskeleton functions. Because
`cytoskeleton is involved in signaling pathways medi-
`ated by growth factor receptors, the pharmacologic
`effects of taxanes could be at least in part caused by
`their interference with signal transduction. Because
`squamous cell carcinomas of different tissue origin
`(lung, head/neck, cervix) are characterized by overex-
`pression of epidermal growth factor (EGF) receptors,
`the efficacy of paclitaxel in the treatment of these
`tumor types could reflect an interference of this tax-
`ane in specific processes mediated by growth factor
`receptors. This hypothesis should be addressed by
`specific approaches of modulation of receptor func-
`tion. A better documentation of this additional molec-
`ular effect could allow a more rational design of clin-
`ical studies with taxanes.23
`Squamous cell carcinoma of the anal canal has a
`high curability rate at presentation when treated by a
`combination of chemotherapy, radiotherapy, and sur-
`gery, but no further systemic therapeutic regimen is
`available for effective management of recurrence.24,25
`The rationale of intraarterial administration is rein-
`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 1) to
`determine the feasibility of intraarterial administra-
`tion of ABI-007, 2) to determine the maximum toler-
`ated dose (MTD), 3) to determine the dose-limiting
`toxicity, 4) to establish the recommended dose for a
`Phase II study, and 5) to seek preliminary evidence of
`antitumor activity.
`
`MATERIALS AND METHODS
`Comparative In Vitro Cytotoxic Evaluation of ABI-007
`and Taxol
`A comparative study of the cytotoxic effects of Taxol
`and ABI-007 was performed in two human ovarian
`carcinoma cell lines, including a cell line sensitive to
`cisplatin (IGROV-1) and a subline selected for resis-
`tance to cisplatin (IGROV-1/Pt1), exhibiting a col-
`lateral sensitivity to taxane and in a squamous cell
`carcinoma of the cervix (A431) exhibiting overex-
`pression of the EGF receptor. The cytotoxic activity
`
`FIGURE 2. Comparison of cytotoxic activity of paclitaxel (TX) and ABI-007 in
`ovarian cell carcinoma IGROV-1, in a subline selected for resistance to cisplatin
`IGROV-1/Pt 1 and in cervical squamous cell carcinoma cells. Cells were
`exposed to the drug for 24, 48, or 72 hours as indicated. The antiproliferative
`effect was determined by the growth inhibition assay (cell counting 72 hours
`after the start of exposure). IC50 values refer to drug concentrations required for
`50% inhibition of cell growth.
`
`was evaluated using an antiproliferative assay (de-
`termination of the number of surviving cells 72
`hours after drug exposure) and variable exposure
`times (24, 48, and 72 hours). The cell systems were
`chosen because the cytotoxic effect of paclitaxel was
`predictive of antitumor efficacy after in vivo treat-
`ment of tumor xenografts in athymic mice.
`Because the drug formulation could interfere
`with cellular uptake of the drug, a comparative cel-
`lular pharmacology study was performed to exam-
`ine the cytotoxic potential of the drug in various
`formulations using a panel of human tumor cell
`lines. The results are shown in Figure 2 as dose–
`response curves. It is evident that the cytotoxic ac-
`tivity of paclitaxel is retained completely in its for-
`mulation with albumin. Although the observed
`difference in cellular response should be regarded
`as marginal, an increased cytotoxicity of ABI-007
`was consistently found in all experiments. A similar
`result was found in the A431cell line, which exhib-
`ited an increased sensitivity to taxanes.
`
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`Intraarterial Polyoxyethylated Castor Oil Free Paclitaxel/Damascelli et al.
`
`2595
`
`Group performance status of less than 2; previous
`chemotherapy, with exclusion of taxanes, completed
`at least 4 weeks before study enrollment; life expect-
`ancy longer than 3 months; and adequate bone mar-
`row (platelet count . 75,000 3 109 cells/L, absolute
`neutrophil count . 1.5 3 109 cells/L), hepatic function
`(total bilirubin within normal limits, transaminases
`, 2 times normal), and renal function (creatinine
`, 1.5 times the upper limit of normal). Patients with
`formal 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-
`quired to sign the informed consent document to be
`enrolled in the trial, which was approved by the Eth-
`ical and Scientific Committee of the institution.
`
`Dosage and Administration of ABI-007
`ABI-007 was supplied by American BioScience, Inc.
`(Los Angeles, CA) in vials containing a lyophil equal to
`30 mg of paclitaxel/albumin. The solution obtained by
`diluting each vial with 10 mL of 0.9% sodium chloride
`solution was administered over 30 minutes by selec-
`tive percutaneous catheterization of the neck vessels
`in patients with head and neck carcinoma, with access
`from the femoral artery under local anesthesia, with-
`out premedication. A guiding catheter (Envoy H1 5F;
`Cordis/Johnson & Johnson, Miami, FL) first was posi-
`tioned in the common carotid artery for digital an-
`giography. Bilateral catheterization was performed for
`tumors that exceeded the median line. Intraarterial
`chemotherapy was performed by selectively or super-
`selectively catheterizing the external carotid artery or
`its branches with coaxial microcatheters in a guiding
`catheter (Transit Infusion Catheter; Cordis/Johnson &
`Johnson).
`In patients with recurrence of anal canal carci-
`noma, unilateral or bilateral transfemoral percutane-
`ous catheterization of the internal iliac arteries was
`performed (Tempo 4 C3, 4F; Cordis/Johnson & John-
`son) after pelvic aortography, with placement of a
`coaxial microcatheter (Rapid Transit; Cordis/Johnson
`& Johnson) distal to the gluteal artery. To prevent
`clotting within the catheter, we used a continuous
`washing set of our own design produced by SIDAM
`(Mirandola,
`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-limiting toxicity in
`greater than a third of cycles at the same dose level (at
`least three cycles of a group of six).
`
`FIGURE 3. Carcinoma of left margin of tongue. At presentation (top left), after
`one cycle of ABI-007 into the lingual artery (top right), after two cycles (bottom
`left), after three cycles (bottom right). This patient received a fourth cycle of
`intraarterial chemotherapy, and no tumor was found at surgery. The patient
`also underwent total laterocervical lymph node resection with negative histol-
`ogy. 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 tumor margins. Result after three
`cycles of intraarterial chemotherapy (top right). Angiogram of right common
`carotid artery (bottom left). Catheterization and angiography of lingual artery
`(bottom right).
`
`PATIENTS
`Patient Selection
`Patients considered eligible for this study were 1)
`those with histologic diagnosis of locally advanced
`squamous cell carcinoma of the head and neck with or
`without previous treatment; and 2) patients with re-
`current squamous cell carcinoma of the anal canal.
`Inclusion criteria were age older than 18 years and
`younger than 75 years; Eastern Cooperative Oncology
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`2596
`
`CANCER November 15, 2001 / Volume 92 / Number 10
`
`The dose increase scheme was empiric and arbi-
`trarily designed by us.
`The starting dose of 120 mg/m2 was increased by
`30 mg/m2 at each subsequent level. Each level con-
`sisted of a group of six cycles. In the first 4 cycles,
`Grade 4 hematologic toxicity occurred in 3 cases in the
`group receiving 300 mg/m2. The MTD therefore was
`defined as 270 mg/m2. The total number of cycles
`“necessary” to define the dose-limiting toxicity and
`the MTD was 40 (29 cycles for 12 patients with head
`and neck carcinoma and 11 cycles for 6 patients with
`carcinoma of the anal canal).
`Of the 18 patients participating in dose escalation
`(5 of whom completed treatment after determination
`of the MTD, receiving 250 mg/m2 for the remaining
`cycles), 1) 8 patients received 3 cycles; 2) 6 patients
`received 2 cycles (1 discontinued treatment because of
`progression, 1 withdrew despite evidence of complete
`clinical response, and 4 received the third cycle at the
`dose 250 mg/m2), 3) 4 patients received only 1 cycle (1
`completed the treatment at 250 mg/m2, 2 discontin-
`ued it because of progression, 1 patient died after
`rupture of esophageal varices complicating concomi-
`tant cirrhosis).
`To better define the importance of the intraarte-
`rial chemotherapy procedure and make a preliminary
`evaluation of the tolerability of the ABI-007 dose to be
`recommended for Phase II study, we enrolled an ad-
`ditional 19 patients with head and neck carcinoma
`and 6 with recurrence of anal canal carcinoma. Treat-
`ment 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. The MTD, as
`already stated, was defined as the dose level below
`that which induced a limiting toxicity in at least three
`of six cycles. Grade 4 neutropenia lasting 5 days or
`longer, Grade 4 thrombocytopenia or anemia of any
`duration, and Grade 3 or 4 nonhematologic toxicities
`were considered as dose-limiting.
`
`Pretreatment and Follow-Up Studies
`Complete clinical history, physical examination, he-
`matologic examination, serum electrolytes, and chem-
`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 performed at baseline and
`before each treatment cycle to assess tumor response,
`which was graded according to WHO criteria.
`
`Pharmacokinetic Analyses
`To study the pharmacokinetics of ABI-007, extensive
`blood samples 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
`(11 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).
`Whole blood paclitaxel concentrations were de-
`termined by high-performance liquid chromatogra-
`phy after solid phase extraction, as described by Willey
`et al.26 with some modifications. Standard curves were
`obtained using paclitaxel C (Indena, Milan, Italy) as
`internal standard. The drug quantitation limit was
`0.06 mmol/L and the linearity up to 30 mmol/L with a
`precision range between 8.1% and 18% and an accu-
`racy that exceeded 85%. The recovery of paclitaxel was
`95%. The same method was used to check the pacli-
`taxel contents in administered ABI-007 solutions.
`Pharmacokinetic modeling and parameters were
`performed using the nonlinear regression program
`Kinetica 2000 version 3.0 (Innaphase Co., Philadel-
`phia, PA). The concentration versus time curves were
`fitted using a three-compartment open pharmacoki-
`netic model.
`The data were compared with pharmacokinetic
`profiles with intravenous infusion of ABI-007 (Ibrahim
`NK, Ellehorst JA, Theriault RL, et al. Phase I and phar-
`macokinetic study of ABI-007, a cremophor-free, pro-
`tein-stabilized, nanoparticle formulation of paclitaxel,
`unpublished).
`
`RESULTS
`Thirty-one patients with head and neck carcinoma
`received a total of 86 cycles (median, 3). Twelve pa-
`tients with recurrent anal canal carcinoma received 34
`cycles (median, 3).
`Patient characteristics are summarized in Table 1.
`
`Toxicity
`Tables 2 and 3 summarize the hematologic and non-
`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-
`noma of the anal canal who participated in dose es-
`calation to define the MTD of intraarterial chemother-
`apy with ABI-007.
`Neutropenia was the main dose-limiting toxicity
`for intraarterial administration of paclitaxel. Of the
`three episodes recorded, two were short-lasting and
`did not require hospitalization. These episodes oc-
`curred in two patients with recurrent anal canal car-
`
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`Intraarterial Polyoxyethylated Castor Oil Free Paclitaxel/Damascelli et al.
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`
`TABLE 1
`Patient Characteristics
`
`Characteristic
`
`No. of patients
`Gender
`Male
`Female
`Age, median (range)
`Previous treatment
`Surgery 1 CHT 1 RT
`CHT 1 RT
`Surgery 1 RT
`Surgery
`CHT
`RT
`None
`Surgery 1 CHT
`Tumor site
`Tongue
`Maxillary sinus
`Floor of mouth
`Soft tissues of the neck
`Laryngopharynx
`Overlapping lesion of oro/
`hypopharynx
`Larynx
`Piriform sinus
`Retromolar trigone
`Oropharynx
`Overlapping lesion of
`tonsil and palate
`Lower pelvis
`
`Total
`
`43
`
`Head and neck
`carcinoma
`
`Anal canal
`carcinoma
`
`31
`
`12
`
`27
`16
`58 (36–75)
`
`25
`6
`63 (36–75)
`
`2
`10
`56 (41–75)
`
`5
`1
`3
`1
`2
`1
`17
`1
`
`10
`2
`1
`5
`3
`
`1
`1
`1
`2
`2
`
`3
`—
`
`5
`5
`—
`2
`—
`—
`—
`—
`
`—
`—
`—
`—
`—
`
`—
`—
`—
`—
`—
`
`—
`12
`
`CHT: chemotherapy; RT: radiation therapy.
`
`TABLE 2
`Hematologic Toxicity
`
`Cycles with neutropenia/grade
`
`Head and neck (grade)
`
`Anal canal (grade)
`
`Dose
`(mg/m2)
`
`Total no.
`of cycles
`
`120
`150
`180
`210
`240
`270
`300
`
`6
`6
`6
`6
`6
`6
`4
`
`1
`
`4
`2
`4
`2
`
`1
`
`2
`
`1
`
`1
`
`3
`
`4
`
`1
`
`2
`
`3
`
`4
`
`1
`
`2
`
`1
`
`2
`
`cinoma who previously had been treated with radia-
`tion therapy (RT) and chemotherapy and with
`chemotherapy plus RT 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 with esophageal varices. The patient was
`admitted to the hospital because of rupture of the
`varices 6 days after intraarterial chemotherapy and
`died of esophageal bleeding.
`Neutropenia never was associated with infection,
`occurred approximately 8 days after the chemother-
`apy, and resolved within a week in the 2 assessable
`cases. At a dose of 270 mg/m2, Grade 4 neutropenia
`occurred in 1 previously untreated patient with carci-
`noma of the head and neck. Grade 2 neutropenia
`occurred in 15.7% of patients in the series with tumors
`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 nonhematologic toxicities
`from the point of view of their impact on the quality of
`life were neuropathy lasting approximately 2 weeks,
`flu-like syndrome (of shorter duration), and ocular
`toxicity (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 catheterizations, 3 complications
`(2.5%) were observed in 3 patients during catheteriza-
`tion of the neck vessels for infusion of ABI-007. These
`complications were two transient ischemic attacks
`and one hemiparesis, the latter resolving within a few
`days. The patient who had the hemiparesis previously
`had undergone surgery,
`including radical bilateral
`neck dissection, chemotherapy, and RT. The two ce-
`rebral transient ischemic attacks occurred in two pa-
`tients who had received previous treatment, one RT
`and one chemotherapy. In all three cases, the external
`carotid artery was selectively catheterized by the
`method described. The accidents occurred at the time
`of removal of the catheter, most likely due to detach-
`ment of debris at
`the carotid bifurcation, which
`showed atheromatous plaque in all three cases, par-
`ticularly in the patient with hemiparesis.
`No complications related to the catheterization
`procedure occurred in the population treated for re-
`current anal canal carcinoma.
`
`Antitumor Activity
`Forty of 43 patients were assessable for antitumor
`activity of intraarterial chemotherapy with ABI-007.
`Three patients (all previously treated with combined
`regimens) received only one cycle and were not as-
`sessable: one died after rupture of esophageal varices
`complicating cirrhosis and the other two discontinued
`treatment because of disease progression. The latter
`two patients were treated with alternative chemother-
`apy regimens without success.
`
`CIPLA EXHIBIT 1017
`Page 6 of 11
`
`

`

`2598
`
`CANCER November 15, 2001 / Volume 92 / Number 10
`
`TABLE 3
`Nonhematologic Toxicity for Head and Neck Carcinoma and Anal Canal Carcinoma
`
`Total
`no. of
`cycles
`
`6
`6
`5
`5
`2
`3
`2
`
`1
`
`2
`
`1
`3
`
`3
`
`Dose (mg/m2)
`
`Head and neck
`carcinoma
`120
`150
`180
`210
`240
`270
`300
`
`Neuropathy
`(grade)
`
`Gastrointestinal
`(grade)
`
`Flu syndrome
`(grade)
`
`Ocular (grade)
`
`Cutaneous (grade)
`
`Alopecia (grade)
`
`2
`
`3
`
`4
`
`1
`
`1
`
`2
`
`2
`1
`1
`
`1
`
`2
`
`3
`
`4
`
`1
`1
`
`2
`
`3
`
`4
`
`1
`1
`1
`
`1
`
`1
`
`4
`
`1
`
`1
`
`2
`
`4
`2
`2
`2
`
`2
`
`3
`
`4
`
`1
`
`1
`1
`
`1
`1
`1
`
`2
`
`3
`
`3
`
`4
`
`1
`
`1
`
`3
`
`4
`
`2
`
`3
`3
`4
`5
`2
`2
`1
`
`Neuropathy
`
`Gastrointestinal
`
`Flu syndrome
`
`Cutaneous
`
`Alopecia
`
`2
`
`3
`
`4
`
`Dose (mg/m2)
`
`Anal canal carcinoma
`120
`150
`180
`210
`240
`270
`300
`
`Total No.
`of Cycles
`
`—
`—
`1
`1
`4
`3
`2
`
`1
`
`2
`
`3
`
`4
`
`1
`
`2
`
`3
`
`4
`
`1
`
`2
`
`3
`
`4
`
`1
`
`2
`
`3
`
`4
`
`1
`
`1
`
`1
`
`2
`1
`
`1
`2
`2
`1
`
`2
`
`1
`
`2
`
`1
`3
`3
`1
`
`TABLE 4
`Hematologic and Nonhematologic Toxicity in 25 Patients Treated Intraarterially with ABI-007 at a Dose of 250 mg/m2
`(Total of 80 Cycles, Median 3)
`
`Characteristic
`
`Total
`
`Head and neck cancer
`
`Anal canal cancer
`
`1 (%)
`
`2 (%)
`
`3 (%)
`
`4 (%)
`
`1 (%)
`
`2 (%)
`
`3 (%)
`
`4 (%)
`
`Grade
`
`Grade
`
`25
`
`19
`
`3
`16
`64 (36–72)
`
`6
`
`5
`1
`57 (41–64)
`
`No. of patients
`Gender
`Female
`Male
`Age, median (range)
`Hematologic toxicity
`Nonhematologic toxicity
`Alopecia
`Gastrointestinal
`Flu-like syndrome
`Cutaneous
`Ocular
`Neurologic
`
`47.3
`
`15.7
`
`6
`7
`7
`1
`1
`4
`
`12
`1
`3
`2
`
`1
`
`50.0
`
`16.6
`1
`3
`
`2
`
`33.3
`
`83.3
`1
`3
`1
`
`1
`
`Of the 40 assessable patients, 29 belonged to the
`head and neck carcinoma group in which there were 3
`complete responses (2 pathologic and 1 clinical). The
`three patients had received no previous treatment and
`were treated with radical surgery (1 patient with car-
`cinoma of the tongue who had received 4 cycles), with
`radical neck dissection and radiotherapy (1 patient
`
`with carcinoma of the piriform sinus), and with sur-
`gery and radiotherapy (1 case of carcinoma of the
`retromolar trigone).
`Nineteen partial 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,
`
`CIPLA EXHIBIT 1017
`Page 7 of 11
`
`

`

`Intraarterial Polyoxyethylated Castor Oil Free Paclitaxel/Damascelli et al.
`
`2599
`
`FIGURE 5. Carcinoma of right piriform sinus. Computed tomography (CT) of
`pharynx/larynx with arrows indicating the tumor margins (top left). CT with
`arrows indicating adenopathy (top right). CT after third cycle of intraarterial
`chemotherapy (bottom left); arrow indicates the primary tumor site no longer
`evident at histologic examination. CT of neck also shows a partial response for
`adenopathy (bottom right).
`
`FIGURE 6. Recurrent anal canal carcinoma. Computed tomography (CT) with
`contrast medium at presentation (top 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 were offered alternative
`chemotherapy. Of the 13 not previously treated, 9
`received surgery after intraarterial chemotherapy, 1
`chemotherapy, 1 RT, and 2 RT and chemotherapy. Six
`
`FIGURE 7. (A and B) Mean paclitaxel concentration versus time profiles in
`patients with head and neck (A) or anal canal (B) carcinomas during and after
`30-minute constant infusion of ABI-007 (250 mg/m2 of paclitaxel). The dotted
`line in each panel represents the profile of an intravenous injected dose. iv:
`intravenous; ia: intraarterial; svc: superior vena cava; ivc: inferior vena cava.
`
`of the remaining seven assessable patients had re-
`ceived previous treatment, and of these one pro-
`gressed, four had stable disease, and one developed a
`massive tumor necrosis with fistulization after the sec-
`ond cycle of intraarterial chemotherapy, and therefore
`treatment was discontinued. The last patient, not pre-
`viously treated, showed stable disease.
`In the 22 responding patients, the median dura-
`tion of follow-up for patients who had not received
`previous treatment was 12 months (range, 3–13
`months); for previously treated patients, the median
`was 5 months (range, 3–13 months).
`Twelve previously treated patients belonged to the
`group with recurrent anal canal carcinoma. Eleven of
`these were assessable; one patient received only one
`cycle and showed progression. Three complete re-
`sponses were recorded, two pathologic and one clin-
`ical. One patient with pathologic complete response
`received four cycles of ABI-007 (Fig. 6); the patient
`with clinical complete response received two cycles
`after which she refused to continue treatment because
`she wished to be reoperated on as soon as possible.
`Four patients showed partial response, three previ-
`
`CIPLA EXHIBIT 1017
`Page 8 of 11
`
`

`

`Administration
`
`Sampling
`
`Paclitaxel
`(mg/m2)
`
`No. of
`patients
`
`Cmax
`(mg/L)
`
`Tmax
`(min)
`
`a
`T1/2
`(min)
`
`b
`T1/2
`(min)
`
`g
`T1/2
`(min)
`
`AUC (mg/L
`min)
`
`Vss (L)
`
`Cl (L/min)
`
`2600
`
`CANCER November 15, 2001 / Volume 92 / Number 10
`
`TABLE 5
`ABI-007 Pharmacokinetic Parameters
`
`Cancer
`type
`
`Head and
`neck
`
`Anal
`canal
`
`Solid
`tumors
`
`i.a. infusion
`
`i.a. infusion
`i.a. infusion
`
`i.a. infusion
`i.v. infusion
`
`Superior vena
`cava
`Peripheral vein
`Inferior vena
`cava
`Peripheral vein
`Peripheral vein
`
`250
`
`250
`250
`
`250
`250
`
`5
`
`5
`6
`
`6
`8
`
`21.01 (6.5)
`
`7.53 (1.8)
`18.58 (5.9)
`
`7.45 (2.6)
`9.944 (3.1)
`
`30
`
`30
`30
`
`30
`30
`
`15.13
`
`560.59
`
`1146.0 (280)
`
`107.55 (85)
`
`0.338 (0.18)
`
`0.45
`
`3.42
`1.94
`
`38.35
`13.61
`
`3.066
`7.35
`
`14.64
`114.88
`
`764.67
`529.47
`
`530.22
`932.87
`
`753.52 (150)
`872.29 (210)
`
`345.55 (45)
`114.86 (73)
`
`0.536 (0.09)
`0.445 (0.1)
`
`548.58 (120)
`761.86 (140)
`
`244.56 (58)
`312.27 (40)
`
`0.707 (0.21)
`0.509 (0.12)
`
`AUC: area under the curve; i.a.: intraarterial; i.v.: intravenous.
`
`ously treated with chemotherapy and RT and 1 with
`surgery. The remaining four patients (36.36%) showed
`stable disease. All assessable patients had surgical
`control (reoperation in six cases). The median dura-
`tion of follow-up in responding patients (7 cases) was
`10 months (range, 7–13 months).
`
`Pharmacokinetics
`The concentration/time curve calculated on samples
`from the superior vena cava and peripheral veins is
`shown in Figure 7 and compared with the profile of
`the same dose administered by intravenous infusion.
`From the three-compartmental model fit
`the
`elimination half-time