Up-regulation of thymidine phosphorylase (TP) by radiotherapy (RT): a phase I study of capecitabine (CAP) with concurrent RT for pts with locally advanced (LA) pancreatic cancer (Pan Ca)

Abstract

4104 Introduction: Concurrent 5-FU-RT is the standard Rx for LA Pan Ca. CAP is metabolized by TP to its metabolite, 5-FU. Preclinical studies suggest that RT prior to CAP leads to synergistic cytotoxicity and better antitumor effects than 5-FU-RT due to up-regulation of TP. Objective: This is a hypothesis-driven phase I study which examines the effect of RT on TP and TNF-alpha expression, defines MTD of CAP with RT and determines if there is a correlation between pt response and intra-tumor TP/DPD ratio. Patients and Methods: During Part A (CAP-RT) pts received concurrent RT (50.4 Gy) with escalating doses of CAP (600mg/m2 PO BID; 800mg/m2 PO BID; 1000mg/m2 PO BID) on days 1–5, 8–12, 15–19, 22–26, 29–33, and 36–40 in consecutive cohorts of 3–6 pts till MTD is achieved. After finishing Part A, pts were assessed for tumor response and resectability. During Part B (CAP), stable, responding and resected pts were treated with CAP 1000mg/m2 PO BID for 14d q 3 wks until disease progression. Re-staging asessment was performed q 3 cycles. Tumor specimens procured by EUS pre- and post-therapy (wk 2) were evaluated for TP, TNF-alpha and DPD mRNA levels by RT-Q-PCR. Results: From April to Dec 2003, 11 pts (4M/ 7F; Median age: 63 yrs; PS ECOG: 0–2) were enrolled. Toxicities are summarized in Table 1. DLT [Grade 3 diarrhea] was observed at 1000mg/m2 BID, and a total of 6 pts will be enrolled at this level to define MTD and DLT. No occurrence of Hand-Foot syndrome (HFS) was seen during Part A, and Grade 2 HFS was observed in 2 pts during Part B. With 5 pts still on study, 24 cycles have been administered, with a median of 3. Three pts responded to Rx (2 PR: 54% and 43%; 1 SD; 1 PD; 3 off-study due to delay > 2 wks). Intra-tumor expression of TP, TNF-alpha, and DPD are pending and will be available at the meeting. Conclusions: CAP-RT appears to be well tolerated and active in LA Pan Ca. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche; Sanofi Roche Pharmaceuticals