A dose-escalating study of oral eniluracil/5-fluorouracil plus oxaliplatin in patients with advanced gastrointestinal malignancies

D. Yip1, C. Karapetis1, A. H. Strickland1, C. Steer1, C. Holford2, S. Knight2,+ and P. Harper1

1 Department of Medical Oncology, Guys Hospital, London; 2 Glaxo Wellcome Research and Development, Greenford, Middlesex, UK,§

Received 19 August 2002; revised 8 January 2003; accepted 22 January 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Oral eniluracil/5-fluorouracil (5-FU) was shown in early clinical studies to have promising activity against gastrointestinal malignancies. Oxaliplatin in combination with 5-FU also has activity against these tumour types. The primary objective of this study was to determine a tolerable dose for oral eniluracil/5-FU in combination with oxaliplatin.

Patients and methods:

Twenty-three patients with advanced gastrointestinal malignancies were recruited into this open-label study. Patients received a fixed dose of oxaliplatin (130 mg/m2 on the first day of a 21-day cycle), and the dose intensity of oral eniluracil/5-FU was gradually increased by escalating the number of days of treatment per course.

Results:

The maximum tolerated dose intensity was eniluracil/5-FU 10.0/1.0 mg/m2 twice daily for 16 days in combination with oxaliplatin 130 mg/m2 on the first day of a 21-day cycle. Dose-limiting toxicities included vomiting and diarrhoea. The objective tumour response rate was 26% with a median duration of response of 15.3 weeks (95% confidence interval 8.5–22.1). Twenty-two patients (96%) experienced neurotoxicity (sensory neuropathy or cold-related dysaesthesia), although only two events were severe (grade 3).

Conclusions:

The recommended dose for future study in patients with advanced gastrointestinal cancer is 10.0/1.0 mg/m2 oral eniluracil/5-FU twice daily for 14 days in combination with oxaliplatin 130 mg/m2 on the first day of each treatment cycle.

Key words: eniluracil, 5-fluorouracil, gastrointestinal cancer, maximum tolerated dose intensity, oxaliplatin


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Gastrointestinal malignancies include colorectal, gastric, pancreatic and oesophageal cancers, the majority of which are currently treated with systemic chemotherapy. Until recently it was felt that non-surgical therapies were of little value for treating advanced gastrointestinal cancer. However, the emergence of more effective chemotherapy for metastatic disease has led to new treatment options being pursued [1].

Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase, the first enzyme in the catabolism of 5-fluorouracil (5-FU) [2]. Eniluracil enables low oral doses of 5-FU to be administered, resulting in predictable plasma concentrations comparable with those reported for continuous intravenous infusion of 5-FU [3, 4]. Oral eniluracil/5-FU was shown in early clinical studies to have encouraging efficacy against colorectal and pancreatic cancer [5, 6]. Oxaliplatin is a third-generation cisplatin analogue with demonstrated activity in a wide variety of tumour types. Oxaliplatin in combination with 5-FU has significant activity against advanced colorectal cancer [7] as well as in metastatic gastric cancer [8]. Cisplatin in combination with infusional 5-FU has demonstrated efficacy against pancreatic cancer [9, 10]. Therefore, it was hypothesised that a combination of oral eniluracil/5-FU and oxaliplatin would have activity in the treatment of patients with advanced gastrointestinal cancer.

The primary objective of this study was to determine a tolerable dose for oral eniluracil/5-FU in a 21-day cycle in combination with oxaliplatin in patients with advanced gastrointestinal cancer. Secondary objectives were to estimate the objective tumour response rate, the durations of response and of progression-free survival, and to evaluate the toxicity profile of this regimen.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Patients were eligible for inclusion in this study (protocol number FUMB4002) if they were at least 18 years old and had a histologically or cytologically confirmed diagnosis of advanced gastrointestinal malignancy that was not amenable to curative surgery or radiation, with at least one measurable lesion. Patients had to have a Karnofsky performance status (KPS) score ≥70 and a life expectancy of at least 12 weeks. Patients who had received prior radiotherapy were eligible, providing measurable disease existed outside any previously irradiated site. Patients were excluded if they had received treatment with cytotoxic chemotherapy or a biological agent within the previous 4 weeks, or had received flucytosine or any investigational drug in the previous 2 weeks. Patients had to have adequate bone marrow, renal and hepatic function. Patients with pre-existing severe motor or sensory neuropathies or known allergies to platinum compounds were considered ineligible. All patients provided written informed consent before participating in the study.

Study design
The study protocol was approved by the Guy’s Hospital Ethics Committee and the study was conducted according to the Declaration of Helsinki. This was an open-label, cohort-design, single-centre study of escalating doses of oral eniluracil/5-FU in combination with a fixed dose and regimen of oxaliplatin (130 mg/m2 on the first day of every 21 days) (supplied by Sanofi Synthelabo). The dose intensity of eniluracil/5-FU was gradually increased by cohort depending on the toxicities observed. Each treatment course was repeated every 21 days. Treatment continued up to a maximum of eight cycles, or until disease progression or unmanageable toxicity. Patients were recruited in cohorts of three. A cohort was expanded to six if dose-limiting toxicity was observed. If no dose-limiting toxicity was observed when three patients had completed two courses, enrolment into the next cohort was started. The maximum tolerated dose intensity (MTDI) was defined as the highest daily dose (given for two courses) at which at least two out of six patients experienced dose-limiting toxicity. Patients who did not complete the first two cycles of treatment were not evaluable for the determination of MTDI.

Dose-limiting toxicity was defined as any of the following: grade ≥3 mucositis; grade 3 palmar–plantar erythrodysaesthesia; grade 3/4 other non-haematological toxicity; grade 4 haematological toxicity; unresolved non-haematological toxicity that resulted in a delay of the subsequent course of chemotherapy >7 days; haematological toxicity that resulted in a delay of the subsequent course of chemotherapy >7 days. Toxicity was graded using criteria adapted from the South West Oncology Group (SWOG) [11].

Patients were assessed at regular intervals by clinical, laboratory and radiological methods to determine their tumour response, as well as the durations of response, survival, and progression-free survival. The tumour response criteria and definitions of measurable, evaluable and non-evaluable disease were adapted from those established by the SWOG [11]. Patients who had a complete response or a partial response had a confirmatory disease assessment at least 4 weeks later. Time-to-event parameters were analysed using Kaplan–Meier product limit estimates. Safety assessments included monitoring adverse events, clinical chemistry and haematology parameters.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Twenty-three patients were recruited into this study. The median age was 64 years (range 33–80), 14 patients were male and nine female. Twenty patients had colorectal primary tumours, the remaining three had gastro-oesophageal primary tumours. Twenty patients had a baseline KPS of 100 or 90, one patient had a baseline KPS of 80, and two had a baseline KPS of 70. Sixteen patients (69.6%) received protocol therapy as second-line treatment (excluding prior adjuvant therapy), five as third-line, one as fourth-line and one as fifth-line.

The dose-limiting toxicities seen in each cohort of patients are shown in Table 1. Based on early toxicity from the first cohort (eniluracil/5-FU 11.5/1.15 mg/m2 twice daily), the dose of eniluracil/5-FU was reduced to 10.0/1.0 mg/m2 twice daily. The highest dose intensity studied was eniluracil/5-FU 10.0/1.0 mg/m2 for 16 days in a 21-day cycle. One patient in this cohort died of disease progression after only one cycle, and another was considered non-compliant as he took only 50% of his tablets (not due to toxicity). Consequently, there was only one evaluable patient in this cohort. This patient experienced such severe gastrointestinal toxicity that it was not considered justified to expand the cohort to replace the two unevaluable patients. Therefore, the MTDI for this study was eniluracil/5-FU 10.0/1.0 mg/m2 twice daily for 16 days in combination with oxaliplatin 130 mg/m2 on the first day of a 21-day cycle.


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Table 1. Dose-limiting toxicities per cohort
 
Twenty-two of the 23 patients experienced some form of neurotoxicity (cold-related dysaethesia, paraesthesia, etc.), although only two of these events were severe (grade 3 numbness in feet, and cold-related neuropathy in feet). In addition to the dose-limiting haematological toxicities shown in Table 1, grade 3 anaemia occurred in two patients, three patients had grade 3 thrombocytopenia and one patient had grade 3 neutropenia. Other grade 3/4 toxicities which occurred in >5% of patients and which were not dose-limiting (due to onset after first two courses) were: grade 3 diarrhoea in three patients, grade 4 vomiting in one patient, grade 3 abdominal pain in two patients. Grade 3/4 toxicities occurring in >5% patients are shown in Table 2.


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Table 2. Grade 3/4 toxicities occurring in >5% patients
 
The objective tumour response rate was 26% [six partial responses in 23 patients, including two patients who died (due to disease progression) before a second disease assessment could be performed]. The median duration of response was 15.3 weeks [95% confidence interval (CI) 8.5–22.1], the median progression-free survival was 21.0 weeks (95% CI 9.9–32.1) and the median duration of survival was 33.4 weeks (95% CI 26.5–40.3).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The dose-limiting toxicities of two different regimens of oral eniluracil/5-FU were previously established in patients with advanced cancer [12]. Using a protracted 28-day regimen of oral eniluracil/5-FU (repeated every 35 days) the MTDI of 5-FU was 1.8 mg/m2 with diarrhoea as the dose-limiting toxicity [4]. The dose-limiting diarrhoea seen in our study is a characteristic of treatment with continuous infusion of 5-FU alone. The neurotoxicity seen in our study is characteristic of treatment with oxaliplatin [13].

Eniluracil/5-FU has been studied in two large randomised phase III studies for the first-line treatment of patients with advanced colorectal cancer, comparing eniluracil/5-FU (11.5 mg/m2/1.15 mg/m2 twice daily for 28 days every 35 days) with intravenous 5-FU/leucovorin [14, 15]. In the European study [14], response rates were similar across both treatment arms, although the 5-FU/leucovorin arm was associated with an improved survival benefit. However, compliance with the oral eniluracil/5-FU regimen and the unusually high median survival associated with the intravenous 5-FU/leucovorin control arm may have been confounding factors. In the USA study [15], both treatment arms were similar in terms of response rates and overall survival. These results limit the opportunity to develop eniluracil/5-FU in patients with advanced colorectal cancer.

In the current study we showed that the MTDI was eniluracil/5-FU 10.0/1.0 mg/m2 twice daily for 16 days in combination with oxaliplatin 130 mg/m2 on the first day of a 21-day cycle. The recommended dose of eniluracil/5-FU with oxaliplatin in patients with advanced gastrointestinal malignancy is therefore 14 days at the same doses.

The regimen of oral eniluracil/5-FU used in this study in combination with a recommended dose of oxaliplatin demonstrated anti-tumour activity in a heavily pre-treated group of patients with colorectal and gastro-oesophageal malignancy.


    Acknowledgements
 
We thank D. Harrison for writing and editing assistance during preparation of the manuscript. Preliminary results of this study were reported at the 10th Congress on Anti-Cancer Treatment, Paris, 30–31 January 2000 and the Clinical Oncological Society of Australia Annual Scientific Meeting, Adelaide, 29–30 November 2000, and final results in abstract form at the American Society for Clinical Oncology Annual Meeting, San Francisco, 12–15 May 2001.


    Footnotes
 
+ Correspondence to: Dr S. Knight, GlaxoSmithKline, Greenford Road, Greenford, Middlesex UB6 0HE, UK. Tel: +44-20-8966-2367; Fax: +44-20-8966-2030; E-mail: sidonie.x.knight{at}gsk.com Back

§ Now GlaxoSmithKline. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Waters J, Cunningham D. The changing face of chemotherapy in colorectal cancer. Br J Cancer 2001; 84: 1–7.

2. Spector T, Harrington JA, Porter DJT. 5-Ethynyluracil (776C85): inactivation of dihydropyrimidine dehydrogenase in vivo. Biochem Pharmacol 1993; 46: 2243–2248.[CrossRef][ISI][Medline]

3. Baker SD, Khor SP, Adjei AA et al. Pharmacokinetic, oral bioavailability and safety study of fluorouracil in patients treatment with 776C85, an inactivator of dihydropyrimidine dehydrogenase. J Clin Oncol 1996; 14: 3085–3096.[Abstract]

4. 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 2000; 18: 915–926.[Abstract/Free Full Text]

5. 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 2000; 18: 2894–2901.[Abstract/Free Full Text]

6. Wilking N, Glimelius B, Schueller J et al. Promising early results of oral 5-fluorouracil plus eniluracil (776C85) in patients with advanced adenocarcinoma of the pancreas. Ann Oncol 1998; 9: 46–47.

7. Bleiberg H, DeGramont A. Oxaliplatin plus 5-fluorouracil: clinical experience in patients with advanced colorectal cancer. Semin Oncol 1998; 25: 32–39.

8. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938–2947.[Abstract/Free Full Text]

9. Louvet C, Andre T, Tiguad J et al. Phase II trial of oxaliplatin (OXA) in combination with 5-FU and folinic acid (FA)—FOLFOX6 regime—as first-line treatment for advanced or metastatic gastric cancer (A/MGC) patients. Proc Am Soc Clin Oncol 2000; 19: 265a (Abstr 1031).

10. Evans TRJ, Lofts FJ, Mansi JL. A phase II study of continuous infusion 5-fluorouracil with cisplatin plus epirubicin in operable pancreatic cancer. Br J Cancer 1996; 73: 1260–1264.[ISI][Medline]

11. Green S, Weiss GR. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 1992; 10: 239–253.[ISI][Medline]

12. 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 1998; 16: 1450–1457.[Abstract]

13. Cvitkovic E, Bekradda M. Oxaliplatin: a new therapeutic option in colorectal cancer. Semin Oncol 1999; 26: 647–662.[ISI][Medline]

14. van Cutsem E, Sorensen J, Cassidy J et al. International phase III study of oral eniluracil (EU) plus 5-fluorouracil (5-FU) versus intravenous (IV) 5-FU plus leucovorin (LV) in the treatment of advanced colorectal cancer (ACC). Proc Am Soc Clin Oncol 2001; 20: 131a (Abstr 522).

15. Schilsky R, Levin J, West W et al. 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. J Clin Oncol 2002; 20: 1519–1526.[Abstract/Free Full Text]





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