Introduction: Gemcitabine (Gem) and oxaliplatin (Ox) based chemotherapy represent a relevant therapeutic option in BTC given the promising activity and favorable tolerability of m - GEMOX1. Combining the potential benefits of targeting VEGF and the Ras/Raf pathway with chemotherapy could be a good therapeutic strategy in BTC patients2. We propose a two-step program to evaluate the feasibility (Phase Ib) and the efficacy (Phase II) of the combination of regorafenib (Reg) with m-GEMOX in advanced BTC. BREGO is a multicenter phase Ib, followed by a phase II, randomized trial. Primary objective of the phase Ib is to determine the recommended dose of Reg in combination with a fixed dose of mGEMOX. The phase II part of the study will assess the efficacy of m-GEMOX with or without Reg. Ancillary studies are also planned focusing on early tumor evaluation by FDG-PET-scan and on K-Ras mutational status using circulating-DNA analysis.Methods: Three daily dose-levels of oral Reg are planned (80mg, 120mg and 160mg) from day 1 to day 14, with fixed doses of Gem and Ox (900 mg/m2 of Gem over 30 minutes IV followed by 80 mg/m2 of Ox over 120 minutes IV) on day 1 and 8 followed by 2 weeks rest (Figure 1). Three to six patients by dose-level are planned and the recommended dose will be confirmed in an extension cohort of six patients. The phase II randomized trial will assess the safety and efficacy of m-GEMOX plus Reg versus m-GEMOX alone. The stratification (1:2) of the 63 planned-patients will be made according to center and tumor localization (intra- versus extra-hepatic) (Figure 2). Since September 2014, three patients have been included and treated at the first level (80 mg of Reg). The phase Ib will be followed by an intermediate analysis before starting the phase II. The BREGO trial was developed to propose an alternative and probably a highly active regimen in front-line metastatic or locally advanced biliary tract cancer patients. This project is supported by Bayer HealthCare. Authors thank the numerous participating teams. 1Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, Raina V, Shukla NK, Thulkar S, Garg P, Chaudhary SP. Best Supportive Care Compared With Chemotherapy for Unresectable Gall Bladder Cancer: A Randomized Controlled Study. JCO 2010; 28: 4581–4586. 2Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, Thierauch K-H, Zopf D. Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. International Journal of Cancer 2011; 129: 245–255.Figure 1: P-158Figure 2: P-158 Introduction: Gemcitabine (Gem) and oxaliplatin (Ox) based chemotherapy represent a relevant therapeutic option in BTC given the promising activity and favorable tolerability of m - GEMOX1. Combining the potential benefits of targeting VEGF and the Ras/Raf pathway with chemotherapy could be a good therapeutic strategy in BTC patients2. We propose a two-step program to evaluate the feasibility (Phase Ib) and the efficacy (Phase II) of the combination of regorafenib (Reg) with m-GEMOX in advanced BTC. BREGO is a multicenter phase Ib, followed by a phase II, randomized trial. Primary objective of the phase Ib is to determine the recommended dose of Reg in combination with a fixed dose of mGEMOX. The phase II part of the study will assess the efficacy of m-GEMOX with or without Reg. Ancillary studies are also planned focusing on early tumor evaluation by FDG-PET-scan and on K-Ras mutational status using circulating-DNA analysis. Methods: Three daily dose-levels of oral Reg are planned (80mg, 120mg and 160mg) from day 1 to day 14, with fixed doses of Gem and Ox (900 mg/m2 of Gem over 30 minutes IV followed by 80 mg/m2 of Ox over 120 minutes IV) on day 1 and 8 followed by 2 weeks rest (Figure 1). Three to six patients by dose-level are planned and the recommended dose will be confirmed in an extension cohort of six patients. The phase II randomized trial will assess the safety and efficacy of m-GEMOX plus Reg versus m-GEMOX alone. The stratification (1:2) of the 63 planned-patients will be made according to center and tumor localization (intra- versus extra-hepatic) (Figure 2). Since September 2014, three patients have been included and treated at the first level (80 mg of Reg). The phase Ib will be followed by an intermediate analysis before starting the phase II. The BREGO trial was developed to propose an alternative and probably a highly active regimen in front-line metastatic or locally advanced biliary tract cancer patients. This project is supported by Bayer HealthCare. Authors thank the numerous participating teams. 1Sharma A, Dwary AD, Mohanti BK, Deo SV, Pal S, Sreenivas V, Raina V, Shukla NK, Thulkar S, Garg P, Chaudhary SP. Best Supportive Care Compared With Chemotherapy for Unresectable Gall Bladder Cancer: A Randomized Controlled Study. JCO 2010; 28: 4581–4586. 2Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, Thierauch K-H, Zopf D. Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. International Journal of Cancer 2011; 129: 245–255.Figure 1: P-158 Figure 2: P-158

BACKGROUND:Biweekly schedule of capecitabine combined with irinotecan (XELIRI), consecutively with irinotecan and oxaliplatin (XELIRINOX), was evaluated in patients with metastatic cancer from any solid tumors.PATIENTS AND METHODS:In this two-step phase I trial, seventeen and eleven patients were enrolled in the XELIRI and XELIRINOX stages, respectively.RESULTS:In XELIRI, a total of 136 chemotherapy cycles were administered with a median number of 8 cycles per patient (2-16). Main dose-limiting toxicities (DLT) were grade 3-4 neutropenia, with one toxicity-related death. Maximum tolerated dose (MTD) for capecitabine combined with 180 mg/m(2) of irinotecan was 3,500 mg/m(2)/day. In XELIRINOX, capecitabine starting dose was 2,500 mg/m(2)/day. Fifty-eight chemotherapy cycles were administered with a median of 4 cycles per patient (1-16). DLT included 3 grade 4 neutropenia, associated with 1 grade 3 diarrhea, and 1 grade 4 pneumopathy leading to patient death. MTD for capecitabine with 180 mg/m(2) of irinotecan and 85 mg/m(2) of oxaliplatin was 3,000 mg/m(2)/day. The recommended doses for capecitabine were 3,000 and 2,500 mg/m(2)/day D1-D7 in combination with 180 mg/m(2) of irinotecan in XELIRI, plus 85 mg/m(2) of oxaliplatin in XELIRINOX (D1 = D14), respectively.CONCLUSION:XELIRI and XELIRINOX regimens are feasible and warrant further investigation in combination with targeted therapy in metastatic colorectal cancer patients.

The aim of this study was to evaluate, in a prospective study, the predictive role of p53 status analysed at four different levels in identifying the response to preoperative radiotherapy in rectal adenocarcinoma. Before treatment, 70 patients were staged and endoscopic forceps biopsies from the tumour area were taken. p53 status was assessed by total cDNA sequencing, allelic loss analysis, immunohistochemistry, and p53 antibodies. Neoadjuvant treatment was based on preoperative radiotherapy or radiochemotherapy. Response to therapy was evaluated after surgery by both pathologic downstaging and histologic tumour regression grade. In all, 35 patients (50.0%) had p53 gene mutations; 44.4% of patients had an allelic loss; nuclear p53 overexpression was observed in 39 patients (55.7%); and p53 antibodies were detected in 11 patients (16.7%). In the multilevel analysis of p53 status, gene mutations correlated with both nuclear protein overexpression (P<0.0001) and loss of heterozygosity (P=0.013). In all, 29 patients (41.4%) were downstaged by pathologic analysis, and 19 patients (29.2%) were classified as tumour regression grade 1. Whatever the method of evaluation of treatment response, no correlation between p53 alterations and response to radiotherapy was observed. Our results do not support the use of p53 alterations alone as a predictive marker for response to radiotherapy in rectal carcinoma.