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Randomized, Open-Label, Phase III Study of a 28-Day Oral Regimen of Eniluracil Plus Fluorouracil Versus Intravenous Fluorouracil Plus Leucovorin as First-Line Therapy in Patients With Metastatic/Advanced Colorectal Cancer

From the University of Chicago, Chicago, IL; GlaxoSmithKline, Research Triangle Park, NC; Response Oncology, Inc, Memphis, TN; Tom Baker Cancer Centre, Calgary, Alberta, Nova Scotia Cancer Center, Halifax, Nova Scotia, and Montreal General Hospital, Montreal, Ontario, Canada; Michiana Hematology-Oncology, South Bend, IN; and University of Texas, M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Richard L. Schilsky, MD, Biological Sciences Division, The University of Chicago, 5841 S. Maryland Ave, Chicago, IL 60637-1463.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To compare the efficacy and tolerability of eniluracil (EU)/fluorouracil (5-FU) with that of 5-FU/leucovorin (LV) as first-line therapy for patients with metastatic/advanced colorectal cancer.

PATIENTS AND METHODS: This multicenter, randomized, open-label, phase III study (FUMA3008) conducted in the United States and Canada compared the safety and efficacy of EU/5-FU (11.5 mg/m²/1.15 mg/m² twice daily for 28 days every 35 days) with that of intravenous 5-FU/LV (425 mg/m²/20 mg/m² once daily for 5 days every 28 days) in patients with previously untreated metastatic colorectal cancer. Overall survival (OS) was the primary end point.

RESULTS: A total of 981 patients were randomized and 964 patients received treatment (485 EU/5FU, 479 5FU/LV). Survival for EU/5-FU was not statistically equivalent (but not statistically inferior) to that for 5-FU/LV (hazard ratio, 0.880; 95% confidence interval [CI], 0.75 to 1.03). Median duration of survival was 13.3 months in the EU/5-FU group and 14.5 months in the 5-FU/LV group. Median duration of progression-free survival for EU/5-FU was statistically inferior to that of the control group (20.0 weeks [95% CI, 19.1 to 20.9 weeks] v 22.7 weeks [95% CI, 18.3 to 24.6 weeks]; P = .01). Both treatments were well tolerated. Diarrhea was the most common nonhematologic toxicity in both groups; treatment-related grade 3 or 4 diarrhea occurred in 19% of patients treated with EU/5-FU and 16% of patients receiving 5-FU/LV (P = .354). Grade 3 or 4 granulocytopenia occurred in 5% of EU/5-FU patients and 47% of 5-FU/LV patients.

CONCLUSION: Safety profiles of both treatments were acceptable. Although antitumor activity was observed, EU/5-FU did not meet the protocol-specified statistical criteria for equivalence to 5-FU/LV in terms of OS.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
FOR THE PAST 40 YEARS, fluorouracil (5-FU) has been the primary systemic therapy for patients with colorectal cancer. Over 100,000 patients in the United States receive this treatment for colorectal cancer each year in the adjuvant or advanced disease setting, and it remains the chemotherapy agent most frequently administered to patients with this disease.¹ Strategies to improve the efficacy of 5-FU have been based on biochemical modulation and prolonged-infusion schedules. These efforts have led to increased response rates, especially for 5-FU/leucovorin (LV) and continuous-infusion 5-FU, but the impact on patient survival has been minimal.^2-4 At the time this study was initiated, the Mayo Clinic regimen (intravenous [IV] 5-FU/LV administered daily for 5 consecutive days every 4 or 5 weeks) and the Roswell Park regimen (IV 5-FU administered weekly with LV) were standards of care in the United States for patients with previously untreated advanced colorectal cancer (ACC).^5,6

More recently, irinotecan, in combination with 5-FU/LV, was approved by the United States Food and Drug Administration as first-line therapy for ACC, and oxaliplatin was approved for this indication in Europe. It has yet to be determined whether sequential or combination therapy with these agents is more beneficial. Despite the availability of these new therapeutic options, 5-FU remains the agent invariably given to patients with newly diagnosed ACC. Thus, an oral 5-FU preparation that preserves efficacy or reduces toxicity would be useful to clinicians for treatment of patients with ACC.

Dihydropyrimidine dehydrogenase (DPD) is the principal and rate-limiting enzyme in the 5-FU catabolic pathway.⁷ Eniluracil (EU; ethynyluracil) is a potent and highly effective inactivator of DPD which acts by covalently binding to the active site of the enzyme.^8,9 In preclinical studies, doses of EU sufficient to inactivate more than 99% of endogenous DPD were nontoxic and exhibited no antiproliferative activity.^10-12 In humans, EU changes the elimination of 5-FU from primarily catabolism (50% to 80%) to renal excretion (30% to 80%).¹³ Administration of EU in combination with 5-FU significantly increases the oral bioavailability, decreases the clearance, and reduces the pharmacokinetic variability of 5-FU.¹⁴

Phase I studies have been conducted using a 5-day regimen and a 28-day regimen of EU/5-FU.^14,15 The latter was selected for further evaluation because the 5-day regimen produced similar efficacy but substantially more hematologic toxicity.¹⁶ In a multicenter phase II study conducted in 55 patients with previously untreated ACC, EU/5-FU doses of 10.0 mg/m²/1.0 mg/m² and 11.15 mg/m²/1.15 mg/m² given daily for 28 days were investigated.¹⁷ The 11.15 mg/m²/1.15 mg/m² EU/5-FU dose was determined to best meet the desired efficacy and safety profiles for the patient population and was, therefore, selected for comparison to a standard regimen in a randomized clinical trial.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Study Design and Entry Criteria
This was a randomized, multicenter, open-label, phase III trial comparing oral EU/5-FU to IV 5-FU/LV as first-line treatment for patients with ACC. The study (FUMA3008) was conducted in centers across the United States and Canada.

Eligible patients were required to have a Karnofsky performance status 70, no prior chemotherapy for advanced disease, and no adjuvant therapy in the12 months before the first dose of study drug. Patients were 18 years of age with a histologically confirmed diagnosis of colorectal cancer which was metastatic or advanced disease that was not amenable to curative surgery. Patients were required to have measurable and/or assessable disease assessed within 2 weeks before the first dose of study drug. All patients provided written informed consent, and the study was approved by the ethics committees or institutional review boards of all participating centers.

Stratification, Randomization, and Therapy
Patients were stratified according to the following criteria: assessable versus measurable disease, sites of metastasis (liver only v other), prior adjuvant therapy (yes or no), and baseline Karnofsky performance status (70 to 80 v 90 to 100). Patients randomized to the EU/5-FU treatment arm received 5-week courses starting at a dose of 11.5 mg/m² EU and 1.15 mg/m² 5-FU (a 10:1 ratio of EU:5-FU). Each 5-week course consisted of 28 days of treatment with EU/5-FU administered orally twice daily followed by a 7-day period during which no drug was taken. EU/5-FU was supplied to study sites by Glaxo Wellcome Inc (Research Triangle Park, NC) as 10-mg/1.0-mg and 2.5-mg/0.25-mg combination tablets in patient-specific blister cards; each card contained drug supply for 1 week. Patients randomized to the 5-FU/LV treatment arm received 20 mg/m² LV immediately followed by 425 mg/m² IV 5-FU once daily for the first 5 days of each 28-day cycle. LV and 5-FU for injection were obtained commercially in 15-mg and 250-mg/5-mL vials, respectively.

Drug dosage was modified in both treatment arms based on the intensity of adverse events that occurred in the preceding course. Toxicity was graded according to criteria adapted from the Southwest Oncology Group.¹⁸ Patients randomized to the EU/5-FU arm were instructed to discontinue drug immediately if grade 2 or greater drug-related granulocytopenia, thrombocytopenia, diarrhea, mucositis, or hand-foot syndrome occurred. Patients were permitted to receive full supportive care during the trial, including transfusion of blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals and analgesics when appropriate.

At the beginning of this study, patients on the EU/5-FU arm were not permitted to receive subsequent therapy with other fluoropyrimidines within 28 days of their final dose of EU/5-FU, in order to allow sufficient time for regeneration of DPD activity. During the course of this study, the mandatory waiting period was increased to 56 days due to reports of serious toxicity in patients on other EU studies who received other fluoropyrimidines at 29 to 32 days after their last dose of EU/5-FU.

Efficacy and Tolerability Assessments
Efficacy assessments were performed at baseline and repeated at the beginning of course 3 and every other course thereafter until discontinuation of treatment. Response and progression were determined for each patient based on investigator-reported disease measurements using criteria established by the Southwest Oncology Group.¹⁸ A confirmed objective response required two consecutive assessments performed at least 4 weeks apart.

Patients continued treatment until one of the following occurred: disease progression, unacceptable toxicity, or withdrawal of consent by the patient. At the end of study treatment, all patients were followed quarterly for survival.

Safety and tolerability assessments included the following: adverse events, clinical laboratory data (hematology, clinical chemistry, and urinalysis), prothrombin time and/or international normalized ratio measurements for patients receiving coumarin, and physical examinations.

Statistical Analysis
Efficacy and safety were summarized for all patients who received at least one dose of study drug. The primary end point was duration of overall survival (OS), defined as the time from randomization to the date of death due to any cause. If a patient had not died, duration of survival was censored on the date of last contact.

The planned sample size of 944 patients (472 per treatment arm) was sufficient to detect a 25% improvement in median OS (from 12 months to 15 months) with 80% power at alpha = 0.05. This sample size also provided 80% power to demonstrate that the median survival for the EU/5-FU treatment group was at least 80% that of the 5-FU/LV group (9.6 months v 12 months), assuming that either treatment would produce equal survival (12.0-month median). Two-sided 95% confidence intervals (CIs) around the hazard ratio were used to evaluate treatment effects.¹⁹

The primary analysis of OS was planned after 631 events were documented and utilized a stratified Cox proportional hazards model with treatment as the only covariate. The two-sided 95% CI around the hazard ratio (5-FU/LV:EU/5-FU) was used to compare the treatment groups. A lower limit of the 95% CI exceeding 0.80 would indicate equivalence demonstrating EU/5-FU was at least 80% as effective as 5-FU/LV. Secondary efficacy end points included response rate, duration of progression-free survival (PFS), and duration of response. The primary method of analysis for these end points utilized a stratified Cox proportional hazards model. All time-to-event end points were also summarized utilizing Kaplan-Meier product-limit estimates.²⁰ PFS was defined as the time from randomization until the first observation of disease progression or death due to any cause, while duration of response was calculated as the time from first tumor response to the first observation of progression or death due to any cause. Tumor response rates (including 95% CIs) were calculated as the proportion of patients who experienced a complete or partial response. Fisher’s exact test was used to detect differences in response rates between the treatment groups.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Characteristics
A total of 964 patients from 136 centers across North America were enrolled and treated between October 1997 and May 1999 (EU/5-FU, n = 485; 5-FU/LV, n = 479). The groups were well balanced with respect to demographic and prognostic characteristics (Table 1). Most patients received subsequent anticancer therapy after study treatment failed. The most commonly administered subsequent therapies are shown in Table 2.

View larger version (9K): [in this window] [in a new window]   Fig 1. Duration of survival: Kaplan-Meier survival estimates.

Dosing
Of the 981 randomized patients, 17 patients did not receive study medication (three patients in the EU/5-FU group and 14 patients in the 5-FU/LV group). Median weeks on treatment was 19.0 (range, 0.1 to 112 weeks) for the EU/5-FU arm and 15.7 weeks (range, 0.3 to 110 weeks) for the 5-FU/LV arm. Median number of courses was four on both treatment arms, with a range of 1.0 to 22.0 on the EU/5-FU arm and 1.0 to 28 on the 5-FU/LV arm.

Eighty-four percent of patients treated with EU/5-FU were 100% compliant with dosing, as compared with 97% of patients receiving 5-FU/LV. Median percentage of projected dose-intensity was 91.6% for the EU/5-FU arm and 87.2% for the 5-FU/LV arm. Therefore, compliance as measured by percent dose-intensity was higher on the EU/5-FU arm due in part to the large number of dose reductions after course 1 on the 5-FU/LV arm.

Dose reductions between the first and second courses were more prevalent on the 5-FU/LV arm (46%) than on the EU/5-FU arm (24%). Later courses were more comparable.

Tolerability
All patients who received at least one dose of therapy were included in the safety analysis. Granulocytopenia of any grade and severe (grade 3 or 4) granulocytopenia were observed more frequently on the 5-FU/LV arm than on the EU/5-FU arm (Table 5). A higher incidence of febrile neutropenia was also observed on the 5-FU/LV arm (P < .001). The frequency and severity of thrombocytopenia and anemia were similar on both study arms. Six patients on the EU/5-FU arm (1%) and only one patient on the 5-FU/LV arm (< 1%) received platelet transfusions. Thirty-three EU/5-FU patients (7%) and 43 5-FU/LV patients (9%) received RBC transfusions.

The deaths of four EU/5-FU patients (0.8%) and nine 5-FU/LV patients (2%) who died during the treatment period were considered by the investigator to be possibly related to study drug. On the EU/5-FU arm, two of the deaths were due to diarrhea/sepsis, one was due to vomiting/sepsis, and one was due to exacerbation of chronic obstructive pulmonary disease. In addition, two patients enrolled onto the experimental arm died due to mucositis, diarrhea, dehydration, and sepsis after therapy with 5-FU and LV that was administered beginning 13 and 14 days after their last dose of EU/5-FU, in violation of the protocol’s mandatory waiting period. In the patients randomized to 5-FU/LV, seven deaths were due to treatment-related mucositis, diarrhea, sepsis, and small bowel obstruction. Myocardial infarction and pulmonary embolism were each the cause of one treatment-related death on the control arm.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Continuous-infusion 5-FU offers theoretical advantages over bolus administration of 5-FU and has therefore been investigated in a variety of solid tumors. A meta-analysis of studies that included continuous-infusion 5-FU therapy in patients with ACC concluded that it achieves a slight increase in survival compared with bolus administration, with less hematologic toxicity but increased hand-foot syndrome.²¹ With the advent of oral fluoropyrimidines (capecitabine, uracil and tegafur, and EU/5-FU), efforts have focused on simulation of continuous-infusion 5-FU with oral drugs that eliminate the need for central catheters and pumps.

This study was designed to demonstrate that oral therapy with EU/5-FU results in OS that is at least equivalent to that produced by 5-FU/LV in patients with previously untreated ACC. The population enrolled onto this study was a good representation of the general population of patients with ACC who receive chemotherapy, and the stratification factors were well balanced between the two treatment arms.

The results clearly indicate that both treatments have activity in ACC, but EU/5-FU did not meet the protocol-specified definition of equivalence to 5-FU/LV. For each of the end points investigated, 5-FU/LV was slightly more efficacious than EU/5FU, and it was statistically superior for PFS. The long survival observed in patients on the control arm (median, 14.5 months) is one possible explanation of why this study did not meet the protocol objective. The survival results observed for 5-FU/LV were superior to those reported in most other studies using this therapy.

This was one of two randomized multicenter trials of similar design that compared the efficacy of EU/5-FU and 5-FU/LV in this patient population. The other study (FUMB 3002), performed in 531 patients outside of North America, enrolled patients primarily in Western Europe and Australia/New Zealand.²² Although OS was not the primary end point of that study, the patients who received EU/5-FU demonstrated statistically inferior OS to that of patients treated with 5-FU/LV. Median survival on that study was 10.9 months for patients randomized to EU/5-FU and 14.7 months for patients who received 5-FU/LV. It is only possible to speculate on the reason for the disparity in the results of the two EU/5-FU studies. The survival results observed in patients on the control arms of the two studies were almost identical, and the patient populations were very similar with respect to performance status and other prognostic factors. Notably, the frequency of diarrhea on the experimental arm of the other study was much lower (34% overall, 7% grade 3 or 4) than the frequency of diarrhea reported here, possibly due to differences in reporting practices. Another possible explanation is a difference in patient compliance with the oral regimen on the two studies. In the study reported here, EU/5-FU was dispensed in blister packs, with each dose contained in a separate blister; on the European study, oral drug was dispensed in bottles. It is possible that the blister packs led to greater compliance as well as increased frequency of adverse events and greater efficacy. Our conclusion is that patients receiving oral chemotherapy agents, especially those that require frequent or extended dosing periods, must be followed closely by their physician to ensure compliance with the prescribed regimen.

During the period of this study, second-line therapy with irinotecan was reported to prolong survival in ACC patients who had progressed on 5-FU–based therapy, and irinotecan thus became more commonly administered to these patients. After completion of accrual on this study, the combination of irinotecan/5-FU/LV was reported by Saltz et al²³ to be superior to the Mayo Clinic regimen. However, it is unlikely that second-line therapy with irinotecan had a major impact on the results of this study, since approximately equal numbers of patients on each treatment arm received irinotecan after disease progression.

In the past 2 years, the results of six phase III studies have been reported that compare orally administered fluoropyrimidines, given on schedules similar to the one used here, to 5-FU/LV as first-line therapy for patients with ACC.^22,24-27 The goal of the experimental arm in each of these studies was to demonstrate noninferiority to 5-FU/LV. In addition, the study by Saltz et al²³ used 5-FU/LV as the control therapy. A total of 4,581 patients were treated on these studies, and selected results from each are shown in Table 7. All of these studies have shown median survival times on the control arms in excess of 1 year, with the exception of the study performed by Carmichael et al,²⁵ which used a less dose-intensive version of the Mayo Clinic regimen. Each of the studies performed with the oral fluoropyrimidines produced similar survival results, with median survival times also in excess of 1 year, with the exception of FUMB 3002. Although the oral fluoropyrimidines may offer the convenience of oral therapy and possibly improved safety profiles, they have not demonstrated survival that is superior to the Mayo Clinic regimen. In contrast, treatment with irinotecan/5-FU/LV produced improved PFS and OS. As a result, that therapy is now considered by many to be the preferred first-line therapy for patients with ACC. Recently, capecitabine was approved by the Food and Drug Administration as first-line therapy for patients with ACC when fluoropyrimidine therapy alone is preferred. A question that remains to be answered is whether the oral fluoropyrimidines can be combined with irinotecan as first-line therapy with results at least equivalent to those achieved with irinotecan/IV 5-FU/LV.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

	NOTES

 
The views expressed herein are the result of independent work and are not the opinion of the Food and Drug Administration.)

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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11. 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[Abstract/Free Full Text]

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13. Khor SP, Lucas S, Hsieh AY, et al: 776C85: Effect on renal elimination of 5-fluorouracil and uracil in cancer patients. Proc Am Assoc Cancer Res 37: 371, 1996 (abstr)

14. Baker SD, Diasio R, O’Reilly S, et al: Phase I and pharmacologic study of oral 5-fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase (DPD) inactivator eniluracil. J Clin Oncol 18: 915-926, 2000[Abstract/Free Full Text]

15. Schilsky RL, Hohneker J, Ratain MJ, et al: Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer. J Clin Oncol 16: 1450-1457, 1998[Abstract/Free Full Text]

16. Schilsky RL, Bukowski R, Burris H, et al: A multicenter phase II study of a five-day regimen of oral 5-fluorouracil plus eniluracil with or without leucovorin in patients with metastatic colorectal cancer. Ann Oncol 11: 415-420, 2000[Abstract/Free Full Text]

17. Mani S, Hochster H, Beck T, et al: Multicenter phase II study to evaluate a 28-day regimen of oral fluorouracil plus eniluracil in the treatment of patients with previously untreated metastatic colorectal cancer. J Clin Oncol 18: 2894-2901, 2000[Abstract/Free Full Text]

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24. Pazdur R, Douillard J-Y, Skillings JR, et al: Multicenter phase III study of 5-fluorouracil (5-FU) or UFT in combination with leucovorin (LV) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 18: 263a, 1999 (abstr 1009)

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Submitted July 16, 2001; accepted November 19, 2001.

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