Preliminary phase II SOCRATES study results: Capecitabine (CAP) combined with oxaliplatin (OX) and preoperative radiation (RT) in patients (pts) with locally advanced rectal cancer (LARC).

3575 Background: CAP, an oral fluoropyrimidine preferentially activated to 5-FU in tumors by the enzyme thymidine phosphorylase (TP), has superior antitumor activity and favorable safety compared with bolus i.v. 5-FU/LV in pts with metastatic colorectal cancer (MCRC). OX plus 5-FU/LV further improves outcomes in MCRC. Preclinical xenograft models show that RT and OX both upregulate tumor TP vs normal tissue. The aim of this study was firstly to determine the recommended dose of neoadjuvant CAP in combination with OX and pelvic RT in pts with LARC, and secondly to assess the efficacy and safety of this regimen. METHODS: Pts with primary unresectable LARC took CAP (500, 650, 825mg/m(2) twice daily) 7 days/week during RT and received i.v. OX 130mg/m(2), days 1 and 29, and RT (25 fractions of 1.8Gy; 45Gy total over 25 days). After identifying the maximum tolerated dose (MTD) of CAP, the study continued into phase II for a total sample size of 80 pts. RESULTS: Currently we have enrolled 52 patients; six in each phase I cohort, and another 34 in phase II. Median age is 55 years (24-75); most pts are male (76%), and Caucasian (97%). All pts were staged T3/T4 by pre-operative MRI. Dose-limiting toxicities (DLTs) occurred in 2/6 pts receiving CAP 825mg/m(2) (grade 3 diarrhea and moist desquamation), establishing the MTD at this dose. CAP 650mg/m(2) twice daily is being used in the ongoing phase II. To date, 42 pts have undergone surgery. Complete pathologic responses occurred in 9 (21%) of pts, a further 10 (24%) were downstaged to ypT1T2N0 and 36 (77%) had tumor-free circumferential resection margins. Among 34 pts evaluable for safety, the most common (≥20%) treatment-related adverse events (AEs) were paresthesia (79%), diarrhea (62%), neuropathy (38%), and nausea (38%). Most AEs were mild (64% G1-2). In phase II 2/34 pts had G3-4 diarrhea and 1/34 had G3-4 lethargy. CONCLUSIONS: The recommended dose of neoadjuvant CAP is 650mg/m(2) twice daily with OX 130mg/m(2) (days 1 and 29) and pelvic RT. The regimen is well tolerated and shows promising activity in LARC. [Table: see text].