RX-3117, an oral antimetabolite to treat advanced solid tumors (ST): Phase 1 and ongoing phase 2a results

Abstract

Background: RX‐3117 is an oral small‐molecule antimetabolite, cyclopentyl pyrimidyl nucleoside, that is activated by uridine cytidine kinase 2. RX‐3117 shows efficacy in various xenograft models, including those of gemcitabine resistant pancreatic, bladder and colorectal cancers. Data from a Phase 1/2a clinical study of RX‐3117 as a single agent in subjects with advanced ST are described below. Methods: The Phase 1/2a study (NCT02030067) is designed to evaluate safety, tolerability and pharmacokinetics (PK) following increasing doses and schedules of RX‐3117 in eligible subjects (aged > 18 years) with relapsed/refractory ST. Primary objectives include safety and tolerability to determine the MTD and a recommended phase 2 dose and schedule (RP2D); secondary objectives were PK and antitumor activity. Subjects received oral RX‐3117 at 3, 5 or 7 times per week for 3 weeks with 1 week of rest in each 4 week cycle. Phase 2a is ongoing in patients with metastatic pancreatic or bladder cancer in a 2‐stage design, where 10 patients will be treated and if 2 responses are seen, 40 additional patients will be added to the corresponding arm. Results: As of May 2016, 48 subjects were enrolled (30 Females, 18 males), with 4 subject enrolled in the Phase 2a portion. Sixteen subjects experienced stable disease for 1 to 10 cycles; with 11 subjects treated from 82 to 276 days. A tumor burden reduction was seen in 3 subjects with pancreatic, breast and mesothelioma cancers. RX‐3117 PK was dose proportional and was rapidly absorbed with a median Tmax of 2 to 3 hours; accumulation was minimal. The most frequent related adverse events were moderate to severe anemia, mild to moderate fatigue and nausea, mild diarrhea, vomiting, and anorexia. Dose limiting toxicity of anemia was observed at 2000 mg administered 3 times per week. The RP2D is 700 mg for 5 consecutive days per week, 3 weeks on, one week off, per each 4‐week cycle. Conclusions: RX‐3117 is safe and well tolerated. Early anti‐tumor activity has been observed in pancreas, colorectal and mesothelioma cancers. The 2‐stage Phase 2a trial for pancreatic and bladder cancers is ongoing. Final results from the phase 1 and data on the first stage of the Phase 2a will be presented.