Standard Versus Continuous Capecitabine in Advanced Breast Cancer

Study Overview
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Brief Summary
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Capecitabine is active in metastatic breast cancer but the conventional schedule (1250 mg/m2/12 hr 2 weeks on, one week off) produces grade 2 or greater hand and foot syndrome in up to 50% of patients leading to those reductions. There are theoretical reasons to administer S-phase specific agents in continuous, protracted rather than intermittent schedules. The investigators study compares the standard schedule (1250 mg/m2/12 hr 2 weeks on, one week off) with a continuous administration schedule (800 mg/m2/12hr). The latter administer approximately the same cumulative dose of capecitabine as the standard schedule. The study hypothesis is that grade 2 or greater hand and foot syndrome will be reduced from 50% (standard arm) to 20% (experimental arm). The investigators assume similar antitumor activity in both arms.

Detailed Description
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Capecitabine is active in metastatic breast cancer but the conventional schedule (1250 mg/m2/12 hr 2 weeks on, one week off) produces grade 2 or greater hand and foot syndrome in up to 50% of patients leading to those reductions. Some authors have tested continuous administration schedules of capecitabine, showing better tolerance and apparently similar antitumor activity. Capecitabine is a pro-drug of 5-FU and mimics an i.v. continuous infusion administration of this antimetabolite. On the other hand, there are theoretical reasons to administer S-phase specific agents in continuous, protracted rather than intermittent schedules. Our study compares the standard schedule(1250 mg/m2/12 hr 2 weeks on, one week off)with a continuous administration schule (800 mg/m2/12hr). The latter schedule administer approximately the same cumulative dose of capecitabine as the standard one. The study hypothesis is that grade 2 or greater hand and foot syndrome will be reduced from 50% (standard arm) to 20% (experimental arm). The investigators assume similar antitumor activity in both arms.

Official Title
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Randomized Phase II Trial of Continuous Versus Standard Capecitabine in Advanced Breast Cancer.

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients diagnosed with metastatic breast cancer Patients that either have received previous treatment with anthracyclines and/or taxanes or not (either as advance or in metastatic disease). The patient is ambulatory with a functional ECOG < 2 status (see Appendix 2). Patient presents, at least one lesion measurable according to RECIST criteria (see Appendix 3) Patients with a life expectancy of at least 3 months. Patients that agree to and are able to fulfill the requirements of the whole protocol through the whole study. Exclusion criteria: Patients that have previously shown unexpected severe reactions to therapy with fluoropyrimidines or with a known sensitivity to 5-fluorouracile. Patients previously treated with capecitabine. Patients with organ transplants. Other diseases or severe affections: Patients with previous convulsions, central nervous system diseases or psychiatric diseases, including dementia, that the investigator might consider clinically significant and which adversely affect therapeutic compliance. Patients with severe intellectual impairment, unable to carry out basic daily routines and established depression. Clinical significant cardiac disease (e. g. . congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmia not fully controlled with medication) or myocardial infarction within the last 12 months. Severe renal impairment (baseline creatinine clearance < 30 ml/min) Patients with signs of metastasis in the CNS. Patients with a history of uncontrolled convulsions, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant precluding informed consent or interfering with compliance for oral drug intake should be excluded. Patients with an active infection. Patients with a history of other neoplasias during the previous five years, except for basal cell skin cancer or cervical cancer in situ, both cured. Patients showing the following laboratory values: Neutrophil count < 555 x 109/l Platelet count< 100 x 109/l Serum creatinine > 1,5 x upper normality limit seric bilirubin > 2,0 x upper normality limit ALAT, ASAT > 2,5 x upper normality limit or > 5 x upper normality limit in case of liver metastases Alkaline phosphatase > 2,5 x upper normality limit > 5 x upper normality limit in case of liver metastases o > 10 x upper normality limit in case of bone metastases. Patients under radiotherapy four weeks prior to the initiation of the study treatment, or under previous radiotherapy on the marker lesions be measured during the study (new marker lesions that appear in previously irradiated areas are accepted) or patients who are receiving programmed radiotherapy. Patients under major surgery within 4 weeks prior to study treatment or who have not completely recovered from the effects of major surgery. Patients who lack upper gastrointestinal tract physical integrity or with malabsorption syndrome. Patients who have received more than two cycles of chemotherapy for the metastatic disease. Patients Her2 + per FISH ó +++ Immunohistochemistry

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 |
| --- | --- |
| Active Comparator: A Cint<br>Capecitabine will be administered orally at a dose of 1250 mg/m2 twice-daily (in the morning and in the evening, the equivalent of a total daily dose of 2500 mg/m2) for 14 days, in 3 week cycles with a resting period of 7 days,until disease progression or severe toxicity. Dose adjustments were made in patients with grade 3 or greater diarrhea or hand and food syndrome. | Drug: Capecitabine<br> <br> * Other names: xeloda;|
| Experimental: B Ccont<br>Capecitabine 800 mg/m2 orally twice-daily (in the morning and in the evening the equivalent of one dose of 1600 mg/m2) for 21 days, in 3 week cycles without resting period, until disease progression or severe toxicity. Dose adjustments were made in patients with grade 3 or greater diarrhea or hand and food syndrome. | Drug: Capecitabine<br> <br> * Other names: xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Time to Progression (TTP) is defined as the time (in months) from the moment the patient starts the study treatment to the date of progressive disease. That is, a patient has an event is she progresses or dies due to progressive disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0). | After 1 year from the treatment start day. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Response was evaluated using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), every 3 cycles of chemotherapy (each cycle lasts 3 weeks) and at the end of treatment (at 21 weeks from the start of treatment). | Through the study treatment, an average of 5 months. | 
| Response Duration | Response duration is computed for all patients with Partial Response or Complete Response, during the treatment period, as the time from the moment the Partial or Complete Response is reported to the date the patient Progresses or Dies, whichever happens first. A patient is censored if she does not progress or die. In these cases Response duration is computed as the time from the moment the Partial or Complete Response is reported to the last contact date. | Time from the moment the Partial or Complete Response is reported to the date the patient Progresses or Dies, whichever happens first, assessed up to 72 weeks. | 
| Time to Treatment Failure | Time to treatment failure (TTF) is defined as the time (in months) from the moment the patient starts the study treatment to the end of treatment date (due to death, progressive disease, adverse events, patient's decision or investigator criteria. If a patient did not end the treatment, it is censored. The censoring date is the date of the last dose received. | Time (in months) from the moment the patient starts the study treatment to the end of treatment date (due to death, progressive disease, adverse events, patient's decision or investigator criteria, assessed up to 72 months. | 
| Overall Survival | An event is defined as death. A patient is censored if she does not die. The censoring date is last contact date. | Time to survival is the number of months from the study treatment start date to the date of death, assessed up to 100 months. | 
| Clinical Benefit | A patient experiences a Clinical Benefit if the following is satisfied: Criterion: The patient has Complete response, Partial Response or Stable Disease and it continues during more than 3 months. | Months from CR,PR or SD (the first one) until Progression date, new treatment or last contact date. | 
| Progression Free Survival | Progression Free Survival is defined as the time (in months) from the moment the patient starts the study treatment to the date of progressive disease. That is, a patient has an event is she progresses or dies for any reason. | Time (in months) from the moment the patient starts the study treatment to the date of progressive disease assessed up to 84 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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schedule, capecitabine, breast cancer