Abstract CT059: A phase I, open-label, multi-center dose-finding and expansion study to investigate the safety, tolerability, and preliminary efficacy of CR1-02 (5-FU-miR-15a) in patients with acute myeloid leukemia

Abstract Introduction: Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease where most patients relapse and have limited long-term survival. Previous studies have shown that tumor suppressor microRNA such as miR-15a plays a key role in AML and other tumor types by suppressing oncogenic targets/pathways such as BCL-2, BMI-1, WEE-1, CHK1, DCLK-1, and MCL-1. By modifying miR-15a with the cytotoxic pyrimidine 5-fluorouracil (5-FU), the 5-FU-miR-15a (CR1-02) miRNA has exhibited enhanced therapeutic efficacy, stability, as well as deliverability in multiple tumor types in pre-clinical testing. Aim: CR1-02 (EudraCT number: 2021-006332-46) is a phase I dose-escalation study evaluating the safety and tolerability of CR-001 in adults with relapsed/refractory (R/R) AML. Methods: A 3+3 study design was used with patients receiving dose levels of the synthetic double-stranded mimic of miR-15a (miRNA) (CR1-02) of 7.5 mg, 11.25 mg, 15 mg, and 18.75 mg/administration, weekly dosing. Route: administered intravenously. Excipient: GMP-grade linear polyethyleneimine (α-Methyl-ω-hydroxy-poly[(iminioethylene)chloride]; Poly[imino(1,2-ethanediyl)]; CAS Number 26913-06-4; PEI) as fixed-dose: 15 mg PEI with 7.5 mg CR1-02 and 20 mg PEI with all other dose levels of CR1-02. Biomarker data utilizing mass cytometry (CyTOF) of full blood leukocytes of peripheral blood and bone marrow was used to quantify labeled targets on the surface and interior of single cells. Results: Treatment of 11 AML patients (average age 70 y, 10 of 11 ELN2017 adverse risk) with CR1-02 was well-tolerated through 58 doses (range 1-8, average 5) administered across the 4 dose levels. The most common event was chills during the infusion, which were reduced by increasing the infusion time to two hours. One patient (NRAS VAF 48%, ASXL1 41%, TP53 23%) responded with elimination of extramedullary pericardial AML disease after 4 doses of CR1-02 but progressed in bone marrow after 8+8 doses of CR-001 (eight study doses and an additional eight doses given under compassionate use approval from the Norwegian Medicines Agency) followed by trametinib-treatment as part of another study. Five of 11 patients experienced ELN-stable disease on CR1-02. Single-cell profiling mass cytometry showed signs of molecular activity of CR1-02 on known targets of miR-15a (e.g., BMI1, WEE1, and MCL-1) at the lowest dose level (7.5 mg). At the same time BAX, a marker of pro-apoptosis, showed an increase following treatment. Conclusion: Treatment with CR1-02 was well tolerated and showed biological activity as evidenced by disease stabilization in R/R AML patients. Reduction of CR1-02 targets was achieved beginning at the lowest dose given (7.5 mg/administration), and clinical efficacy signals starting at 11.25 mg/administration. Future investigation is warranted as a promising microRNA-based cancer therapeutics either alone or in combination with other therapeutic agents. Citation Format: Bjørn T. Gjertsen, Andrea Lenartova, Irini Ktoridou-Valen, Cara E. Wogsland, Adam S. Dowrick, Mark Wood, Thomas Dahl, Andrew Fesler, Jingfang Ju. A phase I, open-label, multi-center dose-finding and expansion study to investigate the safety, tolerability, and preliminary efficacy of CR1-02 (5-FU-miR-15a) in patients with acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT059.