CLINICAL TRIAL: STUDY OF CAPECITABINE, OXALIPLATIN AND BEVACIZUMAB FOR METASTATI

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. STUDY RATIONALE Given the lack of other viable treatment options for metastatic neuroendocrine tumors, contrasted with our positive anecdotal experience, and the relative tolerability of the treatment regimen for colorectal cancer patients, we propose a single-institution phase II trial investigating the efficacy of capecitabine, oxaliplatin and bevacizumab for patients with metastatic neuroendocrine tumors. STUDY DESIGN This will be a single-institution, phase II single-arm study. All patients enrolled will receive the experimental treatment regimen. DESCRIPTION OF THE STUDY All enrolled patients will receive bevacizumab 7.5 mg/kg intravenously followed by oxaliplatin 130 mg/m2 intravenously on day 1 of a 21 day cycle. Patients will receive capecitabine 1000 mg/m2 twice daily by mouth on days 1-14, followed by a one week break. Computed tomography (CT) imaging will be done at baseline and every 3 cycles to assess for response or progression. After 12 weeks (4 cycles) on study, patients will discontinue oxaliplatin and only receive capecitabine and bevacizumab according to the above schedule until disease progression or unacceptable toxicity. Patients will be assessed by clinical and laboratory exam at least once per cycle (more frequently as needed) and dose reductions will be allowed for unacceptable toxicity. Patients will be assessed for response by CT imaging once every 4 cycles, or until symptoms suggestive of progressive disease arise. RATIONALE FOR STUDY DESIGN Capecitabine, oxaliplatin, and bevacizumab (XELOX+A) is a well-established regimen for metastatic colorectal cancer in the schedule described above. However, the cumulative neurotoxicity of oxaliplatin often limits its continued use, despite its effectiveness in producing a treatment response. For metastatic colorectal cancer, a new schedule of FOLFOX (a predecessor regimen of XELOX using infusional fluorouracil instead of capecitabine) called the OPTIMOX regimen incorporates intermittent breaks from oxaliplatin (25). With reintroduction of oxaliplatin after a twelve week break, the OPTIMOX investigators found no significant difference in major efficacy parameters, but a trend towards decreased toxicity with the intermittent schedule. Given that patients with metastatic neuroendocrine tumors are not uniformly demonstrating rapid progression, the risk-benefit ratio of continuous oxaliplatin and increased neurotoxicity favors the OPTIMOX concept. Therefore, we have incorporated a discontinuation of oxaliplatin after 4 cycles, with reintroduction of oxaliplatin upon evidence of disease progression by RECIST criteria. During the hiatus from oxaliplatin, patients will continue on capecitabine and bevacizumab, both of which have far more acceptable safety profiles for patients with disease that has the potential for long-term stability. OBJECTIVES: PRIMARY 1.Determine an estimation of median time to progression (TTP) for patients treated with bevacizumab in combination with capecitabine and oxaliplatin 2.Assess the toxicities associated with this regimen SECONDARY 1.Determine objective response rate (RR) for patients treated with this regimen 2.Conduct exploratory analyses of efficacy according to degree of tumor differentiation and primary location 3.Determine utility of biochemical markers as a surrogate endpoint for tumor response