Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation.
Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used.
Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively.
The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.
Departments of *Hematology Oncology
¶¶Hematology Oncology, Emory University, Atlanta, GA
Departments of ¶Medicine
†††Radiation Oncology, Vanderbilt University, Nashville, TN
***Basic Research Miller School of Medicine, Miami, FL
N.F.S., J.L., and A.B.C.: conceptualization. N.F.S., S.F., C.S., F.F., F.W., A.P., K.C., Z.C., L.G., D.C., E.L., J.N., A.K., K.H., J.L., and A.B.C.: data curation. N.F.S., Z.C., S.S., W.E.-R., and A.B.C.: formal analysis. N.F.S. and A.B.C.: funding acquisition, project administration, resources, and validation. N.F.S., A.K., R.D.H., T.O., S.S.R., D.M.S., J.J.B., B.F.E.-R., S.S., W.E.-R., J.L., and A.B.C.: investigation. Z.C. and W.E.-R.: methodology. N.F.S.: supervision and writing—original draft.
This study was approved and funded by Novartis to NFS. The biomarker studies were supported by the Vanderbilt-Ingram Cancer Center Support Grants P30CA68485, NCI U01CA142565, and UL1TR000445.
The authors declare no conflicts of interest.
Reprints: Nabil F. Saba, MD, 1365 Clifton Road, building C, Atlanta, GA 30322. E-mail: email@example.com.