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Originally published as JCO Early Release 10.1200/JCO.2004.08.116 on May 10 2004 © 2004 American Society of Clinical Oncology. Safety and Pharmacokinetics of Escalated Doses of Weekly Intravenous Infusion of CCI-779, a Novel mTOR Inhibitor, in Patients With CancerFrom the Department of Medicine, Gustave Roussy Institute, Villejuif, France; Onkologische Tagesklinik, Munich, Germany; and Wyeth, Collegeville, PA Address reprint requests to Eric Raymond, MD, PhD, Department of Medical Oncology, Saint-Louis Hospital, 1 Avenue Claude Vellefaux, 75475 Paris Cedex 10, France; e-mail: eric.raymond{at}sls.ap-hop-paris.fr
PURPOSE: To establish the safety, tolerability, and pharmacokinetic parameters of CCI-779, a selective inhibitor of the mammalian target of rapamycin, in patients with advanced cancer. PATIENTS AND METHODS: Using a modified continuous reassessment method, we performed a phase I with pharmacokinetic study of CCI-779 given as a weekly 30 minutes intravenous (IV) infusion. RESULTS: Twenty-four patients received CCI-779 at doses ranging 7.5 to 220 mg/m2. No immunosuppressive effect was reported. Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m2. At 220 mg/m2, dose-limiting toxicities consisted of manic-depressive syndrome, stomatitis, and asthenia in two of nine patients, preventing further dose escalation. The most frequent drug-related toxicities were acne-like, maculopapular rashes and mucositis or stomatitis. All toxicities were reversible on treatment discontinuation. Maximum concentration and area under the concentration-time curve increase sub-proportionally with dose. Mean steady-state volume of distribution ranged from 127 to 385L. Sirolimus was a major metabolite (metabolite-to-parent ratio range, 2.5 to 3.5). Whole blood clearance was nonlinear, ranging from 19 to 51 L/h (34 to 220 mg/m2). Variability predicted with flat doses appears comparable with data based on body-surface area–normalized treatment. Partial responses were observed in one patient with renal clear-cell carcinoma and in one patient with breast adenocarcinoma. CONCLUSION: CCI-779 displayed no immunosuppressive effects with manageable and reversible adverse events at doses up to 220 mg/m2, the highest dose tested. Based on our results, weekly doses of 25, 75, and 250 mg CCI-779 not based on classical definitions of maximum-tolerated dose are being tested in phase II trials in patients with breast and renal cancer.
The mammalian target of rapamycin (mTOR), a member of the phosphatidyl inositol 3' kinase family, is a multifunctional serine-threonine kinase that acts as central regulator of cell growth, proliferation, and apoptosis.1-4 mTOR is activated in response to growth stimuli such as nutrients and/or growth factors including insulin, insulin growth factor, platelet-derived growth factor, and the stem-cell factor.1,2,5 Stimulation of mTOR results in a series of events involving phosphorylation of translational regulation factors such as eukaryotic initiation factor 4E-binding protein and p70s6 kinase.6,7 Rapamycin (sirolimus), an immunosuppressant macrolide produced by Streptomyces hygroscopicus, binds FKBP-12 (FK506 binding protein), creating a molecular complex that specifically inhibits mTOR functions.8 Inhibition of mTOR by rapamycin leads to downregulation of G1 cyclin/cdk complexes and p27 accumulation that blocks progression in late G1/S phase of cell cycle.9,10 In addition to immunosuppression, sirolimus is thought to retard proliferation of endothelial and vascular smooth muscle cells required for tumor angiogenesis.11 Recently, studies showed that sirolimus also inhibited the oncogenic transformation of human cells induced by either PI3K or AKT in mice with loss of the normal PTEN allele (PTEN±).12-14 Sirolimus can also induce apoptosis and sensitize cancer cells to apoptosis induction by DNA-damaging agents such as cisplatin.15 In humans, sirolimus was usually well tolerated at daily doses ranging 0.5 to 60 mg/d; hypercholesterolemia, hypertriglyceridemia, lymphopenia, thrombocytopenia, mucositis, arthralgia, and infection are the main toxicities.16 CCI-779 (Fig 1), a water-soluble ester of sirolimus,9-17 was identified by the Developmental Therapeutic Branch of the National Cancer Institute as a noncytotoxic agent that delayed tumor proliferation.18 At several nontoxic doses, CCI-779 demonstrated antitumor activity in a variety of human cancer models, such as gliomas; rhabdomyosarcoma; primitive neuroectodermal tumor, such as medulloblastoma; and prostate and breast cancer.19-23 Treatment of mice with CCI-779 normalizes p70s6 kinase activity and reduces neoplastic proliferation. As with sirolimus, PTEN-deficient human tumors are more sensitive to CCI-779-mediated growth inhibition than PTEN-expressing cells.12,14,24 Interestingly, preclinical studies indicate that intermittent administration of CCI-779 reduces its immunosuppressive properties while retaining its antitumor activity (CCI-779 investigator brochure).
Based on the promising antitumor activity and safety data showing limited immunosuppression with intermittent exposure to CCI-779 in animals, this phase I dose-escalation study was undertaken to determine the safety, basic pharmacokinetic characteristics, and preliminary antitumor effects of weekly intravenous (IV) infusion of CCI-779 in patients with advanced malignancies.
Patient Selection Patients entered onto this study met the following criteria: histologically confirmed diagnosis of solid tumor refractory to standard therapy or for whom no standard therapy existed; age  18 years; life expectancy 3 months; Eastern Cooperative Oncology Group (ECOG) performance status  2; no chemotherapy, hormonal therapy, immunotherapy or radiotherapy within 4 weeks before treatment with CCI-779 (6 weeks for previous treatment with nitrosoureas, mitomycin, or extensive radiotherapy) and no immunosuppressive agents within 3 weeks before study entry (except corticosteroids used as antiemetics); adequate hepatic function defined as serum bilirubin less than 25 µmol/L (< 1.5 mg/dL), transaminases 3.0 times the upper limit of normal (or 5 in the case of liver metastases); adequate bone marrow function defined as absolute neutrophil count > 1,500/µL, platelets > 100,000/µL, and hemoglobin > 8.0 g/dL; adequate renal function with serum creatinine less than 2.0 mg/dL) and/or creatinine clearance (Cockroft formula) 60 mL/min; baseline cholesterol < 350 mg/dL, triglycerides < 300 mg/dL, no history of alcoholism, drug addiction, or psychotic disorders; no medical condition which, in the opinion of the investigator, was incompatible with the protocol; no uncontrolled systemic infection; and signed informed consent according to institutional and national guidelines. Patients were excluded if they were pregnant or breast feeding, had symptomatic brain metastases or leptomeningeal tumor involvement, active infection or serious intercurrent illness, known hypersensitivity to macrolide antibiotics, or were receiving any of the following: concomitant antitumor therapy, anticonvulsant therapy, or cardiac antiarrhythmic drugs. Patients were not required to have evaluable or measurable disease. Based on known toxicities of rapamycin, patients entered onto this trial were also required to have baseline serum cholesterol < 350 mg/dL, triglycerides < 300 mg/dL, no immunosuppressive agents within 3 weeks before study entry (except corticosteroids used as antiemetics), and no known concomitant genetic or acquired immunosuppressive diseases (such as AIDS).
Pretreatment and Follow-Up Examinations Total serum testosterone, follicle stimulating hormone, and luteinizing hormone were determined in males at baseline and every 4 weeks. A serum pregnancy test was performed in females of childbearing potential. Lymphocyte subsets CD45, CD14, CD3, CD4, CD8, and CD56 and mitogen proliferation assays were done in the prestudy period, before the first three infusions, and then every 2 months.Tumors were measured by computed tomography scans 4 weeks before starting CCI-779 and then every 8 weeks.
Drug Administration
Dose-Escalation Procedure
Additional rules were applied to determine the proportion by which the dose was escalated or reduced. If grade Infusions could be delayed for less than 2 weeks for the patient to recover from toxicities. No intrapatient dose escalation was allowed. Dose reduction of 0% to 33% was allowed in response to unacceptable toxicity if the patient exhibited evidence of clinical benefit from CCI-779. If unacceptable toxicity occurred after this dose reduction, the patient was no longer allowed to take CCI-779 at any dose level. These reduced doses were not included in the MTD calculations.
Bioanalytic Method CCI-779 and sirolimus concentrations in whole blood were validated from 0.25 to 100 ng/mL (CCI-779) and from 0.1 to 100 ng/mL (sirolimus) using separate, slightly differing methods (Taylor Technology Inc, Princeton, NJ). Briefly, to 0.1 mL of methanol was added an aliquot of d7-CCI-779 or 32-desmethoxyrapamycin internal standard. The spiked mixtures were added to 1 mL of whole blood treated with sodium EDTA. Analytes were extracted into 1-chlorobutane, evaporated, reconstituted with a 70:30 methanol:water solution, and chromatographed using either a C18 column (for CCI-779) or C4 column (for sirolimus) with a gradient of methanol and water containing ammonium acetate and acetic acid as the mobile phase solvents. The analytes were detected and quantified by tandem mass spectrometry using atmospheric pressure chemical ionization.
CCI-779 concentrations in plasma were validated from 0.25 to 100 ng/mL. To 0.1 mL of methanol was added an aliquot of d7-CCI-779 internal standard. The spiked mixture was then added to 1 mL of plasma. Analytes were extracted into tert-butyl methyl ether and analyzed as described previously. These methods exhibit adequate inter- and intrasubject variability (
Pharmacokinetic Analyses
General A total of 24 patients were enrolled onto the study and received at least one cycle (four weekly doses) of CCI-779 at doses of 7.5 to 220 mg/m2. A total of 273 infusions were administered. Patient characteristics at study entry are summarized in Table 1. Dose escalation was based on acute toxicity evaluated during the first four infusions of CCI-779. As shown on Table 2, no grade 3 to 4 toxicity was observed up to the dose of 22.5 mg/m2. At a dose of 34 mg/m2, one patient developed a grade 3 neutropenia, thrombocytopenia, and hypophosphatemia. Bone marrow aspiration found no megacaryocyte. This patient had previously received extensive radiation therapy that could have participated to CCI-779 hematologic toxicity. This event led us to enter two additional patients at the dose level of 34 mg/m2 without further evidence of severe toxicity. Therefore, the dose escalation was resumed. At a dose of 45 mg/m2, one patient had grade 3 thrombocytopenia, asthenia, and diarrhea. Three additional patients were entered at this dose level without additional DLT. Dose escalation continued without additional DLT up to 220 mg/m2. At the 220 mg/m2 dose-level, a 51-year-old woman with metastatic breast cancer and no history of psychiatric disorders developed grade 2 euphoria and insomnia after 2 weeks of treatment. At week 4, the patient was hospitalized for grade 3 depression and received antidepressive treatment with paraxetine and cyanemazine (no evidence of brain and leptomeningeal metastasis); grade 3 stomatitis; and grade 3 transaminases elevation. The toxicity was reversible within 2 weeks of treatment discontinuation. The patient was subsequently restarted at a dose of 165 mg/m2 without further evidence of psychiatric disorder. At the 220 mg/m2 dose level, two additional patients without prior neuropsychiatric disorder developed reversible grade 1 to 2 depression preceded by grade 1 to 2 euphoria. Among subsequent patients entered at this dose level, one developed DLTs that consisted of grade 3 asthenia and grade 3 stomatitis. Therefore, although the formal definition of MTD was not met, it was decided to stop the dose escalation.
Safety and Tolerability After Repeated Cycles Tables 3 and 4 summarize drug-related toxicities observed with a total frequency of 20% during this study. No immunosuppressive effects were detected during treatment with CCI-779. For example, in eight patients treated at the highest tested doses, the median changes (± standard deviation [SD]) from the pretreatment value for lymphocytes (all CD45+) including CD14+, CD3+, CD58+/CD3–, CD56+/CD3+, CD4+/CD3+, and CD8+/CD3+ were 6.5% (SD, 6.4%), –3.1% (SD, 7.8%), –1.4% (SD, 6.5%), 0.07% (SD, 0.6%), 0.2% (SD, 5.5%), and –0.2% (SD, 1.7%), respectively. Likewise, large interpatient variability in mitogene proliferation assay was observed with a 4.5% (SD, 37%) increase in median values of concanavaline A after 1 month of treatment (P > .5). Thrombocytopenia was grade 1 to 2 in five patients and grade 3 to 4 in two patients. Asthenia was grade 1 to 2 in nine patients and grade 3 in two patients.
The most frequent drug-related adverse events were dermatologic toxicities and mucositis/stomatitis (18 of 24 patients; Table 3). Stomatitis consisted mainly of 1 to 3 round grade 1 to 2 aphtous lesions in the mouth and tongue. Stomatitis was severe (grade 3) in only one of nine patients treated at the highest dose and was reversible despite treatment continuation. Antiseptic mouthwashes were inconsistently effective in preventing stomatitis. Specific dermatologic toxicities are presented in Table 4. Skin toxicity consisted of grade 1 to 2 herpes simplex lesions (five patients; Fig 2A), acne-like rash (nine patients; Fig 2B), maculopapular rash (12 patients; Fig 2C), dry skin (nine patients), pruritus (seven patients), and nail disorders (11 patients; Fig 2D).
Herpes lesions were documented using viral cultures and both topic and systemic treatments with acyclovir were given to patients with herpetic lesions. Maculopapular rashes, generally consisting of 5 to 10 cm reactions on face and neck, mainly occurred during the first few weeks of treatment and were spontaneously reversible. Grade 1 to 2 acne-like rash on erythematous base occurred on the face and the upper part of the trunk. Histopathologic examination revealed a nonspecific accumulation of neutrophils in dermis and epidermis. This skin reaction was reversible with and without topical steroid cream. Grade 3 elevations of total cholesterol and triglycerides were observed in five and three patients, respectively, across the range of doses explored. Three patients had grade 1 to 2 and one patient had grade 3 ALT elevations. Among 11 males who had normal baseline testosterone levels, nine showed reduction of these levels with increased follicle-stimulating hormone and/or luteinizing hormone levels during CCI-779 treatment. At doses of 15 and 45 mg/m2, two patients reported reduced sexual activity (considered grade 2).
Pharmacokinetic Results
Following treatment, CCI-779 decreased in a polyexponential manner. AUC increased proportionally with doses up to 150 mg. Doses higher than 300 mg CCI-779 yielded high AUCs and low clearance in some patients. Thus, the interpatient variability made difficult to assess the linearity of AUC with doses greater than 300 mg (Fig 4). CCI-779 did not exhibit preferential partitioning into RBCs, and yielded mean end-of-infusion blood/plasma ratio values of 0.64-1.15 (Coefficient of variation [CV]: 17% to 68%). Mean steady-state volume of distribution was large with mean values of 127 to 384 L (CV, 7% to 44%). Interestingly, Vdss appeared to exhibit an inverted U-shaped profile throughout the dose range, suggestive of saturable drug distribution at very high doses. Clearance of CCI-779 from whole blood increased with increasing dose with mean values ranging 19 to 51 L/h (CV, 14% to 32%). Two-way analysis of variance showed that doses significantly affected the Clearance of CCI-779 (P < .001). Mean terminal half-life for CCI-779 appeared to decrease with increasing dose from 22 hours following the 34 mg/m2 dose to 13 hours following the 220 mg/m2 dose (CV, 7% to 29%). No significant change was observed in the pharmacokinetic profile of CCI-779 with multiple dosing (mean AR values < 1).
Sirolimus appears as early as 15 minutes after CCI-779 infusion with a peak at 0.5 to 2.0 hours, followed by a monoexponential decrease (Fig 3). Exposure to sirolimus was typically higher than that of CCI-779, with a mean AUC ratio (sirolimus/CCI-779) of  2.5 to 3.5 (CV, 0.2% to 69%), and AR less than 1 (Table 6). Dose-related increases in AUCsum were significantly less than proportional. Mean terminal half-life for sirolimus ranged 61 to 69 hours (CV, 7% to 60%). At doses higher than 34 mg/m2, residual concentrations of sirolimus were detectable before the next infusion for subsequent cycles. However, this did not resulted in higher AUC of sirolimus after repeated cycles. To gain information regarding the need for dosing based on BSA, a simulation was performed in which observed values for AUCsum based on the 34, 45, and 220 mg/m2 doses were adjusted to reflect fixed IV doses of CCI-779 of 60, 85, and 375 mg, respectively. Simulated AUCsum values were approximated based on actual AUCsum and actual dose (mg) each patient received during cycle 1 (Fig 5). The mean AUCsum for the 220 mg/m2 group was determined to be 27,058 ng·hr/mL (CV, 50.4%) whereas AUCsum for the 375 mg group (the average of flat doses received in the 220-mg/m2 cohort) was 27,015 ng·hr/mL (CV, 48.2%). The data indicated that the degrees of variability between BSA-normalized and flat dosing were comparable and that no improvement in variability was expected from normalizing the dose. Therefore, flat dosing on a milligram basis could also be considered appropriate for this once-weekly regimen and does not afford improvement in exposure variability.
Tumor Responses Confirmed partial responses were observed in two patients. One patient with renal cell carcinoma received 15 mg/m2 CCI-779 after documented tumor progression of lung and pleural metastasis under treatment with interferon-  and interleukin 2. The partial response was observed after 8 weeks of treatment and lasted for 6.5 months under therapy (Fig 6). A second patient with breast cancer and measurable disease in liver and cervical lymph nodes (previously treated with anthracycline, docetaxel, and vinorelbine) received 220 mg/m2 CCI-779 and had, after 4 weeks, a partial response lasting 5.4 months. Minor responses corresponding to 34% and 39% tumor reductions and lasting for 3 and 4.9 months were reported in two additional patients with renal cell carcinoma treated at the dose of 15 mg/m2 and 45 mg/m2, respectively.
In this study, we show that IV weekly infusion of CCI-779 at a broad range of doses can be administered to patients with advanced malignancies without clinically relevant immunosuppressive effects. No opportunistic infection and no significant modification of lymphocyte counts and functions were detected after repeated injections. However, occurrence of labial herpes simplex infection was frequently observed and subsequently complicated by a severe staphylococci infection in one patient. Thus vigorous treatment of herpes simplex infection in patients treated with CCI-779 seems advisable. The main dose-limiting toxicity of CCI-779 was reversible thrombocytopenia. Thrombocytopenia could be schedule-dependent as it was less frequent in our study compared with that in the study where CCI-779 was administered once daily for 5 days every 2 weeks and in which thrombocytopenia prevented dose-escalation above 19.1 mg/m2/d.29 Unexpectedly, the dose of 220 mg/m2 CCI-779 induced striking euphoria followed by melancholy, mimicking biopolar disorder. This toxicity occurred in patients without previous medical history of any psychiatric disorders and required hospitalization for IV antidepressive treatment in one patient. The relationship of this neutrotoxicity to CCI-779 is supported by reversibility on treatment discontinuation. The physiopathology of this event is not understood; recent evidence has suggested that sirolimus could interfere with the neurotransmitter metabolism.30,31 The most frequent adverse events that limited the tolerability of CCI-779 were skin toxicity and stomatitis. Skin toxicity was observed at all doses from 7.5 to 220 mg/m2. Maculopapular rash observed on the face and neck and acne-like rash observed on the face and upper chest were the predominant forms of dermatologic injury. These types of rash have also been reported with several epidermal growth factor receptor targeted agents such as the tyrosine kinase inhibitors gefitinib (ZD1839) and erlotinib (OSI-774) and monoclonal antibody cetuximab (IMC-225).32-34 Since mTOR appears to mediate intracellular signaling from EGFR in normal skin, a similar toxicity for an mTOR inhibitor might be expected. Pathologic examinations revealed nonspecific accumulation of neutrophils in dermis. Skin toxicity was spontaneously reversible during treatment and usually did not required dose reduction or treatment delay. Topical steroids showed variable effectiveness in preventing and resolving these toxicities. Thinning of nails with dystrophic changes was also reported in patients receiving treatment for more than 2 months. Grade 1 to 2 stomatitis was also observed at a broad range of doses and was frequently associated with acne-like skin reactions. Grade 3 stomatitis with multiple painful ulceration requiring IV nutrition were observed at the highest dose level. A recent report further indicated that combination of CCI-779 with drugs that also induce mucositis/stomatitis, such as fluorouracil, would lead to unacceptable toxicity.35 Pharmacokinetic parameters of sirolimus have been obtained from studies performed in patients with renal transplantation.36-37 Sirolimus given as an oral solution or tablet is characterized by a rapid but poor oral absorption (oral availability = 14%). Sirolimus distributes widely in tissues (large apparent volume of distribution) and display a prolonged terminal half-life. Sirolimus underwent multiple biotransformations including simple demethylations and hydroxylations with 41-O-demethyl-rapamycin being the major metabolite both in vivo and in vitro. At doses ranging from 2 to 24 mg sirolimus showed a linear dose-proportionality with good correlation between steady-state trough concentration and AUC. Extensive partitioning into formed blood elements with the majority of the drug is sequestered in erythrocytes, resulting in whole blood concentrations being considerably higher than plasma concentrations. As a result of its complex metabolism and pharmacokinetic profile, sirolimus displays large intersubject and intrasubject variability. In our pharmacokinetic analysis, we showed that IV CCI-779 was progressively converted into sirolimus. CCI-779 was prevalent only during the first 2 hours; after 2 hours, concentrations of sirolimus were higher than that of CCI-779. In our study, blood concentrations of CCI-779 and sirolimus were in the range that inhibited cancer cell proliferation in vitro (IC50 range, 0.0005 to 5.9 µmol/L) and cause tumor growth delay in animals (8.7 to 40 mg/kg).12,21 This study explored very high doses of CCI-779, resulting in high blood concentrations of sirolimus. So far, little pharmacokinetic information is available on pharmacokinetic blood parameters of sirolimus and its derivative at such extreme concentrations. Below the dose of 150 mg CCI-779, the pharmacokinetic parameters of CCI-779 and sirolimus resemble those described for rapamycin with AUC, Cl, and Vdss being fairly proportional to doses. Interestingly, at doses less than 150 mg, variability of Cmax, AUC, Cl, and Vdss of CCI-779 was modest to moderate. Strikingly, doses greater than 300 mg were associated with a nonproportional increase of pharmacokinetic parameters. For doses greater than 300 mg, the clearance seems to increase less than proportional, and the volume of distribution of CCI-779 seems to decrease. Saturation of CCI-779/sirolimus metabolism and modification of protein binding and/or erythrocyte sequestration might account for those pharmacokinetic modifications. Further compartmental analysis in a larger number of patients would help to clarify this unexpected pharmacokinetic profile. Furthermore, because sirolimus is a major observed metabolite of CCI-779 and has significant presence and intrinsic biologic activity, it was incorporated into the metrics of exposure along with CCI-779. Assessments of exposure based on BSA-normalized and simulated fixed doses indicate that interpatient variability is comparable. Therefore, our results suggest that a fixed-dose regimen could also be appropriate for CCI-779 treatment in patients with cancer. Unlike standard chemotherapeutic agents, the optimal dose of CCI-779 would produce inhibition of the target mTOR kinase and may be well below the conventional MTD. A biologically active dose and schedule might be identified by dose-efficacy relationship, by achievement of pharmacokinetic end points, or biologic activity in tumor or surrogate tissues.18 Because no validated surrogate end point was available at the time of this study, the trial was conduced to explore the widest possible ranges of doses and obtain pharmacokinetic information for CCI-779 doses selected for phase II trials. Evidence of activity was observed over the entire dose range (15 to 220 mg/m2) in patients with renal and breast cancer, with no apparent relationship between exposure and clinical benefit, suggesting that the inhibition of mTOR may be achieved at doses well below dose levels that result in dose-limiting toxicity. Based on these results, weekly doses of 25, 75, and 250 mg CCI-779 that are not based on classical definitions of MTD are currently being tested in phase II trials in patients with breast and renal cancer. In summary, this study shows that weekly infusion of CCI-779 at doses of 7.5 to 220 mg/m2 in patients with advanced cancer produced reversible toxicity and early evidence of antitumor activity. Pharmacokinetic results showed that dosing of CCI-779 was compatible with the use of a fixed-dose regimen.
The following authors or their immediate family members have 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. Owns stock (not including shares held through a public mutual fund): Joan Korth-Bradley, Wyeth. Acted as a consultant within the last 2 years: Eric Materman, Wyeth. Received more than $2,000 a year from a company for either of the last 2 years: Joseph Boni, Wyeth; Cathie Leister, Wyeth; Joan Korth-Bradley, Wyeth.
We thank for their contribution to the pharmacokinetic study: P. Dielenseger, M. Granier, and D. Leleu (sampling), J. Snodgrass (bioanalytical analyses), D. Simcoe (data analysis), and S. Leinbach (assistance with manuscript preparation). We also thank all the patients and clinical research personnel who participated in this study.
Supported by Wyeth Research, Collegeville, PA. Eric Raymond and Jérôme Alexandre contributed equally to this work and shall be considered as joint first authors. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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