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    Optimizing Oral Chemotherapy in Breast Cancer Using Fixed Dose Schedules: The Identification of Predictive Markers of Response and Toxicity to Capecitabine

    Scientific Abstract:
    Background: There is a need for reliable, predictive markers of response and toxicity to commonly used chemotherapy drugs. The oral 5-FU prodrug capecitabine is FDA-approved to treat anthracycline/taxane-resistant metastatic breast cancer, and is now being tested as adjuvant therapy. However, excessive gastrointestinal/skin toxicity is observed with the complex/inaccurate body surface area (BSA)-based dosing schedule. BSA fails to explain the significant interpatient pharmacokinetic (PK) variability of capecitabine and its metabolites, and ignores individual host/tumor factors that might better correlate with pharmacodynamic (PD) effects of toxicity and response. Objective/Hypothesis: A non BSA-based fixed dose schedule of oral capecitabine will simplify the determination of PK parameters and pharmacogenetic (PG) profiles, and facilitate development of predictive models of response and toxicity to individualize therapy. A fixed dose schedule is expected to be feasible, active, less toxic, and facilitate compliance. Specific Aims: (1) Determine the efficacy, toxicity, and adherence parameters using a fixed dose schedule of oral capecitabine; (2) Identify parameters that explain the wide interpatient PK variability and develop correlations with PD effects and PG profiles; (3) Correlate PG profiles and polymorphisms of drug transporters, activation enzymes, cellular targets, and degradation proteins of the capecitabine drug pathway with PD effects; (4) Determine the sensitivity/specificity and predictive value of novel assays in serum (hypermethylated DNA markers and proteomic profile) and correlation with tumor burden and response. Study Design: Open label, single-arm trial of oral capecitabine with a fixed starting dose of 3,000 mg (three 500 mg tablets 2x/day, electronic bottle cap, free study drug) x 14 days every 21 days. Eligible pts: age >= 18 w/ histologically confirmed adenocarcinoma of the breast, evidence of metastatic involvement, measurable disease, and able to provide informed consent. Up to two dose escalations/three dose reductions (a 500 mg tablet each) per NCI CTCAE v3.0. Samples for PK/PD (sequential) and PG (baseline) studies; response evaluation after 4 cycles (RECIST criteria). Pts will remain on study therapy until disease progression, unacceptable toxicity, or consent withdrawal. Potential Outcomes and Benefits of Research: (1) Develop simpler, individualized, and more reliable dosing schedule (less toxicity, fewer errors, greater compliance and adherence); (2) Establish predictive models of toxicity and response to capecitabine.

    Lay Abstract:
    Background: Factors present in breast cancers and patients (pts) can help identify those likely to benefit from specific therapies, such as anti-estrogens and Herceptin®. Unfortunately, little is know about predictive factors for response and toxicity to most chemotherapy drugs. Capecitabine (Xeloda® or C) is an oral chemotherapy drug active in many pts with advanced refractory disease, now being tested in early stages. Current dosing guidelines based on body surface area (BSA, a function of height and weight) are complex, imprecise, and error prone. BSA ignores individual factors, like kidney function and the individual genetic make-up that regulates pathways responsible for drug effects (pharmacogenetics or PG). Therefore, many pts receive inadequate doses that may diminish chances of response or expose them to excessive toxicity (pharmacodynamics or PD). Objective/Hypothesis: Use of a fixed starting dose of C will allow the identification of pharmacokinetic (PK) parameters that correlate with PG profiles, development of predictive PD markers, and individualization of therapy. This schedule is expected to be feasible, active, less toxic, and facilitate compliance. Specific Aims: (1) Determine the efficacy, toxicity, and adherence parameters with a fixed dose schedule of C; (2) Identify parameters that explain the wide interpatient PK variability of C and develop correlations with PD effects and PG profiles; (3) Correlate PG profiles and polymorphisms of drug transporters, activation enzymes, cellular targets, and degradation proteins of the C drug pathway with PD effects; (4) Determine the sensitivity/specificity and predictive value of novel assays in serum (hypermethylated DNA markers and proteomic profile) and correlation with tumor burden and response. Study Design: Single-arm trial with a fixed starting dose of oral C 3,000 mg (three 500 mg tablets 2x/day, electronic bottle cap, free study drug) for 14 days every 21 days. Pts age >= 18 w/ breast cancer and evidence of metastatic disease, and able to provide informed consent (voluntary participation). Dose escalations/reductions per established toxicity criteria. Blood samples collected at multiple times for special tests (no extra costs). Pts to remain on study until disease progression, excessive toxicity, or consent withdrawal. Potential Outcomes and Benefits of Research: (1) Develop simpler, individualized, and more reliable dosing schedule (less toxicity, fewer errors, greater compliance); (2) Establish predictive models of toxicity/response to C to identify patients most likely to benefit from it.