Phase IB study of induction chemotherapy with XELOX, followed by radiation therapy, carboplatin, and everolimus in patients with locally advanced esophageal cancer (EC).

Abstract

e15607 Background: Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation and platinum agents in EC. We conducted a multi-institutional phase IB trial to determine the recommended phase II dose (RP2D) of concurrent everolimus with carboplatin and radiation in non-metastatic EC pts. Methods: Patients with untreated, localized EC and ECOG performance status 0-1 were eligible. Following two cycles of induction Capecitabine/Oxaliplatin (XELOX), pts without evidence of disease progression, received concurrent chemoradiation (total dose: 50.4Gy in 28 fractions), weekly carboplatin (AUC = 2), and escalating doses of everolimus. A standard 3+3 dose escalation design was used. Results: Nineteen patients were enrolled. There were two screen failures (thrombocytopenia, metastases) and 4 pts were removed due to poor tolerance of XELOX (2 pts) or disease progression (2 pts). A total of 13 pts with stage II/III (6/7) EC completed concurrent therapy. Median age 58 (44-71yrs), 85% males; all had adenocarcinoma deemed resectable. One pt at dose level 1 (2.5 mg/QOD), was replaced due to ongoing anxiety. One of 6 pts had a DLT (bowel ischemia). At dose level 2 (2.5mg/QD), 2 out of 6 patients had a DLT (fever with neutropenia and nausea). The RP2D of everolimus was 2.5 mg QOD. Clinically relevant ≥ grade 3 toxicities included lymphopenia (25%), dehydration (12%), fatigue, leukopenia, hyponatremia, abdominal pain, vomiting (each 6%). R0 resection was achieved in 100%; a pathologic response rate (RR) of 40% and a pathologic complete response (pCR) rate of 23% were observed. The 2-year PFS and OS were 50% and 49.6% respectively. Conclusions: The RP2D of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD. Despite the 100% R0 resection rate, the pCR and OS rates were within the expected historical controls. (The study was funded by Novartis Pharmaceuticals) Clinical trial information: NCT01490749.