Abstract 491TiP
Background
Cyclins and cyclin-dependent kinases (CDK) regulate cell growth/proliferation. Several aggressive solid tumor types harbor cyclin E1 gene (CCNE1) amplification, while activated CDK4/6 complex increases expression of cyclin E1 and E2. CDK4/6 inhibitors (CDK4/6i) are effective in patients with estrogen receptor-positive, human epithelial growth factor receptor-2-negative breast cancer (ER+HER2- BC), but treatment resistance generally occurs. BLU-222 is an oral, investigational, potent, selective CDK2 inhibitor. Preclinically, BLU-222 has shown potent CDK2 inhibition and antitumor activity, and combination with carboplatin/paclitaxel led to significant tumor regression.
Trial design
VELA (NCT05252416) is an international, open-label, first-in-human phase I/II study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of BLU-222 in adult patients with either CCNE1-amplified tumors or ER+HER2- BC (progression on CDK4/6i), and an Eastern Cooperative Oncology Group performance status 0–2. Primary endpoints: phase I (maximum tolerated dose, recommended phase II dose), phase II (overall response rate), and phase I and II (safety of BLU-222 monotherapy and in combination with carboplatin, ribociclib and/or fulvestrant). Phase I dose escalation: part 1A (any advanced solid tumor and progression on standard of care [SOC]; BLU-222); part 1C (gastric or endometrial cancer [EC] and ≥2 prior therapies [≥1 platinum-based therapy] or with platinum-resistant/refractory ovarian cancer [OC]; BLU-222 and carboplatin); part 1D (ER+HER- BC [progression on CDK4/6i]; BLU-222, ribociclib, and fulvestrant). Phase II dose expansion: part 2A (CCNE1-amplified tumors including EC [≥2 prior therapies], platinum-resistant/refractory OC, or other advanced solid tumors [progression on SOC]; BLU-222], part 2B and 2D (CDK4/6i-resistant ER+HER2- BC; BLU-222 and fulvestrant with/without ribociclib), part 2C (CCNE1-amplified platinum-resistant/refractory OC; BLU-222 and carboplatin). Approximately 50 sites are anticipated to enroll patients across North America, Europe, and Asia/Pacific.
Clinical trial identification
NCT05252416.
Editorial acknowledgement
Medical writing support was provided by Kyle Wiid, MSc, and George Hsu, PhD, and editorial support was provided by Elke Sims, all of Paragon, Knutsford, UK, supported by Blueprint Medicines Corporation, Cambridge, MA, according to Good Publication Practice guidelines.
Legal entity responsible for the study
Blueprint Medicines Corporation.
Funding
Blueprint Medicines Corporation.
Disclosure
T.A. Yap: Financial Interests, Personal, Other, Consultant: Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Clovis, Cybrexa, EMD Serono, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Varian, Zai Labs, AbbVie, Acrivon, Adagene, Amphista, Artios, Athena, Avoro, Baptist Health Systems, Beigene, Boxer, C4 Therapeutics, Calithera, Cancer Research UK, Diffusion, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Idience, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Kyn, MEI Pharma, Mereo, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Piper-Sandler, Prolynx, resTORbio, Theragnostics, Versant, Vibliome, Xinthera, ZielBio; Financial Interests, Personal, Other, University of Texas MD Anderson Cancer Center, where I am Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios): MD Anderson Cancer Center, Institute for Applied Cancer Sciences; Financial Interests, Personal, Stocks/Shares: Seagan; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GlaxoSmithKline, Karyopharm, Pfizer, Repare, Sanofi, Artios, AstraZeneca, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Eli Lilly, Forbius, F-Star, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, KSQ, Kyowa, Merck, Mirati, Novartis, Ribon Therapeutics, Regeneron, Rubius, Scholar Rock, Seattle Genetics, Tesaro, Vivace, Acrivon, Zenith. K.N. Moore: Financial Interests, Institutional, Other, Advisory boards, scientific steering committees: AstraZeneca, GSK/Tesaro; Financial Interests, Institutional, Advisory Board: Aravive, Alkemeres, Blueprint Medicines Corporation, Elevar, Genentech/Roche, Hengrui, ImmunoGen, INXmed, IMAB, Mersana, Merck, Myriad, Mereo, Novartis, OncXerna, OncoNova, VBL Therapeutics.; Financial Interests, Institutional, Research Grant: PTC Therapeutics, Lilly, Merck, GSK/Tesaro. B.S. Henick: Financial Interests, Institutional, Advisory Board: AstraZeneca, Ideaya. D. Do: Financial Interests, Full or part-time Employment: Blueprint Medicines Corporation; Financial Interests, Stocks/Shares: Blueprint Medicines Corporation. A. Iheanacho: Financial Interests, Personal, Full or part-time Employment: Blueprint Medicines Corporation; Financial Interests, Personal, Ownership Interest: Blueprint Medicines Corporation. H. Zhang, M. Roche, K. Newberry, A. Hsieh: Financial Interests, Personal, Full or part-time Employment: Blueprint Medicines Corporation; Financial Interests, Personal, Stocks/Shares: Blueprint Medicines Corporation. D. Juric: Financial Interests, Personal, Other, Consulting Fees: Novartis, Genentech, Syros, Eisai, Vibliome, Mapkure, and Relay Therapeutics; Financial Interests, Personal and Institutional, Other, Contracted Research: Novartis, Genentech, Syros, Pfizer, Eisai, Takeda, Ribon Therapeutics, Infinity, InventisBio, Cyteir, Blueprint Medicines and Arvinas; Financial Interests, Personal, Ownership Interest: Relay Therapeutics and PIC Therapeutics. All other authors have declared no conflicts of interest.