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Originally published as JCO Early Release 10.1200/JCO.2005.03.0981 on November 21 2005 © 2005 American Society of Clinical Oncology. Phase I Dose-Finding Study of Weekly Single-Agent Patupilone in Patients With Advanced Solid TumorsFrom the Cancer Institute of New Jersey, New Brunswick; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Pharma Société par Actions Simplifiée, Rueil-Malmaison, France; and Princess Margaret Hospital, Toronto, Ontario, Canada Address reprint requests to Eric H. Rubin, MD, the Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901; e-mail: ehrubin{at}umdnj.edu
PURPOSE: To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated with patupilone (0.3 to 3.6 mg/m2) for 6 weeks on/3 weeks off or 3 weeks on/1 week off. Dose-limiting toxicities (DLTs), MTD, and pharmacokinetics were determined for each schedule of administration. RESULTS: Ninety-one patients were enrolled. The most common tumor types included ovarian, breast, and colon cancers. Doses of patupilone less than 2.5 mg/m2 using either the 6 weeks on/3 weeks off or the 3 weeks on/1 week off schedule were tolerated well. At higher doses, DLTs were observed using both dosing schedules, with diarrhea the most common DLT. The MTD for both treatment schedules was 2.5 mg/m2. After a short infusion, patupilone blood concentrations declined in a multiphasic manner with a terminal half-life of 4 days. Drug clearance was nonrenal and was not related to body-surface area. Over the dose range evaluated, systemic drug exposure was approximately dose proportional. Three patients achieved a partial response, and 31 patients had stable disease. Two patients experiencing a partial response had received prior taxane therapy. CONCLUSION: Patupilone is well tolerated when administered at a dose of 2.5 mg/m2, using either a 6 weeks on/3 weeks off or a 3 weeks on/1 week off schedule. In contrast with murine studies, patupilone has a relatively prolonged terminal half-life in humans. The partial responses in patients previously treated with taxanes is consistent with promising preclinical results.
Alteration of microtubule function is one of the most effective means of inhibiting tumor growth and inducing cell death. The cytotoxic activity of taxanes, including paclitaxel and docetaxel, is based on interference with microtubule dynamics.1-5 Both paclitaxel and docetaxel are widely used in the treatment of a broad range of tumor types, including non–small-cell lung, breast, and ovarian cancers. However, several cancers, including colorectal and renal cancers, are generally poorly responsive to taxanes.6 The effectiveness of taxane therapy may be limited by the development of drug resistance, possibly resulting from the overexpression of P-glycoprotein.7 Despite the broad use of taxane therapy, the impact of taxanes on patient survival has been modest at best, and the overwhelming majority of metastatic solid tumors remain incurable. Taxanes are also associated with a number of significant toxicities, including dose-limiting myelosuppression and peripheral neuropathy.3,8-11 These toxicities may limit the use of taxanes in the treatment of heavily pretreated patients with advanced disease, patients with comorbidities and poor performance status, and older patients. Therefore, there is a clear need for identifying novel microtubule-targeting agents with improved overall safety and broader antitumor activity, particularly in multidrug-resistant tumors. Patupilone (EPO906; Novartis Pharmaceuticals Corp, East Hanover, NJ), a natural epothilone B, is a macrolide secondary metabolite produced by Sorangium cellulosum. Patupilone stabilizes microtubules by binding tubulin in a manner similar to that of paclitaxel (Fig 1). 12 However, patupilone exhibits more potent binding to tubulin and induces and stabilizes tubulin polymerization at lower concentrations compared with paclitaxel.13 In vitro, patupilone is a potent inhibitor of cell growth in a variety of cancer cell lines.13 In contrast with paclitaxel, patupilone is equally cytotoxic to multidrug-resistant cell lines that overexpress P-glycoprotein.2,12,13 In addition, when administered using a weekly schedule, patupilone demonstrated broad antitumor activity in vivo in human tumor models, including colon, prostate, and breast cancer.12,14 Further, patupilone also inhibited tumor growth in paclitaxel-resistant human lung carcinoma A549, where resistance to paclitaxel is most likely not mediated by P-glycoprotein overexpression.15 Because of these promising preclinical results, particularly in paclitaxel-resistant models, we investigated the safety, pharmacokinetic profile, and maximum-tolerated dose (MTD) of weekly patupilone in patients with advanced solid tumors.
Eligibility Criteria Patients  18 years of age with histologically confirmed advanced solid tumors who had experienced treatment failure with one or more standard systemic therapy regimens or for whom standard systemic therapy did not exist were enrolled onto the study. Patients had one measurable or nonmeasurable but assessable site of disease as defined by the Southwestern Oncology Group Solid Tumor Response Criteria.16 Eligible patients were required to have a WHO performance score of  2 and adequate hepatic function (bilirubin 1.5x the upper limit of normal [ULN] and ALT or AST 5x ULN). In a cohort that examined the effect of moderate hepatic dysfunction on patupilone toxicity and pharmacokinetics, bilirubin levels of up to 3x the ULN were allowed. Patients with impaired hematologic function, including platelet count less than 100 x 109/L and absolute neutrophil count less than 1.5 x 109 cells/L, were excluded. Patients who had received chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin), prior radiation therapy to 25% of the bone marrow, prior surgery within 2 weeks of study entry, or prior bone marrow or peripheral-blood progenitor cell transplantation were not eligible. All patients provided informed written consent.
Study Design Additional patients were enrolled at the MTD to verify the toxicity rate and pharmacokinetics at this dose level. After determination of the MTD for the 6 weeks on/3 weeks off schedule, the protocol was amended to a 3 weeks on/1 week off administration schedule, with a starting dose of 1.1 mg/m2. Furthermore, after determination of the MTD for the 3 weeks on/1 week off schedule, an additional cohort of patients with elevated serum bilirubin levels and liver enzymes was enrolled to assess the toxicity and pharmacokinetics of patupilone in this setting. A summary of the dose escalation and dosing schedule for each cohort of patients is provided in Table 1.
Treatment Patupilone was prepared for administration by dilution of an appropriate volume of concentrated stock solution in 0.9% normal saline. The stock solution contained 1 mg/mL patupilone in polyethylene glycol 300. The diluted drug was administered via intravenous infusion, initially over a 15-minute interval. Subsequently, as a result of additional preclinical safety results, the protocol was amended to a 5-minute infusion time. A cycle was defined as 9 weeks for the 6 weeks on/3 weeks off schedule and as 6 weeks for the 3 weeks on/1 week off schedule. Patients achieving a complete response, partial response, or stable disease after one cycle (6 weeks on/3 weeks off schedule) or two cycles (3 weeks on/1 week off) could continue further treatment until either unacceptable toxicity or disease progression.
Patient Assessments Pharmacokinetics. Blood samples were collected on day 1 before study drug administration of dose 1 (all patients), dose 3 (a subset of patients receiving patupilone 3 weeks on/1 week off), and dose 6 (a subset of patients receiving patupilone 6 weeks on/3 weeks off); immediately before the end of infusion (15-minute infusion only) and after the infusion at the following time points: 5 (5-minute infusion only), 10, 20, and 40 minutes and 1, 1.5, 2, 4, 8, 10, 24, 48, 72, and 168 hours (before the next dose). Blood samples for trough drug concentrations were collected before each drug administration at weeks 3, 4, 5, and 6. Blood pharmacokinetics were evaluated by a noncompartmental model. The area under the concentration-time curve (AUC) data were calculated by a linear-log trapezoidal method. All pharmacokinetic analyses were performed using WINNonlin (Pharsight, Mountain View, CA). Urine patupilone concentrations (two 24-hour collections) were assessed after doses 1 and 6. Patupilone concentrations in blood and urine were analyzed by a liquid chromatography tandem mass spectrometry method with atmospheric pressure chemical ionization interface and positive ions detection. Briefly, patupilone was extracted from 0.5 mL of blood with tert-butyl methyl ether in alkaline medium (35% Na2CO3 solution). After evaporation of the organic phase, the dry residues were dissolved in 300 µL of mobile phase, and 100 µL were injected into the analytic system. Separation was performed on a ChromCart Nucleosil (Machery-Nagel Inc, Easton, PA) 50-C18EC 5-µm (125 x 4 mm) column protected by a precolumn (8 x 4 mm, same phase) at 60°C. The mobile phase consisted of 0.05 mol/L of CH3COONH4-methanol (35:65, volume to volume) with a gradient elution process. The flow rate was 1 mL/min, and 13C5-labeled patupilone was used as an internal standard. The limit of quantification was 0.1 ng/mL. Antitumor activity. Antitumor activity was evaluated using the Southwest Oncology Group response criteria.16 For the 6 weeks on/3 weeks off schedule, tumors were assessed by computed tomography scan or magnetic resonance imaging at baseline and at the beginning of week 7 of every cycle of treatment. In the cohorts treated on the 3 weeks on/1 week off schedule, tumors were assessed after every two cycles of therapy. Duration of stable disease was calculated from the study start date to the date of documented disease progression or date of study discontinuation.
Statistical Measurements
Patient Characteristics and Disposition A total of 91 patients were enrolled onto the trial. All 91 patients received one dose of patupilone and were eligible for toxicity assessment. Demographic and disease characteristics of these patients are listed in Table 2. The most common primary tumor types included ovarian (n = 17), breast (n = 17), colon (n = 14), lung (n = 9), and rectal (n = 6) cancers. Nearly all (96%) of the patients had received prior chemotherapy, with 89% receiving two or more prior chemotherapy regimens. Of the 87 patients who received prior chemotherapy, 41 patients (47%) had received paclitaxel and 12 patients (13%) had received docetaxel. Forty-six percent of patients had received prior radiotherapy.
Eighty-five (93%) of the 91 patients remained on study for at least 18 weeks. Doses were held or decreased during these 18 weeks in 20 patients. One patient discontinued because of protocol violation. Four patients discontinued because of adverse events considered related to patupilone (two patients because of diarrhea, one patient because of lower extremity numbness, and one patient because of anorexia). One patient discontinued because of death; this patient had a history of jaundice and bile-duct stent insertion and died because of acute renal failure, with this adverse event not considered related to patupilone.
DLT and MTD Three weeks on/1 week off dosing schedule. Because the severity of the patupilone-associated diarrhea often peaked during the fourth week of treatment, the dosing regimen was modified to a 3 weeks on/1 week off schedule, with a starting dose of 2.5 mg/m2. There were no significant toxicities among the initial patients treated at this dose level, and thus the dose was escalated to 3.0 mg/m2. However, two of five patients treated at this level experienced grade 3 diarrhea, and one patient experienced grade 3 nausea. Therefore, the dose was decreased to 2.5 mg/m2. Among a total of 28 patients treated at this dose level, there was only a single occurrence of DLT (diarrhea). Thus, similar to the 6 weeks on/3 weeks off schedule, 2.5 mg/m2 was defined as the MTD for this schedule. Among the four patients with abnormal liver function (mean ± SD for bilirubin, AST, and ALT were 3.5 ± 1.6 mg/dL, 123 ± 31.8 units/L, and 79 ± 22 units/L, respectively) treated at the 2.0 mg/m2 dose level (3 weeks on/1 week off schedule), one patient experienced DLT (grade 3 diarrhea).
Nonhematologic Toxicity
Hematologic Toxicity There was minimal hematologic toxicity observed in this heavily pretreated patient population. Grade 3 or 4 anemia, thrombocytopenia, neutropenia, and leukopenia were reported in only seven patients (8%), one patient (1%), one patient (1%), and one patient (1%), respectively. Grade 3 anemia was reported in six patients who received less than 2.5 mg/m2 patupilone. However, four of these patients had grade 2 anemia at baseline. Mild to moderate anemia attributed to study drug was reported in two patients treated at the MTD. There were no other hematologic toxicities attributed to the study drug. Therefore, it seems that patupilone, when administered using a weekly administration schedule, is not associated with clinically significant myelosuppression.
Pharmacokinetics
A representative blood concentration-time profile from a patient who received multiple doses is depicted in Figure 3. Multiple-dose blood patupilone concentration-time data were analyzed using a steady-state approach. A summary of multiple-dose pharmacokinetics by infusion schedule is provided in Table 5. Compared with estimates after a single dose, AUC during a dosing interval (1 week) at steady-state (AUC  ,ss) was approximately 60% higher, and total-body clearance at steady-state was reduced by approximately 40%. There were no changes in the t1/2 (4 days) or the apparent volume of distribution (> 1,000 L). The decrease in drug clearance rate and increase in drug exposure were more pronounced in patients after they had received more than three doses. As a whole, the accumulation ratio (AUC ,ss/AUC, dose 1) was less than two after three to six doses with a weekly dosing schedule.
Patients With Hepatic Dysfunction The drug clearance of patupilone in patients with hepatic dysfunction was reduced by 50% compared with patients with normal liver function (Table 6). The reduction in clearance resulted in an increase in systemic drug exposure. The terminal t1/2 was also increased while apparent volume of distribution at steady-state remained unchanged. Although these results indicate that pharmacokinetics of patupilone are altered in patients with hepatic dysfunction, there was no statistically significant difference in drug clearance between patients with or without liver metastases (P > .05).
Correlative analyses. The relationship between dose and systemic exposure was investigated by fitting a power model to AUC versus dose data (Fig 4). Doubling the dose resulted in an increase in exposure by a factor of 2.14 over a dose range of 0.3 to 3.6 mg/m2 after the first dose and by a factor of 1.71 after the sixth dose. This suggests that over a dose range of 0.3 to 3.6 mg/m2, systemic drug exposure was nearly dose proportional after a single dose; however, it was slightly less than dose proportional after repeated drug administration. The blood clearance of patupilone was not related to body-surface area (R2 = 0.000004; P = .9852). Similarly, no statistically significant dependence was found for the blood clearance of patupilone as a function of age, sex, or body weight (P > .05 for each analysis). The occurrence of severe diarrhea was associated with dose (P = .0017), systemic exposure (AUC0-inf; P = .0008), and Cmax (P = .0424), where dose was the initial dose received and AUC0-inf and Cmax values were obtained from concentration-time data after the first dose. The occurrence of diarrhea was not associated with body-surface area. In a multivariate analysis of dose, Cmax, and AUC0-inf, only dose remained significantly (P < .05) associated with the occurrence of diarrhea; neither AUC (P > .5) nor Cmax (P > .4) were found to be significantly associated with the occurrence of diarrhea after adjustment for dose.
Urine pharmacokinetics. All 53 patients who received weekly patupilone on the 6 weeks on/3 weeks off schedule provided urine samples after the first dose, and 33 patients provided urine samples after the sixth dose over a 48-hour period. Renal excretion of unchanged patupilone was negligible, accounting for 0.08% of the total dose infused after the first dose and sixth dose.
Antitumor Response
This study demonstrates that weekly patupilone is safe and well tolerated in heavily pretreated patients with advanced solid tumors. The most common adverse events were gastrointestinal in nature and included diarrhea, nausea, and vomiting. Fatigue was also a common adverse event. The toxicity profile associated with weekly administration of patupilone is strikingly different from those associated with the most commonly used microtubule-targeting drugs, the taxanes. Paclitaxel is associated with significant schedule-dependent neutropenia, especially in heavily pretreated patients and in patients who have just received cisplatin.8 In addition, paclitaxel is associated with severe skin and hypersensitivity reactions because of its Cremophor-containing formulation and requires premedication with corticosteroids and antihistamines to reduce the risk and severity of these adverse reactions.9 Peripheral neuropathy is also a frequent DLT of paclitaxel.3,10 Docetaxel is associated with dose-limiting myelosuppression, with the majority of patients experiencing grade 4 neutropenia.11 Docetaxel is also associated with severe fluid retention and severe skin and hypersensitivity reactions. Compared with taxanes, patupilone seems to have an improved safety profile and is not associated with any significant myelosuppression, severe neuropathy, alopecia, or hypersensitivity reactions. The lack of hypersensitivity reactions associated with patupilone allows for a significantly shorter infusion time (5 minutes) compared with taxanes (typically 1 hour or more).
The most common adverse event requiring dose adjustment or treatment delay for patupilone was diarrhea. Severe diarrhea was reported in 17 patients; however, diarrhea was usually manageable with dose adjustment and proactive management based on standard diarrhea treatment regimens, including loperamide.17,18 Although not statistically significant, the incidence of severe diarrhea in patients who received Pharmacokinetic analysis demonstrated that the blood disposition of patupilone was multiphasic. Blood drug concentrations declined rapidly followed by a prolonged terminal elimination phase with a t1/2 of approximately 4 days. This prolonged terminal phase is twice as long as the terminal elimination t1/2 (0.7 to 2 days) recently reported for BMS-247550, an epothilone B semisynthetic analog, in patients with solid tumors.19 Because preclinical metabolism studies indicated that a predominant inactive metabolite of epothilone B represents lactone hydrolysis, the difference in epothilone B elimination rates in mice versus humans is likely because of the relatively higher levels of plasma and tissue esterases in mice.20 Systemic drug exposure of patupilone was nearly dose proportional after a single dose over a range of 0.3 to 3.6 mg/m2. However, systemic drug exposure was slightly less than dose proportional after repeated drug administration. These findings contrast with the pharmacology of paclitaxel, which typically exhibits nonlinear pharmacokinetics.3,6 Furthermore, in the current study, toxicity associated with patupilone correlated with both dose and systemic exposure, whereas the severity and duration of toxicity associated with paclitaxel often increases disproportionately with dose.3 Drug accumulation of patupilone was less than two-fold after three to six doses with a weekly dosing schedule. Drug exposure was independent of infusion schedule, and the clearance seems to be primarily via nonrenal elimination. Notably, the clearance of patupilone was significantly decreased in patients with hepatic dysfunction, and although 2.0 mg/m2 was tolerated well by two of the four patients, this study did not determine a MTD for patients with hepatic dysfunction. The blood clearance rate of patupilone was independent of age, sex, body weight, or body-surface area, and there was no statistically significant difference in blood clearance rate of patupilone between patients with or without liver metastases. Therefore, the relatively high coefficient of variation for patupilone blood clearance among patients with normal hepatic function is not accounted for by any of the clinical variables analyzed. The variation in clearance may reflect significant interpatient differences in the activity of carboxylesterase or other metabolizing enzymes. Because the incidence of severe diarrhea was correlated significantly with systemic drug exposure, individual differences in patupilone clearance may be an important determinant in the occurrence of this toxicity. Given that patupilone blood clearance was not associated with body-surface area, fixed dosing could be considered in future studies. In conclusion, patupilone was generally well tolerated in this patient population and preliminary results suggest that patupilone may be active in several tumor types. Three phase II studies investigating every 3 weekly patupilone with diarrhea management are currently underway.
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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank the patients for their participation and the study coordinators, nurses, physicians, and laboratory technicians for their assistance.
Supported by Novartis Pharmaceuticals Corp, East Hanover, NJ. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Hamel E: Antimitotic natural products and their interactions with tubulin. Med Res Rev 16:207-231, 1996[CrossRef][Medline] 2. Bollag DM, McQueney PA, Zhu J, et al: Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res 55:2325-2333, 1995 3. Kearns CM, Gianni L, Egorin MJ: Paclitaxel pharmacokinetics and pharmacodynamics. Semin Oncol 22:16-23, 1995[Medline] 4. Horwitz SB, Cohen D, Rao S, et al: Taxol: Mechanisms of action and resistance. J Natl Cancer Inst Monogr 55-61, 1993 5. Jordan MA, Wendell K, Gardiner S, et al: Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res 56:816-825, 1996 6. Rowinsky EK: The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents. Annu Rev Med 48:353-374, 1997[CrossRef][Medline] 7. Yusuf RZ, Duan Z, Lamendola DE, et al: Paclitaxel resistance: Molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets 3:1-19, 2003[Medline] 8. Rowinsky EK, Gilbert MR, McGuire WP, et al: Sequences of taxol and cisplatin: A phase I and pharmacologic study. J Clin Oncol 9:1692-1703, 1991[Abstract] 9. Weiss RB, Donehower RC, Wiernik PH, et al: Hypersensitivity reactions from Taxol. J Clin Oncol 8:1263-1268, 1990[Abstract] 10. Garrison JA, McCune JS, Livingston RB, et al: Myalgias and arthralgias associated with paclitaxel. Oncology (Williston Park) 17:271-277, 2003[Medline] 11. Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens: The TAX 320 Non-Small-Cell Lung Cancer Study Group. J Clin Oncol 18:2354-2362, 2000 12. Altmann KH, Wartmann M, O'Reilly T: Epothilones and related structures: A new class of microtubule inhibitors with potent in vivo antitumor activity. Biochim Biochim Biophys Acta 1470:M79–M91, 2000[Medline] 13. Kowalski RJ, Giannakakou P, Hamel E: Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J Biol Chem 272:2534-2541, 1997 14. O'Reilly T, McSheehy PM, Wenger F, et al: Patupilone (epothilone B, EPO906) inhibits growth and metastasis of experimental prostate tumors in vivo. Prostate 65:231-240, 2005[CrossRef][Medline] 15. Martello LA, Verdier-Pinard P, Shen HJ, et al: Elevated levels of microtubule destabilizing factors in a Taxol-resistant/dependent A549 cell line with an alpha-tubulin mutation. Cancer Res 63:1207-1213, 2003 16. Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10:239-253, 1992[CrossRef][Medline] 17. Wadler S, Benson AB 3rd, Engelking C, et al: Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol 16:3169-3178, 1998 18. Kornblau S, Benson AB, Catalano R, et al: Management of cancer treatment-related diarrhea: Issues and therapeutic strategies. J Pain Symptom Manage 19:118-129, 2000[CrossRef][Medline] 19. Mani S, McDaid H, Hamilton A, et al: Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors. Clin Cancer Res 10:1289-1298, 2004 20. Blum W, Aichholz R, Ramstein P, et al: In vivo metabolism of epothilone B in tumor-bearing nude mice: Identification of three new epothilone B metabolites by capillary high-pressure liquid chromatography/mass spectrometry/tandem mass spectrometry. Rapid Commun Mass Spectrom 15:41-49, 2001[CrossRef][Medline] Submitted June 14, 2005; accepted August 22, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
x doseß to the AUC versus dose data, where AUC represents AUC0-inf and dose is in milligrams. The correlation between patupilone blood clearance rate and age, body weight, or body-surface area was analyzed by linear regression, where clearance rate was log transformed. The significance of the mean difference in clearance rate by sex and the presence or absence of liver metastases were analyzed using a t test. The relationship between dose, systemic exposure, or maximum peak blood drug concentration (Cmax) after a single dose and the occurrence/severity of diarrhea in a 21-day period were evaluated by polytomous logistic regression. Both simple and multivariate regression models were used. 
), 1.65 mg/m2 (n = 1); (
), 1.85 mg/m2 (n = 4); (
), 2.5 mg/m2 (n = 35); (
), 3.0 mg/m2 (n = 14); and (
), 3.6 mg/m2 (n = 5).
