Study of Eniluracil + 5-Fluorouracil (5-FU) + Leucovorin Versus Capecitabine in Metastatic Breast Cancer

Study Overview
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Brief Summary
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The purpose of the study is to determine if eniluracil/5-FU/leucovorin in metastatic breast cancer (MBC) may have efficacy and tolerability advantages over capecitabine monotherapy.

Official Title
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A Comparative, Multicenter, Open-Label, Randomized, Phase 2 Study of the Safety and Antitumor Activity of Oral Eniluracil + 5 Fluorouracil + Leucovorin Versus Capecitabine Monotherapy in Subjects With Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Eniluracil
* Drug: 5-Fluorouracil
* Drug: Leucovorin
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed metastatic (Stage IV) adenocarcinoma of the breast Prior exposure to anthracyclines either in the neoadjuvant/adjuvant setting, or as treatment for metastatic disease Either evidence of a recurrence or development of metastatic disease at least 12 months after the last dose of a taxane as neoadjuvant/adjuvant therapy, or evidence of disease progression while receiving a taxane for metastatic disease ECOG Performance Status of 0 or 1 Measurable disease according to RECIST 1.1 Criteria Adequate renal, hematologic, and hepatic function Negative pregnancy test and willing to use effective contraception Willing to avoid any other dose or form (iv, oral, or topical) of 5 FU or related derivatives for 8 weeks following the last dose of eniluracil Willing to be closely monitored for changes in coagulation parameters (prothrombin time and/or international normalized ratio [INR] values) if receiving concomitant warfarin Exclusion Criteria: Pregnant or lactating females Prior treatment with capecitabine More than one prior chemotherapy regimen for metastatic disease Prior radiation must not have included ≥ 30% of major bone marrow-containing areas (pelvis, lumbar spine). If prior radiation was < 30%, then a minimum interval of 6 weeks must be allowed between the last radiation treatment and administration of either study arm. Currently receiving anti-cancer therapy Residual ≥ Grade 2 clinically significant side effects (excluding alopecia) associated with prior radiotherapy, chemotherapy, and investigational treatments Unstable CNS metastases. However, subjects that are asymptomatic and off systemic steroids and anticonvulsants for at least 3 months are not excluded. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, ulcerative colitis, recent history of GI bleeding or perforation History of other malignancy, except subjects who have been disease-free for 5 years or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma Concurrent disease or condition that would make the subject inappropriate for study participation, or any serious medical disorder that would interfere with the subject's safety Known history or clinical evidence of leptomeningeal carcinomatosis Active or uncontrolled infection Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent Known history of uncontrolled or symptomatic angina, arrhythmia or congestive heart failure Concurrent treatment with an investigational agent Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication Taking phenytoin Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to capecitabine, fluorouracil, leucovorin, or any excipients Known dihydropyrimidine dehydrogenase (DPD) deficiency

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Eniluracil/5-FU/Leucovorin<br>Arm 1: (weekly, 28-day cycle): Approximately eighty subjects will orally self-administer eniluracil approximately 13 hr (range of 11-16 hr) before receiving 5 FU and leucovorin. The next day they will orally self-administer 5-FU and leucovorin. On the third day, they will orally self-administer leucovorin. The regimen is taken once per week for three consecutive weeks followed by one-week off-treatment. | Drug: Eniluracil<br>* Eniluracil (40 mg) orally at 18:00 ± 1 hour (6:00 PM) on Days 1, 8, & 15<br>Drug: 5-Fluorouracil<br>* 5-FU (30 mg/m2) orally at 7:00 AM ± 1 hour on Days 2, 9, & 16<br>Drug: Leucovorin<br>* Leucovorin (30 mg) orally at 7:00 AM ± 2 hours on Days 2, 3, 9, 10, 16, & 17<br>|
| Active Comparator: Arm 2: Capecitabine<br>Arm 2: (bid daily, 21-day cycle): Approximately sixty subjects will self-administer oral capecitabine (1000 mg/m2) twice daily (12 hr apart) for 14 consecutive days followed by 7 days off-treatment | Drug: Capecitabine<br>* Capecitabine (1000 mg/m2) twice daily (12 hr apart) for 14 consecutive days followed by 7 days off-treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival |  | 7.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the tolerability and toxicity of orally administered eniluracil/5 FU/leucovorin regimen vs. capecitabine monotherapy |  | 7.5 months |