A phase I/II study of RX-3117, an oral antimetabolite nucleoside, in combination with nab-paclitaxel (nab-pac) as first-line treatment of metastatic pancreatic cancer (met-PC): Preliminary results.

Abstract

420 Background: RX-3117 is an oral small molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by cancer-enriched uridine cytidine kinase 2. Single agent RX-3117 has demonstrated efficacy in a phase III single agent clinical study of RX-3117 in met-PC and bladder cancer. RX-3117 in combination with nab-pac is being evaluated as first line treatment of met-PC cancer. Methods: This is a multicenter, open label phase I/II study (NCT03189914). Eligible subjects (aged ≥ 18 years) have histologically or radiologically proven met-PC with no prior therapies for metastatic disease, ECOG PS 0-1, and normal lab values. phase I identified the MTD dose that is being further evaluated in the phase II: RX-3117 (700 mg administered orally once-daily for 5 consecutive days with 2 days off per week) and nab-pac (125 mg/m2 administered once weekly) for 3 weeks with 1 week off per 4-week cycle. The Safety Committee reviewed data from phase I before moving to phase II. The primary endpoint of phase II (dose expansion) is an adequate number of responders based on PFS at 4 months and/or objective clinical response per RECIST v1.1. Results: As of September 21, 2018, 8 phase I subjects and 13 phase II subjects were enrolled and treated (9 males and 12 females, median age 67 years). The most common (≥ 15%) related adverse events were nausea, diarrhea, fatigue, alopecia, decreased appetite, rash, vomiting, and anemia. Fourteen subjects had at least one on-study scan (after 2 cycles). One subject experienced a complete response (CR) after 6 cycles of therapy with normalization of CA19.9 (-76%). Three subjects exhibited a partial response (PR): two after 2 cycles (39-47%) and one after 4 cycles of therapy (36%). Eight subjects had stable disease for at least 2 months, and 4 subjects had PFS of at least 4 months. The disease control rate (CR+PR+SD) was 86% in evaluable subjects while the overall response rate (CR+PR) was 29%. Conclusions: RX-3117 in combination with nab-pac appears to be safe and well tolerated in subjects with met-PC. Antitumor activity per RECIST was observed in 12 subjects. Phase II of the clinical study is currently ongoing. Clinical trial information: NCT03189914.

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

“…weekly) for 3 weeks with one week off in patients with metastatic pancreatic cancer [37]. Preliminary updated data (Clinical Trial number NCT03189914; Jan 2019 [38]) revealed a disease control rate of 92% (22/24 patients) at 8 weeks, including a CR after 6 cycles of therapy, 8 PR and 13 SD [38]. PK analyses indicated that RX-3117 and nab-paclitaxel did not interfere with each other, with comparable Cmax and AUC for RX-3117 as in the single-agent study.…”

Enzymatic Synthesis of Aptamer-Polynucleotide Nanoparticles with High Anticancer Drug Loading for Targeted Delivery

“…We have reported here a new methodology for the synthesis of polymers of nucleoside-mimetic drugs by TcEP. , The development of this simple and potentially scalable synthetic methodology was motivated by the observation that nucleoside drugs such as 5FU and gemcitabine are currently used to treat solid tumors ,, and that several nucleoside and nucleotide analog drugs are currently in clinical trials for treatment of various cancers. − Unfortunately, these drugs have a high IC 50 and a narrow therapeutic window, thus methods to deliver a high drug payload to tumor cells to enhance its efficacy and avoid systemic toxicity are clearly needed. To increase the payload of such drugs, polymerization of prodrugs or encapsulation in nanoparticles (NPs) are common approaches.…”