A first-in-human study of ATX-295, an oral inhibitor of KIF18A, in patients with advanced or metastatic solid tumors, including ovarian cancer.

TPS3167 Background: ATX-295 is an oral inhibitor of KIF18A, an adenosine triphosphate (ATP)-dependent, plus end-directed mitotic kinesin. KIF18A facilitates chromosomal alignment and spindle microtubule dynamics during mitosis in certain advanced solid tumors with chromosomal instability (CIN). In preclinical studies, ATX-295 demonstrated robust antiproliferative activity in chromosomally instable solid tumor models, including in high grade serous ovarian cancer. In vivo, oral administration of ATX-295 induced dose-dependent tumor growth inhibition in CIN platinum-resistant ovarian and squamous non-small cell lung cancer cell-line derived xenograft (CDX) and patient derived xenograft (PDX) models. Methods: NCT06799065 is a multi-center, first-in-human, Phase 1/2, open-label, single-arm, dose-escalation and expansion study to evaluate the safety profile of ATX-295 and determine the recommended phase 2 dose (RP2D) in subjects with locally advanced or metastatic solid tumors. The study in progress will be conducted in two parts: dose escalation, followed by dose expansion. Participant enrollment and continuous safety assessment will be guided by a mTPI-2 design (Guo, 2017) to identify an optimal dose. To assess evidence of preliminary antitumor activity, a Simon 2-stage design (Simon, 1989) will be used during dose expansion. Key eligibility criteria: patients with histologically confirmed solid tumors who have locally recurrent or metastatic disease, including high grade serous ovarian cancer (HGSOC) and squamous non-small cell lung cancer (sqNSCLC); refractory to or relapsed after all standard therapies with proven clinical benefit. For the expansion cohorts, participants must have histological confirmation of HGSOC and be determined to be platinum-resistant, platinum-refractory, or platinum-intolerant; have measurable disease; have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Primary endpoints will evaluate safety and tolerability of ATX-295 at pharmacologically active dose(s) and/or schedule(s) and determine the recommended phase 2 dose (RP2D). Secondary endpoints will evaluate pharmacokinetics (PK) of ATX-295 in plasma and evaluate pharmacodynamic (PD) effects of ATX-295 to assess preliminary evidence of anti-tumor activity. The study is actively recruiting. Clinical trial information: NCT06799065 .