Abstract CT252: A modular, open-label, phase I/II study to evaluate the safety, tolerability, pharmacokinetics and efficacy of EP0031, a next generation selective RET inhibitor, in patients with advanced RET-altered malignancies
Authors: Gianoukakis Andrew G. , Arnold Susanne , Khan Saad , Taylor Matthew , Arkenau Hendrik-Tobias , Clark Liz , Fisher Geoffrey , Subbiah Vivek 
Published: April 2023

Abstract
Background: Addressing resistance to 1st generation selective RET inhibitors (SRI) is an area of high unmet need, with a number of RET dependent and independent pathways identified1,2. The ideal profile of a next generation SRI has been proposed: broad activity against RET fusions/mutations, inhibition of both V804M/L gatekeeper and G810C/S/R solvent front mutations and penetration of the CNS to address brain metastases1,2. This trial is evaluating whether EP0031, an orally available next generation SRI, can address resistance to 1st generation SRIs and improve on their clinical profile.
Methods: This Phase 1/2 study (NCT05443126) is recruiting up to 265 patients with NSCLC, thyroid cancer or other solid tumors with RET aberrations. The 1st part of the study is a dose escalation to investigate safety, tolerability, PK and PD and to define the maximum tolerated dose (MTD) and/or Recommended Phase II Dose (RP2D). Dose escalation is based on a rolling 6 design and is expected to recruit up to 40 patients.
Once an RP2D is established, expansion cohorts of approximately 25 evaluable patients each will further explore the safety and tolerability of EP0031, and provide preliminary efficacy data in selected patient populations with RET-altered tumors:•Four cohorts of patients with NSCLC and medullary thyroid cancer who have progressed on 1st generation SRI therapy and in patients with no prior SRI•Two cohorts of patients with other solid tumors, including differentiated thyroid cancer, who have progressed following 1st generation SRI therapy, and in patients with no prior SRI
Key inclusion criteria are as follows:•Male or female ≥ 18 years of age, with a diagnosis of an advanced solid tumor with documented RET altered malignancy •ECOG Performance Status of 0 or 1 at screening with no deterioration over the previous 2 weeks. For expansion cohorts patients must have a solid tumor measurable by RECIST v1.1, with/without asymptomatic, stable brain metastases
Recruitment was initiated in the US in November 2022 and is expanding to centers across Europe and rest of world. A parallel Phase I/II trial is ongoing in China (A400, NCT05265091, Kelun Biotech).
1Annals of Oncology 32(2) S66 (2021)2Journal Thoracic Oncol 15(4) 542 (2020)
Citation Format: Andrew G. Gianoukakis, Susanne Arnold, Saad Khan, Matthew Taylor, Hendrik-Tobias Arkenau, Liz Clark, Geoffrey Fisher, Vivek Subbiah. A modular, open-label, phase I/II study to evaluate the safety, tolerability, pharmacokinetics and efficacy of EP0031, a next generation selective RET inhibitor, in patients with advanced RET-altered malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT252.