Background: Normal human prostate epithelium and prostate carcinoma exhibit high levels of oxidative stress, which is thought to play a role in the pathogenesis of prostate cancer. APC-100 (2,2,5,7,8-Pentamethyl-6-chromanol) is an oxidative stress modulator that reduces reactive oxygen species (ROS) in prostate cancer cells and inhibits growth of cultured androgen-dependent and independent human prostate cancer cells. We aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of APC-100 in men with castrate-resistant prostate cancer (CRPC). Methods: This open label phase 1/2a study utilizes a time-to-event reassessment method (TITE-CRM) design. Patients (pts) in cohorts of 3 were treated with escalating doses of APC-100 (900mg-2400mg) orally once daily continuously in 150 mg capsules. Cycles were 28 days. All patients were evaluable with PSAs and imaging studies. Results: Twenty pts (median age 72 [range 54-87]) with metastatic and non-metastatic CRPC were enrolled in the dose escalation cohort. Pts remained on study for a median of 12 weeks (range 4-36) and received therapy for a median of 3 cycles (range 1-9). One possible DLT (elevated ALT) was seen at dose level 1 and the patient was taken off study. No other DLTs at least possibly related to therapy were seen and no dose reductions were required. Most frequent AEs at least possibly related to therapy included nausea (grade 1 in 6 pts) and elevated transaminases (grade 1-3 in 5 patients). After enrolment of 20 pts the MTD was not reached, however the maximal feasible dose was exceeded due to the number of capsules required. Five of the 20 patients had stable disease per PSA and/or RECIST 1.1 as their best response. The median progression free survival (PFS) for the cohort was 2.8 months (range 1-8). Conclusions: APC-100 appears to be well tolerated with the MTD not reached. Limited PK assessment supports the need for alternative formulation to allow dose escalation to doses necessary to achieve exposures required for response. Once MTD is established, future studies will explore the activity of APC-100 as a therapeutic and chemopreventive intervention. Clinical trial information: NCT01436214