A Phase I Study of Capecitabine in Combination with Oral · A low-dose p.o. leucovonin modulation was included in this Phase I study. The dose of 60 mg/day was selected after two

Vol. 4, 2755-2761, November 1998 Clinical Cancer Research 2755

A Phase I Study of Capecitabine in Combination with Oral

Leucovorin in Patients with Intractable Solid Tumors’

Jim Cassidy,2 Luc Dirix, Donald Bissett,

Bruno Reigner, Tom Griffin, David Ailman,

Bruno Osterwalder, and Alan T. Van Oosterom

Institute of Medical Sciences, Forcstcrhill, Aberdeen, AB25 2ZD

United Kingdom [J. C., D. B.]; UZ UIA Oncology, 1520 Edcgcm,

Belgium [L. D., A. T. V. 0.]; F. Hoffmann-La Roche Ltd., Bascl,Switzerland [B. R.]; Hoffmann-La Roche Inc., Nutley, New Jersey07110 [T. G.]; and Quintiles Oncology, Strasbourg, France

[D.A., B.O.]

ABSTRACTCapecitabine (XelodaTM) is a novel rationally designed

fluoropyrimidine carbamate. It passes through the intestinal

mucosal membrane intact and is subsequently activated by acascade of three enzymes resulting in preferential release of5-fluorouradil (5-FU) at the tumor site. Preclimcal studiesindicated an enhancement of the therapeutic index when

capecitabine was combined with leucovorin. This Phase Itrial was designed to determine the safety profile, maximaltolerated dose, and pharmacokinetic profile of the combina-

tion of capecitabine plus a fixed dose of p.o. leucovorin (60

mg/day) during administration to patients with refractory

advanced cancers. The intention was to administer bothdrugs continuously, but the starting dose ofcapecitabine wasalso the maximum tolerated dose (1004 mg/m2/day) in six

patients treated with this regimen. A cycle of treatment wasthen redefined as leucovorin and capecitabine given p.o.,twice daily for 2 consecutive weeks followed by a 1-week restperiod. Capecitabine doses from 1004 mg/m2/day to 2510

mg/m2/day were evaluated with the intermittent schedule

over approximately 80 courses in an additional 25 patients.

The dose-limiting toxicities that defined the maximum tol-erated dose at 2000 mg/m2/day were diarrhea, nausea, vom-

iting, and palmar plantar erythrodysesthesia. The recom-

mended Phase II dose using this schedule was 1650 mg/m2/day of capecitabine plus leucovorin 60 mg/day. Plasma

concentrations of capecitabine, intermediate metabolites,and 5-FU were measured in 26 patients on days 1 and 14 of

therapy. The pharmacokinetics of capecitabine were char-acterized by rapid GI absorption, with Cmax at 1 h, followedby conversion to active drug. The coadministration of leu-

covorin had no effect on the pharmacokinetics of capecitab.

Received 6/5/98; revised 8/20/98; accepted 8/24/98.The costs of publication of this article were defrayed in part by the

payment of page charges. This article must therefore be hereby markedadvertisement in accordance with I 8 U.S.C. Section 1734 solely to

indicate this fact.1 Sponsored by Hoffmann-La Roche Inc.2 To whom requests for reprints should be addressed. Phone: 44-01224-681818, ext. 53019; Fax: 44-01224-273066; E-mail: j.cassidy@abdn.

ac.uk.

me. Two patients with colorectal cancer, both previously

treated with 5-FU, had partial responses. Phase II studieshave confirmed the promising antitumor activity of this

drug, and capecitabine is currently in Phase III evaluation.

INTRODUCTION5-FU3 has been the mainstay of chemotherapeutic manage-

ment of 01 malignancies for 30 years. In that time, many

derivative compounds have been evaluated, but none has

surpassed the clinical utility of the parent. Capecitabine

(XclodaTM) is a novel fluoropyrimidine carbarnate (Fig. 1 ) that

was rationally designed to be absorbed intact from the 01 tract

and then metabolically activated to 5-FU selectively in tumors.

After p.o. administration, capecitabine passes through the intes-

tinal mucosa into the portal circulation as the intact molecule.

Capecitabine is metabolyzed in the liver to 5’-DFCR, which is

then converted to 5’-DFUR by cytidine deaminase, principally

located in the liver and tumor tissue. Further catalytic activation

of 5’-DFUR to 5-FU then occurs within the tumor by the

tumor-associated angiogenic factor thyrnidine phosphorylasc

(also known as PD-EGF) which is preferentially expressed in

tumor (1). This results in prolonged exposure of 5’-DFUR as

well as the targeting of tumor cells because of the principle location

ofcytidine deaminase and PyNPase. Capecitabine was shown to be

highly active in preclinical xenograft models in a variety of solid

tumor types, including 5-FU-rcsistant tumors (1-5).

The therapeutic advantage of continuous infusion 5-FU

over bolus administration (6, 7) is hampered by the inconven-

ience and complications of central venous access (8). Delivery

of capecitabine by continuous p.o. administration may obviate

these difficulties. Leucovorin modulates the inhibition of thy-

midylate synthase by 5-FU by stabilization of the quaternary

complex formed by the binding of fluoro-dUMP to thyrnidylate

synthase. Preclinical studies demonstrated an improvement of

activity without worsening of toxicity when leucovorin was

coadministered with capecitabinc (4). It was, therefore, decided

to initiate a human Phase I study with this combination regimen.

In parallel, Phase I studies were conducted with single-agent

intermittent and continuously administered capecitabine (9, 10).

The intention in this study was to explore continuous adminis-

tration of capecitabine with leucovorin, but this resulted in

sufficient toxicity to define the MTD at the starting dose. The

study schedule was, therefore, modified to 2 weeks of drug

administration followed by 1 week of rest, with 3 weeks con-

stituting one cycle of therapy.

3 The abbreviations used are: 5-FU, 5-fluorouracil; GI, gastrointestinal;

5’-DFCR, 5’-deoxy-fluorocytidine; 5’-DFUR, 5’-deoxy-S-fluorouri-dine; MTD, maximum tolerated dose; PPE, palmar plantar erythrodys-esthesia; NCIC-CTC, National Cancer Institute of Canada-CommonToxicity Criteria; AUC, area under the curve; CV. coefficient of vari-ation; FUH.,, dihydro-5-fluorouracil: FBAL, a-fluoro-�3-alanine.

Research. on March 27, 2021. © 1998 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

http://clincancerres.aacrjournals.org/

NH-CO-O�� NH2

N�F0�L �iJ Carboxyl-

� esterase H�C- -�

(liver)HOOH HOOH

XELODA 5’-DFCRCyd /

deaminase/’

�f (liver, tumors)

dThdPase

(tumors)

5-FU

2756 Capecitabine Phase I

H�bH

5’-DFUR

Fig. 1 Capecitabine (XelodaTM) is absorbed intact from the GI tract

and then metabolically activated to 5-FU.

Preclinical toxicology studies of capecitabine were con-

ducted in mice, rats, and cynornolgus monkeys, the latter chosen

because of the similar substrate specificitics of hepatic and

intestinal acylamidases compared with man. Briefly, the toxicity

profile in all of the species was similar to 5-FU, with diarrhea

and leukopenia. In monkeys, the highest nontoxic dose levels

with continuous p.o. administration of capecitabine for 4 and 13

weeks were 35.9 and 54 mg/kg/day. respectively ( 1 1 ). The

starting dose for this human Phase I study was guided by

preliminary clinical experience with continuous single-agent

capecitabine and was 1004 mg/rn2/day (9, 10). Because there

was little information on both acute and chronic toxicity of

capecitabine in humans, a novel overlapping-dose escalation

scheme was devised and implemented in this study.

A low-dose p.o. leucovonin modulation was included in

this Phase I study. The dose of 60 mg/day was selected after two

publications in colorectal cancer that showed no difference in

objective response rate for low-dose (20 mg/m2/day) versus

high-dose (200 mg/rn2/day) leucovorin combined with 5-FU

given for 5 consecutive days per month (12, 13). The effective-

ness of low-dose leucovorin was confirmed in a subsequent

clinical trial (14). Although these trials used the iv. route, the

active isomer of leucovorin has been shown to be completely

bioavailable for p.o. doses up to 40 mg with a selective uptake

of the active isomer. Absorption is, however, saturable at doses

of 50 and 100 mg (15). This information together with the

potentiation of both 5-FU and doxifluridine by p.o. leucovorin

and the obvious advantage of a completely p.o. combination

using identical schedules provides the logical rationale for the

selection of this dose and schedule of p.o. leucovorin.

PATIENTS AND METHODS

This was an open label, two-center, Phase I study to de-

termine the MTD and to evaluate the safety, tolerance, and

pharmacokinetics of twice daily p.o. administration of capecit-

abine when combined with p.o. leucovonin. All of the patients

gave written informed consent to the study before entry, and the

study was reviewed and approved by the local Ethics Review

Board. The study was conducted to Good Clinical Practice

guidelines and monitored by Hoffmann-La Roche and Quintiles

personnel.

Patient Selection. Patients with histologically confirmed

rnetastatic cancer refractory to conventional treatment were en-

tered into the study after fully informed written consent had

been obtained. Specific eligibility criteria included: (a) age � 18

years; (b) Karnofsky performance status of �70%, life expect-

ancy of at least 3 months; and (c) ability to comply with protocol

and follow-up requirements. Specific exclusion criteria were:

(a) pregnant or lactating females; (b) failure to use reliable

contraception for the duration of the study; (c) previous organ

allograft; (d) clinically significant cardiac disease (defined by

New York Heart Association, class III or IV); (e) brain metas-

tases; (I) impaired renal function (serum creatinine � 180 pmol/

liter); (g) hyperuricemia or hypercalcemia (urate �0.52 mrnol/

liter, calcium �2.88 mmol/liter); (h) impaired hepatic function

(bilirubin �33 p.mol/liter, transaminases or alkaline phospha-

tase >2.5 X the upper limit of normal); (i) previous chernother-

apy or radiotherapy within 4 weeks of the start of treatment (6

weeks for nitrosoureas, mitomycin C, or melphalan); (j) major

surgery in the preceding 4 weeks that could impact on drug

absorption, metabolism, or excretion; and (k) other serious un-

controlled intercurrent illness.

A total of 3 1 patients were entered into the study; their

characteristics are summarized in Table 1 . Pretreatment evalu-

ation involved: (a) a complete physical examination; (b) ECG;

(c) chest radiograph; (d) urinalysis, and (e) the measurement of

standard hematological and biochemical parameters. In addi-

tion, measurements of evaluable disease were made by appro-

pniate radiological imaging. Patients attended weekly for 6

weeks, then every 2-3 weeks for treatment, monitoring of

adverse events (using NCIC-CTC criteria), physical examina-

tion, and repeat estimations of hematological and biochemical

parameters. PPE was graded: (a) mild (grade 1, asymptomatic

reddening of the palms of the hands and/or soles of the feet); (b)

moderate (grade 2, exfoliation of the skin and/or some discom-

fort but no loss of function), and (c) severe (grade 3, fissuring of

the skin and/or functional impairment). Evaluation of tumor

response was performed every 6 weeks by appropriate clinical

and radiological assessment.

Drug Administration. Capecitabine was supplied as

film-coated tablets at four dose strengths: 100 mg, 150 mg, 500

mg, and 750 mg. The tablets were packed in Triplex blister

packing strips of seven tablets, with strengths of different tablets

identified by color-coded cards. Capecitabine was taken p.o., as

two equally divided doses given 12 h apart, within 30 mm of the

end of a meal. In addition, all of the patients were to receive p.o.

leucovonin (30-mg/dose) twice daily, to be taken at the same

time as the capecitabine dose. Compliance with medication was

assessed by tablet counts at each clinic visit.

The starting dose of capecitabine was selected as the high-

est drug dose fully explored in the ongoing continuous twice

daily p.o. single-agent Phase I study (9) for which no grade 3

adverse events had been noted. The available clinical data at that

time suggested a safe starting dose of 1004 mg/m2/day, given in



Clinical Cancer Research 2757

Table 1 Dosing groups

Capecitabinc Mean no. of(mg/m2/day) Patients, n Age (yr. median) Male/Female Prior chemotherapy cycles given Wk on study

1004(cont)” 6 64.3 4/2 4 3.3 3-17

l004(int) 6 54.5 2/4 6 4.2 6-411657 6 57.7 2/4 4 3.0 1-19

2000 7 65.3 4/3 4 3.2 2-1 1

2510 6 54.6 4/2 3 2.5 2-12

a cont, continuous; int, intermittent.

two divided doses with leucovorin. This approach was adopted

to minimize the number of patients treated at potentially sub-

therapeutic levels. A modified Fibonacci scheme of dose esca-

lation that paralleled the ongoing single-agent Phase I studies

was planned (9, 10). If, after a minimum of 3 weeks of treatment

in three patients and 6 weeks in at least one patient, drug-related

toxicity did not exceed grade 1 in any patient, the decision was

made to escalate dosage for the next cohort of patients. This

staggered entry and follow-up scheme allowed experience in all

of the cohorts with varied duration of therapy to be simulta-

neously evaluated to assess both acute and chronic toxicities.

The study was designed to expose all of the patients to a

combination of capecitabine plus leucovorin for at least 6

weeks. Patients with good tolerance of therapy and stable or

responding disease were allowed to continue therapy beyond

this time point until disease progression.

The following guidelines were applied for dose modifica-

tions for toxicity. For any grade 1 toxicity, treatment continued

without modification. In the event of grade 2 toxicity that did

not resolve with suitable symptomatic therapy, then drug ad-

ministration was withheld until resolution to grade 0-1 at which

time, treatment was restarted at the same dose with prophylactic

therapy where necessary. If the same grade 2 toxicity recurred,

treatment was stopped until resolution and then restarted at the

previous dose level. If grade 3 toxicity was observed, drug

administration was withheld until resolution to grade 0-1 and

then restarted at the preceding dose level. In the event of any

grade 4 toxicity, treatment could only be restarted if the inves-

tigator felt this to be in the patient’s best interest. After any dose

reduction, this dose was then maintained with no re-escalation

of doses in subsequent cycles.

The first six patients were treated with capecitabine plus

leucovorin using a continuous dosing regimen. The starting dose

with this regimen (1004 mg/m2/day capecitabine) proved to be

the MTD, and the study protocol was amended to allow for an

intermittent dosing schedule, with a 3-week cycle comprising 2

weeks of treatment and 1 week of rest. The MTh was then

defined as the twice daily p.o. dose of capecitabine which, given

over a 6-week period as two cycles of intermittent therapy in

combination with leucovorin (60 mg/day), caused NCIC-CTC

grade 3 or 4 toxicity in one-third or more of the patients treated.

Clinical Pharmacological Studies. Blood sampling was

performed in all of the patients for the estimation of plasma

concentrations of capecitabinc and its metabolites. To define

any potential pharmacokinetic interactions between capecitab-

inc and leucovorin, each patient had serial blood samples taken

on both days 1 and 14 of the first cycle of therapy. On the 1st

day, leucovorin was omitted but was taken with capecitabine on

day 14. Thus, each patient served as his/her own control for

comparisons of with- and without-leucovorin capecitabine phar-

macokinetic parameters. Serial blood samples were obtained

from a single indwelling cannula before capecitabine adminis-

tration and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 h after capecitabine

administration on both days. Samples were collected into glass

heparinized tubes and centrifuged. The plasma was transferred

into a plain plastic tube on day 1, but on day 14, heparmnized

plasma was transferred into a plastic tube containing ascorbic

acid as an antioxidant. Plasma samples were stored at - 20#{176}C

until analysis.

Drug Analysis. Concentrations of capecitabine and its

metabolites 5’-DFCR, 5’-DFUR, 5-FU, FUR,, and FBAL were

measured using a validated liquid chromatography mass spec-

trometry technique and a high-performance liquid chromatog-

raphy-UV technique as described previously (15).

Plasma concentrations of leucovorin and 5-methyltetra-

hydrofolic acid were measured using a validated, specific

high-performance liquid chromatography-MSIMS method at

Hoffmann-La Roche Inc. (Nutley, NJ). Folinic acid and

5-methyltetrahydrofolic acid were extracted from plasma using

solid phase extraction. The extracts were applied to a Waters

Nova-Pak C-l8 (4 pm), 3.9 X 150-mm column and quantified

by mass spectrometry. Samples were assayed according to

in-house standard operating procedures and Good Laboratory

Pratice standards. Interassay and intra-assay CVs were less than

10%.

Pharmacokinetic Calculations. Estimation of the phar-

macokinetic parameters of capecitabine and its metabolites was

performed according to standard noncompartmental methods

(6). The Cmax and tmax were taken from the observed data; t112

was estimated from ln(2)/k, where the apparent rate constant of

elimination (k) was estimated by linear regression on the loga-

rithm of the plasma concentration versus time data; area under

the concentration time curve from time 0 to infinity was esti-

mated from the sum of AUC0, and Ctiast/k. AUC0, was esti-

mated using the linear trapezoidal method.

The effect of leucovorin on the pharmacokinetics of cape-

citabine and its metabolites were investigated by comparing the

results without leucovorin (day 1) and with leucovorin (day 14).

RESULTSFifteen female and 16 male patients (ages 42-76 years;

mean, 59.4) were enrolled. All of the patients were Caucasians

with Karnofsky Performance status between 70 and 100%




Table 2 Hematological toxicity (NCIC-CTC)

HemoglobinDose level

(no. of patients) 0 1 2 3 4 0

Platelets Leukocytes Granulocytes

1 2 3 4 0 1 2 3 4 0 1 2 3 4

1004c”(6) 0 4 2 0 0 6

1004i(6) 1 2 3 0 0 6

1657(6) 0 2 4 0 0 6

2000(7) 0 4 3 0 0 4

2510(6) 0 5 1 0 0 5

0 0 0 0 5 1 0 0

0 0 0 0 5 0 0 1

0 0 0 0 5 1 0 0

3 0 0 0 4 1 1 1

1 0 0 0 6 0 0 0

0

0

0

0

0

6

5

5

5

6

0

1

1

1

0

0

0

0

0

0

0

0

0

1

0

0

0

0

0

0

a �, continuous; i, intermittent.

Table 3 Nonhem atological adverse events (NCIC-CTC)” (Part 1)

Nausea Vomiting Diarrhea Stomatitis ConjunctivitisDose level

(no. of patients) 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

l004c5(6) 2 0 1 0 0 2 1 0 1 3 1 0 1 1 0 0 1 0 0 0

1004i(6) 3 0 0 0 1 0 1 0 2 0 0 0 0 0 0 0 0 0 0 0

1657(6) 3 1 0 0 1 1 0 0 0 2 1 0 1 0 1 0 1 0 0 0

2000(7) 4 1 0 0 3 1 0 0 3 2 1 0 1 1 0 0 0 0 0 0

2510(6) 2 0 1 0 2 0 1 0 1 3 1 0 3 1 0 0 1 0 0 0

a Number of patients experiencing toxicity at maximum grade per patient at each dose level within the first 42 days of treatment.b c, continuous; i, intermittent.

Table 4 Nonh ematolo gical adverse events ( NCIC-CT C)’� (Part 2)

Dose levelPPE Nail loss Xeroderma Fatigue

(no. of patients) 1 2 3 1 2 3 1 2 3 1 2 3

lOO4c”(6) 1 3 1 1 0 0 1 1 0 0 1 1

lOO4i(6) 0 1 0 1 0 0 1 0 0 1 0 0

1657(6) 1 2 0 0 0 0 0 0 0 1 0 0

2000(7) 1 1 2 0 1 0 0 0 0 0 0 0

2510(6) 1 2 1 0 0 0 1 0 0 0 1 0

(S Number of patients experiencing toxicity at maximum gradeper person at each dose level within the first 42 days of treatment.1� �, continuous; i, intermittent.

(median 90%). The most commonly represented tumor types

were colorectal (13), breast (2), pancreas (2), gastric (2), renal

(2), mesothelioma (2), and adenocarcinoma of unknown pri-

mary (3). Over 80% had previously received chemotherapy for

the malignancy. Doses of capecitabine of 1004 mg/m2/day con-

tinuous schedule and between 1004 and 2510 mg/m2/day on the

intermittent schedule were explored (Table 1). The mean dura-

tion of exposure to therapy ranged from 52.2 ± 22.9 days (2510

mg/m2/day group) to 87.7 ± 42.7 days (1004 mg/m2/day inter-

mittent-dose group). The trial treatment was generally well

tolerated for all of the treatment groups with excellent compli-

ance throughout.

Adverse Events in Patients with Capecitabine plus Leu-covorin. A total of 229 clinical adverse events were reported

by the 3 1 patients in this study. Of these, 126 were judged by the

investigators as drug-related. Among all of the events, 56%

were mild (grade 1), 33% were moderate (grade 2), 1 1% were

severe (grade 3), and two (1%) were life-threatening. Both of

these life-threatening events were in the same patient, and both

were considered unrelated to treatment. There were no treat-

ment-related deaths. No routine prophylactic treatment to pre-

vent adverse events was given. A summary of the major hema-

tological and clinical adverse events observed for each dose

level is presented in Tables 2-5.

The most commonly reported drug-related adverse events

were diarrhea, nausea, vomiting, stomatitis, and PPE (or hand-

foot syndrome). These were very similar to the well-known

adverse events experienced by patients treated with continuous

infusion 5-Hi (6, 7). These side-effects appeared to be both

dose- and schedule-dependent with capecitabine and leucovorin

and were more frequent in the continuous-treatment group and

in the higher-dose intermittent-treatment groups.

The first cohort of 6 patients was treated at the dose level

of capecitabine 1004 mg/m2/day (continuous schedule). Three

patients at this dose level suffered from grade 3 adverse events

(nausea, vomiting, and diarrhea). Because the criteria for MTD

had been met by this continuous schedule, the protocol was

amended to switch to an intermittent dosage schedule (cycles of

2 weeks of treatment followed by a 1-week treatment-free rest

period; Ref. 10). At the (intermittent) dose level of 25 10 mg/

m2/day, three of six patients suffered grade 3 treatment-related

adverse events. One had grade 3 nausea and vomiting, one had

diarrhea, and one had hand-foot syndrome. This dose level was,

therefore, considered at or above the MTh as defined in the




Table 5 Drug-related grade HI-IV (NCIC-CTC) adverse events pdose level within 42 days of the start of treatment

er

Dose No. of Grade Gradelevel patients III IV Symptoms

1004c 6 5 0 Diarrhea 1, nausea I, vomitingAsthenia 1, PPE 1

1,

1004i 6 0 0

1657 6 2 0 Diarrhea 1, stomatitis 12000 7 2 0 Diarrhea 1, PPE I2510 6 4 0 Diarrhea 1, nausea 1, vomiting

PPE 1

1.

protocol. In an attempt to maximize the exposure to capecitabine

and in view of the large step between 1657 and 2510 mg/m2/

day, it was decided to explore an intermediate dose of 2000

mg/m2/day. Of the seven patients entered at this dose level, one

had grade 3 diarrhea and two had grade 3 hand-foot syndrome;

hence the criteria for MTD had been achieved. All of the

adverse events observed tended to be more common and more

severe with increasing duration of exposure to capecitabine.

However, low-grade toxicities such as mild hand-foot syn-

drome, nausea, and stomatitis tended to improve or resolve

completely during the 1-week treatment-free intervals.

Only one patient (at dose level 2000 mg/m2/day) experi-

enced clinically relevant myelosuppression during the study. On

day 7, she experienced grade 3 decreases in absolute granulo-

cytes, neutrophils, and total leukocyte counts. These were con-

sidered to be disease related by the investigator. The patient was

withdrawn from the study, and these events were still ongoing at

follow-up approximately 45 days after the end of treatment. No

grade 2-4 thrombocytopenia was observed in this study.

Three patients had grade 3-4 transient increases from

baseline in total bilirubin levels. In all of the three, the baseline

bilirubin was normal. In one patient, this was associated with

raised transaminases and attributable to biliary infection second-

ary to blockage of an indwelling biliary stent. Two additional

patients had elevated aspartate aminotransferase levels at enrol-

ment and experienced one episode each of transient elevations

from baseline �grade 2.

The MTD for the continuous regimen was 1004 mg/m2/day

of capecitabine. The MTD on the intermittent schedule was

2000 mg/mm2/day of capecitabine, with three of seven patients

experiencing grade three adverse events; (a) diarrhea in one; (b)

PPE in one with unrelated lethargy; and (c) PPE in one at day 82

(this was outside our strict definition of adverse events occur-

ring in the first six weeks and is therefore not shown in Table 5).

The recommended dose for Phase II evaluation was, therefore,

1650 mg/m2/day of capecitabine plus leucovorin 60 mg/day

given for 2 weeks of every 3.

Therapeutic Responses. A total of three patients

showed evidence of antitumor efficacy during this Phase I stidy:

(a) a 72-year-old male with previously treated lung and liver

metastases from a colon carcinoma. The patient’s best response

to previous therapy had been stable disease. He had a confirmed

partial response at day 70 (dose level 1657 mg/m2/day), which

was maintained beyond day 125; (b) a 56-year-old male rectal

cancer patient with soft tissue and nodal disease. He had previ-

ously been treated with adjuvant radiotherapy and 5-FU/leucov-

orin. He was treated at 1004 mg/rn2/day and had a confirmed

partial response at day 127; and (c) a patient with previously

treated metastatic colorectal carcinoma who showed a signifi-

cant volume reduction of >25% but <50% in liver metastasis at

day 92 of therapy on a dose of 1657 mg/rn2/day. An additional

16 patients had a best response of stable disease after receiving

1-5 months of treatment.

Pharmacokinetic Studies. A total of twenty-two pa-

tients are evaluable for pharmacokinetic analysis on both days 1

and 14. Table 6 shows summaries of statistics for capecitabine

and its major metabolites on day 1 after a single dose of 829

mg/rn2 in six cancer patients. Figs. 2 and 3 illustrate the same

data graphically. Statistical analyses do not show deviation from

linearity for these or any other measured parameters (data not

shown), but in view of the small numbers involved in each dose

group and the degree of inter-patient variability, this conclusion

should be interpreted with caution.

The effect of leucovorin on the pharmacokinetics of cape-

citabine and its metabolites was investigated by comparing the

results without leucovorin (day 1) and with leucovorin (day 14),

using the pharmacokinetic parameters estimated after doses of

829 and 1000 mg/rn2. There was no significant difference in any

of these parameters (Table 7). The intrapatient pharmacokinetic

variability was estimated from the ANOVA used to compare the

pharmacokinetic results obtained with and without leucovorin

(Table 7). The intrapatient variability (CV, %) in AUC was 26%,

8.3%, 7.4%, 78%, 84%, and 5.5% for intact drug, 5’-DFCR,

5’-DFUR, 5-FU, FUH2, and FBAL, respectively.

DISCUSSION

5-FU has been the mainstay of treatment in a number of

cancers, notably colorectal cancer, for the last 40 years (6).

Capecitabine is a rationally designed selectively tumor-activated

fluoropyrimidine carbamate. Capecitabine itself is not cytotoxic

but is ultimately metabolyzed to 5-FU in tumor tissue (16). This

study has demonstrated the feasibility of both continuous and

intermittent therapy when the compound is given along with a

standard dose of p.o. leucovorin. The MTD for continuous

administration was 1004 mg/m2/day; for the intermittent sched-

ule (2 weeks on, 1 week off), the MTD was 2000 mg/m2/day.

The dose-limiting adverse events of this combination were

predictably similar to those associated with infusional regimens

of 5-FU, namely hand foot syndrome and diarrhea (6, 7). This

combination was almost devoid of hematological toxicity,

which should facilitate its acceptability to patients and clini-

cians. The adverse events that were observed in this study were

mainly of a minor nature, particularly at the recommended

Phase II dose, with many resolving in the planned 1-week rest

period in each 3-week cycle of therapy. Simple dose-adjustment

guidelines were adopted in this protocol and have gone on to be

applied in additional studies of capecitabine. None of the ob-

served adverse events attributable to drug therapy were life

threatening and all of them proved manageable in this Phase I

setting.

It is noteworthy that, in this setting of refractory cancers,

evidence of antitumor efficacy was seen, in particular in 3 of 13

patients with colorectal cancer. The parallel Phase I studies of

single-agent capecitabine have also shown promising antiturnor



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-U-FUH2

-�--FBAL

0 2 4 6 8 10 12Time (h)

Time (h)

0 2 4 6 8 10 12


Table 6 Descriptive statistics on the pharmacokinetic parameters obtained after the first administration of capecitabinc (829 mg/m2) on day I insix cancer patients

Geometric means (geometric CV) are reported for Cmax, AUC0_,. and AUC0,. Median values (mm-max) are reported for tmax. Arithmetic means

(CV) are reported for t,,2. AUC0_, is the AUC for time zeero to the last sampling time at which the concentration could be measured.

Parameter Capecitabine 5’-DFCR 5’-DFUR 5-FU FUH, FBAL

Cmax (p.g/ml) 3.32 (102%) 4.23 (77%) 4.1 1 (60%) 0.216 (63%) 0.31 1 (91%) 4.68 (9%)T,nax (h) 1.00 (0.50-3.00) 1.00 (0.50-4.00) 1.00 (0.50-4.00) 2.00 (1.00-3.00) 2.00 (1.00-4.00) 2.00(2.00-5.00)AUCQ, (p.g � h/ml) 3.98 (42%) 8.01 (46%) 7.35 (35%) 0.364 (42%) 0.476 (275%) 20.0 (9%)AUCQ�. (p.g . h/ml) 5.03 (124%) 8.21 (46%) 7.42 (35%) 0.370 (81%) NC� 22.7 (12%)ti,2 (h) 0.64 (71%) 0.95 (39%) 0.59 (18%) 0.78 (39%) NC 2.43 (16%)

U NC, not calculated.

-J

E.�I

C

0

CSC0C0

C.)SC

E(I)

SC

a-

Fig. 2 Plasma concentration (mean values) versus time data of 5-Hiand its precursors (capecitabine, 5’-DFCR, and 5’-DFUR) after theadministration of 829 mg/m2 (dose level of 1657 mg/m2/day) on day I

(a = 6).

activity in colorectal and breast cancer, with both continuous

and intermittent dose schedules (9, 10). In these studies, iden-

tical patterns of toxicity were observed. A randomized Phase II

study in advanced colorectal cancer has been conducted to

compare the three capecitabine dose schedules: (a) 1331 mg/

m2/day continuous; (b) 2510 mg/m2/day intermittent; and (c)

1657 mg/m2/day intermittent with leucovorin. Again, promising

response rates have been reported with each schedule ( 17).

The pharmacokinetics of capecitabine indicate rapid and

consistent GI absorption, followed thereafter by stepwise con-

version into active metabolites including 5-FU (18). Subsidiary

clinical studies (16) have demonstrated that 5-FU is preferen-

tially found in tumor tissue, as predicted by the in vitro studies

of the metabolic activation of capecitabine; this may in part

explain the tumor responses seen in colorectal patients whose

tumors have been resistant to standard regimens of 5-FU and

folinic acid. The addition of leucovorin had no significant in-

fluence on the pharmacokinetic behavior of capecitabine, and,

likewise, the administration of capecitabine had no effect on the

pharmacokinetics of leucovorin (data not shown).

After the administration of capecitabine, concentrations of

5-Hi in plasma are low (Figs. 2 and 3). These concentrations of

Fig. 3 Plasma concentration (mean values) versus time data of 5-Hi

and its metabolites (FUH2 and FBAL) after the administration of 829mg/m2 (dose level of 1657 mg/m2/day) on day 1 (n = 6).

5-Hi can be compared with those reported in the literature after i.v.

infusion of 5-FU. Although inconsistent results have been reported

in the literature about plasma concentrations of 5-FU after admin-

istration of 5-Hi as iv. infusion (16), it appears that the plasma

concentrations of 5-FU are lower after administration of capecit-

abine. Findlay et aL (19) reported a median value of 0.22 p.g/mL

for steady-state plasma concentrations of 5-PU after administration

of 5-Hi continuous infusion (300 mg/m2/day). After the adminis-

tration of capecitabine at the recommended dose for Phase 2, 5-Hi

concentrations in plasma (AUC) are approximately eight times

lower than those observed after 5-Hi infusion (16).

A number of other p.o. fluoropyrimidine analogues or mod-

ulators of 5-Hi are in various stages of clinical development. This

group of compounds have some fundamental conceptual and prac-

tical differences. As yet, there have been no published clinical

comparisons between these compounds. The dihydropyrimidine

dehydrogenase inhibitor 5-eniluracil is being developed by Glaxo-

Welicome; it acts by inhibiting the catabolic breakdown of 5-Hi.

This has the dual effect of allowing low-dose p.o. 5-Hi to become

highly bioavailable and reducing the levels of catabolites of 5-Hi

that may cause toxicity and may interfere with cytotoxicity of the

parent compound (20). LiFT, which is a mixture of tegafur and

uracil in a 4:1 molar ratio is being developed by Bristol Myers




Table 7 Pharmacokinetic parameters of S ‘-DFUR estimated without

LV� (day 1 ) and with LV (day 14) in cancer patients afteradministration of 829 and 1000 mg/m2, respectively

Geometric means (geometric CV) are reported for Cmax, AUC0_,and AUC#{216}_. Median values (mm-max) are reported for tmax. Arithmetic

means (CV) are reported for t,,2.

Without LV With LV

Parameter (day I ) (day 14)

Dose of 829 mg/m2 (a = 5)

Cmax (�ig/m liter) 3.84 (65%) 3.87 (67%)

tmax (h) 1 .00 (0.50-4.00) 2.00 (0.323.00)

AUCQ�. (�j.g . Wm liter) 7.19 (38%) 6.86(37%)ti,2 (h) 0.56 (13%) 0.63 (14%)

Dose of 1000 mg/m2 (n = 5)

Cmax (p.g/m liter) 6.17 (27%) 5.81 (39%)

tmaX (h) 2.00 (1.00-2.00) 2.00(0.50-3.08)

AUC(,�. (�i.g . �tJm liter) 10.56 (20%) 1 1.25 (28%)

ti,2 (h) 0.70 (14%) 0.67 (24%)

(1 LV, Leucovorin.

Squibb. Tegafur is a prodrug of 5-Hi, whereas uracil is a compet-

itive inhibitor of 5-Hi catabolism. The molar ratio of 4:1 has been

shown to be optimal in terms of tumor:blood ratios of 5-Hi in

experimental animals, and the compound has shown impressive

response rates in Phase II trials (21). It is now incorporated in an

ongoing National Surgical Adjuvant Breast and Bowel Project

protocol (NSABP CO-6).

The recommended Phase II dose for this compound is 1650

mg/m2/day of capecitabine when given in combination with

leucovorin (60 mg/day) taken for 14 of every 21 days. This

regimen has been further explored in the first-line treatment of

advanced and/or metastatic colorectal cancer (17) confirming

the adverse event profile and the antitumor efficacy. Phase III

evaluation for colorectal cancer versus the Mayo regimen of

5-FU and folinic acid has now completed recruitment, and

results are eagerly awaited. Capecitabine has recently been

approved for use in the United States by the Food and Drug

Administration in the setting of advanced breast cancer that is

resistant to both anthracycline and paclitaxel therapy. This ad-

celerated approval was granted after demonstration of an objec-

tive response rate of 20% in this patient group.

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