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).

MethodsStudy 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.

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2025
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