No approved medical therapies prevent progression of low-grade prostate cancer (PCa). Rapamycin inhibits cell proliferation and augments immune responses, producing an antitumor effect. Encapsulated rapamycin (eRapa) incorporates rapamycin into a pH-sensitive polymer, ensuring consistent dosing. Here, we present results from a phase I trial evaluating the safety and tolerability of eRapa in patients with PCa. Patients with Gleason <=7 (3+4) disease (low- and intermediate-risk) under active surveillance were enrolled in a 3+3 study with three eRapa dosing cohorts (cohort 1: 0.5mg/week; cohort 2: 1.0 mg/week; and cohort 3: 0.5mg/day). Patients were treated for three months and followed for an additional three months to assess safety, pharmacokinetics, quality of life (QoL), immune response, and disease progression. Fourteen patients (cohort 1: n=3; cohort 2: n=3; cohort 3: n=8) were enrolled. In cohort 3, one dose-limiting toxicity (DLT; neutropenia) and two non-DLT grade 1-2 adverse events (AEs) occurred that resulted in patient withdrawal. All AEs in cohorts 1-2 were grade 1. Peak serum rapamycin concentration was 7.1ng/mL after a 1mg dose. Stable trough levels (~2.0ng/mL) developed after 48-72 hours. Daily dosing mildly worsened QoL, though QoL recovered after treatment cessation in all categories except fatigue. Weekly dosing increased naïve T-cell populations. Daily dosing increased central memory cell populations and exhaustion markers. No disease progression was observed. In conclusion, treatment with eRapa was safe and well-tolerated. Daily dosing produced higher frequencies of lower-grade toxicities and transient worsening of QoL, while weekly dosing impacted immune response. Future studies will verify clinical benefit and long-term tolerability.
Cancer prevention research (Philadelphia, Pa.). 2021 Jan 29 [Epub ahead of print]
Phillip M Kemp Bohan, Robert Connor Chick, Anne E O'Shea, Timothy J Vreeland, Annelies T Hickerson, Jessica L Cindass, Daniel C Ensley, Diane Hale, Guy T Clifton, Vance Y Sohn, Ian M Thompson, George E Peoples, Michael A Liss
Surgery, Kaiser Permanente Fontana Medical Center ., Surgery, Kaiser Permanente Fontana Medical Center., Kaiser Permanente Fontana Medical Center., Surgical Oncology, Kaiser Permanente Fontana Medical Center., Urology, Kaiser Permanente Fontana Medical Center., Madigan Army Medical Center., Administration, CHRISTUS Santa Rosa Hospital - Medical Center., Metis Foundation, Cancer Vaccine Development Program., Urology, The University of Texas Health Science Center at San Antonio.