Trial in progress: A phase I study evaluating the safety of cirtuvivint (CIRT) as monotherapy and in combination with ASTX727 in patients with myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML)

Abstract Background and Signficance Patients with relapsed and/or refractory (R/R) MDS or AML have poor outcomes. Outcomes after resistance to venetoclax-based therapy are particularly poor with a median OS of 2.5 months independent of the type of salvage therapy used (Maiti et al., Haematologica 2020). Cirtuvivint (CIRT; SM08502) is an oral, potent inhibitor of the CLK and DYRK kinase families and modulates pre-mRNA splicing by inhibiting the phosphorylation of serine/arginine-rich splicing factors. This trial proposal is based on in vitro and in vivo preclinical data showing that SM08502 (CIRT) overcomes venetoclax resistance and synergizes with venetoclax by impairing X-linked inhibitor of apoptosis protein (XIAP) and a variety of splicing-dependent kinases (Wang et al., Cancer Cell 2023). CIRT has been evaluated in a phase I study in solid tumors and demonstrated potential therapeutic benefit (Scott et al., Ann Oncol. 2022). Methods Study design: This is a phase I, open-label, multi-center investigator-initiated Cancer Therapy Evaluation Program (CTEP) study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and recommended phase 2 dose (RP2D) of CIRT as monotherapy and in combination with ASTX727, a fixed-dose combination of oral decitabine and cedazuridine (NCT06484062). Treatment will be administered in cycles of 28 days. CIRT will be administered orally as monotherapy at different dose levels on a 5-day-on/2-day-off per week schedule (cohort I), or a 2-day-on/5-day-off per week schedule (cohort II). The RP2D determined from cohorts I and II will inform CIRT dosing for cohort III, in which ASTX727 will be administered days 1-5 of each cycle in combination with CIRT. Patients will undergo safety monitoring, including blood sample collection and bone marrow aspiration, at baseline and during treatment. Participants: Adult patients with R/R AML or R/R MDS (both eligible for cohorts I and II) or untreated higher-risk MDS (cohort III), Eastern Cooperative Oncology Group performance status ≤ 3, and adequate organ function will be eligible. Patients must not have received prior treatment with CIRT or similar agents. Primary Objective: The primary objective is to determine the RP2D of CIRT as monotherapy and in combination with ASTX727. Secondary Objectives: Secondary objectives include assessing safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy. Correlative studies investigating biomarkers of response and RNA splicing patterns are also integral to this trial. Statistical methods: The study uses a 3+3 dose escalation design. Determination of the RP2D will consider safety and tolerability data after the end of the DLT period, pharmacokinetic/pharmacodynamic data, and preliminary efficacy data from both cohorts I and II. A minimum of 6 and a maximum of 18 patients will be enrolled in each cohort for a total of 18-54 patients. The planned accrual rate is approximately 1-2 patient(s) per month for a total enrollment period of about 36 months. The RP2D determined will inform CIRT dosing for cohort III. Conclusions This phase I trial will establish the safety and RP2D for CIRT as monotherapy in R/R AML or R/R MDS (cohort I and II) and in combination with ASTX727 for untreated higher-risk MDS (cohort III). The trial is actively recruiting and aims to inform future phase II studies.