Abstract CT407: Phase I study of preoperative continuous 5-fu and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma

Abstract

Abstract Background: Preoperative treatment with fluoropyrimidine-based chemoradiotherapy is considered standard therapy for locally advanced rectal cancer( T3, T4 or N1). Sorafenib is an inhibitor of ras/raf, PDFGR and VEGFR with synergistic activity with radiation. The phase I trial evaluated the safety and efficacy of sorafenib in combination with infusional 5-FU and radiation Methods: Patients with stage II or III patients confirmed by EUS and CT scan were recruited in cohorts of 3 patients per dose level (DL). A 3+3 dose escalation design was used. On all dose levels RT was given in 25 fractions at 1.8Gy (45Gy) day 1- 5. Surgery was done 6-10 weeks after the completion of neoadjuvant treatment. Results: At Moffitt Cancer we enrolled 12 patients in 4 cohorts. 8 females(67%) and 4 males(33%); Median age is 55(range: 40-72). After observing toxicity in first cohort ( 2 pts with with G2 and G3 skin toxicity and 1 pt with G2 mucositis) which required dose interruptions, amendment was made to change the schedule of chemotherapy and sorafenib to days 1-5 instead of daily. After the amendment, hypertension was the only grade III toxicity observed. 2 patients had G3 hypertension at 200mg adjusted dose(day1-5); 1 patient had G3 hypertension at 400 mg PO BID dose level and no grade IV toxicities were seen. No perioperative complications related to the study drugs were seen. 2 patients never went to surgery due to patient refusal. KRAS testing information was available on 10 patients. pCR rate was 30 % and downstaging was observed in 80% of the patients. pCR was 50% in patients with Kras mutant tumors ( 2/4 pts) Conclusion: After changing the schedule of the chemotherapy, the regimen was very well tolerated. pCR and downstaging rate of the tumor seems to be encouraging. Plan is to open up an expansion cohort at DL3 to gather more safety and efficacy data. Schedule of sorafenib dose escalationDose level ( 3 patients each)Sorafenib5-FU infusion Rate (mg/m2/24hrsDL 1 before amendment200mg PO QD225 on day 1-7 for 5½ weeksDL 1 after amendment200mg PO QD( Day1-5)225 on day 1-5 for 5½ weeksDL 2 after amendment400mg PO QD( Day1-5)225 on day 1-5 for 5½ weeksDL 3 after amendment400mg PO BID( Day1-5)225 on day 1-5 for 5½ weeks Citation Format: Richard Kim, Kun Jiang, Xiuhua Zhao, Dung-Tsa Chen, Tiffany Campos, Sara Hoffe, Ravi Shridhar, David Shibata. Phase I study of preoperative continuous 5-fu and sorafenib with external radiation therapy in locally advanced rectal adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT407. doi:10.1158/1538-7445.AM2014-CT407