CapOx given concurrently to neoadjuvant RT improved pathologic response and tumor regression 2 in phase II trials. Synergy of cetuximab and RT has been demonstrated, e.g. with improved overall survival compared to RT alone in squamous cell cancer of head and neck. This trial was initiated to evaluate the feasibility and efficacy of adding cetuximab to our previously described preoperative concurrent regimen of RT with CapOx in advanced RC 1. Determination of the maximal tolerated dose (MTD) was the endpoint of phase I whereas phase II endpoint was to determinate efficacy in terms of pathohistologic complete response (pCR). Method: Patients (pts) had to have resectable adenocarcinoma of the rectum (max. 16 cm from anal verge), T3,4 and/or N+ disease, synchronous distant metastases were allowed. Tumor staging: CT scan with endoscopic ultrasound or MRI. Cetuximab, Capecitabine and Oxaliplatin (Cet-CAPOX) with Concurrent Radiotherapy (RT) in Advanced Rectal Cancer: Final Results of a Phase I/II Trial ASCO 2007, Abstract #4042 Rationale Phase I/II cohort; n=60 Median age, years [range]61.5 [35-83] Male / Female63% / 37% ECOG 0 / 180% / 20% Cetuximab can be safely added to CapOx-RT without dose compromise to either chemotherapy or concurrent RT. Toxicity profile and post-surgical complication rates are comparable to CapOx-RT alone. In our study, the addition of cetuximab produced down-staging and downsizing, but a relatively low rate of pathologic responses and therefore did not meet statistical hypothesis criteria. Further preclinical and clinical research is necessary to clarify the mechanism and define the reason of this phenomenon. Acknowledgements: This trial was supported by Merck KGaA, Sanofi-Aventis and Roche Pharma AG, Germany Dirk Arnold 1, Matthias Hipp 2, Torsten Liersch 3, Kathrin Dellas 1, Oliver Kölbl 2, Werner Hohenberger 4, Florian Lordick 5, Heiko Sülberg 6, Rolf Sauer 4, Claus Rödel 4 1 Martin Luther University, Halle; 2 University of Regensburg; 3 Georg August University, Göttingen; 4 Friedrich Alexander University, Erlangen; 5 Technical University, Munich; 6 WiSP Langenfeld; all: Germany Schedule Phase I doses Level Cetuximab* mg/m² Oxaliplatin mg/m² Capecitabine mg/m²/day Pts. included I(400)/ II(400)/ III(400)/ Patient characteristics Response Conclusions * Cetuximab: Initial dose 400 mg/m 2 given one week prior to RT followed by 250 mg/m 2 weekly 1 Rödel C, Liersch T, Hermann RM, Arnold D, Reese T, Hipp M, Fürst A, Schwella N, Bieker M, Hellmich G, Ewald H, Haier J, Lordick F, Flentje M, Sülberg H, Hohenberger W, Sauer R. Multicenter phase II trial of chemoradiation with Oxaliplatin for rectal cancer. J Clin Oncol 2007; 25: Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative chemoradiation. Int J Colorectal Dis 1997; 12(1):19-23 References Initial Tumor stage and localisation; n = 60 Clinical staging (CT + endoscopic US or MRI) Primary tumour (n / %) T2 N+1 pt. (2%) T3 N0 7 pts. (12%) T3 N+43 pts. (72%) T4 N0 2 pts. (3%) T4 N+ 7 pts. (12%) Distant metastases Yes11 pts. (20%) Distance of lower tumor margin to anal verge Range (cm)0 – 14 Lower third (<6cm)27 (45%) Middle third (6-12cm)27 (45%) Upper third (>12cm) 6 (10%) Day Capecitabine Level I-III Cetuximab RT* 28 x 1.8 Gy Twice daily dose every day Twice daily dose every day Twice daily dose every day Twice daily dose every day * RT: 3D conformation technique, a dummy run was organized between the different centers Oxaliplatin 50 mg/m² 400 mg/m² 250 mg/m² Dose administration Toxicity: Phase II analysis Toxicity (NCI CTC v.2.0); n = phase II cohort (dose level 3) CTC grade1, 234 Leukocytopenia Thrombocytopenia Infection 35% 21% 4% 2% 6% 2% * Diarrhea Liver enzymes Proctitis Radiation dermatitis Hypersensitivity reaction Acne-like rash 56% 52% 14% 42% 10% 68% / 28% 17% 6% 2% 8% 2% 4% 2% * -- Pathologic staging of T- and N-status compared to preoperative clinical staging (N=45) ypT0ypT1ypT2ypT3ypT4 cT3: N= cT4: N= 6231 ypN0ypN1ypN2 cN0: N= 9711 cN+: N= Tumor regression grading (Dworak 3 ); n = 45 TRG 0 (No regression)4% TRG 1 (< 25%)22% TRG 2 (25 – 50%)27% TRG 3 (>50%)38% TRG 4 (complete regression)9% Resections in phase II cohort: 45 (48) pts. Anterior / low anterior resection 31 pts. Intersphincter resection 4 pts. Abdominoperineal resection10 pts. R0 rate93% any complications36% Wound heeling16% Anastomotic leakage11% Ileus 4% Bleeding 4% Re-operation necessary11% Surgical parameters DLT (Diarrhea grade 3-4) occured in 1 pt. at dose level 1. No further DLTs were observed on dose levels 2 and 3. Dose level 3 (with the same dose as in our phase II without cetuximab) was chosen for phase II evaluation. 47 more patients were included for phase II to a total of 50 pts. at the recommended dose level. 48 are evaluable for phase II population (1 withdrawal from further treatment, 1 unrelated death) *Pt. died from multiorgan failure, with underlying DPD deficiency. 1 more pt. died for unrelated reason. 1 pt. with hypersensitivity was excluded from further cetuximab administration T-level „downsizing“: 21/45 (47%) N-level „downstaging“: 21/36 (58%)