MYC targeting by OMO-103 in solid tumors: a phase 1 trial

Abstract

MYC; Solid tumors

MYC; Tumores sólidos

MYC; Tumors sòlids

Among the ‘most wanted’ targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg−1). ClinicalTrials.gov identifier: NCT04808362.

The authors from Vall d’Hebron Institute of Oncology (VHIO) thank the Cellex Foundation for providing research facilities and equipment, and the CERCA Program from the Generalitat de Catalunya for their support on this research. They also acknowledge the State Agency for Research (Agencia Estatal de Investigación) for financial support as Center of Excellence Severo Ochoa (no. CEX2020-001024-S/AEI/10.13039/501100011033). We thank the teams at Abzu and Biognosys for their valuable service and feedback, and M.-A. Morcillo for his help in the interpretation of PK data. This research has received funding from the Generalitat de Catalunya (AGAUR grant no. 2021/SGR 01509); from the European Union Horizon 2020 research and innovation program under grant agreement nos. 872212 and 101144681; from the Ministerio de Ciencia e Innovación, grant no. RTC2019-007067; from the Ministerio de Ciencia, Innovación y Universidades, grant nos. CPP2022-009808 and PLEC2021-007959 by MCIN/AEI/10.13039/501100011033 and European Union NextGenerationEU/PRTR.