A phase 1 study of 4'-thio-2'-deoxycytidine in patients with solid tumors.
Geraldine O'Sullivan Coyne, Shivaani Kummar, Larry Rubinstein et al.
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In 30 seconds
This phase 1 dose-escalation study evaluated oral 4′-thio-2′-deoxycytidine (TdCyd) in adults with advanced solid tumors. Twenty-seven patients received treatment on days 1–5 and 8–12 of 21-day cycles. The maximum tolerated dose was not reached, and prolonged stable disease was the best response; three patients remained on treatment for at least six cycles. Among evaluable patients, p16 expression increased in cytokeratin-positive circulating tumor cells in 71% (15 of 21). The investigators concluded that longer exposure to low TdCyd concentrations merits further study.
Key findings
- The maximum tolerated dose was not reached in the 27-patient dose-escalation study.
- Prolonged stable disease was the best response, with 3 patients treated for ≥ 6 cycles; no dose-response relationship was observed.
- Increased p16 expression in cytokeratin-positive circulating tumor cells occurred in 71% (15 of 21) of evaluable patients.
- TdCyd metabolite plasma levels were largely dose proportional and higher in patients with more frequent and severe drug-related adverse events.
Why it matters
The study provides early clinical evidence of pharmacodynamic activity, including p16 re-expression in circulating tumor cells, alongside prolonged stable disease in some patients. These findings help characterize TdCyd’s dose, exposure, and biological effects in advanced solid tumors, while the absence of a maximum tolerated dose and dose-response relationship leaves the optimal dosing strategy uncertain.
What to keep in mind
This was a small phase 1 dose-escalation study, and the abstract reports stable disease rather than objective tumor responses. Pharmacodynamic findings were available only for evaluable subsets.