Phase I trial of 5-aza-4’-thio-2’-deoxycytidine (Aza-TdC) in patients with advanced solid tumors.
Authors: Nguyen James , O'Sullivan Coyne Geraldine Helen , Takebe Naoko , Naqash Abdul Rafeh , Mukherjee Jessica , Bruns Ashley , Piekarz Richard , Collins Jerry M. , Anderson Larry , Miller Brandon , Parchment Ralph E. , Rubinstein Larry V , Kummar Shivaani , Sharon Elad , Streicher Howard , Chen Alice P. , Doroshow James H. 
Published: June 2021

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Background: The nucleoside analog Aza-TdC inhibits DNA methyltransferase 1 (DNMT1), which regulates methylation-mediated silencing of tumor suppressor genes. Aza-TdC offers an improvement over traditional DNA methyltransferase inhibitors by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity. Aza-TdC has also shown improved preclinical antitumor activity compared to other hypomethylating agents in some solid tumor xenograft models. In an ongoing phase I trial, we evaluate the safety and activity of Aza-TdC in patients (pts) with advanced solid tumors. Methods: Adult pts with solid tumors whose disease has progressed on standard therapy or for which there is no standard therapy were treated with Aza-TdC administered orally once a day for 5 days of each week for 2 weeks in 21-day cycles. The study followed Simon accelerated titration design 3, with 1 pt per dose level at 100% dose increments. Accelerated titration continued until 1 pt experienced a dose-limiting toxicity (DLT) or 2 pts experience drug-related grade 2 toxicity at any dose level, after which, a 3 + 3 dose escalation design was used. Intrapatient dose escalation was allowed. Correlative studies included pharmacokinetic assays and pharmacodynamic assays in circulating tumor cells. Results: As of January 2021, a total of 18 pts have been enrolled on study. Median pt age is 61.5 years (range 35-84). Tumor types included colorectal adenocarcinoma (5 pts), sarcoma (3), breast carcinoma (2), and ovarian carcinoma (2). The DLTs at 48 mg were grade 3 rash and grade 3 acute kidney injury in one pt and < 75% of dosing completed in another pt due to grade 3 myelosuppression. Among the 10 pts treated at 32 mg, 1 pt experienced a DLT: grade 4 neutropenia. The maximum tolerated dose (MTD) is 32 mg. Grade 3 or 4 toxicities across all cycles possibly attributable to study drug were leukopenia (6), lymphopenia (6), neutropenia (4), rash (2), febrile neutropenia (1), anemia (1), thrombocytopenia (1), acute kidney injury (1), elevated AST (1), elevated ALT (1), diarrhea (1), and dehydration (1). Of the 14 pts evaluable for response, 11 had a best response of stable disease, and 3 had a best response of progressive disease. Median cycles on study is 4 (range 1-10+). A pt with clear cell ovarian carcinoma has been on study for > 10 cycles with stable disease. Conclusions: At the MTD of 32 mg, Aza-TdC is safe and well tolerated with a toxicity profile similar to currently approved hypomethylating agents. Global DNA methylation profiling, RNAseq, and DNMT immunohistochemical analyses of tumor biopsies are planned for the currently accruing dose expansion cohort. Funded by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT03366116.