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© 2002 American Society for Clinical Oncology Multicenter Phase II Study of a 28-Day Regimen of Orally Administered Eniluracil and Fluorouracil in the Treatment of Patients With Anthracycline- and Taxane-Resistant Advanced Breast CancerByFrom Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; QE2 Health Sciences Center, Nova Scotia Cancer Center, Halifax, Nova Scotia, Canada; and Duke University Medical Center, Durham; Division of Hematology/Oncology, University of North Carolina School of Medicine, Chapel Hill; and GlaxoSmithKline, Research Triangle Park, NC. Address reprint requests to Edgardo Rivera, MD, Breast Medical Oncology, University of Texas M.D. Anderson Cancer Center, Box 424, Houston, TX 77030; email: erivera{at}notes.mdacc.tmc.edu
PURPOSE: Eniluracil (776C85), a potent inactivator of dihydropyrimidine dehydrogenase, allows fluorouracil (5-FU) to be administered orally on a schedule that simulates continuous-infusion 5-FU. The primary objective of this study was to estimate the objective tumor response rate of orally administered eniluracil and 5-FU in the treatment of anthracycline- and taxane-resistant advanced breast cancer. PATIENTS AND METHODS: Patients with anthracycline- and taxane-resistant advanced breast cancer were enrolled onto this open-label, phase II, multicenter study. Patients received orally administered 5-FU 1.0 mg/m2 with eniluracil given in a 10:1 ratio (eniluracil:5-FU) twice daily for the first 28 days of each 35-day cycle. RESULTS: Eighty-four patients were enrolled. Eight partial responses were observed in 84 patients (10%; 95% confidence interval [CI], 4.2% to 17.9%), and 20 patients (24%) had stable disease. The median duration of partial response was 20.1 weeks (95% CI, 12 to 26.7 weeks). The median duration of progression-free survival and overall survival for all patients was 9.9 weeks and 40.4 weeks, respectively. Most adverse events were grade 1 or 2 in intensity. Diarrhea, nausea, malaise/fatigue, vomiting, and mucositis were the most common treatment-related nonhematologic adverse events. The most frequently occurring grade 3 or 4 treatment-related adverse events were malaise/fatigue and diarrhea, occurring in 17% and 7% of patients, respectively. The incidence of grade 3 or 4 hematologic toxicity was low. Grade 3 or 4 hyperbilirubinemia occurred in 17% of patients. CONCLUSION: Eniluracil–5-FU has modest antitumor activity and an acceptable safety profile in anthracycline- and taxane-resistant breast cancer. Treatment was convenient, and patient compliance was high.
BREAST CANCER IS the most common malignancy in American women. It is estimated that in the year 2000, 182,800 women were diagnosed with breast cancer in the United States and 40,800 women died from their disease.1 Few women who develop metastatic breast cancer are cured. The median survival time for patients with metastatic disease has been estimated to be between 2 and 3 years.2 For these women, the goals of systemic therapy are to palliate symptoms and improve survival.2 Anthracyclines and taxanes are among the most active chemotherapeutic agents used for this purpose. More recently, capecitabine has been approved for the treatment of patients with anthracycline- and taxane-resistant disease.3 Fluorouracil (5-FU) is also commonly used for the treatment of breast cancer, both in the adjuvant and advanced settings, but its efficacy may be limited by its pharmacokinetics. Dihydropyrimidine dehydrogenase (DPD), the first enzyme in the catabolic pathway, rapidly reduces 5-FU to inactive metabolites.4,5 When provided orally, the bioavailability of 5-FU is variable (0% to 80%), probably as a result of incomplete absorption and first-pass elimination in the liver.6-8 In an effort to improve the efficacy of 5-FU, different schedules of administration have been studied. In several small studies of 5-FU provided as a continuous infusion to women with previously treated advanced breast cancer, response rates ranging from 16% to 54% have been reported.9-12 Eniluracil, a potent inactivator of DPD, allows 5-FU to be administered orally with predictable bioavailability. In preclinical studies, eniluracil inactivated more than 96% of DPD in the liver, made orally administered 5-FU essentially 100% bioavailable, and increased the half-life and area under the curve of orally administered 5-FU.13,14 Inhibition of the primary route of metabolism of 5-FU could allow chronic oral dosing and provide an alternative to protracted intravenous infusion of 5-FU. Therefore, a phase I study was performed to determine the tolerability of 10 or 20 mg of eniluracil administered orally once or twice daily together with orally administered 5-FU at doses of 1.0, 1.35, or 1.8 mg/m2.15 Dose-limiting gastrointestinal toxicity was observed in patients receiving eniluracil 10 mg and 1.35 mg/m2 orally administered 5-FU, both provided twice a day for 28 days. Doses of 20 mg of eniluracil and 1.0 mg/m2 5-FU administered orally twice a day were well tolerated. Pharmacokinetic analysis demonstrated dose linearity for the maximum concentration of 5-FU and the area under the curve, and plasma concentrations comparable to those reported for protracted intravenous infusion of 5-FU.16,17 The ratio of 10:1 for eniluracil to 5-FU was then established in order to allow dosing with a combination tablet, with the dosage based on the patient’s body-surface area. Eniluracil therefore allows the oral administration of 5-FU on a schedule similar to continuous-infusion 5-FU without the complications, expense, and inconvenience of a central venous access device and ambulatory pump. The study we report here was conducted to estimate the objective tumor response rate of a 28-day regimen of orally administered eniluracil and 5-FU in the treatment of anthracycline- and taxane-resistant advanced breast cancer. The secondary objectives were to evaluate the safety of this regimen and to estimate the duration of response, progression-free survival, and overall survival.
This was a multicenter, open-label, phase II study (GlaxoSmithKline protocol FUMA2003) of orally administered eniluracil–5-FU in which patients received twice-daily dosing of eniluracil and 5-FU for the first 28 days of each 5-week course, followed by a 7-day period during which patients received no study drug. Between January 1997 and August 1998, 14 centers in the United States and Canada enrolled 84 patients with anthracycline- and taxane-resistant breast cancer. The ethics committees of all participating institutions approved this study. All patients provided signed informed consent according to institutional and federal guidelines before study registration.
Patients All patients were also required to have received prior therapy with a taxane that resulted in one of the following: progression during or within 3 months of treatment for advanced disease, relapse during or within 6 months of adjuvant therapy, or severe peripheral neuropathy (documented by diagnostic testing or examination by a neurologist), which precluded further taxane therapy.
Patients were required to have a Karnofsky performance score
Exclusion criteria included the following: prior treatment with continuous-infusion 5-FU (ie, continuous infusion > 7 consecutive days); more than two prior chemotherapy regimens for advanced disease or more than three total prior chemotherapy regimens for the treatment of breast cancer; and previous high-dose chemotherapy with bone marrow or peripheral stem-cell rescue for the treatment of advanced breast cancer (allowed in the adjuvant setting if received
Drug Dosage and Administration GlaxoSmithKline (Research Triangle Park, NC) supplied both the 5-FU and eniluracil tablets. The 5-FU was supplied as 0.25-mg and 1-mg tablets. Eniluracil was supplied as 2.5- and 10-mg tablets. Site pharmacies filled blister cards with the appropriate number of eniluracil and 5-FU tablets. Patients were instructed to return all blister cards to the pharmacy at the end of each course so that compliance could be evaluated. The use of any other fluoropyrimidine therapy, including flucytosine, was prohibited during and up to 28 days after the last dose of eniluracil–5-FU. The mandatory waiting period was increased to 8 weeks during the study to ensure full regeneration of DPD in all patients.
Dose Modifications
Assessment of Efficacy and Safety In addition, all known areas of disease were assessed within 2 weeks before the first dose of study drug by performing, at a minimum, an abdominal computed tomographic scan or magnetic resonance imaging scan, chest x-ray, and radionuclide bone scan (performed within 6 weeks before the first dose of study drug). Disease assessments were repeated before course 3 and every other course thereafter (ie, approximately every 10 weeks) by using the same assessment methods as at baseline. All complete and partial responses were confirmed by repeat disease assessment at least 4 weeks later. Skeletal x-rays were performed as clinically indicated. Ultrasound was not an acceptable disease assessment method. Physical examination, assessment of Karnofsky performance status and clinical signs and symptoms of cancer, serum chemistries, urinalysis, and estimated creatinine clearance were repeated before the start of each course. Complete blood counts with differential and coagulation studies were repeated weekly throughout the study. Adverse events were assessed throughout the study and were graded according to modified SWOG criteria.18 After discontinuing study drug, patients were observed quarterly for survival.
Objective tumor response rate was the primary end point of the study. Measurable disease and response were also defined according to modified SWOG criteria.18 Measurable disease was defined as lesions with clearly defined margins, outside of any previous radiation portal (unless a biopsy had been performed), and bidimensionally measurable by one of the following methods: direct measurement, medical photograph (skin or oral lesions) or plain x-ray, with at least one diameter
A complete response required all of the following on at least two consecutive assessments at least 4 weeks apart: complete disappearance of all measurable and assessable disease; no new lesions; no evidence of nonassessable disease; and the disappearance of all baseline clinical signs and symptoms of cancer. Partial response applied only to patients with at least one measurable lesion and required all of the following on at least two consecutive assessments at least 4 weeks apart:
Statistical Methods
A two-stage design was used to determine whether there was sufficient activity to warrant complete enrollment. If fewer than two of the first 21 assessable patients or fewer than five of the first 41 assessable patients across both strata experienced an objective tumor response, enrollment onto the study was to be terminated. With this strategy, there was less than a 5% chance that the study would continue if the true response rate was All study results are reported for the intent-to-treat population, which included all patients who received the study drug. Response rate was calculated as the percentage of patients who experienced a best response of complete or partial response. For responding patients, the duration of response was calculated as the time from first documentation of complete or partial response until the first observation of disease progression or death. Duration of stable disease (for patients achieving a best response of stable disease) and duration of progression-free survival were calculated as the time from first dose of study drug to the first observation of disease progression or death attributable to any cause. Duration of survival was defined as the time from first dose of study drug to death attributable to any cause. Time-to-event parameters were summarized by Kaplan-Meier product-limit estimates.
Patient Characteristics Eighty-four patients with anthracycline- and taxane-resistant advanced breast cancer were enrolled onto and treated in this study. Seventy-eight patients were enrolled onto stratum 1, and six patients were enrolled onto stratum 2. Three patients (two in stratum 1 and one in stratum 2) did not meet the anthracycline resistance criteria, and one patient (stratum 1) did not meet the taxane resistance criteria. These four patients are included in all analyses.
Patient characteristics are summarized in Table 1. All patients had stage IV disease except for one patient in stratum 1, who had stage IIIB disease. Fifteen patients (18%) were
Patients demonstrated resistance to the following anthracyclines: doxorubicin (86% of patients), epirubicin (8%), liposomal encapsulated doxorubicin (4%), and daunorubicin (1%). In addition, one patient demonstrated resistance to losoxantrone; this patient had also previously received doxorubicin. Patients also demonstrated resistance to either paclitaxel (65% of patients) or docetaxel (35%). Most patients (75%) had also received previous 5-FU therapy.
Response Seven of the eight responding patients had previously experienced disease progression during or within 3 months of having received a taxane for advanced disease. Of the six responders in stratum 1, two had disease progression within 3 months of receiving an anthracycline for advanced disease, two received doses exceeding 400 mg/m2 of doxorubicin, one experienced relapse within 6 months of receiving an anthracycline for adjuvant therapy, and one patient did not meet the anthracycline-resistance criteria. Half of the responding patients had previously received 5-FU. Responding patients had measurable lesions located in the liver (n = 5), lung (n = 2), lymph nodes (n = 2), skin (n = 1), and breast (n = 1). The median duration of response for the eight patients who experienced a partial response was 20.1 weeks (95% CI, 12 to 26.7 weeks). The median duration of stable disease for the 20 patients who had stable disease as their best response was 23.8 weeks (95% CI, 20.3 to 47.1 weeks).
Progression-Free Survival and Overall Survival
Treatment and Dosing Data A total of 268 treatment courses (full and partial) were administered. The median number of courses administered to all 84 patients was two (range, 1.0 to 12.0 courses), and the median duration of treatment was 9.5 weeks (range, 0.4 to 60.4 weeks). Patient compliance for this oral dosing regimen was high, with 64 patients (76%) demonstrating 100% compliance. A total of 237 courses (88%) were completed with 100% compliance, and 257 courses (96%) were completed with  95% compliance. The median percentage of projected dose intensity for both eniluracil and 5-FU was also high (91.3% and 91.6%, respectively). Dose delays and dose reductions due to toxicity were infrequent. Of the 184 courses administered after course 1, 25 (14%) were delayed as a result of toxicity, and 26 (14%) required reductions of the prescribed dose as a result of toxicity. Toxicities that led to dose reductions were diarrhea (10 courses), granulocytopenia (six courses), thrombocytopenia (two courses), decreased estimated creatinine clearance (one course), mucositis (one course), hand-foot syndrome (one course), and other (not specified) toxicity (five courses).
Safety
The incidence of grade 3 and 4 hematologic toxicity was also low (Table 3). Grade 3 or 4 granulocytopenia and leukopenia were each observed in 5% of patients; grade 3 or 4 thrombocytopenia and anemia were observed in 4% and 1% of patients, respectively. Grade 3 or 4 clinical chemistry toxicities included hyperbilirubinemia (17% of patients) and elevated alkaline phosphatase (8%). Twelve of the 13 patients who experienced hyperbilirubinemia also had liver metastases.
Four patients (5%) experienced a total of seven serious adverse experiences that were considered to be reasonably attributable to study medication, as follows: dehydration (two patients), nausea, vomiting, weakness, diarrhea, and hepatic cirrhosis (one patient each). The cirrhosis was observed in a patient with liver metastases at the end of course 2, and the study drug was permanently discontinued after course 5. At the time the patient discontinued treatment, her two measurable liver lesions had decreased by 72% when compared with baseline. Three additional patients permanently discontinued eniluracil–5-FU treatment because of the following treatment-related adverse events: malaise/fatigue, nausea and vomiting, and abdominal cramping. There were no treatment-related deaths.
The study we report here has demonstrated that a 28-day regimen of orally administered eniluracil–5-FU has modest antitumor activity and is well tolerated by patients with anthracycline- and taxane-resistant advanced breast cancer. Ten percent of patients experienced a partial response, and 24% of patients maintained stable disease. The median duration of response was 20.1 weeks, and the median duration of progression-free survival was 9.9 weeks. The median duration of survival was 40.4 weeks (  9.3 months). A comparison of the results of this study to similar studies with other agents is difficult because the term resistance is often poorly defined and is frequently retrospectively applied to patient subgroups. At least four studies have been reported in which subsets of anthracycline-pretreated patients have been identified from a prospectively defined taxane-resistant patient population. The response rates for these studies ranged from 0% to 26.9%, and median survival times, for the two studies that reported it, were 10.5 and 12.8 months.21-24 The largest of these studies was a phase II trial of capecitabine, an orally administered 5-FU prodrug, which enrolled 162 patients with paclitaxel-resistant breast cancer, most of whom had also been previously treated with an anthracycline.21 The overall objective response rate in patients with measurable disease was 20% with a median survival time of 384 days (12.8 months).21 In a retrospectively defined subgroup of 42 patients who were also resistant to an anthracycline, the response rate was 29% and the median survival 255 days (approximately 8.4 months).3,21 The anthracycline- and taxane-resistant patients in the capecitabine study are most similar to the patients enrolled onto the present study. Although the response rate for eniluracil–5-FU was lower than that observed in the capecitabine study, the median duration of overall survival for the anthracycline- and taxane-resistant patients was higher in this study.3,21 Resistance was more stringently defined (ie, disease progression while the patient was receiving the drug) in the capecitabine study than in the present study; however, the anthracycline-resistant patients were retrospectively identified, whereas the current study enrolled patients with prospectively defined anthracycline- and taxane-resistant disease.21 In the current study, most treatment-related adverse events were mild to moderate in intensity. Grade 3 or 4 treatment-related diarrhea occurred in only 7% of patients in the current study. The overall incidence of hand-foot syndrome (2% of patients) was low. There were few patients who experienced grade 3 or 4 granulocytopenia (5% of patients) or thrombocytopenia (4%). Grade 3 or 4 hyperbilirubinemia occurred in 17% of the patients. Although the majority of these patients had liver metastases, a possible treatment-related effect cannot be ruled out. A similar incidence of grade 3 or 4 hyperbilirubinemia (10.5%) was also observed for capecitabine.21 The efficacy and safety results observed in the present study were similar to preliminary results for 35 patients enrolled onto a second phase II trial of a 28-day regimen of eniluracil–5-FU in anthracycline- and taxane-resistant breast cancer. The objective tumor response rate was 11%, with diarrhea being the most commonly reported toxicity (41% all grades; 8.6% grade 3 or 4).25 A second cohort of patients was added to that study to evaluate a higher dose of 5-FU (1.15 mg/m2), and the final results are pending. There was preliminary evidence during phase I evaluation of eniluracil–5-FU that the 5-FU minimum steady-state concentration may be related to antitumor activity.15 Because pharmacokinetic parameters of 5-FU are dose linear in this range, increasing the 5-FU dose may result in an increase in antitumor activity. A higher objective response rate (48%) has been reported for a 28-day regimen of eniluracil–5-FU in the first-line treatment of advanced breast cancer.20 The lower response rate observed in the present study is consistent with a more heavily treated patient population with stringently defined anthracycline- and taxane-resistant disease. Eniluracil–5-FU in anthracycline- and taxane-resistant breast cancer has modest antitumor activity and an acceptable safety profile. Treatment was convenient, and patient compliance was high. Strategies to improve the efficacy of this treatment in women with previously treated breast cancer could include raising the 5-FU dose and the use of eniluracil–5-FU in combination with other drugs, including paclitaxel and docetaxel.
Supported in part by GlaxoSmithKline, Research Triangle Park, NC.
Presented at the Fourteenth Chemotherapy Foundation Symposium, New York, NY, November 11-13, 1998; Twenty-Third Congress of the European Society for Medical Oncology, Athens, Greece, November 6-10, 1998; and Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
1. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics, 2000. CA Cancer J Clin 50: 7-33, 2000[Abstract] 2. Winer EP, Morrow M, Osborne CK, et al: Malignant tumors of the breast, in DeVita VT Jr, Hellman S, Rosenburg SA (eds): Cancer: Principles and Practice of Oncology ( ed 6 ). Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 1651-1717 3. Physicians’ Desk Reference Electronic Library [monograph online]: Xeloda (capecitabine) tablets (Roche Laboratories) prescribing information, revised March 1999. Montvale, NJ, Medical Economics Co Inc, 2000. Available at: http://www.pdrel.com. Accessed November 20, 2000 4. Myers CE: The pharmacology of the fluoropyrimidines. Pharmacol Rev 33: 1-15, 1981[Medline]
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Heggie GD, Sommadossi J-P, Cross DS, et al: Clinical pharmacokinetics of 5-fluorouracil and its metabolites in plasma, urine, and bile. Cancer Res 47: 2203-2206, 1987 6. Cohen JL, Irwin LE, Marshall GJ, et al: Clinical pharmacology of oral and intravenous 5-fluorouracil (NSC-19893). Cancer Chemother Rep 58: 723-731, 1974[Medline] 7. Christophidis N, Vajda FJE, Lucas I, et al: Fluorouracil therapy in patients with carcinoma of the large bowel: A pharmacokinetic comparison of various rates and routes of administration. Clin Pharmacokinet 3: 330-336, 1978[Medline] 8. Almersjö OE, Gustavsson BG, Regårdh C-G, et al: Pharmacokinetic studies of 5-fluorouracil after oral and intravenous administration in man. Acta Pharmacol Toxicol 46: 329-336, 1980[Medline] 9. Jabboury K, Holmes FA, Hortobagyi G: 5-Fluorouracil rechallenge by protracted infusion in refractory breast cancer. Cancer 64: 793-797, 1989[CrossRef][Medline] 10. Huan S, Pazdur R, Singhakowinta A, et al: Low-dose continuous infusion 5-fluorouracil: Evaluation in advanced breast carcinoma. Cancer 63: 419-422, 1989[CrossRef][Medline] 11. Hansen R, Quebbeman E, Beatty P, et al: Continuous 5-fluorouracil infusion in refractory carcinoma of the breast. Breast Cancer Res Treat 10: 145-149, 1987[CrossRef][Medline] 12. Crivellari D, Magri MD, Buonadonna A, et al: Continuous infusion fluorouracil in the management of advanced breast cancer: A phase II study. Tumori 86: 42-45, 2000[Medline]
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Baccanari DP, Davis ST, Knick VC, et al: 5-Ethynyluracil (776C85): A potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Proc Natl Acad Sci U S A 90: 11064-11068, 1993 14. Spector T, Harrington JA, Porter DJT: 5-Ethynyluracil (776C85): Inactivation of dihydropyrimidine dehydrogenase in vivo. Biochem Pharmacol 46: 2243-2248, 1993[CrossRef][Medline]
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Baker SD, Diasio RB, O’Reilly S, et al: Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil. J Clin Oncol 18: 915-926, 2000
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Harris BE, Song R, Soong SJ, et al: Relationship between dihydropyrimidine dehydrogenase activity and plasma 5-fluorouracil levels with evidence for circadian variation of enzyme activity and plasma drug levels in cancer patients receiving 5-fluorouracil by protracted continuous infusion. Cancer Res 50: 197-201, 1990 17. Grem JL: 5-Fluoropyrimidines, in Chabner BA, Longo DL (eds): Cancer Chemotherapy and Biotherapy: Principles and Practice ( ed 2 ). Philadelphia, PA, Lippincott Raven, 1996, pp 149-217 18. Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10: 239-253, 1992[CrossRef][Medline] 19. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16: 31-41, 1976[Medline]
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Smith IE, Johnston SRD, O’Brien MER, et al: Low-dose oral fluorouracil with eniluracil as first-line chemotherapy against advanced breast cancer: A phase II study. J Clin Oncol 18: 2378-2384, 2000
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Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17: 485-493, 1999 22. Valero V, Jones SE, Von Hoff DD, et al: A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer. J Clin Oncol 16: 3362-3368, 1998[Abstract]
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Seidman AD, Hochhauser D, Gollub M, et al: Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: A phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J Clin Oncol 14: 1877-1884, 1996 24. Fazeny B, Zifko U, Meryn S, et al: Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxel: A phase II study. Cancer Chemother Pharmacol 39: 150-156, 1996[CrossRef][Medline] 25. Burris HA, Ravdin P, Gutheil J, et al: Eniluracil/5-FU in anthracycline and taxane refractory breast cancer. Proc Am Soc Clin Oncol 18: 107a, 1999 (abstr 405) Submitted April 11, 2001; accepted October 12, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1.25 times the upper limit of normal, and ALT 
