Abstract
3743 Background: OT and XRT are synergistic in the laboratory. Methods: To define the MTD, DLT, and PKs (blood samples at time 0 - immediately after taking OT - and at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, and 8 hrs after). The amount and subcellular location of DNA topoisomerase (topo) I and IIα - by intensity of fluorescence using monoclonal and polyclonal antibodies and gene expression by oligonucleotide microarray, were studied in RCA biopsies before and during (after 2 weeks) OT and XRT. Eligible pts had locally advanced, M0, RCA staged by EUS, CT scan +/- PET scan, good PS, and good organ function. OT escalated in cohorts of 3 to 6 pts taken at least 3 hrs prior to 1.8 Gy/fraction XRT to a total of 45Gy (standard pelvic fields), Monday through Friday. All post OT + XRT patients had curative, rectal-sparing surgery. 5-FU-based chemotherapy in the adjuvant setting was offered off protocol. Results: 13 patients enrolled (table). The median age was 69 years (range 38–90). M:F=11:2. ECOG PS: 0 (70%), 1 (30%). Baseline Stage T3N0 (10 pts) and T3N1 (3pts). The prescribed XRT was completed in all patients. The grade III AST/ALT happened in patient with hx chronic hepatitis C. Prolonged grade III ANC with no other complication occurred in a 90 yo pt. 10 out of 13 pts were downstaged; pathologic complete response (PCR) (n = 3), microscopic disease (n = 1), Ca in-situ (n = 1), T1N0 (n = 1) and T2N0 (n = 4). One upstaged from T3N0 to T4N0. All 13 pts had sphyncter preservation. PKs. Topo I/IIα, and gene expression were obtained from all pts. Analysis for relationships to response data will be presented. Enrollment continues at the expanded cohort 3. Conclusion: This preoperative OT/XRT regimen has been well tolerated. Despite the phase I nature of this trial, OT and XRT have resulted in significant downstaging and attractive pathological response rates. A phase II study is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Glaxo Glaxo Glaxo Glaxo
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