Work

A phase 1 study of 4’-thio-2’-deoxycytidine in patients with solid tumors

Year: 2026

Type: article

Abstract: PURPOSE: The DNA methyltransferase (DNMT) inhibitor 4'-thio-2'-deoxycytidine (TdCyd), a second-generation cytidine analog, demonstrated potent preclinical antitumor activity and favorable pharmacokinetics, which led us to explore its safety, efficacy and anti-tumor activity in patients with solid tumors. METHODS: Adult patients with advanced solid tumors received TdCyd orally on days 1-5 and 8-12 in 21-day cycles. Dose escalation proceeded according to design 4 of the Simon accelerated titration design, changing to a 3 + 3 dose escalation design in the event of dose-limiting toxicities. Blood samples were collected for circulating tumor cell (CTC) evaluation of p16 re-expression as a marker of TdCyd epigenetic modulation, and for pharmacokinetic analysis. RESULTS: Twenty-seven patients were enrolled. The maximum tolerated dose was not reached. The best response was prolonged stable disease (SD), with 3 patients on treatment for ≥ 6 cycles, and there was no dose-response relationship. An increase in the proportion of p16-expressing cytokeratin-positive (CK+) CTCs was detected in 71% (15 of 21) of patients evaluable for p16 response at every dose level in which patients were assessable for pharmacodynamic response; p16 re-expression in vimentin-positive CTCs was reported in 38% (6 of 16) of evaluable patients. Plasma levels of TdCyd metabolites were largely dose proportional and higher levels were detected in patients with higher incidence and severity of study drug-related adverse events. CONCLUSION: Prolonged SD and p16 re-expression at lower TdCyd dose levels suggest that longer exposures to low concentrations is worth exploring in future trials, including studies of TdCyd in therapeutic combinations.

Source: Cancer Chemotherapy and Pharmacology

DOI: 10.1007/s00280-026-04969-8