Abstract 494TiP
Background
An effective DNA damage response (DDR) is essential for cell survival. Elimusertib inhibits the ataxia-telangiectasia and RAD3-related (ATR) protein kinase, which is activated in response to DNA damage and mediates cell cycle arrest to maintain genomic integrity. Niraparib inhibits poly (ADP-ribose) polymerases 1/2 (PARP-1/2), which bind damaged regions of DNA and facilitate proper repair. Evidence suggests that combined inhibition of parallel DDR pathways act synergistically to improve anti-tumor responses, and the current study begins a clinical investigation of this hypothesis (NCT04267939).
Trial design
Dose Escalation - Elimusertib will be escalated in combination with niraparib in 28-day cycles to determine the optimal dose for evaluation in Dose Expansion. Dose-limiting toxicities will be evaluated in the first cycle. Patients may have any type of advanced solid tumor (except prostate cancer) harboring a DDR deficiency, such as a deleterious alteration in BRCA1/2, RAD51B/C/D or ATM. Dose Expansion - Patients with advanced ovarian cancer will be evaluated in two cohorts: (1) Naïve to prior PARPi treatment who are platinum resistant/refractory and harbor a DDR deficiency; (2) Progressed on prior PARPi treatment. Inclusion Criteria - ≥18 years of age; ECOG 0-1; adequate bone marrow function (hemoglobin: ≥10 g/dL; platelets: ≥150 x 109/L; neutrophils: ≥2.0 x 109/L); adequate coagulation and organ function (heart, kidney, liver). Exclusion criteria - Prior treatment with PARPi if discontinued for CTCAE grade ≥3 adverse event(s) or grade ≥3 hypersensitivity to PARPi; prior treatment with ATRi. Primary Objectives - Safety/tolerability of elimusertib in combination with niraparib; maximum tolerated dose and/or the recommended phase II dose. Secondary Objectives - Complete or partial response/stable disease/progressive disease; objective response rate; disease control rate); characterization of the pharmacokinetics of elimusertib in combination with niraparib. Biomarkers – Tumor tissue will be collected at baseline and cell-free DNA collected at baseline/during treatment for retrospective analysis. Enrollment - Approximately 56 patients.
Clinical trial identification
NCT04267939.
Editorial acknowledgement
Legal entity responsible for the study
Bayer AG.
Funding
Bayer AG.
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. P. Konstantinopoulos: Non-Financial Interests, Personal, Advisory Role: AstraZeneca, Bayer, GSK, Alkermes, Kadmon, BMS, IMV, Repare, Artios, Mersana; Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca, Bayer, Merck, Pfizer, GSK, Merck KGaA, Lilly. R.N. Grisham: Financial Interests, Personal, Advisory Role: AstraZeneca, GSK, Signatera, Verastem, Corcept. D. Gupta: Financial Interests, Personal, Full or part-time Employment: GSK. G. Wilkinson, A. Cao, M. Jeffers, N. Sharma: Financial Interests, Personal, Full or part-time Employment: Bayer.