A phase 1 study of NTX-301, an oral DNMT1 inhibitor, in patients with MDS and AML (trial in progress).

TPS7077 Background: Patients with relapsed and/or refractory (r/r) myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) who are not candidates for stem-cell transplantation have dismal outcomes. Novel therapies are needed. The nucleoside analogue NTX-301 (5-aza-4’-thio-2’-deoxycytidine or Aza-TdC) is incorporated into DNA, where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes. DNMT1 can become trapped in a covalent complex with DNA, thus depleting free enzyme and inhibiting the normal maintenance methylation of CpG sites, resulting in re-activation of tumor suppressor genes. Preclinical data suggest a correlation between NTX-301 activity in leukemia xenograft models and decreased levels of DNMT1. NTX-301 offers an improvement over traditional DNA methyltransferase inhibitors (azacitidine, decitabine) by virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity. Methods: This is a phase 1, open-label, multi-center, dose-escalation study to assess the safety, tolerability, and recommended myeloid monotherapy dose of NTX-301 in patients with r/r myeloid neoplasms. Patients ≥ 18 years with r/r higher-risk MDS (intermediate, high, very-high risk by IPSS-R), high-risk CMML (int-2/high by CPSS or CPSS-mol), or AML (marrow blasts ≤ 30% or WBC < 20,000 cells/µL without leukoreduction) are eligible. Other key eligibility criteria: Eastern Cooperative Oncology Group performance status 0–2; adequate cardiac, renal, and liver function; and resolved acute effects of any prior therapy. Successive cohorts of patients will receive escalating doses of NTX-301 starting from 2 mg QD. Each cycle is 21 days in duration (treatment for 5 days/week x 2 weeks and 1 week off). The trial incorporates accelerated titration design for dose level 1 and 2 followed by traditional 3+3 dose escalation design (3-6 patients per cohort) from dose level 3. Intrapatient dose escalation is allowed. NTX-301 treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. Primary endpoints: incidence and severity of adverse events, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), biologically effective dose (BED). Secondary endpoints: PK parameters of NTX-301, PD assessment through global hypomethylation assay and other markers in blood and marrow, and clinical efficacy [overall response rate (ORR), complete remission (CR), marrow CR (mCR), partial remission (PR), stable disease (SD), hematologic improvement (HI) per mIWG criteria]. After the MTD/BED is identified, the safety and efficacy of NTX-301 will be explored further in selected myeloid malignancies. The study began enrolling patients in January 2021 and is still recruiting. Clinical trial information: NCT04167917.