Trial In Progress Abstract Phase I Trial Of 5-Aza-4 '-Thio-2 '-Deoxycytidine (Aza-Tdc) In Patients With Advanced Solid Tumors.

TPS3148 Background: The nucleoside analog 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) inhibits DNA methyltransferase 1 (DNMT1), a methyltransferase involved in methylation-mediated silencing of tumor suppressor genes. Attenuation of DNA methylation via DNMT1 inhibitors results in reactivation of silenced tumor suppressor genes and can lead to tumor growth arrest and apoptosis. The DNMT1 inhibitors decitabine and 5-azacytdine are currently FDA-approved for use in myelodysplastic syndromes and are also used in patients with acute myeloid leukemia. Relative to these compounds, Aza-TdC exhibits enhanced stability and incorporation into DNA and has shown improved preclinical antitumor activity in both leukemia and solid tumor xenograft models. This study seeks to evaluate the safety and maximum tolerated dose (MTD) of oral Aza-TdC in patients with advanced solid tumors. Secondary study objectives include assessing objective response by RECIST 1.1, pharmacokinetic (PK) analysis, and examining re-expression of tumor suppressor genes inhibited by methylation in circulating tumor cells (CTCs). Methods: Patients are treated with Aza-TdC on days 1-5 and 8-12 of each 21-day cycle. The study follows Simon accelerated titration design 3, with 100% dose increments and 1 patient per dose level. Accelerated titration will continue until 1 patient experiences a dose-limiting toxicity (DLT) or 2 patients experience drug-related grade 2 toxicity at any dose level, after which, a 3 + 3 dose escalation design will be used. Blood samples are collected for PK and CTC analyses. An MTD expansion cohort is planned, in which tumor biopsies will be collected for further pharmacodynamic assessments. Patients included in this study must be ≥18 years old and have histologically documented solid tumors that have progressed on standard therapy and for which there is no other standard therapy available. Dose level 3 has been completed without any DLTs; enrollment to dose level 4 began in February 2019. Funded by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT03366116.