Download A phase I study of oral uracil–ftorafur plus folinic acid in combination

Original article
Annals of Oncology 13: 755–759, 2002
DOI: 10.1093/annonc/mdf129
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 &
C. Bokemeyer1*
On behalf of the Phase I Study Group of CESAR
1
Abteilung für Onkologie, Hämatologie, Immunologie und Rheumatologie, Universitätsklinikum Tübingen, Tübingen;
Asklepios Fachkliniken München-Gauting, Gauting; 3Johannes Gutenberg Universität Mainz, Mainz; 4St Johannes Hospital, Duisburg, Germany
2
Received 6 August 2001; revised 13 November 2001; accepted 5 December 2001
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
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 [3–5]. 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
*Correspondence to: Dr C. Bokemeyer, Department of Oncology,
Haematology, Immunology and Rheumatology, UKT-Eberhard-KarlsUniversity Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen,
Germany. Tel: +49-7071-2987121; Fax: +49-7071-293675;
E-mail: [email protected]
© 2002 European Society for Medical Oncology
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 [9–11]. 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 [12–14]. 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 [15–19].
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Paclitaxel functions as a microtubule stabilizer and has a
broad spectrum of activity against different solid tumors
[20–22]. 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.
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
Patients and methods
The primary objective of this multicenter trial was to determine the doselimiting 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-FUor 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 × 109/l, platelet count
≥100 × 109/l, total bilirubin <1.5 × upper limit of normal, AST/ALT <1.5 ×
upper limit of normal, serum creatinine <1.5 × 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 premedication 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
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.
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.
Table 1. Patient characteristics
Characteristic
No. of patients (n = 47)
Male/female
32/15
Median age, years (range)
57 (39–71)
Percentage
ECOG performance status
0
10
21
1
29
62
2
8
17
Chemotherapy
40
85
Radiation
18
38
Surgery
30
64
30
64
Head and neck cancer
6
13
Bladder cancer
6
13
SCLC
2
4
Ovarian cancer
1
4
Breast cancer
1
2
Anaplastic thyroidcarcinoma
1
2
Previous treatment
Hisology of primary tumor
NSCLC (stage IIIb–IV)
NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer;
ECOG, Eastern Cooperative Oncology Group.
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Table 2. Toxicity according to the CTC per cycle
Toxicity
Definition of grade 3/grade 4 toxicity
Grade 3 (%)
Grade 4 (%)
Leukocytopenia
WBC <2000/1000/µl
5 (4)
1 (1)
Neutropenia
ANC <1000/500/µl
6 (4)
1 (1)
Thrombocytopenia
PLT <50 000/25 000/µl
–
–
Anemia
Hemoglobin 6.5–7.9 g/dl
8 (7)
–
Diarrhea
Increase of seven to nine stools per day or cramping/increase of 10 stools per day,
grossly bloodly or need for parenteral nutrition
4 (3)
1 (1)
Infection
Severe/life threatening
1 (1)a
Stomatitis
Painful erythema or ulcers and inability to eat solid food
1 (1)
–
5 (4)
–
Fatigue
Polyneuroapthy
Objective weakness, severe sensory loss or parethesia interfering with function
6 (5)
a
Salmonellosis, probably unrelated to the study drug.
WBC, white blood cell count; ANC, absolute neutrophil count; PLT, platelet count.
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.
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
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 developing 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
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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.
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