Background: Ganetespib (G) is a heat shock protein 90 inhibitor . Preclinical data show that G is a potent radiosensitizer for rectal cancer. The aim of this study is to determine the recommended phase II dose of G when combined with capecitabine (C) and radiation (RT) in resectable rectal cancer. Methods: Patients (pts) with stage II or III rectal adenocarcinoma with distal border within 12 cm of anal verge, no prior therapy, and adequate organ functions, were eligible. A 3+3 dose escalation design was used. Pts received 2 weeks of G at 150 mg/m² I.V. on days -14, -11, -7, and -4. Pre and post-treatment tumor biopsies were obtained. C (825 mg/m²) and RT (50.4Gy) were administered 5 days per week for 5.5 to 6 weeks starting day 1. G was administered on days 1, 8, 15, 29 and 36. G dose levels were 60, 80, 100, and 120 mg/m². Pharmacokinetic sampling for C and G were performed on days 1, 2, 15, and 16. Dose limiting toxicities (DLT) were defined as the occurrence of any treatment related: grade (gr) 4 hematologic or gr 3 or higher non-hematologic toxicities, gr 3 nausea, vomiting or diarrhea lasting > 4 days, any interruption of RT > 10 days, more than 2 interruptions in RT, delay in completion of RT for > 14 days, or inability to deliver more than 85% of planned RT dose. Results: 16 pts were enrolled in the study; 1 pt received only day-14 and was not .evaluable for toxicity. Evaluable pts had a median age of 61 yrs, 7 females, and endoscopic stage: T3N0 (6 pts), T3N1 (6), T3N2 (2), T4N1 (1); 3 pts were treated on each dose level, 2 pts on dose level 4 required dose reduction, so we enrolled 3 additional pts on level 3 (100 mg/m²). One DLT was observed (gr 3 diarrhea for more than 4 days). Other toxicities on the study were: diarrhea gr 3 (3 pts), gr 2 (6), gr 1 (2), radiation dermatitis gr 2 (9), gr 1 (3), fatigue gr 2 (5), gr 1 (4), hand foot syndrome gr 2 (1), mucositis gr 1 (2), and nausea/vomiting gr 2 (2), gr 1 (8). 12 pts have completed surgical resection (2 APR and 10 LAR). Pathologic complete response (pCR) rate was 25% (3/12) and 2 pts had residual tumors less than 1 cm (pT1N0). Six of 9 (67%) pts had clearing of lymph nodes disease on pathologic specimen. Conclusions: G can be safely combined with standard C and RT in the neoadjuvant setting in rectal cancer. Preliminary data on activity appear promising. Clinical trial information: 01554969.