Phase I and Pharmacokinetics Trial of ABI-007, a Novel Nanoparticle Formulation of Paclitaxel in Patients With Advanced Nonhematologic Malig
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▲還散笫雖悝◎
the Departments of Pharmacology/Toxicology and Medicine, Division of Hematology/Oncology, Arizona Cancer Center/University of Arizona Health Sciences Center, Tucson
Translational Genomics Research Institute, Phoenix, AZ
American BioScience, Inc, Santa Monica, CA.
ABSTRACT
PURPOSE: ABI-007 is a novel solvent-free, albumin-bound, 130-nm particle formulation of paclitaxel designed to avoid solvent-related toxicities and to deliver paclitaxel to tumors via molecular pathways involving an endothelial cell-surface albumin receptor (gp60) and an albumin-binding protein expressed by tumor cells and secreted into the tumor interstitium (secreted protein acid rich in cysteine). This study determined the maximum-tolerated dose (MTD) of ABI-007 monotherapy administered weekly (three weekly doses, repeated every 4 weeks) and assessed the pharmacokinetics of paclitaxel administered as ABI-007.
PATIENTS AND METHODS: Patients with advanced nonhematologic malignancies received ABI-007 without premedication at dose levels from 80 to 200 mg/m2 as a 30-minute intravenous infusion once a week for 3 weeks, followed by 1 week of rest (one cycle).
RESULTS: Thirty-nine patients were treated with an average of five cycles of ABI-007; 33% of patients received six cycles of treatment. MTDs for heavily and lightly pretreated patients were 100 and 150 mg/m2, respectively; and the dose-limiting toxicities were grade 4 neutropenia and grade 3 peripheral neuropathy, respectively. Maximum paclitaxel concentration and area under the curve increased linearly with dose. Dose-dependent changes in plasma clearance did not occur. Partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had previously been treated with paclitaxel containing polyoxyethylated castor oil in the formulation.
CONCLUSION: This study demonstrated that weekly ABI-007 can be administered at doses exceeding those typically used for paclitaxel containing polyoxyethylated castor oil. Pharmacokinetics were linear over the dose range studied. Antitumor responses occurred in patients previously treated with paclitaxel containing polyoxyethylated castor oil.
INTRODUCTION
Taxanes are cell cycle每specific agents that act via high-affinity binding to microtubules to enhance tubulin polymerization and to suppress spindle microtubule dynamics, resulting in the inhibition of mitosis and apoptotic cell death.1-3 The taxane paclitaxel has substantial antitumor activity and is among the most active of the antineoplastic agents being widely used as therapy for patients with advanced breast, non每small-cell lung, and ovarian carcinomas.4,5
One of the limitations of paclitaxel for clinical use is related to its poor water solubility. First-generation formulations solubilized paclitaxel with the nonionic surfactant polyoxyethylated castor oil (Cremophor EL; BASF, Florham Park, NJ) and ethanol (Taxol; Bristol-Myers Squibb, Princeton, NJ; and generic equivalents).5 However, polyoxyethylated castor oil is biologically and pharmacologically active, and its presence in current formulations results in several well-characterized aspects of polyoxyethylated castor oil每based paclitaxel therapy. First, polyoxyethylated castor oil每based paclitaxel infusion produces well-described, polyoxyethylated castor oil每related hypersensitivity reactions that have affected up to 20% to 40% of treated patients who were not premedicated in early phase I trials.2,3 Longer infusion schedules and premedication were used to decrease the risk of hypersensitivity reactions. Although 3-hour infusions and premedication, including dexamethasone, diphenhydramine, and cimetidine, are now standard when administering polyoxyethylated castor oil每based paclitaxel, fatal hypersensitivity reactions have still been reported.6 Second, polyoxyethylated castor oil entraps paclitaxel in micelles formed in the plasma compartment.7 This entrapment alters drug pharmacokinetics, leading to decreased drug clearance, decreased volume of distribution, and nonlinear pharmacokinetics and possibly contributing to a lack of dose-dependent antitumor activity.7-9 Drug entrapment in polyoxyethylated castor oil micelles may affect not only paclitaxel but also coadministered drugs such as anthracycline compounds.7 Third, polyoxyethylated castor oil leaches plasticizers from standard-infusion sets,10,11 thus requiring the use of special tubing and in-line filters for drug administration. Finally, we have recently demonstrated in vitro that polyoxyethylated castor oil inhibits endothelial transcytosis of paclitaxel that is mediated by an albumin receptor (N. Desai, personal communication, June 2004).
ABI-007 (American BioScience, Santa Monica, CA) is a novel, solvent-free, albumin-bound, 130-nm particle form of paclitaxel designed to avoid the problems associated with the solvents used in polyoxyethylated castor oil每based paclitaxel.12 Albumin has a number of properties that made it an attractive molecule to combine with paclitaxel. Albumin is a natural transporter of endogenous hydrophobic molecules, such as water-insoluble vitamins and hormones,13 and albumin binding to the gp60 receptor (albondin) initiates the caveolar-mediated endothelial transport of protein-bound and unbound plasma constituents.14-16 In addition, osteonectin (also known as secreted protein acid rich in cysteine [SPARC]) has been shown to be expressed in a number of tumors17-26 and, sharing a sequence homology with gp60, has been shown to bind albumin.27,28 Albumin is known to accumulate in some tumors,29 possibly because of binding to SPARC, and may thereby facilitate intratumor accumulation of albumin-bound drugs.
A phase I clinical study of ABI-007 in 19 patients with solid tumors and breast cancer30 established the maximum-tolerated dose (MTD) of ABI-007 for an every 3 weeks regimen at 300 mg/m2, which is approximately 70% higher than the MTD reported for polyoxyethylated castor oil每based paclitaxel (175 mg/m2).31 Dose-limiting toxicities (DLTs) were sensory neuropathy, stomatitis, and superficial keratopathy. No hypersensitivity reactions occurred, despite the absence of premedication. ABI-007 was administered intravenously in shorter infusion periods (30 minutes v 3 hours for polyoxyethylated castor oil每based paclitaxel) and with standard intravenous tubing. The disposition of ABI-007 exhibited a biphasic decline in concentration, with linear pharmacokinetic parameters for the clinically relevant dose range of 135 to 300 mg/m2. A randomized, phase III study compared equitoxic doses of ABI-007 (260 mg/m2) and polyoxyethylated castor oil每based paclitaxel (175 mg/m2) in 454 patients with metastatic breast cancer.32 Response rates were significantly higher for ABI-007 than for polyoxyethylated castor oil每based paclitaxel for all patients (33% v 19%, respectively; P = .001) and for patients who received the study drug as first-line therapy (42% v 27%, respectively; P = .029). The incidence of grade 4 neutropenia was significantly lower in the ABI-007 group than the polyoxyethylated castor oil每based paclitaxel group (10% v 21%, respectively; P < .001) despite the approximately 50% higher dose. Grade 3 sensory neuropathy was more common in the ABI-007 group compared with the group who received polyoxyethylated castor oil每based paclitaxel (10% v 2%, respectively; P < .001), but these events were easily managed and improved rapidly (median, 22 days).
The primary objectives of the current study were as follows: (1) to characterize the toxicities of ABI-007 administered weekly for 3 weeks, with repeated dosing every 4 weeks; (2) to determine the MTD of ABI-007; (3) to assess pharmacokinetic parameters for ABI-007 when administered on a weekly schedule; and (4) to describe any antitumor activity when ABI-007 is administered weekly to patients with advanced nonhematologic malignancies.
PATIENTS AND METHODS
The protocol and all related materials were approved by the University of Arizona Institutional Review Board. The study was conducted in compliance with Good Clinical Practice Guidelines of the International Conference on Harmonisation and the Declaration of Helsinki. Written informed consent was obtained from all patients before participation.
Patient Selection
Eligible patients included males and nonpregnant females practicing adequate birth control who were at least 18 years of age, had a life expectancy of at least 2 months, and had not received any chemotherapy (inclusive of investigational therapies) for at least 3 weeks before study drug administration. Patients had biopsy-proven diagnoses of advanced malignancy or solid tumors for which standard therapy had failed. Patients had a Southwest Oncology Group performance status of 0 to 2, hemoglobin 9 g/dL, WBC count 3.0 x 109/L with an absolute neutrophil count (ANC) 1.5 x 109/L, platelet count 100 x 109/L, serum creatinine less than 2 mg/dL, serum bilirubin less than 1.5 mg/dL, and hepatic transaminases less than 3x the upper limit of normal. Prior taxane therapy was permitted.
Patients were excluded from the trial if they had a history of allergy or hypersensitivity to the study drug or its excipients, had symptomatic brain metastases, had a serious concurrent illness that was likely to limit full compliance with the study, had a pre-existing peripheral neuropathy (grade 1 or higher), were unlikely to complete the study with appropriate follow-up visits, or were currently taking any anticancer medication or protease inhibitor. A washout period of 30 days was required before initiation of therapy.
Study Design
ABI-007 was administered on an outpatient basis weekly for 3 weeks, followed by 1 week of rest. Doses were 80, 100, 125, 150, 175, and 200 mg/m2 administered as intravenous infusions over 30 minutes. A treatment cycle was repeated every 28 days. Premedication to prevent hypersensitivity reactions (H1 or H2 blockers or dexamethasone) was not recommended. Growth factors were not routinely used but were permitted for patients who experienced severe neutropenia.
Doses were escalated according to the standard three plus three rule. A DLT was defined as grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity. Briefly, ABI-007 was administered to three patients at a starting dose of 80 mg/m2. If a DLT did not occur in the first three patients, then three patients were enrolled onto the next dose level. If, at any dose level, a DLT occurred, three additional patients were then enrolled at that dose. If a DLT occurred in only one of six patients at a specific dose level, a new cohort could be opened at the next dose level. Dose reductions were made to the next lower dose level. Dose escalations were not permitted among patients within a specified dosing level, with the exception of a patient having received a dose reduction for an unacceptable toxicity. The MTD was defined as the dose level below which two or more patients experienced a DLT.
Three patients entered at 80 mg/m2 and seven patients entered at 100 mg/m2 experienced no DLT. Starting at 125 mg/m2, patients were enrolled onto two cohorts at each dose level based on the amount of prior cytotoxic chemotherapy they had received (ie, lightly pretreated [LP] or heavily pretreated [HP] patients).33 Patients were considered to be HP if they had received one or more of the following: more than six cycles of an alkylating agent; more than two cycles of carboplatin or mitomycin; irradiation to more than 25% of bone marrow每containing areas; any nitrosoureas; high-dose therapy requiring bone marrow transplantation or peripheral stem-cell support; or more than one cycle of an investigational agent known to cause cumulative toxicity. In addition, patients with widely metastatic bone disease with or without marrow involvement were considered HP. Patients not meeting any of these criteria were considered to be LP.
In the HP cohort, patients experienced dose-limiting neutropenia at the 125 mg/m2 dose level. Because, in retrospect, one of the seven patients entered at 100 mg/m2 was considered to have been HP, an additional five HP patients were then accrued at 100 mg/m2 to confirm the tolerability of this dose level in the HP cohort. In the LP cohort, patients were enrolled sequentially onto the 125, 150, 175, and 200 mg/m2 dose levels. DLT in the LP cohort at 175 mg/m2 (sensory neuropathy) only occurred after 1 month of treatment and after two patients had already been enrolled and treated at 200 mg/m2. Further enrollment at the two highest dose levels was then discontinued.
Assessments
Toxicity was graded according to the National Cancer Institute's Common Toxicity Criteria (version 2.0). Treatment-related toxicities were those toxicities considered by the investigator to be possibly, probably, or definitely related to ABI-007. Predosing CBC and serum chemistries were completed before each cycle of ABI-007 to assess hepatic and renal functions. ABI-007 was not administered until ANC and platelet counts were 1.5 x 109/L and 100 x 109/L, respectively. Before the second and third weekly doses within a treatment cycle, ANC and platelet counts were required to be 1.0 x 109/L and 100 x 109/L, respectively. Throughout the duration of the study, CBC were also drawn once during the rest week. Tumor imaging studies were performed at baseline; restaging was performed after a minimum of two cycles of ABI-007 were administered (week 8), at week 12 (if indicated) for confirmation of response, at end of study, and at follow-up. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria.34
Pharmacokinetic Studies
Pharmacokinetic studies were performed in 23 patients. Whole blood samples (approximately 10 mL) were obtained during administration of the first dose of ABI-007 therapy from an indwelling venous catheter placed in the arm contralateral to the drug infusion arm. Samples were drawn at the following 14 time points: 0 (predose), 15, 30 (immediately before the termination of the infusion), and 45 minutes, and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours after termination of infusion. Deuterated d5-paclitaxel was added to samples as the internal standard. Analytes were extracted from plasma using solid-phase extraction, eluted with acetonitrile, evaporated under nitrogen gas, and reconstituted. Chromatographic separation was achieved with high-performance liquid chromatography, and detection was performed by tandem mass spectrometry using electrospray atmospheric pressure ionization. The lower limit of quantitation for paclitaxel was 1.0 ng/mL, and the linear calibration range was 1.0 to 500 ng/mL.
All drug concentration每time data were analyzed as individual patient data sets. Pharmacokinetic parameters for the individual data sets were determined by a noncompartmental routine using WINNonlin (Scientific Consultant, Apex, NC) software (Pharsight Corp, Mountain View, CA). The peak or maximum paclitaxel concentration (Cmax) and the corresponding peak time were observed values. The elimination constant (z) was obtained by log-linear regression analysis of the terminal phase of the whole blood/plasma concentration versus time profile. The elimination half-life was calculated as ln2/z. The area under the curve (AUC) from time 0 to time infinity (AUCinf) was obtained by summation of AUC from time 0 to last measurable concentration (calculated by the log-linear trapezoid rule) and AUC of extrapolated area (estimated by dividing the last measurable concentration by z). The dose-area relationship (ie, total ABI-007 dose divided by AUCinf) was used to determine total-body clearance. The volume of distribution was calculated as total-body clearance divided by z. 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 correlation coefficient was used to examine the correlation between degree of myelosuppression and Cmax or AUCinf.
RESULTS
Thirty-nine patients were enrolled onto the study and received at least one dose of ABI-007. The most common tumor types were melanoma (36%) and breast (23%; Table 1). All but one patient had a performance status at baseline of 1. Patients received a mean of five cycles of ABI-007 (range, one to 18 cycles; one to 51 doses); 13 patients (33%) received at least six cycles of treatment (Table 2). Premedication with dexamethasone and antiemetics was not routinely provided, although three and eight patients received dexamethasone and antiemetics, respectively, on the first day of dosing in cycle 1.
MTD Determination
No DLTs were observed during the first cycle of treatment for three patients treated at 80 mg/m2. In the HP cohort, six patients were treated at 100 mg/m2 without DLTs; two patients at the 125 mg/m2 dose experienced DLT of grade 4 neutropenia. Therefore, the MTD for the HP cohort was 100 mg/m2. In the LP cohort at 125 to 175 mg/m2, six or seven patients were treated at each dose level. There were two episodes of grade 3 peripheral neuropathy at the 125 mg/m2 dose level that occurred after five and six cycles. Both patients continued on treatment at a reduced dose of ABI-007. Two LP patients receiving 175 mg/m2 experienced a DLT of grade 3 lower extremity peripheral neuropathy after two and three cycles of therapy, at which time two patients had already been enrolled at 200 mg/m2. The MTD was thus identified as 150 mg/m2 for LP patients, and further accrual was stopped.
Hematologic Toxicity
Although grade 4 neutropenia was the DLT for HP patients treated at the 125 mg/m2 dose level, myelosuppression from ABI-007 was generally mild. Grade 4 neutropenia occurred in 4% of cycles, and the median ANC nadirs for doses 150 mg/m2 were all 1.69 x 109/L (Table 3). Life-threatening neutropenic infections did not occur on this study. Growth factor support (filgrastim) was used for five patients who developed neutropenia (two patients at 100 mg/m2 and three patients at 125 mg/m2). Grade 3 anemia and thrombocytopenia were observed in three patients (one patient each at 80, 100, and 150 mg/m2) and one patient (125 mg/m2), respectively; no grade 4 events were noted. Symptomatic anemia was treated with erythropoietin or darbepoetin in 12 patients. No transfusions were required for patients in this trial.
Peripheral Neuropathy
Two LP patients receiving 175 mg/m2 experienced a DLT of grade 3 lower extremity peripheral neuropathy. The DLTs occurred at the conclusion of two and three cycles of therapy, and the MTD was identified as 150 mg/m2 for LP patients. Another episode of grade 3 peripheral neuropathy was recorded after six cycles of treatment in an LP patient receiving a dose of 175 mg/m2. The other two episodes of grade 3 peripheral neuropathy occurred after five and six cycles at the 125 mg/m2 dose level. Both patients continued on ABI-007 at a reduced dose. Of the five patients who developed grade 3 peripheral neuropathy, three were able to continue on study at a reduced dose of ABI-007.
Other Toxicities
Other taxane-associated toxicities occurring in this study included myalgias, vomiting, fatigue, neuropathy, onycholysis, and alopecia (Table 4). Grade 3 nausea occurred once in three different patients; these patients were not premedicated for nausea. One other patient was premedicated for nausea using aprepitant on one occasion. Two episodes of grade 3 fatigue occurred simultaneously with the grade 3 neuropathies, which were recorded as DLTs. Tearing was uncommon (occurring in 13% of patients) and mild (all cases grade 1 or 2).
An LP patient treated at 150 mg/m2 complained of recurrent rash of the extremities and torso. At one point, after three cycles, the rash progressed to a grade 3 rash, and the patient had grade 2 fluid retention and dependent edema as well. This patient was not dyspneic at any time. The patient had a usual week off treatment, and the ABI-007 dose was held for 1 additional week. The rash resolved at that time, and the patient was dose reduced to 125 mg/m2. Two months later, the patient returned to the 150 mg/m2 dose. One month later, the rash and edema returned. The patient was on her rest week when this occurred, and she received an additional week off. During that time, she received diphenhydramine for the rash and furosemide for the edema. The rash resolved, but the edema did not subside. At that time, the patient was taken off study. This patient received ABI-007 for a total of 10 cycles (30 doses).
A female patient, who was also taking hydroxychloroquine, received cycles 1 to 3 of ABI-007 at the 200 mg/m2 dose level and cycles 4 to 9 at a dose of 175 mg/m2 and developed decreased visual acuity after cycle 6. Treatment with ABI-007 was held for 1 week, and hydroxychloroquine was discontinued. Then ABI-007 was continued without dose modification. Visual acuity was documented to have improved during cycle 7, despite continued treatment with ABI-007. Although improvement in vision was temporally related to discontinuation of hydroxychloroquine, a contribution of ABI-007 could not be ruled out. Hypersensitivity reactions, which are common with polyoxyethylated castor oil每based paclitaxel, were not seen in this study of ABI-007.
Response
Partial responses were noted in five patients (ovary, n = 3; breast, n = 1; and lung, n = 1), all of whom were previously treated with paclitaxel (Table 5). Ten additional patients maintained stable disease for at least 4 months of therapy (breast, n = 5; lung, n = 1; ovary, n = 1; and melanoma, n = 3).
Pharmacokinetics
Maximum paclitaxel concentrations were observed immediately after the ABI-007 infusion, and concentrations subsequently declined in a multiphasic manner (Fig 1). The mean plasma half-life ranged from 15 to 18 hours (Table 6). Clearance and half-life were relatively similar across different dose levels. The volume of distribution of paclitaxel was relatively large and exceeded total body water, indicating that ABI-007 was extensively distributed and bound to tissue and extravascular proteins. AUCs were linear with respect to ABI-007 dose and were in agreement with an earlier phase I clinical study (Fig 2).
DISCUSSION
This phase I trial was designed to evaluate the feasibility of administering ABI-007 as a 30-minute intravenous infusion weekly for 3 weeks, followed by 1 week of rest. We have demonstrated that ABI-007 can be administered on a weekly basis without corticosteroid premedication using a short infusion schedule without the development of hypersensitivity reactions, further confirming the prior experience using the administration schedule of every 3 weeks.15,19,20 In HP and LP patients, the doses recommended for further efficacy testing were 100 and 150 mg/m2 based on DLTs of neutropenia and peripheral sensory neuropathy, respectively. Myelosuppression was generally mild, and overall treatment was well tolerated, with 33% of patients receiving at least six cycles of treatment. The 150 mg/m2 dose level was well tolerated in LP patients, but two LP patients at 125 mg/m2 developed grade 3 peripheral neuropathy after five and six cycles. Although both patients were continued at a lower dose, neuropathy may require dose reduction if patients continue on treatment for multiple cycles. No toxicities not already associated with taxanes were identified. In preclinical models (N. Desai, personal communication, June 2004) and in clinical trials using every 3 week administration,30,32,35 the equitoxic paclitaxel dose of ABI-007 was 50% to 70% higher than that of polyoxyethylated castor oil每based paclitaxel. A similar increase in the amount of paclitaxel that can be delivered with ABI-007 compared with weekly polyoxyethylated castor oil每based paclitaxel (80 mg/m2)36 was also observed in this study.
The DLTs observed for ABI-007 on this regimen were well-recognized taxane-associated adverse effects. The neutropenia associated with ABI-007 was typically of short duration, and neutropenia nadirs were generally grade 1 or 2. Peripheral neuropathy was primarily sensory and was dose limiting after multiple cycles at the higher dose levels. Myalgias, vomiting, and fatigue were relatively mild and did not seem to be dose related. The other reported toxicities included an episode of combined rash and fluid retention in an LP patient at 150 mg/m2, which resulted in a dose reduction and eventual discontinuation of ABI-007. The five patients who suffered from chronic onycholysis were entered at dose levels of 150 mg/m2 and received five, six, nine, 10, and 12 cycles of therapy.
In contrast to polyoxyethylated castor oil每based paclitaxel, the paclitaxel pharmacokinetics of ABI-007 were linear with respect to AUC, and dose-dependent changes in plasma clearance were not observed. The nonlinearity of polyoxyethylated castor oil每based paclitaxel pharmacokinetics is a result of the formation of polyoxyethylated castor oil micelles in the plasma, which entrap paclitaxel, sequestering drug in the plasma.7,8 Because the formation of polyoxyethylated castor oil micelles increases with concentration, the effect on paclitaxel sequestration is greatest with high doses and short infusions of polyoxyethylated castor oil每based paclitaxel. In contrast, because ABI-007 consists only of albumin and paclitaxel, pharmacokinetics were predictable and consistent over the clinically relevant dose range.
Chemotherapeutic agents may prove to be more efficacious when administered at the highest dose possible as frequently as possible (ie, dose-dense regimens). In adjuvant trials in breast cancer, a dose-dense regimen improved 4-year disease-free survival from 75% to 82%.37 An ideal agent for such an approach must be able to be administered frequently and, therefore, should be well tolerated and have toxicities that rapidly resolve. In addition, drugs that require extensive pretreatment with corticosteroids and/or prolonged drug administration can become more problematic with increased dosing frequency. ABI-007, which is administered without premedication using short infusion durations, has toxicities that seem to improve rapidly, and thus, ABI-007 seems to be an ideal agent for dose-dense approaches. Clinical trials to test this hypothesis using ABI-007 are currently ongoing.
In studies using tumor-bearing mice, ABI-007 demonstrated superior antitumor activity and 30% to 40% higher intratumor paclitaxel concentrations compared with equal doses of polyoxyethylated castor oil每based paclitaxel (N. Desai, personal communication, June 2004). These data, coupled with the improved efficacy and therapeutic index seen with ABI-007 compared with polyoxyethylated castor oil每based paclitaxel in a recent phase III trial, may reflect fundamental differences between these drugs, particularly with respect to albumin-receptor binding on endothelial cells (gp60) and in the tumor interstitium (SPARC). The results of this phase I trial demonstrate that weekly dosing of ABI-007, the first in a new class of albumin-bound cancer drugs, is safe, produces minimum toxic adverse effects, has predictable pharmacokinetics, and produces objective antitumor responses in patients previously exposed to paclitaxel. Further trials using weekly administration of ABI-007 are warranted.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO＊s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank Deganit Shechter and Aaron Van Etten for assistance in preparing this article.
NOTES
Supported by American BioScience, Inc, Santa Monica, CA.
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; and the 94th Annual Meeting of the American Association of Cancer Research, Washington, DC, July 11-14, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Translational Genomics Research Institute, Phoenix, AZ
American BioScience, Inc, Santa Monica, CA.
ABSTRACT
PURPOSE: ABI-007 is a novel solvent-free, albumin-bound, 130-nm particle formulation of paclitaxel designed to avoid solvent-related toxicities and to deliver paclitaxel to tumors via molecular pathways involving an endothelial cell-surface albumin receptor (gp60) and an albumin-binding protein expressed by tumor cells and secreted into the tumor interstitium (secreted protein acid rich in cysteine). This study determined the maximum-tolerated dose (MTD) of ABI-007 monotherapy administered weekly (three weekly doses, repeated every 4 weeks) and assessed the pharmacokinetics of paclitaxel administered as ABI-007.
PATIENTS AND METHODS: Patients with advanced nonhematologic malignancies received ABI-007 without premedication at dose levels from 80 to 200 mg/m2 as a 30-minute intravenous infusion once a week for 3 weeks, followed by 1 week of rest (one cycle).
RESULTS: Thirty-nine patients were treated with an average of five cycles of ABI-007; 33% of patients received six cycles of treatment. MTDs for heavily and lightly pretreated patients were 100 and 150 mg/m2, respectively; and the dose-limiting toxicities were grade 4 neutropenia and grade 3 peripheral neuropathy, respectively. Maximum paclitaxel concentration and area under the curve increased linearly with dose. Dose-dependent changes in plasma clearance did not occur. Partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had previously been treated with paclitaxel containing polyoxyethylated castor oil in the formulation.
CONCLUSION: This study demonstrated that weekly ABI-007 can be administered at doses exceeding those typically used for paclitaxel containing polyoxyethylated castor oil. Pharmacokinetics were linear over the dose range studied. Antitumor responses occurred in patients previously treated with paclitaxel containing polyoxyethylated castor oil.
INTRODUCTION
Taxanes are cell cycle每specific agents that act via high-affinity binding to microtubules to enhance tubulin polymerization and to suppress spindle microtubule dynamics, resulting in the inhibition of mitosis and apoptotic cell death.1-3 The taxane paclitaxel has substantial antitumor activity and is among the most active of the antineoplastic agents being widely used as therapy for patients with advanced breast, non每small-cell lung, and ovarian carcinomas.4,5
One of the limitations of paclitaxel for clinical use is related to its poor water solubility. First-generation formulations solubilized paclitaxel with the nonionic surfactant polyoxyethylated castor oil (Cremophor EL; BASF, Florham Park, NJ) and ethanol (Taxol; Bristol-Myers Squibb, Princeton, NJ; and generic equivalents).5 However, polyoxyethylated castor oil is biologically and pharmacologically active, and its presence in current formulations results in several well-characterized aspects of polyoxyethylated castor oil每based paclitaxel therapy. First, polyoxyethylated castor oil每based paclitaxel infusion produces well-described, polyoxyethylated castor oil每related hypersensitivity reactions that have affected up to 20% to 40% of treated patients who were not premedicated in early phase I trials.2,3 Longer infusion schedules and premedication were used to decrease the risk of hypersensitivity reactions. Although 3-hour infusions and premedication, including dexamethasone, diphenhydramine, and cimetidine, are now standard when administering polyoxyethylated castor oil每based paclitaxel, fatal hypersensitivity reactions have still been reported.6 Second, polyoxyethylated castor oil entraps paclitaxel in micelles formed in the plasma compartment.7 This entrapment alters drug pharmacokinetics, leading to decreased drug clearance, decreased volume of distribution, and nonlinear pharmacokinetics and possibly contributing to a lack of dose-dependent antitumor activity.7-9 Drug entrapment in polyoxyethylated castor oil micelles may affect not only paclitaxel but also coadministered drugs such as anthracycline compounds.7 Third, polyoxyethylated castor oil leaches plasticizers from standard-infusion sets,10,11 thus requiring the use of special tubing and in-line filters for drug administration. Finally, we have recently demonstrated in vitro that polyoxyethylated castor oil inhibits endothelial transcytosis of paclitaxel that is mediated by an albumin receptor (N. Desai, personal communication, June 2004).
ABI-007 (American BioScience, Santa Monica, CA) is a novel, solvent-free, albumin-bound, 130-nm particle form of paclitaxel designed to avoid the problems associated with the solvents used in polyoxyethylated castor oil每based paclitaxel.12 Albumin has a number of properties that made it an attractive molecule to combine with paclitaxel. Albumin is a natural transporter of endogenous hydrophobic molecules, such as water-insoluble vitamins and hormones,13 and albumin binding to the gp60 receptor (albondin) initiates the caveolar-mediated endothelial transport of protein-bound and unbound plasma constituents.14-16 In addition, osteonectin (also known as secreted protein acid rich in cysteine [SPARC]) has been shown to be expressed in a number of tumors17-26 and, sharing a sequence homology with gp60, has been shown to bind albumin.27,28 Albumin is known to accumulate in some tumors,29 possibly because of binding to SPARC, and may thereby facilitate intratumor accumulation of albumin-bound drugs.
A phase I clinical study of ABI-007 in 19 patients with solid tumors and breast cancer30 established the maximum-tolerated dose (MTD) of ABI-007 for an every 3 weeks regimen at 300 mg/m2, which is approximately 70% higher than the MTD reported for polyoxyethylated castor oil每based paclitaxel (175 mg/m2).31 Dose-limiting toxicities (DLTs) were sensory neuropathy, stomatitis, and superficial keratopathy. No hypersensitivity reactions occurred, despite the absence of premedication. ABI-007 was administered intravenously in shorter infusion periods (30 minutes v 3 hours for polyoxyethylated castor oil每based paclitaxel) and with standard intravenous tubing. The disposition of ABI-007 exhibited a biphasic decline in concentration, with linear pharmacokinetic parameters for the clinically relevant dose range of 135 to 300 mg/m2. A randomized, phase III study compared equitoxic doses of ABI-007 (260 mg/m2) and polyoxyethylated castor oil每based paclitaxel (175 mg/m2) in 454 patients with metastatic breast cancer.32 Response rates were significantly higher for ABI-007 than for polyoxyethylated castor oil每based paclitaxel for all patients (33% v 19%, respectively; P = .001) and for patients who received the study drug as first-line therapy (42% v 27%, respectively; P = .029). The incidence of grade 4 neutropenia was significantly lower in the ABI-007 group than the polyoxyethylated castor oil每based paclitaxel group (10% v 21%, respectively; P < .001) despite the approximately 50% higher dose. Grade 3 sensory neuropathy was more common in the ABI-007 group compared with the group who received polyoxyethylated castor oil每based paclitaxel (10% v 2%, respectively; P < .001), but these events were easily managed and improved rapidly (median, 22 days).
The primary objectives of the current study were as follows: (1) to characterize the toxicities of ABI-007 administered weekly for 3 weeks, with repeated dosing every 4 weeks; (2) to determine the MTD of ABI-007; (3) to assess pharmacokinetic parameters for ABI-007 when administered on a weekly schedule; and (4) to describe any antitumor activity when ABI-007 is administered weekly to patients with advanced nonhematologic malignancies.
PATIENTS AND METHODS
The protocol and all related materials were approved by the University of Arizona Institutional Review Board. The study was conducted in compliance with Good Clinical Practice Guidelines of the International Conference on Harmonisation and the Declaration of Helsinki. Written informed consent was obtained from all patients before participation.
Patient Selection
Eligible patients included males and nonpregnant females practicing adequate birth control who were at least 18 years of age, had a life expectancy of at least 2 months, and had not received any chemotherapy (inclusive of investigational therapies) for at least 3 weeks before study drug administration. Patients had biopsy-proven diagnoses of advanced malignancy or solid tumors for which standard therapy had failed. Patients had a Southwest Oncology Group performance status of 0 to 2, hemoglobin 9 g/dL, WBC count 3.0 x 109/L with an absolute neutrophil count (ANC) 1.5 x 109/L, platelet count 100 x 109/L, serum creatinine less than 2 mg/dL, serum bilirubin less than 1.5 mg/dL, and hepatic transaminases less than 3x the upper limit of normal. Prior taxane therapy was permitted.
Patients were excluded from the trial if they had a history of allergy or hypersensitivity to the study drug or its excipients, had symptomatic brain metastases, had a serious concurrent illness that was likely to limit full compliance with the study, had a pre-existing peripheral neuropathy (grade 1 or higher), were unlikely to complete the study with appropriate follow-up visits, or were currently taking any anticancer medication or protease inhibitor. A washout period of 30 days was required before initiation of therapy.
Study Design
ABI-007 was administered on an outpatient basis weekly for 3 weeks, followed by 1 week of rest. Doses were 80, 100, 125, 150, 175, and 200 mg/m2 administered as intravenous infusions over 30 minutes. A treatment cycle was repeated every 28 days. Premedication to prevent hypersensitivity reactions (H1 or H2 blockers or dexamethasone) was not recommended. Growth factors were not routinely used but were permitted for patients who experienced severe neutropenia.
Doses were escalated according to the standard three plus three rule. A DLT was defined as grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity. Briefly, ABI-007 was administered to three patients at a starting dose of 80 mg/m2. If a DLT did not occur in the first three patients, then three patients were enrolled onto the next dose level. If, at any dose level, a DLT occurred, three additional patients were then enrolled at that dose. If a DLT occurred in only one of six patients at a specific dose level, a new cohort could be opened at the next dose level. Dose reductions were made to the next lower dose level. Dose escalations were not permitted among patients within a specified dosing level, with the exception of a patient having received a dose reduction for an unacceptable toxicity. The MTD was defined as the dose level below which two or more patients experienced a DLT.
Three patients entered at 80 mg/m2 and seven patients entered at 100 mg/m2 experienced no DLT. Starting at 125 mg/m2, patients were enrolled onto two cohorts at each dose level based on the amount of prior cytotoxic chemotherapy they had received (ie, lightly pretreated [LP] or heavily pretreated [HP] patients).33 Patients were considered to be HP if they had received one or more of the following: more than six cycles of an alkylating agent; more than two cycles of carboplatin or mitomycin; irradiation to more than 25% of bone marrow每containing areas; any nitrosoureas; high-dose therapy requiring bone marrow transplantation or peripheral stem-cell support; or more than one cycle of an investigational agent known to cause cumulative toxicity. In addition, patients with widely metastatic bone disease with or without marrow involvement were considered HP. Patients not meeting any of these criteria were considered to be LP.
In the HP cohort, patients experienced dose-limiting neutropenia at the 125 mg/m2 dose level. Because, in retrospect, one of the seven patients entered at 100 mg/m2 was considered to have been HP, an additional five HP patients were then accrued at 100 mg/m2 to confirm the tolerability of this dose level in the HP cohort. In the LP cohort, patients were enrolled sequentially onto the 125, 150, 175, and 200 mg/m2 dose levels. DLT in the LP cohort at 175 mg/m2 (sensory neuropathy) only occurred after 1 month of treatment and after two patients had already been enrolled and treated at 200 mg/m2. Further enrollment at the two highest dose levels was then discontinued.
Assessments
Toxicity was graded according to the National Cancer Institute's Common Toxicity Criteria (version 2.0). Treatment-related toxicities were those toxicities considered by the investigator to be possibly, probably, or definitely related to ABI-007. Predosing CBC and serum chemistries were completed before each cycle of ABI-007 to assess hepatic and renal functions. ABI-007 was not administered until ANC and platelet counts were 1.5 x 109/L and 100 x 109/L, respectively. Before the second and third weekly doses within a treatment cycle, ANC and platelet counts were required to be 1.0 x 109/L and 100 x 109/L, respectively. Throughout the duration of the study, CBC were also drawn once during the rest week. Tumor imaging studies were performed at baseline; restaging was performed after a minimum of two cycles of ABI-007 were administered (week 8), at week 12 (if indicated) for confirmation of response, at end of study, and at follow-up. Response was assessed using Response Evaluation Criteria in Solid Tumors criteria.34
Pharmacokinetic Studies
Pharmacokinetic studies were performed in 23 patients. Whole blood samples (approximately 10 mL) were obtained during administration of the first dose of ABI-007 therapy from an indwelling venous catheter placed in the arm contralateral to the drug infusion arm. Samples were drawn at the following 14 time points: 0 (predose), 15, 30 (immediately before the termination of the infusion), and 45 minutes, and 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours after termination of infusion. Deuterated d5-paclitaxel was added to samples as the internal standard. Analytes were extracted from plasma using solid-phase extraction, eluted with acetonitrile, evaporated under nitrogen gas, and reconstituted. Chromatographic separation was achieved with high-performance liquid chromatography, and detection was performed by tandem mass spectrometry using electrospray atmospheric pressure ionization. The lower limit of quantitation for paclitaxel was 1.0 ng/mL, and the linear calibration range was 1.0 to 500 ng/mL.
All drug concentration每time data were analyzed as individual patient data sets. Pharmacokinetic parameters for the individual data sets were determined by a noncompartmental routine using WINNonlin (Scientific Consultant, Apex, NC) software (Pharsight Corp, Mountain View, CA). The peak or maximum paclitaxel concentration (Cmax) and the corresponding peak time were observed values. The elimination constant (z) was obtained by log-linear regression analysis of the terminal phase of the whole blood/plasma concentration versus time profile. The elimination half-life was calculated as ln2/z. The area under the curve (AUC) from time 0 to time infinity (AUCinf) was obtained by summation of AUC from time 0 to last measurable concentration (calculated by the log-linear trapezoid rule) and AUC of extrapolated area (estimated by dividing the last measurable concentration by z). The dose-area relationship (ie, total ABI-007 dose divided by AUCinf) was used to determine total-body clearance. The volume of distribution was calculated as total-body clearance divided by z. 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 correlation coefficient was used to examine the correlation between degree of myelosuppression and Cmax or AUCinf.
RESULTS
Thirty-nine patients were enrolled onto the study and received at least one dose of ABI-007. The most common tumor types were melanoma (36%) and breast (23%; Table 1). All but one patient had a performance status at baseline of 1. Patients received a mean of five cycles of ABI-007 (range, one to 18 cycles; one to 51 doses); 13 patients (33%) received at least six cycles of treatment (Table 2). Premedication with dexamethasone and antiemetics was not routinely provided, although three and eight patients received dexamethasone and antiemetics, respectively, on the first day of dosing in cycle 1.
MTD Determination
No DLTs were observed during the first cycle of treatment for three patients treated at 80 mg/m2. In the HP cohort, six patients were treated at 100 mg/m2 without DLTs; two patients at the 125 mg/m2 dose experienced DLT of grade 4 neutropenia. Therefore, the MTD for the HP cohort was 100 mg/m2. In the LP cohort at 125 to 175 mg/m2, six or seven patients were treated at each dose level. There were two episodes of grade 3 peripheral neuropathy at the 125 mg/m2 dose level that occurred after five and six cycles. Both patients continued on treatment at a reduced dose of ABI-007. Two LP patients receiving 175 mg/m2 experienced a DLT of grade 3 lower extremity peripheral neuropathy after two and three cycles of therapy, at which time two patients had already been enrolled at 200 mg/m2. The MTD was thus identified as 150 mg/m2 for LP patients, and further accrual was stopped.
Hematologic Toxicity
Although grade 4 neutropenia was the DLT for HP patients treated at the 125 mg/m2 dose level, myelosuppression from ABI-007 was generally mild. Grade 4 neutropenia occurred in 4% of cycles, and the median ANC nadirs for doses 150 mg/m2 were all 1.69 x 109/L (Table 3). Life-threatening neutropenic infections did not occur on this study. Growth factor support (filgrastim) was used for five patients who developed neutropenia (two patients at 100 mg/m2 and three patients at 125 mg/m2). Grade 3 anemia and thrombocytopenia were observed in three patients (one patient each at 80, 100, and 150 mg/m2) and one patient (125 mg/m2), respectively; no grade 4 events were noted. Symptomatic anemia was treated with erythropoietin or darbepoetin in 12 patients. No transfusions were required for patients in this trial.
Peripheral Neuropathy
Two LP patients receiving 175 mg/m2 experienced a DLT of grade 3 lower extremity peripheral neuropathy. The DLTs occurred at the conclusion of two and three cycles of therapy, and the MTD was identified as 150 mg/m2 for LP patients. Another episode of grade 3 peripheral neuropathy was recorded after six cycles of treatment in an LP patient receiving a dose of 175 mg/m2. The other two episodes of grade 3 peripheral neuropathy occurred after five and six cycles at the 125 mg/m2 dose level. Both patients continued on ABI-007 at a reduced dose. Of the five patients who developed grade 3 peripheral neuropathy, three were able to continue on study at a reduced dose of ABI-007.
Other Toxicities
Other taxane-associated toxicities occurring in this study included myalgias, vomiting, fatigue, neuropathy, onycholysis, and alopecia (Table 4). Grade 3 nausea occurred once in three different patients; these patients were not premedicated for nausea. One other patient was premedicated for nausea using aprepitant on one occasion. Two episodes of grade 3 fatigue occurred simultaneously with the grade 3 neuropathies, which were recorded as DLTs. Tearing was uncommon (occurring in 13% of patients) and mild (all cases grade 1 or 2).
An LP patient treated at 150 mg/m2 complained of recurrent rash of the extremities and torso. At one point, after three cycles, the rash progressed to a grade 3 rash, and the patient had grade 2 fluid retention and dependent edema as well. This patient was not dyspneic at any time. The patient had a usual week off treatment, and the ABI-007 dose was held for 1 additional week. The rash resolved at that time, and the patient was dose reduced to 125 mg/m2. Two months later, the patient returned to the 150 mg/m2 dose. One month later, the rash and edema returned. The patient was on her rest week when this occurred, and she received an additional week off. During that time, she received diphenhydramine for the rash and furosemide for the edema. The rash resolved, but the edema did not subside. At that time, the patient was taken off study. This patient received ABI-007 for a total of 10 cycles (30 doses).
A female patient, who was also taking hydroxychloroquine, received cycles 1 to 3 of ABI-007 at the 200 mg/m2 dose level and cycles 4 to 9 at a dose of 175 mg/m2 and developed decreased visual acuity after cycle 6. Treatment with ABI-007 was held for 1 week, and hydroxychloroquine was discontinued. Then ABI-007 was continued without dose modification. Visual acuity was documented to have improved during cycle 7, despite continued treatment with ABI-007. Although improvement in vision was temporally related to discontinuation of hydroxychloroquine, a contribution of ABI-007 could not be ruled out. Hypersensitivity reactions, which are common with polyoxyethylated castor oil每based paclitaxel, were not seen in this study of ABI-007.
Response
Partial responses were noted in five patients (ovary, n = 3; breast, n = 1; and lung, n = 1), all of whom were previously treated with paclitaxel (Table 5). Ten additional patients maintained stable disease for at least 4 months of therapy (breast, n = 5; lung, n = 1; ovary, n = 1; and melanoma, n = 3).
Pharmacokinetics
Maximum paclitaxel concentrations were observed immediately after the ABI-007 infusion, and concentrations subsequently declined in a multiphasic manner (Fig 1). The mean plasma half-life ranged from 15 to 18 hours (Table 6). Clearance and half-life were relatively similar across different dose levels. The volume of distribution of paclitaxel was relatively large and exceeded total body water, indicating that ABI-007 was extensively distributed and bound to tissue and extravascular proteins. AUCs were linear with respect to ABI-007 dose and were in agreement with an earlier phase I clinical study (Fig 2).
DISCUSSION
This phase I trial was designed to evaluate the feasibility of administering ABI-007 as a 30-minute intravenous infusion weekly for 3 weeks, followed by 1 week of rest. We have demonstrated that ABI-007 can be administered on a weekly basis without corticosteroid premedication using a short infusion schedule without the development of hypersensitivity reactions, further confirming the prior experience using the administration schedule of every 3 weeks.15,19,20 In HP and LP patients, the doses recommended for further efficacy testing were 100 and 150 mg/m2 based on DLTs of neutropenia and peripheral sensory neuropathy, respectively. Myelosuppression was generally mild, and overall treatment was well tolerated, with 33% of patients receiving at least six cycles of treatment. The 150 mg/m2 dose level was well tolerated in LP patients, but two LP patients at 125 mg/m2 developed grade 3 peripheral neuropathy after five and six cycles. Although both patients were continued at a lower dose, neuropathy may require dose reduction if patients continue on treatment for multiple cycles. No toxicities not already associated with taxanes were identified. In preclinical models (N. Desai, personal communication, June 2004) and in clinical trials using every 3 week administration,30,32,35 the equitoxic paclitaxel dose of ABI-007 was 50% to 70% higher than that of polyoxyethylated castor oil每based paclitaxel. A similar increase in the amount of paclitaxel that can be delivered with ABI-007 compared with weekly polyoxyethylated castor oil每based paclitaxel (80 mg/m2)36 was also observed in this study.
The DLTs observed for ABI-007 on this regimen were well-recognized taxane-associated adverse effects. The neutropenia associated with ABI-007 was typically of short duration, and neutropenia nadirs were generally grade 1 or 2. Peripheral neuropathy was primarily sensory and was dose limiting after multiple cycles at the higher dose levels. Myalgias, vomiting, and fatigue were relatively mild and did not seem to be dose related. The other reported toxicities included an episode of combined rash and fluid retention in an LP patient at 150 mg/m2, which resulted in a dose reduction and eventual discontinuation of ABI-007. The five patients who suffered from chronic onycholysis were entered at dose levels of 150 mg/m2 and received five, six, nine, 10, and 12 cycles of therapy.
In contrast to polyoxyethylated castor oil每based paclitaxel, the paclitaxel pharmacokinetics of ABI-007 were linear with respect to AUC, and dose-dependent changes in plasma clearance were not observed. The nonlinearity of polyoxyethylated castor oil每based paclitaxel pharmacokinetics is a result of the formation of polyoxyethylated castor oil micelles in the plasma, which entrap paclitaxel, sequestering drug in the plasma.7,8 Because the formation of polyoxyethylated castor oil micelles increases with concentration, the effect on paclitaxel sequestration is greatest with high doses and short infusions of polyoxyethylated castor oil每based paclitaxel. In contrast, because ABI-007 consists only of albumin and paclitaxel, pharmacokinetics were predictable and consistent over the clinically relevant dose range.
Chemotherapeutic agents may prove to be more efficacious when administered at the highest dose possible as frequently as possible (ie, dose-dense regimens). In adjuvant trials in breast cancer, a dose-dense regimen improved 4-year disease-free survival from 75% to 82%.37 An ideal agent for such an approach must be able to be administered frequently and, therefore, should be well tolerated and have toxicities that rapidly resolve. In addition, drugs that require extensive pretreatment with corticosteroids and/or prolonged drug administration can become more problematic with increased dosing frequency. ABI-007, which is administered without premedication using short infusion durations, has toxicities that seem to improve rapidly, and thus, ABI-007 seems to be an ideal agent for dose-dense approaches. Clinical trials to test this hypothesis using ABI-007 are currently ongoing.
In studies using tumor-bearing mice, ABI-007 demonstrated superior antitumor activity and 30% to 40% higher intratumor paclitaxel concentrations compared with equal doses of polyoxyethylated castor oil每based paclitaxel (N. Desai, personal communication, June 2004). These data, coupled with the improved efficacy and therapeutic index seen with ABI-007 compared with polyoxyethylated castor oil每based paclitaxel in a recent phase III trial, may reflect fundamental differences between these drugs, particularly with respect to albumin-receptor binding on endothelial cells (gp60) and in the tumor interstitium (SPARC). The results of this phase I trial demonstrate that weekly dosing of ABI-007, the first in a new class of albumin-bound cancer drugs, is safe, produces minimum toxic adverse effects, has predictable pharmacokinetics, and produces objective antitumor responses in patients previously exposed to paclitaxel. Further trials using weekly administration of ABI-007 are warranted.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO＊s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank Deganit Shechter and Aaron Van Etten for assistance in preparing this article.
NOTES
Supported by American BioScience, Inc, Santa Monica, CA.
Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; and the 94th Annual Meeting of the American Association of Cancer Research, Washington, DC, July 11-14, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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