A phase I and biological correlates study of capecitabine (CAP) + oxaliplatin (OX) + radiation therapy (RT) in locally advanced rectal cancer (LARC).

3633 Background: Weekly CAPOX (825/50) + RT schedule has been used in phase II studies in LARC with an increased rate of toxicity. Given the lack of adequate support for the selected (825/50) dose, we conducted a phase I study with biological correlates. The objectives of the study were to determine the optimal dose of CAPOX and identify predictors of pathological response.,A standard 3+3 escalation/de-escalation schema was followed. Patients (pts) with untreated LARC (T3-4 or N1-2) were eligible. OX was given weekly x 5 [50mg/m: dose level 1 (DL1)]. CAP was given BID M-F on RT days (825mg/m BID). RT was given daily M-F (1.8 Gy/fraction x 28). CAPOX and RT started on day 1. Endorectal tumor biopsies (ERTB) were done prior to and on day 3 of treatment. ERTB were assayed for TS, TP, and ERCC1 by RT-PCR and for TS, TP, DPD, and apoptosis by IHC. Baseline and changes in expression were correlated with pathological response.,12 pts were enrolled (median age 61; M/F 7/5; ECOG 0/1 7/5; T3/4 11/1; N0/N+ 6/6). 6 pts were treated on DL1 (825/50): 2 had a DLT of G3 diarrhea. 6 patients were then treated on DL (-1) (CAPOX 725/50): 1 pt had a DLT of G3 diarrhea/ileus. 8 pts underwent surgery: 2 pts had a complete pathological response (pCR) and 3 a near-pCR (foci of microscopic disease); 5/8 pts had T down-staging; 2/3 pts had nodal down-staging. A complete endoscopic response was seen in 9 pts but did not correlate with pathological response. No upregulation in day 3 TP levels was seen by RT-PCR or IHC. RT-PCT TP expression correlated poorly with expression by IHC. TS (RT-PCR), TP (IHC or RT-PCR), ERCC-1 baseline expression or up/down-regulation with CAPOX/RT did not predict for pathological response. The medians for apoptosis at baseline differed: 5 apoptosis/HPF for "T-down-staged group" (n=4) versus 2 for "no T-down-staging group" (n=3) (p=0.09, exact 2-sided Wilcoxon test).,Weekly CAPOX is a convenient schedule that is associated with considerable efficacy. Elevated baseline apoptosis may be related to pathological down staging. CAPOX (725/50) is the maximum tolerated dose (MTD) and has been selected for an ongoing phase II study. No significant financial relationships to disclose.