A Phase 2 Study of a Fixed Combination ofUracil and Ftorafur and Leucovorin GivenOrally in a Twice-Daily Regimen to TreatPatients With Recurrent Metastatic BreastCancerGabriel N. Hortobagyi, MD1; Robyn R. Young, MD2; Mark Karwal, MD3; Nuhad K. Ibrahim, MD1,4; Robert Hermann, MD4,5;

James L. Murray, MD1,6; Stanley P. Watkins, MD5,7,8; and Ira Gore, Jr, MD6,9

BACKGROUND: UFT, a combination of uracil and ftorafur, was developed to combine the cytotoxic effects of 5-fluo-

rouracil (5-FU) with convenient oral dosing. Leucovorin is combined with UFT to further potentiate the effect of 5-FU

on tumor cells. Orally administered UFT and leucovorin provide higher peak plasma concentrations of 5-FU and pro-

longed therapeutic 5-FU concentrations compared with continuous infusion of 5-FU. METHODS: Ninety-four patients

with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with

UFT and leucovorin, given orally, for the first 28 days of a 35-day cycle. The total daily dose of UFT was 300 mg/m2,

which was given in 2 divided doses every 12 hours. The primary endpoint was time to disease progression (TTP). Sec-

ondary objectives included overall tumor response rate (OR ¼ complete response [CR] þ partial response [PR]) and

overall survival (OS). RESULTS: Of the 94 patients enrolled, 68 were evaluable for efficacy. Although no CRs were

observed, 9 patients achieved PRs, for an OR of 13.2% in the evaluable population. The median TTP for the evaluable

population was 10.3 weeks, and the proportion of patients free of disease progression at 6 months was 17%. The me-

dian OS was 61.6 weeks for all patients enrolled. The most common drug-related � grade 3 adverse events (graded

using the National Cancer Institute Common Toxicity Criteria version 2) were diarrhea, asthenia, nausea, and dehydra-

tion. CONCLUSIONS: The combination of UFT and leucovorin administered orally in a twice-daily regimen was found

to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with met-

astatic breast cancer previously treated with anthracyclines and/or taxanes. Cancer 2010;116:2301–6. VC 2010 Ameri-

can Cancer Society.

KEYWORDS: uracil and ftorafur (UFT), breast cancer, metastatic, leucovorin, 5-flurouracil.

To the best of our knowledge, the optimal regimen for treating metastatic breast cancer has not yet been determined.Thus, novel compounds and various combinations of both investigational and approved therapeutic agents are beingtested in clinical studies. Among the new therapies being explored is an oral combination therapy of UFT (uracil and ftor-afur [FT]; Taiho Pharmaceutical Ltd, Tokyo, Japan; BMS-200604; Bristol-Myers Squibb, Princeton, NJ) andleucovorin.

5-Fluorouracil (5-FU) is frequently used to treat metastatic breast cancer and colorectal cancer. 5-FU is rapidlymetabolized by the liver. Its mean plasma half-life when given as an intravenous (iv) infusion in humans is 16 minutes.1

Results of a meta-analysis of randomized clinical studies in patients with advanced colorectal cancer that compared 5-FUbolus with 5-FU as a continuous infusion demonstrated that continuous infusion was superior in terms of tumor response

DOI: 10.1002/cncr.25042, Received: July 10, 2009; Revised: September 3, 2009; Accepted: September 8, 2009, Published online March 11, 2010 in Wiley Inter-

Science (www.interscience.wiley.com)

Corresponding author: Gabriel N. Hortobagyi, MD, The University of Texas M. D. Anderson Cancer Center, 155 Pressler, Box 1354, Houston, TX 77030-4009; Fax:

(713) 794-4385; ghortoba@mdanderson.org

1Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 2The Center For Cancer and Blood, Fort Worth,

Texas; 3Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, Iowa; 4Department of Breast Medical Oncology, The Uni-

versity of Texas M. D. Anderson Cancer Center, Houston, Texas; 5Northwest Georgia Oncology Centers, Marietta, Georgia; 6Department of Breast Medical Oncol-

ogy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 7Department of Clinical Oncology, Johns Hopkins Hospital, Baltimore, Maryland;8Oncology Center, Anne Arundel Medical Center, Annapolis, Maryland; 9Bruno Cancer Center/St. Vincents Hospital, Birmingham, Alabama

Cancer May 15, 2010 2301

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(14% for bolus vs 22% for continuous infusion) and me-dian survival time (11.3 months for bolus vs 12.1 monthsfor continuous infusion).2 The primary side effectsobserved with 5-FU therapy were gastrointestinal, myelo-toxic, or dermatologic (hand-foot syndrome).3 When 5-FU was administered iv, the most frequently reported gas-trointestinal side effects were oral mucositis and poten-tially severe diarrhea.4 Attempts to reduce side effectswhile maintaining the antitumor effects of 5-FU led tothe development of FT and, ultimately, of UFT.

FT, also known as tegafur, is a fluorinated pyrimi-dine that has efficacy similar to that of 5-FU.5 Develop-ment of an injectable formulation of FT in the UnitedStates was discontinued in the 1980s due to its neurotox-icity when given at doses of 1 to 3 g. FT was subsequentlydeveloped as an oral formulation in Japan, where it is usedas adjuvant therapy for gastrointestinal, head and neck,breast, and lung cancers. The 5-FU released when FT ismetabolized is itself metabolized by the same pathway asiv 5-FU and therefore has the same cytotoxic mechanism.

UFT, a combination of uracil and FT in a 4:1 Mratio, was developed in Japan to combine the cytotoxiceffects of 5-FU with the convenience of oral dosing. Ura-cil is also metabolized by dihydropyrimidine dehydrogen-ase and competes with 5-FU for the enzyme when the 2are coadministered,6 resulting in a significantly prolongedhalf-life for 5-FU.

Leucovorin (folinic acid), is a tetrahydrofolic acidderivative that can enhance the therapeutic and toxiceffects of fluoropyrimidines such as 5-FU.1 It is combinedwith UFT to further potentiate the effect of 5-FU on tu-mor cells.

Preclinical studies using combination therapy oforally administered UFT and leucovorin revealed thatUFT provides higher peak plasma concentrations of 5-FUand prolonged therapeutic 5-FU concentrations com-pared with the continuous infusion of 5-FU. In addition,the combination may reduce the toxic effects on normaltissue observed with the administration of 5-FU or FTalone.

The oral combination therapy of UFT and leucovo-rin was initially developed in the United States for thetreatment of metastatic colorectal cancer. The efficacy andsafety profiles of the combination have been examined inseveral phase 2 and phase 3 studies, which either usedUFT and leucovorin alone or compared the combinationwith 5-FU and leucovorin.7-15 The phase 2 studiesfocused primarily on response rates and toxicity evalua-tion in patients with metastatic colorectal cancer. Overall

response rates ranged from 16.9% to 42%. Toxicity wasgenerally less severe than that noted when 5-FU was usedsingly or in combination with leucovorin; the absence ofhand-foot syndrome was most notable.7-11

The phase 3 studies compared the oral UFT and leu-covorin combination with iv 5-FU and leucovorin.13-15 Adose of 300 mg/m2/day of UFT with 25 to 30 mg of leu-covorin given 3 times daily (3 times a day of leucovorinfor 28 days, repeated every 35 days) was the most com-mon regimen for these metastatic colorectal cancer stud-ies. Results from 1 study indicated that patients whoreceived the oral combination experienced less diarrheaand mucositis, with minimal need for dose interruptionor reduction, compared with patients who received iv 5-FU and leucovorin.13

5-FU has been used with leucovorin as second-linetherapy in the treatment of metastatic breast cancer. FT,with and without leucovorin, has been explored as an oral,less-toxic alternative to 5-FU. In a phase 2 study ofpatients with previously treated metastatic breast cancer,25 patients received 750 mg/m2/day of FT with 45 mg/day of leucovorin for 21 days, repeated every 28 days.16

An overall response rate of 32% was observed, and 48%of patients experienced disease stabilization (median dura-tion, 6 months). The median time to disease progression(TTP) was 9 months. The results of this study were strik-ing considering the patients’ advanced conditions andnumber of previous chemotherapy regimens. The mostcommon grade 3 toxicities observed were mucositis (24%of patients) and diarrhea (12% of patients).

In the current study, UFT was divided into 2 dailydoses, each administered with 30 mg of leucovorin duringthe first 28 days of a 35-day cycle. The effectiveness ofcombining UFT with leucovorin in a twice–daily regimenwas examined in patients with metastatic breast cancer.

MATERIALS AND METHODS

Patient Eligibility

Eligible patients who had histologically confirmed breastcancer with metastases and had received prior chemother-apy with anthracyclines and/or taxanes as adjuvant treat-ment, neoadjuvant treatment, or as treatment formetastatic disease were eligible. Treatment with at least 1,but not more than 2, regimens of prior chemotherapyfor metastatic disease was required. Eastern CooperativeOncology Group (ECOG) performance status had to be�2. Patients who demonstrated no evidence of diseaseprogression since their last treatment regimen were

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2302 Cancer May 15, 2010

excluded, as were patients who had received prior treat-ment with UFT, capecitabine, ethynyl uracil, or low-dosecontinuous infusion 5-FU. The patient must have hadadequate hematologic, renal, and liver function. Beforethe initiation of the study, the protocol was approved byan Institutional Review Board and, for each patient, writ-ten informed consent was obtained and documented bythe appropriate signatures.

Treatment

Patients were given 300 mg/m2/day of UFT, divided into2 doses and administered orally every 12 hours. A 30-mgdose of leucovorin was given with each dose of UFT.Patients received study medication for the first 28 days ofeach 35-day cycle. If toxicity occurred, the UFT dose wasdecreased in increments of 50 mg/m2/day. Once the UFTdose level was decreased, it was not to be increased. If apatient required a dose reduction that brought her dose tobelow 200 mg/m2/day, she was removed from the study.

The dose of leucovorin was not modified unless theUFT dose was actually withheld, in which case the leucov-orin was also withheld. If the UFT dose was withheld dueto toxicity, the patient resumed treatment once theadverse effects resolved. If the patient did not fulfillretreatment criteria within 2 weeks, she was removedfrom the study. For patients remaining in the study, treat-ment was continued until disease progression occurred orintolerable toxicities developed.

It should be noted that if study medication waswithheld due to toxicity, the days it was withheld werecounted as treatment days. Therefore, the administrationof study medication did not extend beyond Day 28.

Endpoints

The primary endpoint was TTP from the on-study date.Patients who had no disease progression were censored attheir off-study date. Planned secondary endpoints wereoverall tumor response rate (OR), overall survival (OS),and toxicity.

Disease was categorized as measurable, evaluable, ornonevaluable. Measurable disease response criteria weredefined as follows. A complete response (CR) was consid-ered to be the complete disappearance of all tumor lesionsfor at least 4 weeks from the date of documentation ofCR. A partial response (PR) was indicated by a decreaseby>50% in the sum of the products of the largest perpen-dicular dimensions of all measurable lesions, as deter-mined by 2 consecutive observations at least 4 weeksapart. No lesions, measurable or not, should have pro-

gressed, and no new lesions should have appeared. Stabledisease (SD) was considered to be a failure to observeremissions as defined above, in the absence of any progres-sive or new lesions, as determined by 2 consecutive obser-vations at least 4 weeks apart. Progressive disease (PD)was considered to be an increase of �25% in the size ofany measurable or evaluable lesion, and/or the appearanceof any new lesions or the occurrence of malignant pleuraleffusion or ascites.

Evaluable disease response criteria were defined asfollows. A CR was considered to be the complete disap-pearance of all known disease for at least 4 weeks (forbone lesions, complete recalcification of lytic lesions ornormalization of a bone scan for blastic lesions and nor-malization of tumor markers, if previously abnormal). APR was an estimated decrease in tumor size of �50% forat least 4 weeks (for bone lesions, substantial recalcifica-tion of lytic lesions). SD was indicated by no significantchange in disease status for at least 4 weeks, includingunchanged disease, estimated decrease of <50%, andlesions with an estimated increase of <25%. PD was con-sidered to be the appearance of any new lesion not previ-ously identified, or an estimated increase of �25% inexisting lesions. Death secondary to malignant disease wasdocumented as PD.

Response Evaluations

Tumor response was evaluated every 2 cycles, and theevaluations were continued until disease progression.Patients who were removed from the study before the firsttumor response assessment were not considered evaluablefor response unless there was clear evidence of clinical dis-ease progression. All suspected responses were docu-mented with a repeat measurement at 4 weeks.

Statistical Analyses

A total of 81 eligible patients were needed to demonstratethat a 6-month progression-free survival proportion of30% had a 95% confidence interval (95% CI) between20% and 40%. A total of 90 patients were planned. The95% CIs were calculated for rates of 6-month progres-sion-free survival and overall response. The Kaplan-Meierestimator was used to examine overall TTP and survival.Cox proportional hazards regression models were used torelate TTP with patient age, ECOG performance status,estrogen/progesterone receptor (ER/PR) status, disease-free interval, presence of visceral metastases, presence ofbone metastases, number of prior chemotherapy regi-mens, and prior hormone therapy.

Oral UFT for Advanced Breast Cancer/Hortobagyi et al

Cancer May 15, 2010 2303

RESULTSBetween March 1999 and January 2002, 94 patients (93females and 1 male) were enrolled at 18 sites. The medianage of the patients was 54.5 years. All 94 patients receivedstudy medications and were evaluable for safety. Patientbaseline characteristics, including ECOG performancestatus, prior therapy, and sites of metastases, are summar-ized in Table 1. Sixty-three patients (67.0%) had priorhormonal therapy, 62 patients (66%) received prior adju-vant chemotherapy, and 34 patients (36.2%) had receivedprior metastatic chemotherapy (34 with 1 prior regimen,43 with 2 prior regimens, and 15 with �3 prior regi-mens). Two patients did not receive prior chemotherapyfor metastatic disease and were therefore consideredineligible.

Fifty patients (53.2%) had visceral metastases and48 (51.1%) had bone metastases. Fifty patients (53.2%)had ER-positive tumors, 39 (41.5%) had ER-negativetumors, and 5 (5.3%) had unknown ER status.

The metastatic disease-free interval (calculated fromthe time of initial diagnosis to recognition of metastaticdisease) was �12 months for 76 patients (80.9%),between 6 and 12 months for 5 patients (5.3%), and <6months for 13 patients (13.8%).

Two populations were analyzed for efficacy: the eli-gible population and the efficacy-evaluable population.The eligible population included all patients who receivedat least 1 dose of study medication and was used for thesafety and tolerability analysis. The eligible populationexcluded 7 patients: 3 had no measurable or evaluable dis-ease, 2 had received prior adjuvant or neoadjuvant chemo-therapy (rather than chemotherapy to treat metastaticdisease), 1 had exceeded the 2 allowable prior chemother-apy treatments for metastatic disease, and 1 did not haveprestudy blood chemistries obtained. The efficacy-evalu-able population (n ¼ 68 patients) also excluded an addi-tional 16 patients who did not have a tumor assessmentafter receiving at least 2 cycles of therapy. Only the evalu-able population will be discussed in this document.

Summary of Drug Administration

A total of 312 cycles of therapy were administered; themean was 3.3 cycles. The average number of treatmentdays per cycle was 24.9, and the average dose administeredper day was 277.6 mg/m2. All patients began treatment atthe same dose level: 300 mg/m2/day of UFT with 60 mg/day of leucovorin, each divided into 2 oral doses.

Dose Modifications

Dose reductions were required for 15 patients (16%),most frequently for grade 2 or grade 3 diarrhea, nausea,and vomiting. Twelve patients (13%) had their dosereduced by 1 level (50 mg/m2) and 3 patients (3%) hadtheir dose reduced by 2 levels (100 mg/m2). Thirty of 94patients (32.0%) had drug administration interruptionsfor a maximum of<5 days, 25 patients (27.0%) had drugadministration interruptions for a maximum of 5 to 10days, and 11 patients (12.0%) had drug administrationinterruptions for >10 days. Of the 312 cycles adminis-tered, dose interruptions occurred in 60 patients (63.8%)as a result of toxicity.

Table 1. Patient Demographics and Baseline Characteristics:All Patients (N¼94)

Characteristic Value

Sex, no. (%)Female 93 (98.9)

Male 1 (1.1)

Race, no. (%)White 73 (77.7)

Black 11 (11.7)

Hispanic 9 (9.6)

Asian 1 (1.1)

Age, yMedian 54.5

Range 29-81

ECOG performance status, no. (%)0 32 (34)

1 47 (50)

2 15 (16)

Prior therapy, no. (%)Chemotherapy 94 (100)

Prior adjuvant chemotherapy 62 (66)

Prior metastatic chemotherapy 34 (36.2)

Prior 5-FU bolus regimen 45 (47.8)

Hormone therapy 63 (67)

Radiotherapy 63 (67)

Immunotherapy 12 (12.8)

Bone marrow transplantation 5 (5.3)

Sites of metastases, no. (%)a

Bone 48 (51.1)

Liver 46 (48.9)

Lung 45 (47.9)

Lymph 44 (46.8)

Skin 16 (17.0)

Breast 11 (11.7)

ECOG indicates Eastern Cooperative Oncology Group; 5-FU, 5-fluorouracil.aMost frequently reported sites of metastases (>10% of patients enrolled).

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2304 Cancer May 15, 2010

Efficacy

Table 2 summarizes tumor response for the 68 patientswho were evaluable for efficacy. None of the patients hada CR. Nine patients had a PR and the OR (CRþ PR) was13.2% (95% CI, 7.1-23.3%). Nineteen patients (27.9%)had SD (95% CI, 18.7-39.6%), and 40 patients (58.8%)had PD (95%CI, 47.0-69.7%).

The median TTP for the efficacy-evaluable popula-tion was 10.3 weeks (95% CI, 9.4-14.4 weeks). The pro-portion of patients free of disease progression at 6 monthswas 17% (95% CI, 8-25%). A Cox proportional hazardsregression model was used to relate TTP with ECOG per-formance status, patient age, ER/PR status, the intervalbetween diagnosis and on-study, the presence of visceralmetastases, the presence of bone metastases, the numberof prior metastatic chemotherapy regimens (1 or 2), andprior hormone therapy. There were no significant predic-tors of TTP (P< .05) found in the evaluable population.

The median OS (Kaplan-Meier estimate) was 61.6weeks (95% CI, 42.3-81.3 weeks). The 6-month survivalrate was 77% (95% CI, 68-85%), and the 12-month sur-vival rate was 56% (95%CI, 46-66%).

Safety and Tolerability

Of the 94 patients who received at least 1 dose of studymedication, 93 (98.9%) experienced at least 1 adverseevent. The most commonly reported drug-related adverseevents included nausea (72.3%), diarrhea (70.2%), vom-iting (55.3%), asthenia (54.3%), abdominal pain(36.2%), and stomatitis (28.7%).

Side effects were graded using the National CancerInstitute Common Toxicity Criteria version 2 (NCI CTCv.2). Thirty-nine patients (41.5%) experienced at least 1adverse event that was NCI CTC grade 3 or higher andwas considered related to study medication. The most

commonly reported of these were diarrhea (19.1%), as-thenia (12.8%), nausea (9.6%), and dehydration (7.4%).

Ten patients (10.6%) experienced at least 1 grade 3or higher serious adverse event (SAE) that was consideredrelated to study medication. Study drug-related SAEsincluded abdominal pain, dehydration, increased pro-thrombin time, diarrhea, vomiting, asthenia, fever, ano-rexia, and electrolyte abnormalities.

DISCUSSIONThe combination of UFT and leucovorin given orally wasdesigned to be a potentially less-toxic and more conven-ient alternative therapy compared with the combinationof 5-FU and leucovorin given by iv infusion. This multi-center phase 2 study evaluated the safety and efficacy ofthe oral combination given twice daily for the first 28 daysof a 35-day cycle in patients with recurrent metastaticbreast cancer who had been previously treated withanthracyclines and/or taxanes.

Of the 68 patients who were evaluable for efficacy, 9acheived PRs, for an OR of 13.2%. The median TTP wasapproximately 10 weeks, and the median OS was approxi-mately 62 weeks. Approximately 17% of patients werefree of disease progression at 6 months. Greater than halfof the patients experienced nausea, diarrhea, vomiting, orasthenia. Approximately 40% experienced at least 1 grade3 or higher adverse event.

These findings suggest that the oral combinationtherapy of UFT and leucovorin, given in a twice-daily reg-imen, produces objective responses, although in this heav-ily pretreated population its activity appeared to bemodest. This is reflected in the low response rate and the17% progression-free survival rate at 6 months. Grade 3toxicities were manageable with appropriate dose adjust-ments in patients with metastatic breast cancer previouslytreated with anthracyclines and/or taxanes. However,grade 3 or higher events were reported with greater fre-quency (41.5%) than with capecitabine (11.1%), anotherfluoropyrimidine approved for the management of refrac-tory breast cancer since these investigations began.17

Although intertrial comparisons are hazardous, capecita-bine had substantial activity, with an 18% response ratereported in a group of patients with disease that was re-fractory to anthracyclines and taxanes. It could behypothesized that, in addition to the different pharmaco-kinetic properties of UFT and capecitabine, the activationof capecitabine at the local tumor site by thymidine phos-phorylase, an enzyme highly expressed by many breast

Table 2. Tumor Response: Efficacy-Evaluable Patientsa

(N¼68)b

Response No. (%) 95% CI

Complete response þ partial response 9 (13.2) 7.1-23.3

Complete response 0

Partial response 9 (13.2) 7.1-23.3

Stable disease 19 (27.9) 18.7-39.6

Progressive disease 40 (58.8) 47.0-69.7

95% CI indicates 95% confidence interval.aThe efficacy-evaluable population included patients who completed a tu-

mor response assessment after receiving at least 2 cycles of therapy.bIneligible and unevaluable patients were excluded.

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Cancer May 15, 2010 2305

cancer cells, might provide higher concentrations of theactive metabolite at the site of metastatic deposits, thusexplaining the significant activity and modest systemictoxicity of capecitabine.

When this trial was conducted, there were fewattractive new drugs under development. Today, there areseveral exciting new drugs with demonstrated activityagainst breast cancer. In that context, further trials withUFT in metastatic breast cancer are less attractive.

CONFLICT OF INTEREST DISCLOSURESSupported by Bristol Myers Squibb Company, Princeton, NewJersey. Dr. Hortobagyi has received research funding fromNovartis. Honoraria for consultancy or advisory roles have beenreceived by Dr. Gabriel N. Hortobagyi (Bristol-Myers Squibb)and Dr. Karwal (Abraxis, Bristol-Myers Squibb, Genentech,GlaxoSmithKline, and Novartis).

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