Background: Approximately 20% of patients with localized prostate cancer who undergo curative-intent radiotherapy develop a clinical recurrence after radiation. Half of these clinical recurrences are a local radio-recurrence (LRR). Patients with LRR have multiple potential salvage local therapy options, but there are limited data guiding management. Prospective clinical trials demonstrate 5-year freedom from biochemical recurrence of ~50-70% with salvage brachytherapy using primarily whole-gland low dose rate or high dose rate (HDR) brachytherapy. However, the risk of severe grade ≥3 late toxicity is 5-15% in prior series, suggesting an opportunity to improve the therapeutic ratio. The F-SHARP trial was designed to study focal salvage HDR brachytherapy as a means to treat LRR after definitive radiotherapy and reduce the toxicity of re-irradiation. Methods: F-SHARP is a two-staged non-randomized phase I/II trial of focal salvage HDR brachytherapy for LRR prostate cancer. The study originated at a single center but will be opening at 3 other institutions in late 2020. Eligibility criteria include biopsy-proven local recurrence after curative radiation therapy (any form) for cT1-T3a N0 M0 prostate adenocarcinoma, no radiographic evidence of nodal or metastatic disease prior to enrollment on CT/MRI and bone scan (fluciclovine PET/CT encouraged), current IPSS ≤20, and no grade ≥3 CTCAE v 4.03 toxicity from prior RT. Initially, study HDR was delivered as a single fraction of up to 30 Gy to the target volume (gross recurrent tumor + 5 mm), with priority given to normal tissue constraints. Based on data in the definitive HDR brachytherapy setting suggesting inferior outcomes with single fraction HDR, a 2 fraction regimen (again delivering up to 30 Gy to the gross recurrent tumor + 5 mm) was added as an option as well. The primary endpoint is Grade ≥3 CTCAE V4.03 RT-related toxicity at 3 months. Assuming that the true toxicity rate in the population is 10% or less, the study has 81% power to reject the null hypothesis that the toxicity rate is 33% or higher. In the first stage, 7 patients will be accrued. If there are 2 or more toxic responses in these 7 patients, the study will be stopped for safety reasons. Otherwise, 17 additional patients will be accrued for a total of 24 patients to evaluate the primary endpoint. After completion of the 24 patient toxicity assessment, the cohort expands to 50 subjects to study freedom from biochemical recurrence (secondary endpoint). Other secondary endpoints include local control, freedom-from local failure, freedom from elsewhere-prostate control, freedom from distant metastasis, freedom from hormonal therapy, disease-free survival, cause-specific survival, and overall survival. The study has completed the initial 24 patient toxicity assessment and continues accrual in the expansion cohort. Clinical trial information: NCT03312972