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

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.