Patients with confirmed stage II or III rectal cancer were recruited in 4 cohorts of 3 patients per dose level, with an expansion cohort at the maximum tolerated dose. A 3 + 3 dose escalation design was used. Radiation was given in 28 fractions at 1.8 Gy (50.4 Gy) day 1–5 at all dose levels. Initial dose of sorafenib was 200 mg qd and titrated up to 400 mg BID to determine the MTD. Standard dose of infusional 5-FU was used (225 mg/m2/24 h). Patients underwent surgery 6–10 weeks after neoadjuvant therapy.
Between August 2011 and August 2014, 17 patients (median age of 54 years) were enrolled. After toxicities requiring dose interruptions were observed in cohort 1 (2 patients with grade 2 (G2) and grade 3 (G3) hand foot skin reaction and 1 patient with G2 mucositis), the protocol was amended, changing administration of chemotherapy and sorafenib from daily to days 1–5 only. With the amended protocol, the primary G3 toxicity was hypertension in 2 patients at the 200-mg adjusted dose level (day1–5) and 1 patient at the 400-mg twice daily dose level. One patient had G3 ALT elevation at 400 mg, and no grade IV toxicities were observed. G1 and G2 toxicities included hand-foot skin reaction, diarrhea, mucositis, nausea, fatigue, and proctitis. No perioperative complications were seen. Two patients refused to undergo surgery. The pathological complete remission (pCR) rate was 33%, and downstaging was observed in 85.7% of patients. Median neoadjuvant rectal cancer score was 8.7.
With the changed dosing schedule, this regimen was very well tolerated. The tumor pCR and downstaging rates are encouraging and support further clinical investigation of this regimen.