Cetuximab + Capecitabine + Irinotecan (CCI) Versus Cetuximab + Capecitabine + Oxaliplatin (CCO) as 1st-Line Therapy for Patients With Metastatic Colorectal Cancer (CRC): Randomized Phase II Trial of the AIO CRC Study Group. V. Heinemann University of Munich – Klinikum Großhadern, Munich, Germany

Recruiting Centres AbenhardtOnkologische Praxis München DeckerOnkologische Praxis Weingarten DietzfelbingerPrivatklinik Herrsching EggersKreiskrankenhaus Torgau Fischer von WeikersthalKlinikum St. Marien Amberg FleckDRK Krankenhaus Luckenwalde FuchsSt. Antonius Hospital Eschweiler GabiusOnkologische Praxis Rosenheim HaberlKlinikum St. Elisabeth Straubing HeinemannKlinikum Großhadern München HeniKreiskrankenhaus Biberach HitzOnkologische Schwerpunktpraxis München JungOnkologische Praxis Traunstein KappaufOnkologische Praxis Starnberg KleinKlinikum Bayreuth GmbH KubinKlinikum Traunstein LambertzKlinikum Garmisch-Partenkirchen MahlOnkologische Praxis Schrobenhausen MaubachOnkologische Praxis Ingolstadt MittermüllerOnkologische Praxis Germering NuschOnkologische Praxis Velbert OruzioZentralklinikum Augsburg PerkerOnkologische Praxis Weilheim-Schongau PuchtlerKlinikum Rosenheim SchlagOnkologische Praxis Würzburg SchulzeOnkologische Praxis Zittau SeipeltOnkologische Praxis Bad Soden SlawikOnkologische Praxis Augsburg StauchOnkologische Praxis Kronach StötzerOnkologische Praxis München Vehling-KaiserOnkologische Praxis Landshut WagnerKlinik für Chirurgie, Chemnitz gGmbH WaltherMarienhospital Stuttgart WeißOnkologische Praxis Weiden ZellmannSchlossbergklinik Oberstaufen

Treatment Regimens Day: Arm A: (*) Irinotecan 200mg/m², 30min i.v. Cetuximab (**) 250mg/m², 60min i.v. Capecitabine 800mg/m² p.o., twice daily Arm B: Oxaliplatin 130mg/m², 120min i.v. Cetuximab (**) 250mg/m², 60min i.v. Capecitabine 1000mg/m² p.o., twice daily (*): 20% dose reduction for patients > 65 years, arm A (**):Cetuximab loading dose (only week 1): 400mg/m², 120min q 3 weeks

Primary Endpoint:Response rate. Secondary Endpoints:Time to progression Disease stabilisation rate (CR+PR+SD) Tolerability Grade 3/4- toxicities.

Recruitment and Evaluation TotalCCICCO Patients recruited137*6968 Patients evaluable for toxicity7437 Patients evaluable for response Evaluable cycles * The recruitment goal was extended with an amendment of the protocol

Patient Characteristics Parameter Total (n = 74) CCI (n = 37) CCO (n = 37) Age (years, median + range)61 (38-74)63 (38-72)59 (38-74) Gender (m/f)2.5 : 12.4 : 12.7 : 1 Karnofsky PFS 70%8.1%10.8%5.4% 80%25.7%32.4%18.9% 90%27.0%24.3%29.7% 100%39.2%32.4%46.0% Localisation (colon/rectum)1.7 : 11.3 : 12.2 : 1 Metastatic sites: 139.2%32.4%46.0% 229.7%32.4%27.0% 317.6%18.9%16.2% >310.8% unknown2.7%5.4%-

Type of Adjuvant Pretreatment Total (%) (n = 74) CCI (%) (n = 37) CCO (%) (n = 37) Adjuvant chemotherapy Adjuvant 5-FU Adjuvant 5-FU+FA Unknown Prior radiotherapy

Location of Metastases Localisation Total (n = 74) CCI (n = 37) CCO (n = 37) Liver63 (85.1%)28 (75.7%)35 (94.6%) Lungs28 (37.8%)15 (40.5%)13 (35.1%) Lymph Nodes23 (31.1%)12 (32.4%)11 (29.7%) Peritoneum11 (14.9%)6 (16.2%)5 (13.5%) Intestine4 (5.4%)3 (8.1%)1 (2.7%) Bones1 (1.4%)1 (2.7%)- Pleura1 (1.4%)1 (2.7%)- Brain1 (1.4%)1 (2.7%)- Others12 (16.2%)6 (16.2%) Unknown2 (2.7%)2 (5.4%)-

EGF-Receptor Status Total (n = 74) CCI (n = 37) CCO (n = 37) EGFR detectable71.62 %70.27 %72.97 % EGFR not detectable27.03 % unknown1.35 %2.70 %-

Dose Reductions / Delayed Cycles Total (%) (357 cycles) CCI (%) (198 cycles) CCO (%) (159 cycles) Dose reductions * Delayed cycles **

Localisation Total (n = 74) CCI (n = 37) CCO (n = 37) Liver63 (85.1%)28 (75.7%)35 (94.6%) Lungs28 (37.8%)15 (40.5%)13 (35.1%) Lymph Nodes23 (31.1%)12 (32.4%)11 (29.7%) Peritoneum11 (14.9%)6 (16.2%)5 (13.5%) Intestine4 (5.4%)3 (8.1%)1 (2.7%) Bones1 (1.4%)1 (2.7%)- Pleura1 (1.4%)1 (2.7%)- Brain1 (1.4%)1 (2.7%)- Others12 (16.2%)6 (16.2%) Unknown2 (2.7%)2 (5.4%)- Allergic Reactions Related to Cetuximab (Manifestation at First Application)

Non-Hematological Toxicity Non-Hematological Toxicity per patient analysis % 10,8 8,1 10,8 0,0 5,4 2,7 0,0 2,7 0, Anemia Leukopenia Neutropenia Thrombopenia Fever Neutrop. Fever CCI CCO

Hematological Toxicity Hematological Toxicity per patient analysis % 13,5 18,9 2,7 0,0 2,7 18,9 10,8 0,0 16,2 21,6 0,0 2,7 18,9 29,7 5, Nausea/Vomiting Diarrhoe Obstipation Stomatitis Alopecia Neurotoxicity Skin Toxicity Pain Fatigue CCI CCO

Best Response During Treatment CCICCO p-value n%n% evaluable patients CR PR SD PD CR + PR CR + PR + SD

Conclusions: Both treatment arms – CCI and CCO – are feasible and highly effective. In the CCI arm, most common Grade 3-4 toxicities were diarrhea (19%), skin toxicity (19%), nausea and vomiting (14%), pain (11%), and anemia (11%). In the CCO arm, most common Grade 3-4 toxicities were skin toxicity (30%), diarrhea (22%), neurotoxicity (19%) and nausea and vomiting (16%). Non-hematological toxicity appears to be greater in the CCO arm, possibly also related to the higher dose of capecitabine used in this arm. Hematological toxicity appears to be greater in the CCI arm. Disease control rates are equally high: 88.9% in the CCI arm and 92.0% in the CCO arm (p=1.0). The accrual of the CIOX-trial is ongoing.