A phase I study of oral uracil–ftorafur plus folinic acid in combination with weekly paclitaxel in patients with solid tumors

F. Mayer1, J. T. Hartmann1, J. von Pawel2, J. Beck3, M. Schroeder4, I. Boehlke1, L. Kanz1 and C. Bokemeyer1,+

1Abteilung für Onkologie, Hämatologie, Immunologie und Rheumatologie, Universitätsklinikum Tübingen, Tübingen; 2Asklepios Fachkliniken München-Gauting, Gauting; 3Johannes Gutenberg Universität Mainz, Mainz; 4St Johannes Hospital, Duisburg, Germany

Received 6 August 2001; revised 13 November 2001; accepted 5 December 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Introduction

Ftorafur is an orally available prodrug of 5-fluorouracil (5-FU). Its combination with uracil in a molar ratio of 1:4 (UFT) increases the 5-FU concentration in tumor cells compared with ftorafur alone. Paclitaxel has a broad spectrum of activity against solid tumors and synergic effects with UFT have been demonstrated in vitro. A phase I study was performed to determine the maximum tolerated dose of the combination of UFT and paclitaxel in patients with advanced solid tumors.

Study design

UFT and folinic acid were applied at 300 mg/m2/day and 90 mg/day, respectively, on days 1–28, repeated on day 36. Paclitaxel was applied on days 1, 8, 15 and 22 of each cycle. The starting dose of paclitaxel was 50 mg/m2 and escalation in 10 mg/m2 steps was performed up to 100 mg/m2 weekly.

Results

Forty-seven consecutive patients with various solid tumors have been included in six different dose levels. One hundred and thirty cycles have been applied. The treatment was well tolerated overall. Most frequently encountered adverse effects were gastrointestinal and hematological toxicity (diarrhea CTC 3/4 in 6% of patients, anemia in 11%, leukocytopenia in 9%, polyneuropathy in 9%, fatigue in 11%, other in 6%). Partial remissions were observed in 28% of patients.

Conclusion

Owing to the lack of overlapping toxicities, UFT/folinic acid plus paclitaxel can be combined at doses of proven single agent activity. Side effects are mainly attributable to the gastrointestinal toxicity of UFT and to the neuro- and hematotoxicity of paclitaxel. The recommended doses for phase II studies are 300 mg/m2 of UFT plus 90 mg of folinic acid on days 1–28, and 90 mg/m2 of paclitaxel weekly.

Key words: dose escalation, paclitaxel, phase I/II, phase I study, solid tumors, UFT


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Ftorafur [1-(2-tetrahydrofuryl)-5-fluorouracil] is an orally available prodrug of 5-fluorouracil (5-FU). Following oral administration, it is rapidly and completely absorbed in the small intestine when not administered simultaneously with food [1, 2]. The substance is activated to 5-FU in vivo by different pathways [35]. Up to a 10-fold increase in the 5-FU concentration in tumor tissue compared with non-tumorous tissue after administration of UFT has been reported [6]. 5-FU is degraded mainly by dehydropyrimidine dehydrogenase (DPD) and in combination with uracil at a molar ratio of 1:4 increases the 5-FU concentration, particularly in tumor cells, by inhibition of DPD [7]. Oral application of UFT in three daily doses for 28 days resulted in an equivalent area under the concentration–time curve and higher peak plasma levels than a continuous infusion of 5-FU at 250 mg/m2/day given for 5 days [8]. The main dose-limiting effect of UFT in previous phase I studies was mucosal toxicity, such as diarrhea, mucositis, abdominal cramping, nausea and vomiting. The maximum tolerated dose (MTD) was 350–400 mg/m2/day for 28 days in combination with calcium folinate [911]. Two preliminary reports on phase III trials demonstrated a comparable efficacy but less toxicity for UFT/folinic acid compared with a 5-day bolus 5-FU/folinic acid schedule in patients with metastatic colorectal cancer [1214]. UFT has shown activity comparable to 5-FU in other tumors, including carcinoma of the stomach, head and neck cancer, non-small-cell lung cancer (NSCLC) and breast cancer [1519].

Paclitaxel functions as a microtubule stabilizer and has a broad spectrum of activity against different solid tumors [2022]. Studies have documented that paclitaxel can be safely applied as a 1-h infusion [23]. This weekly schedule is associated with very limited hematological toxicity but an increased incidence of peripheral neuropathy [24]. In addition to a potential synergic effect when combining paclitaxel and UFT, the toxicity profiles of both drugs hardly overlap. We therefore initiated a phase I study combining UFT at a fixed dose with escalating doses of paclitaxel given weekly.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The primary objective of this multicenter trial was to determine the dose-limiting toxicities (DLT), the MTD and the recommended dose for a subsequent phase II trial. Secondary objectives were to further evaluate safety and to obtain first efficacy data (response rate and time to progression). Patients with the following tumor types, potentially responsive to 5-FU- or paclitaxel-based treatment, were elegible: systemically pre-treated or untreated inoperable NSCLC or small-cell lung cancer (SCLC) extensive disease; head and neck tumors; bladder cancer; or previously treated metastatic breast and ovarian cancer. Patients had to be between 18 and 75 years of age with an Eastern Cooperative Oncology Group (ECOG) performance status <2. Patients had to have adequate hematological, renal and hepatic function (absolute neutrophil count >=2 x 109/l, platelet count >=100 x 109/l, total bilirubin <1.5 x upper limit of normal, AST/ALT <1.5 x upper limit of normal, serum creatinine <1.5 x upper limit of normal). Life expectancy had to be at least 3 months. No other anti-tumor therapy was allowed in the 28 days before the start of treatment. Patients were required to give written informed consent before entering the study. Exclusion criteria were second malignancies, presence of brain metastases, acute infection and polyneuropathy common toxicity criteria (CTC) grade >=2. The study protocol was approved by the ethics committees of all participating centers.

Pre-treatment evaluation included a complete medical history and physical examination, basic laboratory evaluation, and staging of the underlying malignancy with either ultrasound, chest radiograph or computed tomography (CT) scan. Both cytostatic agents were supplied by Bristol-Myers-Squibb, Munich, Germany.

The paclitaxel dose was escalated in 10 mg/m2 steps, starting with a dose of 50 mg/m2 at dose level 1. No intra-individual dose escalation was performed. Paclitaxel was applied as a 1-h infusion after adequate pre-medication with dexamethasone and anti-histamines weekly for 4 weeks. Both, UFT and folinic acid were given at fixed doses of 300 mg/m2/day and 90 mg/day, respectively. UFT and folinic acid were orally given on days 1–28, divided into three doses per day. Patients were asked not to take food for 1 h before and after each dose. The 28 days of treatment were followed by a 1 week rest. In case of CTC grade 3 granulocytopenia or thrombocytopenia, treatment was interrupted until recovery of the hematological parameters. In case of grade >=2 diarrhea or mucositis, treatment was interrupted. On recovery, UFT was restarted with a dose reduced by 50 mg/m2. Depending on the observed non-hematological toxicities, dose reductions of either UFT, paclitaxel or both were recommended for the subsequent courses. Response was evaluated after every second cycle. Patients with progressive disease or intolerable toxicities were taken off protocol. Patients were considered evaluable for response if they received at least one complete cycle of therapy, unless treatment was stopped due to early progression. WHO criteria were used to assess response to treatment.

Three patients per dose level were planned to be included. In case of one DLT, three further patients were treated at that level. After determining the MTD, six additional patients were to be treated at this dose level. MTD was defined as at least two out of three or three out of six patients with DLT at a given dose level. Non-hematological toxicities grade 3/4, febrile neutropenia, granulocytopenia grade 3 and thrombocytopenia grade 4, inability to take at least 75% of the planned dose or necessity to hold therapy for >12 days were all considered dose limiting.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Forty-seven patients (15 female, 32 male) were included at six different dose levels at three participating centers. The median age was 58 years (range 39–71 years). Forty patients had previously received at least one cytostatic treatment. Baseline characteristics of the patients are listed in Table 1.


View this table:
[in this window]
[in a new window]
 
Table 1. Patient characteristics
 
A total of 130 cycles of UFT/folinic acid and paclitaxel was applied. The median number of cycles received per patient was two (range one to six). The regimen was well tolerated overall. Eleven of 47 (23%) patients developed nausea CTC grade 2, vomiting CTC grade 2 was observed in two patients (4%), 29 patients (62%) did not suffer from any nausea or vomiting. One patient developed a significant hypersensitivity reaction to paclitaxel despite adequate pre-medication; however, it was possible to continue treatment.

DLT were encountered at dose levels 1–4 and 6. These consisted of diarrhea (three), mucositis (two), anemia CTC grade 3 (one) and drug-related fatigue syndrome (one). However, with two DLT per dose level at most, the MTD as defined in the protocol was not reached up to the highest dose level of paclitaxel 100 mg/m2. Overall, diarrhea was the most common toxicity, observed in 26 of 47 (55%) patients during 47 of 130 cycles (36%). However, this side-effect remained mild except in two patients with grade 3 and one patient with grade 4 toxicity. The incidence of this side-effect was equally distributed among patients at all dose levels. Myelosuppression of the regimen was moderate, the white blood cell count dropped below 2000/µl (corresponding to CTC grade 3 leukocytopenia) during six of 130 (5%) cycles; all events were observed in patients treated at the upper three dose levels of paclitaxel (80–100 mg/m2 weekly). After eight cycles of UFT/paclitaxel, anemia grade 3 was noted in five patients, red blood cell transfusions were given during nine of the 130 cycles. Four of 47 patients (9%) presented with symptoms of grade 3 polyneuropathy occurring during the third cycle. All cases of polyneuropathy have been observed at dose levels 4–6. Table 2 summarizes the observed adverse effects of CTC grades 3 and 4 that were considered possibly or probably related to treatment. Dose reductions of UFT were necessary in 11 cycles, mainly due to diarrhea. In 32 of 130 cycles (25%) the UFT dose was not applied on at least 1 day. The dose of paclitaxel was reduced in a single patient during nine cycles; one dose of paclitaxel was missed. Nine cycles of the combination treatment started with a delay due to persisting leukocytopenia or thrombocytopenia.


View this table:
[in this window]
[in a new window]
 
Table 2. Toxicity according to the CTC per cycle
 
Thirteen patients completed the treatment; the remaining patients went off study because of disease progression (22), study drug toxicity (seven), patient request (three) or for other reasons (two). Forty-three patients were assessable for response to treatment. Of these, 12 patients (28%) showed a partial remission with a median response duration of 32 weeks (range 7–49 weeks), 13 patients (30%) had stable disease and 18 patients (42%) had progressive disease (WHO criteria were used to define response).

To summarize, the observed side-effects are, in terms of frequency and intensity, in line with those reported previously when both drugs were given as single agents. UFT-induced diarrhea was dose-limiting. No over-additive toxicity of this combination has been observed. With repetitive applications of paclitaxel, polyneuropathy was encountered more frequently.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The combination of UFT and paclitaxel has demonstrated additive anti-tumor efficacy in xenograft models in nude mouse [22]. This effect was only found when paclitaxel was administered before 5-FU [9, 13]. Thus, the schedule of application of both drugs might play an important role in optimizing combinations of fluoropyrimidines and taxanes. Next to a possible synergic effect of paclitaxel and UFT, the toxicity profiles of the two drugs do not overlap, and both agents can be administered in the outpatient setting. While 5-FU has been used in prolonged infusion schedules in recent years, the use of oral derivatives has the benefit of avoiding infusion pumps and port systems while achieving a continuous drug exposure at the same time. This has been the rationale for de-veloping the current schedule of UFT/folinic acid plus weekly paclitaxel. The chosen schedule of UFT (300 mg/m2/day UFT and 90 mg/day folinic acid divided into three doses, given on days 1–28, repeated on day 36) has been shown to be well tolerated in previous studies [25], allowing testing of the combination with paclitaxel at increasing doses. The current study demonstrates that paclitaxel can be safely escalated up to 90–100 mg/m2, given as a 1-h infusion, weekly together with 28 days oral application of full-dose UFT/folinic acid. Thus, in combination therapy both cytotoxic agents can be applied at the doses being established for their single-agent use. The main toxicities of this regimen consisted of gastrointestinal and neurotoxic side-effects; however, the observed frequency is in line with previous reports for the use of each of the drugs when used as single agents. The hematological side-effects encountered were limited, even though some patients were heavily pre-treated.

The response rate of 28% for a heavily pre-treated group of patients is encouraging. However, the study design and the heterogeneity of patients with different underlying malignancies precludes definitive statements concerning the efficacy of this combination.

A recent phase II study has combined another oral fluoropyrimidine, capecitabine, with paclitaxel [26]. In this study, which included 17 patients with solid tumors, paclitaxel had been given every 3 weeks at a dose of 135–175 mg/m2 as a 3-h infusion, and capecitabine was given continuously in doses escalated to 1675 mg/m2/day, divided in to two daily doses. The toxicity profile of the capecitabine–paclitaxel combination differed substantially from that of the present study. Myelosuppression was found to be the principle DLT, with grade 3 or 4 neutropenia occurring during 18 of 66 courses (27%). Otherwise, the side-effects of the capecitabine–paclitaxel combination were considered acceptable. No tumor responses to treatment were noted. The increased hematological toxicity might be explained by the use of the 3-weekly schedule of paclitaxel in this study. In contrast, the weekly paclitaxel schedule used in the current study has allowed a high dose intensity of paclitaxel to be given with low hematological toxicity.

In summary, the combination of UFT and paclitaxel is a well tolerated regimen that can easily be applied on an outpatient basis. The preliminary data on efficacy warrant further investigation. The recommended dose for subsequent phase II studies is paclitaxel given weekly at 90 mg/m2 on days 1, 8, 15 and 22, together with UFT 300 mg/m2 divided into three doses on days 1–28 plus folinic acid 90 mg/day p.o. This combination seems to be attractive for the treatment of patients with breast cancer, adenocarcinoma of the lung, head and neck squamous cell cancer and bladder cancer.


    Footnotes
 
+ Correspondence to: Dr C. Bokemeyer, Department of Oncology, Haematology, Immunology and Rheumatology, UKT-Eberhard-Karls-University Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany. Tel: +49-7071-2987121; Fax: +49-7071-293675; E-mail: Carsten.Bokemeyer@med.uni-tuebingen.de Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Anttila MI, Sotaniemi EA, Kairaluoma MI et al. Pharmacokinetics of ftorafur after intravenous and oral administration. Cancer Chemother Pharmacol 1983; 10: 150–153.[ISI][Medline]

2. Damle B, Ravandi F, Kaul S et al. Effect of food on the oral bioavailability of UFT and leucovorin in cancer patients. Clin Cancer Res 2001; 7: 517–523.[Abstract/Free Full Text]

3. Komatsu T, Yamazaki H, Shimada N et al. Involvement of microsomal cytochrome P450 and cytosolic thymidine phosphorylase in 5-fluorouracil formation from tegafur in human liver. Clin Cancer Res 2001; 7: 675–681.[Abstract/Free Full Text]

4. Koukourakis MI, Giatromanolaki A, Fountzilas G et al. Angiogenesis, thymidine phosphorylase, and resistance of squamous cell head and neck cancer to cytotoxic and radiation therapy. Clin Cancer Res 2000; 6: 381–389.[Abstract/Free Full Text]

5. Saito H, Tsujitani S, Oka S et al. The expression of thymidine phosphorylase correlates with angiogenesis and the efficacy of chemotherapy using fluorouracil derivatives in advanced gastric carcinoma. Br J Cancer 1999; 81: 484–489.[ISI][Medline]

6. Taguchi T, Nakano Y, Fujii S et al. Determination of 5-fluorouracil levels in tumors, blood, and other tissues. Jpn J Cancer Chemother 1978; 5: 1167–1172.

7. Fujii S, Kitano S, Ikenaka K et al. Effect of co-administration of uracil or cytosine on the antitumor activity of clinical doses of 1-(2-tetra-hydrofuryl)-5-fluorouracil. Gann 1979; 70: 209–214.[ISI][Medline]

8. Ho DH, Pazdur R, Covington W et al. Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2'-tetrahydrofuryl)-5-fluorouracil. Clin Cancer Res 1998; 4: 2085–2088.[Abstract]

9. Taguchi T, Furue N, Koyama Y et al. Phase I study of UFT (uracil plus futraful preparation). Jpn J Cancer Chemother 1980; 7: 966–972.

10. Pazdur R, Lassere Y, Diaz-Canton E et al. Phase I trials of uracil–tegafur (UFT) using 5 and 28 day administration schedules: demonstration of schedule-dependent toxicities. Anticancer Drugs 1996; 7: 728–733.[ISI][Medline]

11. Meropol NJ, Rustum YM, Petrelli NJ. A phase I and pharmacokinetic study of oral uracil, ftorafur, and leucovorin in patients with advanced cancer. Cancer Chemother Pharmacol 1996; 37: 581–586.[ISI][Medline]

12. Carmichael J, Popiela T, Radstone D. Randomized comparative study of ORZEL (oral uracil/tegafur [UFT] plus leucovorin [LV]) versus parenteral 5-fluorouracil (5-FU) plus LV in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 1999; 18: 264a (Abstr 1015).

13. Martin M, Casado A, Macias JA et al. Methotrexate, uracil and tegafur, and leucovorin chemotherapy for patients with breast cancer in progression after high-dose chemotherapy with peripheral blood progenitor cell transplant: a phase II study. Am J Clin Oncol 2000; 23: 617–621.[ISI][Medline]

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

15. Feliu J, Gonzalez BM, Garcia-Giron C et al. Treatment of patients with advanced gastric carcinoma with the combination of etoposide plus oral tegafur modulated by uracil and leucovorin. A phase II study of the ONCOPAZ Cooperative Group. Cancer 1996; 78: 211–216.[ISI][Medline]

16. Feliu J, Lopez Alvarez MP, Jaraiz MA et al. Phase II trial of gemcitabine and UFT modulated by leucovorin in patients with advanced pancreatic carcinoma. The ONCOPAZ Cooperative Group. Cancer 2000; 89: 1706–1713.[ISI][Medline]

17. Ichinose Y, Yosimori K, Yoneda S et al. UFT plus cisplatin combination chemotherapy in the treatment of patients with advanced non-small-cell lung carcinoma: a multi-institutional phase II trial. The Japan UFT Lung Cancer Study Group. Cancer 2000; 88: 318–323.[ISI][Medline]

18. Takiuchi H, Ajani JA. Uracil–tegafur in gastric carcinoma: a comprehensive review. J Clin Oncol 1998; 16: 2877–2885.[Abstract]

19. Tanaka J, Inuyama Y, Fujii M et al. Clinical trials on UFT in the treatment of head and neck cancer. Auris Nasus Larynx 1985; 12 (Suppl 2): S261–S266.[Medline]

20. Ajani J, Ilson DH, Kelsen DP. Paclitaxel in the treatment of patients with upper gastrointestinal carcinomas. Semin Oncol 1996; 5 (Suppl 12): 55–58.

21. Tester WJ, Jin PY, Reardon DH et al. Phase II study of patients with metastatic non-small-cell carcinoma of the lung treated with paclitaxel by 3-hour infusion. Cancer 1997; 79: 724–729.[ISI][Medline]

22. Bokemeyer C, Hartmann JT, Kuczyk M et al. Recent strategies for the use of paclitaxel in the treatment of urological malignancies. World J Urol 1998; 16: 155–162.[ISI][Medline]

23. Greco FA, Hainsworth JD. Paclitaxel via 1-hour infusion: clinical experience. Semin Oncol 1996; 23: 91–93.

24. Fennelly D, Aghajanian C, Shapiro F et al. Phase I and pharmacologic study of paclitaxel administered weekly in patients with relapsed ovarian cancer. J Clin Oncol 1997; 15: 187–192.[Abstract]

25. Pazdur R, Lassere Y, Diaz-Canton E, Ho DH. Phase I trial of uracil–tegafur (UFT) plus oral leucovorin: 28-day schedule. Cancer Invest 1998; 16: 145–151.[ISI][Medline]

26. Villalona-Calero M, Weiss GR, Burris H et al. Phase I and pharmacokinetic study on the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies. J Clin Oncol 1999; 17: 1915–1925.[Abstract/Free Full Text]