Background: Up to half of patients treated ith salvage radiation therapy  RT  for rising PSA ultimately develop a second biochemical recurrence  sBCR . Phosphatase and tensin homolog inactivation is implicated in prostate cancer progression, and upregulation of the mammalian target of rapamycin  mTOR  pathay can lead to tumor hypoxia and radioresistance. Everolimus is an mTOR inhibitor ith both anti-tumor and radiosensitizing effects. Methods: We performed an investigator-initiated phase I study using a modified 3+3 dose-escalation design to evaluate the safety and tolerability of everolimus in combination ith standard salvage RT for the treatment of BCR folloing prostatectomy. After a to-eek run-in period of everolimus daily therapy, patients received prostate bed irradiation  15 IMRT, 1 proton  ith daily cone beam CT localization in 37 fractions of 1.8 Gy each  total dose 66.6 Gy . Patients ere monitored for both acute   x2264; 90 days  and chronic     90 days  treatment-related toxicities. sBCR as defined as a rise in PSA of   0.5 ngml above nadir folloing the completion of protocol therapy. Results: 16 patients received everolimus at dose levels of 5 mg  dose level 1 , 7.5 mg, or 10 mg daily in conjunction ith RT. One patient ithdre consent after 7 days of everolimus and is unevaluable for follo-up. No dose-limiting toxicities ere observed. The most common acute treatment related toxicities included: Grade 12 mucositis  63 percent , Grade 12 fatigue  44 percent , Grade 12 rash  56 percent , and Grade 1 urinary symptoms  63 percent . Three patients  19 percent  experienced a Grade 3 acute toxicity  N = 1 for rash, anemia, and neutropenia , and no patients experienced Grade  3 chronic toxicity. After a median follo-up time of 20.1 months, five patients  33 percent  developed sBCR. The median time to sBCR as 33.8 months  IQR 20.1  46.0 months . Conclusions: Everolimus at a dose of x2264; 10 mg daily appears to be safe and tolerable in combination ith fractionated post-prostatectomy RT. As everolimus has anti-tumor efficacy in a variety of solid tumor malignancies, the use of everolimus ith RT could be safely considered for further investigation in multiple solid tumors. Clinical trial information: lta href=http:clinicaltrials.govshoNCT01548807 NCT01548807,J Clin Oncol 34, 2016  suppl; abstr e16617 ,NCT01548807Publication Only Genitourinary  Prostate  Cancer