1038 Vol. 8, 1038 –1044, May 2002
`
`Clinical Cancer Research
`
`Phase I and Pharmacokinetic Study of ABI-007, a Cremophor-free,
`Protein-stabilized, Nanoparticle Formulation of Paclitaxel1
`
`Nuhad K. Ibrahim, Neil Desai, Sewa Legha,
`Patrick Soon-Shiong, Richard L. Theriault,
`Edgardo Rivera, Bita Esmaeli, Sigrid E. Ring,
`Agop Bedikian, Gabriel N. Hortobagyi, and
`Julie A. Ellerhorst2
`Departments of Breast Medical Oncology [N. K. I., R. L. T., E. R.,
`G. N. H.], Melanoma/Sarcoma [S. L., S. E. R., A. B., J. A. E.], and
`Ophthalmology [B. E.], The University of Texas M. D. Anderson
`Cancer Center, Houston, Texas 77030, and American Bioscience,
`Inc., Santa Monica, California 90403 [N. D., P. S-S.]
`
`ABSTRACT
`Purpose: ABI-007 is a novel Cremophor-free, protein-
`stabilized, nanoparticle formulation of paclitaxel. The ab-
`sence of Cremophor EL may permit ABI-007 to be admin-
`istered without the premedications used routinely for the
`prevention of hypersensitivity reactions. Furthermore, this
`novel formulation permits a higher paclitaxel concentration
`in solution and, thus, a decreased infusion volume and time.
`This Phase I study examines the toxicity profile, maximum
`tolerated dose (MTD), and pharmacokinetics of ABI-007.
`Experimental Design: ABI-007 was administered in the
`outpatient setting, as a 30-min infusion without premedica-
`tions. Doses of ABI-007 ranged from 135 (level 0) to 375
`mg/m2 (level 3). Sixteen patients participated in pharmaco-
`kinetic studies.
`Results: Nineteen patients were treated. No acute hy-
`persensitivity reactions were observed during the infusion
`period. Hematological toxicity was mild and not cumulative.
`Dose-limiting toxicity, which occurred in 3 of 6 patients
`treated at level 3 (375 mg/m2), consisted of sensory neurop-
`athy (3 patients), stomatitis (2 patients), and superficial
`keratopathy (2 patients). The MTD was thus determined to
`be 300 mg/m2 (level 2). Pharmacokinetic analyses revealed
`paclitaxel Cmax and area under the curveinf values to in-
`crease linearly over the ABI-007 dose range of 135–300
`mg/m2. Cmax and area under the curveinf values for individ-
`ual patients correlated well with toxicity.
`Conclusions: ABI-007 offers several features of clinical
`interest, including rapid infusion rate, absence of require-
`
`Received 9/25/01; revised 1/23/02; accepted 2/1/02.
`The costs of publication of this article were defrayed in part by the
`payment of page charges. This article must therefore be hereby marked
`advertisement in accordance with 18 U.S.C. Section 1734 solely to
`indicate this fact.
`1 Supported by American Bioscience, Inc., Santa Monica, CA.
`2 To whom requests for reprints should be addressed, at Department of
`Molecular and Cellular Oncology, Box 79, M. D. Anderson Cancer Center,
`1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-8990;
`Fax: (713) 794-0209; E-mail: jaellerh@mail.mdanderson.org.
`
`ment for premedication, and a high paclitaxel MTD. Our
`results provide support for Phase II trials to determine the
`antitumor activity of this drug.
`
`INTRODUCTION
`Paclitaxel is a chemotherapeutic agent with a wide spec-
`trum of antitumor activity when used as monotherapy or in
`combination chemotherapy regimens (1). The drug is used ex-
`tensively in the treatment of advanced carcinomas of the 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 phenomenon
`(2, 3), and in keeping with standard medical oncology practice,
`attempts are generally made to maintain paclitaxel doses at or
`near the MTD.3 Several schedules of administration have been
`studied, each demonstrating a slightly different toxicity profile.
`Short infusions of 1–3 h result in peripheral neuropathy as a
`dose-limiting toxicity, whereas longer, continuous infusion
`schedules produce a higher incidence of neutropenia (2, 4 – 6).
`Other common side effects include alopecia, mucositis, arthral-
`gias, myalgias, and mild nausea.
`The paclitaxel preparation in clinical use (Taxol; Bristol-
`Myers Squibb, Princeton, NJ) is formulated in the nonionic
`surfactant Cremophor EL (polyoxyethylated castor oil) and eth-
`anol to enhance drug solubility (7). Cremophor EL may add to
`paclitaxel’s toxic effects by producing or contributing to the
`well-described hypersensitivity reactions that commonly occur
`during infusion, affecting 25–30% of treated patients (8, 9). To
`minimize the incidence and severity of these reactions, premed-
`ication with histamine 1 and 2 blockers, as well as glucocorti-
`coids (usually dexamethasone), has become standard practice
`(10). 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 peripheral neuropathy (11). An additional prob-
`lem arising from the Cremophor and ethanol solvent is the
`leaching of plasticizers from PVC bags and infusion sets in
`routine clinical use (12). Consequently, Taxol must be prepared
`and administered in either glass bottles or non-PVC infusion
`systems and with in-line filtration. These problematic issues
`have spurred interest in the development of taxanes with im-
`proved solubility in aqueous solutions (13).
`ABI-007 is a novel Cremophor-free formulation of pacli-
`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, ABI-007 dos-
`
`3 The abbreviations used are: MTD, maximum tolerated dose; ANC,
`absolute neutrophil count; AUC, area under the curve; CL, clearance;
`PVC, polyvinyl chloride.
`
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`

`

`Clinical Cancer Research
`
`1039
`
`Table 1 Dose levels
`
`Level
`0
`1
`2
`3
`
`Dose (mg/m2)
`135
`200
`300
`375
`
`No. patients entered
`4
`3
`6
`6
`
`No. cycles
`6
`38
`35
`17
`
`age is determined by the paclitaxel content of the formulation,
`making direct comparison of the two drugs possible. ABI-007
`can be reconstituted in normal saline at concentrations of 2–10
`mg/ml, compared with 0.3–1.2 mg/ml for Taxol. Thus, the
`volume and time required for administration is reduced. In the
`absence of Cremophor EL, the risk of hypersensitivity reactions
`should decrease significantly, and patients receiving ABI-007
`might thus avoid premedication. Moreover, there is no danger of
`leaching plasticizers from infusion bags or tubing, and conven-
`tional PVC infusion systems may be safely used.
`To explore the potential clinical utility of ABI-007, we
`have conducted a Phase I study of this drug for patients with
`advanced solid tumors. The objectives of this trial were to
`determine the toxic effects, MTD, and pharmacokinetic profile
`of this unique paclitaxel preparation.
`
`PATIENTS AND METHODS
`Patient Eligibility and Evaluation on Study. Eligible
`patients included 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 ⱖ 9 g/dl, ANC ⱖ 1,500/mm3, platelet
`count ⱖ 100,000/mm3, serum creatinine ⬍ 2 mg/dl, and serum
`bilirubin ⬍ 1.5 mg/dl. Patients with prior exposure to taxanes
`were eligible for the study.
`Pretreatment evaluations included a complete blood count
`with differential and platelet count, serum chemistry profile,
`chest radiograph, and electrocardiogram. Baseline imaging stud-
`ies and serum tumor marker levels were obtained at the discre-
`tion of the treating physician. Brain imaging by computerized
`tomography or magnetic resonance imaging was required for
`patients with symptoms suggestive of central nervous system
`involvement. Evaluations performed during the study included a
`complete blood count with differential and platelet count at least
`once weekly and a chemistry profile prior to each course.
`Restaging was performed after every 2nd or 3rd cycle of ther-
`apy. Patients were removed from the study for progression of
`disease, unacceptable toxicity, or at the patient’s request.
`Study Design. This Phase I study was conducted at The
`University of Texas M. D. Anderson Cancer Center and was
`approved by the M. D. Anderson Institutional Review Board.
`Informed consent was obtained from all subjects. Toxicity was
`graded according to National Cancer Institute Common Toxicity
`Criteria. Dose levels of ABI-007 are shown in Table 1. Dose
`escalation followed the standard “3 ⫹ 3” rule. Briefly, 3 patients
`were accrued at the starting dose level. If no toxic effects greater
`than grade 2 were observed, 3 patients were entered at the next
`dose level. If, at any level, one of the first 3 patients experienced
`a grade 3 or 4 toxic effect, 3 additional patients were entered at
`that dose level. The MTD was defined as one dose level below
`
`that at which ⱖ2 patients experienced grade 3 or 4 toxic effects.
`Six patients were to be treated at the MTD. Patients were
`permitted to escalate to the next higher dose level if no signif-
`icant toxic effects were observed after the first 2 cycles of
`therapy. Patients with toxicity greater than grade 2 were per-
`mitted to reduce dosage by one dose level and remain on therapy
`at the discretion of the treating physician.
`Treatment. ABI-007 was supplied by American Bio-
`science, Inc. (Santa Monica, CA). All therapy was administered
`in the outpatient treatment center of the M. D. Anderson Cancer
`Center, with the exception of patients participating in pharma-
`cokinetic studies, which required an overnight hospital stay. The
`prescribed dose of ABI-007 was prepared in 100 –150 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 ABI-007 was administered at a rate of
`1.4 mg/kg/h or roughly over 3 h. If no acute hypersensitivity
`reactions were noted, the remainder of the patients were to
`receive treatment over 30 min. One cycle of therapy was 21
`days.
`Studies. Pharmacokinetic
`Pharmacokinetic
`studies
`were performed in 16 patients, with at least 3 patients repre-
`senting each dose level. Whole blood samples of 5 ml each were
`taken to determine the pharmacokinetics of ABI-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-
`tein precipitation with acetonitrile, followed by solid phase
`extraction. The sample extracts were analyzed for paclitaxel
`using liquid chromatography atmospheric pressure ionization
`tandem mass spectrometry. The limit of quantitation for pacli-
`taxel is 5 ng/ml, and the range of reliable response is 5–1000
`ng/ml.
`Pharmacokinetic parameters were determined from each
`patient’s whole blood/plasma paclitaxel concentration profile.
`Analysis was performed by the noncompartmental routine using
`WinNonlin software (Pharsight Corp., Mountain View, CA).
`The peak or maximum paclitaxel concentration (Cmax) and the
`corresponding peak time (tmax) were observed values. The elim-
`ination constant (␭12z) was obtained by log-linear regression
`analysis of the terminal phase of the whole blood/plasma con-
`centration versus time profile. The elimination half-life (T1/2)
`was determined by taking the ratio of natural log of 2 and ␭12z.
`The AUC from time 0 to time infinity (AUCinf) was obtained by
`summation of AUClast (AUC from time 0 to last measurable
`concentration, calculated by the linear trapezoidal rule) and
`AUCext (extrapolated area, estimated by taking the ratio be-
`tween the last measurable concentration and ␭12z). The dose
`area relationship (i.e., total ABI-007 dose divided by AUCinf)
`was used to determine total body CL. The volume of distribution
`(Vz) was determined by taking the ratio between CL and ␭12z.
`Descriptive statistics (mean, median, SD, coefficient of
`variation, maximum, and minimum) were computed for perti-
`nent pharmacokinetic parameters by ABI-007 dose. Regression
`analysis of mean AUCinf versus dose was performed to gain an
`appreciation of pharmacokinetic linearity, if evident, for the
`dose range evaluated in this trial. Differences in the means of
`Cmax and AUCinf between groups of patients were analyzed for
`significance using a two-tailed, two-sample t test. Pearson’s
`
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`

`

`1040 Phase I Trial and Pharmacokinetics of ABI-007
`
`Table 2 Patient characteristics
`
`Enrolled
`Eligible
`Age (yr)
`Median
`Range
`Performance status (Zubrod)
`0
`1
`2
`Gender
`Female
`Male
`Malignancy
`Breast cancer
`Melanoma
`Prior treatment
`Chemotherapy
`Immunotherapy
`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-
`tween degree of myelosuppression and Cmax or AUCinf.
`
`RESULTS
`Patients. Twenty patients were enrolled in the trial. One
`of these chose not to be treated after signing an informed
`consent. Therefore, 19 patients received drug and were evalu-
`able for toxic effects. Patient characteristics are summarized in
`Table 2.
`Treatment and MTD Determination. All
`treatment
`was administered without dexamethasone or histamine 1 or 2
`blockers. The first 3 patients received infusions of ABI-007 over
`2–3 h. No hypersensitivity reactions were observed. Therefore,
`all subsequent infusions were administered over 30 min. Even at
`the faster infusion rate, there were no instances of acute hyper-
`sensitivity to the ABI-007 preparation.
`Three patients were entered initially at level 0, receiving
`135 mg/m2 over 3 h. One of these experienced progression of
`disease over the next several weeks, with rapid clinical deteri-
`oration, making it difficult to ascertain toxic effects of ABI-007
`in this individual. To verify toxicity data at this dose level and
`ascertain the safety of administering the drug over a short
`infusion period, a 4th patient was entered at level 0 and was the
`first patient
`to receive drugs over 30 min. There were no
`instances of grade 3 or 4 toxicity observed at dose levels 0 or 1
`(200 mg/m2). At dose level 2 (300 mg/m2), 1 of the first 3
`patients developed grade 3 sensory neuropathy. Three more
`patients were accrued at this level, with no additional observa-
`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, including sensory neuropathy, stoma-
`titis, and superficial keratopathy; this patient developed grade 3
`vomiting and diarrhea and thrombocytopenia as well. An addi-
`
`Table 3 Median absolute neutrophil and platelet nadirs by dose level
`ANC nadir ⫻
`Platelet nadir ⫻
`103/mm3
`103/mm3
`(range)
`(range)
`2.229 (1.850–5.040)
`204 (174–292)
`1.845 (0.586–3.729)
`197 (118–270)
`0.960 (0.264–3.680)
`200 (105–609)
`0.966 (0.018–1.804)
`173 (25–251)
`
`Dose level
`0
`1
`2
`3
`
`tional case of sensory neuropathy, this time as an isolated grade
`3 toxic effect, was observed in a 3rd patient at level 3. The study
`was thus terminated. 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 effects were sensory neu-
`ropathy, stomatitis, and superficial keratopathy. Specific toxic
`effects are described below.
`Hematological Toxicity. Hematological
`toxicity was
`dose dependent but remained modest throughout the study (Ta-
`ble 3). Of the 96 treatment cycles administered, only 7 (7.3%)
`resulted in an ANC nadir ⬍ 500/mm3, 6 of which occurred
`above the MTD at dose level 3. There was one hospital admis-
`sion for febrile neutropenia. In only one case did the platelet
`count drop below 75,000/mm3. The patient, who was found to
`have a platelet nadir of 25,000/mm3 during her 1st cycle of
`therapy at level 3, also developed a constellation of grade 3
`nonhematological toxic effects. This was the only individual
`who required a platelet transfusion during the study. No patients
`received growth factors for granulocyte support.
`Nonhematological Toxicity. Table 4 summarizes the
`nonhematological toxic effects observed during the first 2 cycles
`of therapy at each dose level. The majority of these were grades
`1 and 2; no patient manifested grade 4 toxicity. Nausea, vom-
`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 universal. Peripheral
`neuropathy, absent at the lower dose levels, was common with
`higher doses, appearing in 11 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-
`tients with peripheral neuropathy developed peri-oral numbness
`as well. 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-
`cial keratopathy, all grade 3.
`A variety of ocular side effects was observed, the severity
`of which appeared to be dose dependent. One patient, entered at
`level 0, complained of dry eyes but noted no visual disturbance.
`No ocular complaints were registered by patients treated at level
`1. Four patients developed ocular toxicity at level 2. One noted
`intermittent “smoky” vision, and another experienced blurred
`vision, both occurring with cycle 1 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 abnormalities on ophthalmologic exam. At
`level 3, 2 patients complained of mild dry eyes throughout
`
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`

`

`Clinical Cancer Research
`
`1041
`
`Table 4 Nonhematologic toxicity by dose levela
`Level 0 (n ⫽ 4)
`Level 1 (n ⫽ 3)
`Level 2 (n ⫽ 6)
`
`Level 3 (n ⫽ 6)
`
`Grade
`Grade
`Grade
`Grade
`Grade
`Grade
`3
`1 or 2
`3
`1 or 2
`3
`1 or 2
`Toxicity
`1
`4
`0
`0
`0
`0
`Sensory neuropathy
`0
`2
`0
`0
`0
`1
`Ocular
`0
`4
`0
`1
`0
`0
`Stomatitis
`0
`3
`0
`1
`0
`1
`Nausea
`0
`0
`0
`1
`0
`1
`Vomiting
`0
`3
`0
`2
`0
`1
`Diarrhea
`0
`4
`0
`3
`0
`3
`Arthralgia/myalgia
`0
`5
`0
`0
`0
`0
`Skin
`0
`2
`0
`0
`0
`0
`Fever (non-neutropenic)
`a Expressed as the number of patients experiencing the toxic effect during the first two cycles of treatment.
`
`Grade
`1 or 2
`3
`2
`3
`4
`2
`1
`4
`2
`3
`
`Grade
`3
`3
`2
`2
`1
`1
`1
`1
`0
`0
`
`of ABI-007
`profile
`Fig. 1 Pharmacokinetic
`showing mean whole blood paclitaxel concentra-
`tions at increasing doses of ABI-007 versus time.
`All infusions were given over 30 min except for
`the first 3 patients who received 135 mg/m2 over
`180 min.
`
`therapy but did not experience visual disturbances. Two other
`patients at dose level 3 developed grade 3 superficial keratopa-
`thy during their 1st cycle of treatment, as described above. All
`cases of keratopathy received full ophthalmologic evaluation,
`and all resolved with the use of topical lubricating drops and
`ointments. No patient developed a permanent loss of vision or
`experienced any other permanent ocular sequellae.
`Occurrences of new types of toxic effects after the first 2
`cycles of therapy were rare. Furthermore, it was uncommon for
`toxic effects to increase in grade after the first 2 treatment
`cycles. Therefore, cumulative toxicity did not appear to be a
`significant problem.
`Response. Partial responses were observed in two breast
`cancer patients, both of whom had prior exposure to Taxol. The
`first patient, entered at dose level 2, experienced a 68% decrease
`in the size of pulmonary metastases. This response lasted a total
`of 15 months, including 9 months after discontinuation of ther-
`apy for toxicity. The 2nd patient, who was also treated at dose
`level 2, had significant improvement in soft tissue disease in-
`volving the chest wall. Because of toxic effects, she was taken
`off treatment on the date of her response. Disease progression
`was noted 6 weeks later.
`Pharmacokinetic Studies. Sixteen of the 19 patients en-
`tered into the study contributed analyzable pharmacokinetic
`
`profiles. Three of these received ABI-007 as a 180-min infusion;
`the remaining 13 were treated over 30 min. A semilog plot of the
`mean values of the whole blood paclitaxel concentration for
`each dose level versus time is shown in Fig. 1. The maximum
`paclitaxel concentrations were observed at the termination of
`ABI-007 infusion; the decline from maximum was biphasic.
`A summary of the pharmacokinetic parameter values de-
`rived by noncompartmental methods is shown in Table 5. The
`pharmacokinetics of ABI-007 administered over 30 min ap-
`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-fold increase in Cmax and a 2.7-fold increase in
`AUCinf over the 2.2-fold increase in dose from 135 to 300
`mg/m2. The decline in CL estimates over this range is 0.8-fold
`(16.1%). If the highest dose level of 375 mg/m2 is included,
`nonlinearity becomes evident (Fig. 2). Individual Cmax and
`AUCinf values versus dose are shown in Fig. 3, a and b,
`respectively.
`The group of 13 patients who received 30-min infusions
`and for whom pharmacokinetic profiles were obtained included
`3 who experienced grade 3 nonhematological toxic effects (neu-
`ropathy with or without stomatitis and keratopathy). The Cmax
`and AUCinf for these 3 patients relative to those of the remaining
`10 patients are plotted in Fig. 4. The differences in mean Cmax
`
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`

`

`1042 Phase I Trial and Pharmacokinetics of ABI-007
`
`Table 5 Summary of noncompartmental pharmacokinetic parameters, mean (% coefficient of variation) values by dosea
`
`Infusion duration
`AUCinf
`Vz liter/m2
`CL liter/h/m2
`Dose mg/m2
`Half-life h
`ng/h/ml
`Cmax ng/ml
`min
`n
`418 (32)
`27.4 (45)
`12.9 (60)
`5654 (42)
`1392 (30)
`3
`180
`135
`442
`21.1
`14.6
`6427
`6100
`1
`30
`135
`384 (64)
`21.4 (21)
`13.4 (67)
`9613 (20)
`7757 (35)
`3
`30
`200
`370 (23)
`17.7 (22)
`14.6 (14)
`17610 (21)
`13520 (7)
`5
`30
`300
`236 (54)
`11.9 (42)
`13.2 (12)
`35805 (40)
`19350 (15)
`4
`30
`375
`a n, number of patients; Cmax, maximum or peak concentration; AUCinf, area under the whole blood/plasma concentration-time curve from time
`0 to time infinity; CL, total body clearance; Vz, volume of distribution.
`
`Fig. 2 Correlation between the mean AUCinf and
`dose level. The data have been fit using a linear
`regression and an exponential regression function.
`
`and mean AUCinf between the two groups were significant (P ⫽
`0.034 and 0.007, respectively). The effect of ABI-007 exposure
`on myelosuppression was also examined in this group of pa-
`tients. The percentage of decrease in ANC from baseline to
`nadir was found to correlate positively with both Cmax (r ⫽
`0.610, P ⫽ 0.027) and AUCinf (r ⫽ 0.614, P ⫽ 0.025).
`
`DISCUSSION
`This clinical trial was conducted to examine the pharma-
`cokinetic properties and spectrum of toxic effects associated
`with ABI-007. Because ABI-007 is not formulated in a Cremo-
`phor-containing solvent, we anticipated that hypersensitivity
`reactions would be diminished or absent. Our results show that
`ABI-007 can indeed be administered safely as a short infusion
`without dexamethasone or antihistamine 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-
`sone premedication), and patient convenience and comfort (less
`time spent in the treatment center). These advantages could
`ultimately translate into an overall decrease in cost of therapy.
`It must be pointed out that, although the absence of Cre-
`mophor is clearly desirable with respect to toxicity, this same
`compound has been proposed to enhance the efficacy of cyto-
`toxic drugs through reversal of the multidrug resistance pheno-
`type (15). Plasma concentrations of Cremophor attainable dur-
`ing Taxol
`infusions are sufficient
`to inhibit P-glycoprotein
`effects in vitro (16). However, there have been questions raised
`as to whether these Cremophor concentrations are relevant to
`
`solid tumors, as pharmacokinetic studies demonstrate the com-
`pound’s distribution to be limited to the central plasma com-
`partment (17). This issue should be clarified with the completion
`of ongoing Phase II trials of ABI-007. If the response rate of
`ABI-007 is not less than that of Taxol and if responses are seen
`in patients who are previous taxane failures, the therapeutic
`contribution of Cremophor to paclitaxel can be considered neg-
`ligible.
`In terms of treatment-related toxicity, a lower incidence of
`myelosuppression was observed than that which we anticipated
`based on the dose of paclitaxel administered. In this regard,
`hematological toxicity was mild and played virtually no role in
`dose and treatment decisions made in this trial. Although direct
`comparisons to Taxol administered at this dose range and sched-
`ule are not possible, the myelosuppression induced by ABI-007
`appeared to be similar to or less severe than that reported for 1-h
`Taxol infusions at lower doses (18). Otherwise, the spectrum of
`toxic effects produced by ABI-007 resembled that of high-dose
`short-infusion Taxol reported in early Phase I trials, with sen-
`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 report of
`superficial keratopathy as a consequence of paclitaxel adminis-
`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 the
`MTD, at a dose of 375 mg/m2. Superficial keratopathy second-
`ary to ABI-007 was similar to that most commonly recognized
`in association with 1-␤-D-arabinofuranosylcytosine, although
`any type of ocular surface irritation, including dry eye syn-
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`Clinical Cancer Research
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`1043
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`Fig. 3 Individual values of Cmax (a) and AUCinf (b) versus dose for
`patients receiving 30-min infusions of ABI-007.
`
`Fig. 4 Individual values of Cmax (a) and AUCinf (b) for patients who
`experienced grade 3 nonhematological toxic effects (“yes”) and those
`who did not (“no”). In the “yes” category, the solid diamond symbols
`(⽧) represent 2 patients with multiple grade 3 toxicities, whereas the
`open circle (E) represents the patient with only grade 3 neuropathy.
`
`drome, can result in similar corneal findings (21). Other ocular
`complications of taxane therapy have been reported. The most
`common adverse ocular effects of Taxol are photopsia and
`blurred vision, usually reported by patients during the infusion
`period (22, 23). Cases of optic nerve disturbances have also
`been documented (24). Cases of grade 2 conjunctivitis necessi-
`tating dose reduction and treatment delay have been reported
`during weekly therapy with docetaxel (25). Similar to our find-
`ings, reported ocular effects from paclitaxel have been noted
`only at higher doses and are usually transient. Although all cases
`of keratopathy in this study resolved completely and without
`permanent sequellae, in the ensuing Phase II trial, patients will
`be aggressively monitored for the development of ophthalmo-
`logic abnormalities.
`Pharmacokinetic analysis of ABI-007 revealed interesting
`similarities and differences relative to Taxol, based on published
`data. Disappearance from the blood is biphasic for both drugs
`(19). ABI-007 displays linear pharmacokinetics over the clini-
`cally relevant dose range of 135–300 mg/m2; over a similar dose
`range, Taxol AUCinf is nonlinear (26 –28). In comparing the
`AUCinf values of ABI-007 infused over 30 min to those reported
`for Taxol infused over 1 or 3 h, ABI-007 in general showed
`lower AUCinf values over a similar range of doses (26 –28).
`Although several explanations are possible for the differences in
`AUCinf, it is reasonable to hypothesize that ABI-007 may be
`distributed more rapidly out of the vascular compartment, a
`suggestion supported by the difference in formulation between
`the two drugs. A substantial amount of solvent (Cremophor/
`ethanol) is infused with Taxol, and the partition of paclitaxel
`from the vascular compartment to the tissues may thus be
`relatively slow. In contrast, ABI-007 is formulated with human
`
`serum albumin at a concentration of 3– 4%, similar to the
`concentration of albumin in the blood. Because paclitaxel has a
`very limited solubility in an aqueous albumin solution (⬍30
`␮g/ml), it may partition more efficiently into the tissues in the
`case of ABI-007. Furthermore,
`lipid, macromolecular, and
`nanoparticle drug carriers have been known to preferentially
`accumulate in tumor beds and tissues in what is known as
`enhanced permeation and retention effect (29). These factors
`may facilitate the partition of ABI-007 into tissues.
`The MTD of ABI-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/m2,
`doses as high as 250 mg/m2 are occasionally administered.
`Therefore, the MTD established by this trial represents a mod-
`erate increase over that of Taxol. The issue of whether one can
`achieve uniform and repeated dosing of ABI-007 at the MTD
`will need to be addressed in Phase II trials.
`In conclusion, ABI-007 appears to represent an improve-
`ment in paclitaxel formulation in that it can be administered
`rapidly and safely without the risk of hypersensitivity reactions,
`eliminating the need for steroid and antihistamine premedica-
`tion. Furthermore, the increased MTD and favorable toxicity
`profile of ABI-007 may ultimately prove advantageous in terms
`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 studies will need to be conducted to
`fully appreciate differences in pharmacokinetic behavior. The
`partial responses seen in 2 patients with prior exposure to Taxol
`are encouraging and support a continued effort to explore the
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`1044 Phase I Trial and Pharmacokinetics of ABI-007
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`spectrum of activity for this drug. We are currently conducting
`a Phase II trial of ABI-007 for patients with metastatic breast
`cancer to establish the antitumor activity of this novel paclitaxel
`formulation.
`
`ACKNOWLEDGMENTS
`We thank Drs. Timothy Madden and Laura Boehnke Michaud for
`their critical reviews of the manuscript.
`
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