Abstract OT3-23-01: VELA: A first-in-human phase 1/2 study of BLU-222, a potent, selective cyclin-dependent kinase (CDK) 2 inhibitor in patients with cyclin E1 gene (CCNE1)-amplified or CDK4/6 inhibitor-resistant advanced solid tumors
Authors: Patel Manish R , Juric Dejan , Henick Brian S , Moore Kathleen N , Do Doreen , Chapman Joshua , Zhang Hui , Roche Maria , Newberry Kate J , Rinne Mikael , Yap Timothy A 
Published: March 2023

Abstract
Background The regulation of cell growth and proliferation is dependent on cyclins and CDKs. The formation of the cyclin D-CDK4/6 complex increases the expression of cyclin E1 and E2. Cyclin E1 and E2 bind to and activate CDK2; this results in a cyclin E/CDK2 complex that assists with downstream expression of DNA synthesis machinery. The use of CDK4/6 inhibitors such as palbociclib or ribociclib is an effective treatment in patients with hormone receptor-positive (HR+), human epithelial growth factor receptor-2 negative (HER2-) breast cancer; however, resistance to treatment eventually occurs. Aberrant cyclin E/CDK2 activity has been identified as a potential resistance mechanism by which tumors can evade CDK4/6 inhibitors. BLU-222 is an oral, investigational, potent, and selective CDK2 inhibitor. In preclinical studies, BLU-222 treatment in combination with ribociclib led to durable tumor regression in both CDK4/6-resistant and sensitive models of HR+HER2- breast cancer. Trial design VELA (NCT05252416) is an international, open-label, first-in-human phase 1/2 study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of BLU-222 in adult patients with CCNE1-amplified tumors or with HR+HER2- breast cancer with disease progression on CDK4/6 inhibitors. In phase 1 and 2, patients aged ≥18 years with an Eastern Cooperative Oncology Group performance status 0–2 are eligible. In phase 2, all patients must have ≥1 measurable target lesion per Response Evaluation Criteria in Solid Tumors version 1.1. Primary endpoints include assessing the safety of BLU-222 as a single agent or BLU-222 in combination with either carboplatin or ribociclib and/or fulvestrant (phase 1 and 2), identifying the maximum tolerated dose and/or recommended phase 2 dose (phase 1), and determining the objective response rate (phase 2). In the phase 1 dose-escalation part, patients with any advanced solid tumor with progression on standard of care (SOC) will receive BLU-222; patients with gastric or endometrial cancer (EC) with progression on ≥2 prior therapies (including ≥1 platinum-based therapy) or with CCNE1-amplified platinum-resistant/refractory ovarian cancer (OC) will receive BLU-222 and carboplatin; patients with HR+HER- breast cancer with progression on CDK4/6 inhibitors will receive BLU-222, ribociclib, and fulvestrant. In the phase 2 dose-expansion part, patients with CCNE1-amplified tumors including EC (progression on ≥2 prior therapies), platinum-resistant/refractory OC, or other advanced solid tumors (progression after SOC) will receive BLU-222 monotherapy; patients with CCNE1-amplified platinum-resistant/refractory OC will receive BLU-222 and carboplatin; and patients with CDK4/6 inhibitor-resistant HR+HER2- breast cancer will receive BLU-222 and fulvestrant with/without ribociclib. Pharmacokinetic parameters will be calculated using standard non-compartmental methods from the plasma concentration–time data. Tissue biopsies will be collected during cycle 1 to assess the phosphorylation of retinoblastoma 1 (Rb1) protein which will be used as a pharmacodynamic marker to assess target inhibition. Dose escalation is ongoing and approximately 50 sites are anticipated to enroll patients across North America, Europe, and the Asia/Pacific region.
Citation Format: Manish R Patel, Dejan Juric, Brian S Henick, Kathleen N Moore, Doreen Do, Joshua Chapman, Hui Zhang, Maria Roche, Kate J Newberry, Mikael Rinne, Timothy A Yap. VELA: A first-in-human phase 1/2 study of BLU-222, a potent, selective cyclin-dependent kinase (CDK) 2 inhibitor in patients with cyclin E1 gene (CCNE1)-amplified or CDK4/6 inhibitor-resistant advanced solid tumors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-23-01.