A Dose-finding and Biomarker Evaluation Phase Ib Study of Everolimus in Association With 5-Fluorouracil and Pelvic Radiotherapy as Neoadjuvant Treatment of Locally Advanced Rectal Cancer (E-LARC Study)

Abstract Background During the past 20 years, considerable improvement has occurred in the treatment of patients with locally advanced rectal cancer (LARC). With the introduction of multimodal treatment, refinements in preclinical staging and improvements in surgical skills, local relapse is no longer the major problem for patients with LARC. However, many patients die of metastatic disease. The present phase Ib study aimed to establish the maximum tolerated dose of everolimus combined with 5-fluorouracil and radiotherapy in patients with LARC. Patients and Methods Patients were sequentially assigned to 4 cohorts with an increasing dose of everolimus, starting from 14 days before 5-fluorouracil and radiotherapy and continuing throughout concomitant treatment. The secondary endpoints were the Dworak tumor regression grade, pathologic complete response rate, neoadjuvant rectal score, biomarker assessment (phosphorylated mTOR [mammalian target of rapamycin] protein and phosphorylated-p70S6K protein). Results At the time of this report, 12 patients had been treated, and no dose-limiting toxicity was recorded. The most frequently reported acute toxicities were rectal tenesmus, skin rash, diarrhea, and dysuria. All 12 patients underwent curative R0 resection. Two patients had Dworak tumor regression grade 4 (pathologic complete response). No everolimus-related postoperative complications were observed. No relationship was found between biomarker expression and the clinicopathologic outcomes. Conclusion Although the addition of everolimus did not appear to worsen the toxicity of chemoradiation in patients with LARC, evaluation of its activity deserves further investigation in larger clinical trials.