Background: At low doses, rapamycin inhibits cell proliferation and angiogenesis while augmenting CD8 T-cell responses, cumulatively producing an antitumor effect. Oral rapamycin is limited by variable bioavailability. Encapsulated rapamycin (eRapa) incorporates submicron rapamycin particles into a pH-sensitive polymer, improving bioavailability and allowing for consistent and lower dosing. Here, we present results of a phase Ib trial evaluating safety and treatment effects of eRapa in patients with low-grade prostate cancer (PCa). Methods: PCa patients with Gleason ≤7 (3+4) under active surveillance were enrolled in a 3+3 study with 3 dosing cohorts (0.5mg weekly, 1mg weekly, and 0.5mg daily) to determine the optimal dosing. Patients were treated for 3 months (m) and followed for 6m. Safety, labs (including PSA), pharmacokinetics, immune response, and quality of life (QOL) were assessed for each cohort. Results: 14 patients were enrolled; 3 in cohort 1, 3 in cohort 2, and 8 in cohort 3. 2 patients withdrew for non-dose limiting toxicity (DLT) (grade 1-2) adverse events (AEs) in cohort 3, leaving 6 evaluable. A single grade 3 DLT (neutropenia) occurred in cohort 3. No AEs > Grade 1 occurred in cohorts 1/2. Peak serum rapamycin concentration ([Rapa]) was 7 ng/mL after a 1 mg dose (2h after administration). Stable trough levels (2 ng/mL) were established after 48 hrs and persisted to 13wks. Central memory CD8 T cells and CD3+/CD56+ NK cells were more prevalent in cohort 3 than other cohorts at 1m (p = 0.027 and p = 0.041) and 3m (p = 0.023 and p = 0.049). There was no significant change in PSA level; no patients clinically progressed on therapy. In cohort 3, there were no differences between baseline and 3m QOL assessments but there was a suggestion of withdrawal effects at 6m. Conclusions: Treatment with low dose eRapa is safe and well-tolerated. The dose of 0.5mg daily produced stable serum [Rapa] through the duration of treatment and resulted in a positive immune impact. Further investigation with low dose and/or intermittent dosing of eRapa as a preventive agent in PCa and other indications will be required to establish clinical benefit. Clinical trial information: NCT03618355