A Phase I/II Study Investigating Karonudib in Patients with Refractory Haematological Malignancies
Authors: Deneberg Stefan , Uggla Bertil , Smith Austin , Sandvall Theresa , Klockare Maria , Breuer Olof , Warpman Berglund Ulrika , Helleday Thomas 
Published: December 2024

Introduction
MutT homologue 1 (NUDT1)(MTH1) protein has been shown to detoxify cells from Reactive Oxygen Species (ROS) damage andappears to be required for cancer survival. Depleting MTH1 in RAS-transformed tumor cells induces proliferative defects by shifting cancer cellular response away from pro-survival mechanisms. MTH1 is overexpressed in various cancer forms, particularly hematological cancers are ranked amongst the top 10 cancers with the most elevated MTH1 levels. High MTH1 levels have been shown to correlate with poor prognosis in multiple myeloma. Karonudib (TH1579), a mitotic MTH1 inhibitor, has a dual mechanism of action; (I) causing mitotic arrest by inhibiting microtubule dynamics and causing disturbed chromosomes alignment and (II) increasing incorporation of toxic oxidized nucleosides into DNA. It is proposed that Karonudib may have therapeutic benefit in patients with hematological cancers. Therefore, we designed a phase I/II, investigator-initiated trial of Karonudib in adults with advanced relapsed/refractory (RR) Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL) , Diffuse Large B-Cell Lymphoma (DLBCL), Multiple Myeloma (MM) and high-risk Myelodysplastic Syndrome (MDS) (NCT04077307).
Methods
This Phase I, single-arm, dose escalation clinical trial enrolled patients 18-75 years and adequate organ function with escalating doses of Karonudib. In Part 1 of this trial, the safety and tolerability of oral Karonudib monotherapy are being assessed by evaluating the dose-limiting toxicity rate during the first 4 weeks of treatment, using a standard 3+3 design. The primary objective is safety and tolerability, secondary objectives include assessment of clinical benefit, pharmacokinetics with exploratory to evaluate biomarkers and further clarification of mechanism of action. In cohort I, the starting oral dose of Karonudib administered is 170 mg BID every second day. The severity of adverse events is being assessed using NCI CTCAE v5.0. Once the recommended phase 2 dose (RP2D) has been determined, an additional expansion group will be opened to explore the potential of Karonudib when added to Idarubicin in patients with RR AML and high risk MDS. Twenty-five additional patients will be enrolled in the dose-expansion as a 2-stage design. Disease assessment, either by standard radiological assessment or bone marrow examination, was performed on cycle 1 day 22 and at the end of the cycle to assess for early morphologic remission and to inform future dose adjustments.
Conclusion
As of 07/22/2024, 14 patients have been recruited across 3 cohorts and marked the end of the dose escalation part of the MAATEO study. Five patients had AML, four MDS, 3 DLBCL, one AUL and one MM. The RP2D has been determined and the trial will now start recruiting the extension cohort with a possibility to combine Karonudib with Idarubicin in patients with R/R AML and high-risk MDS with an aim to optimize delivery of this combination.