PMID- 36871042 OWN - NLM STAT- MEDLINE DCOM- 20230501 LR - 20230724 IS - 1532-1827 (Electronic) IS - 0007-0920 (Print) IS - 0007-0920 (Linking) VI - 128 IP - 10 DP - 2023 May TI - Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours. PG - 1906-1915 LID - 10.1038/s41416-023-02185-2 [doi] AB - BACKGROUND: AZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours. METHODS: AZD2811 was administered in 12 dose-escalation cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses. The primary objective was determining safety and maximum tolerated/recommended phase 2 dose (RP2D). RESULTS: Fifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at /=400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF). RP2D was 500 mg; Day 1; 21-day cycle with G-CSF on Day 8. Neutropenia/neutrophil count decrease were on-target AEs. Best overall responses were partial response (n = 1, 2.0%) and stable disease (n = 23, 45.1%). CONCLUSIONS: At RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker. CLINICAL TRIAL REGISTRATION: NCT02579226. CI - (c) 2023. The Author(s). FAU - Johnson, Melissa L AU - Johnson ML AUID- ORCID: 0000-0001-9874-1314 AD - Sarah Cannon Research Institute, Nashville, TN, USA. Melissa.johnson@sarahcannon.com. AD - Tennessee Oncology, Nashville, TN, USA. Melissa.johnson@sarahcannon.com. FAU - Wang, Judy S AU - Wang JS AD - Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA. FAU - Falchook, Gerald AU - Falchook G AD - Sarah Cannon Research Institute at HealthONE, Denver, CO, USA. FAU - Greenlees, Carol AU - Greenlees C AD - Sarah Cannon Research Institute, Nashville, TN, USA. AD - Avacta Life Sciences, London, UK. FAU - Jones, Suzanne AU - Jones S AD - Sarah Cannon Research Institute, Nashville, TN, USA. FAU - Strickland, Donald AU - Strickland D AD - Sarah Cannon Research Institute, Nashville, TN, USA. FAU - Fabbri, Giulia AU - Fabbri G AD - AstraZeneca, Waltham, MA, USA. FAU - Kennedy, Caroline AU - Kennedy C AD - AstraZeneca, Cambridge, UK. FAU - Elizabeth Pease, J AU - Elizabeth Pease J AD - AstraZeneca, Cambridge, UK. FAU - Sainsbury, Liz AU - Sainsbury L AD - AstraZeneca, Cambridge, UK. FAU - MacDonald, Alexander AU - MacDonald A AD - AstraZeneca, Cambridge, UK. FAU - Schalkwijk, Stein AU - Schalkwijk S AD - AstraZeneca, Cambridge, UK. AD - GlaxoSmithKline, London, UK. FAU - Szekeres, Philip AU - Szekeres P AD - AstraZeneca, Cambridge, UK. FAU - Cosaert, Jan AU - Cosaert J AD - AstraZeneca, Cambridge, UK. FAU - Burris, Howard 3rd AU - Burris H 3rd AUID- ORCID: 0000-0002-1501-2931 AD - Sarah Cannon Research Institute, Nashville, TN, USA. AD - Tennessee Oncology, Nashville, TN, USA. LA - eng SI - ClinicalTrials.gov/NCT02579226 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230304 PL - England TA - Br J Cancer JT - British journal of cancer JID - 0370635 RN - EC 2.7.11.1 (Aurora Kinase B) RN - 0 (AZD2811) RN - 143011-72-7 (Granulocyte Colony-Stimulating Factor) RN - 0 (Antineoplastic Agents) SB - IM MH - Humans MH - Aurora Kinase B/therapeutic use MH - *Neoplasms/pathology MH - *Neutropenia/chemically induced MH - Fatigue/chemically induced MH - Granulocyte Colony-Stimulating Factor/adverse effects MH - Maximum Tolerated Dose MH - Dose-Response Relationship, Drug MH - *Antineoplastic Agents PMC - PMC10147685 COIS- MLJ reports research funding (paid to institution) from AbbVie, Acerta, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Boehringer Ingelheim, Calithera Biosciences, Checkpoint Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly. Elicio Therapeutics, EMD Serono, Erasca, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Memorial Sloan-Kettering, Merck, Mirati Therapeutics, NeoImmune Tech, Neovia Oncology, Novartis, Numab Therapeutics, OncoMed Pharmaceuticals, Pfizer, PMV Pharmaceuticals, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics, Turning Point Therapeutics, University of Michigan, Vyriad, WindMIL, and Y-mAbs Therapeutics, and consulting/advisory roles (paid to institution) for AbbVie, Achilles Therapeutics, Amgen, AstraZeneca, Axelia Oncology, Atreca, Black Diamond, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, EMD Serono, G1 Therapeutics, Genentech / Roche, Genmab, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Ideaya Biosciences, iTeos, Incyte, Janssen, Lilly, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Oncorus, Pfizer, Regeneron Pharmaceuticals, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics, and WindMIL. JSW reports honoraria from AstraZeneca. GFalchook reports advisory roles (paid to institution) for Fujifilm, Silicon, Navire, Turning Point, Predicine and (paid to self) EMD Serono, honoraria from Total Health Conferencing and Rocky Mountain Oncology Society, research funding (paid to institution) from 3-V Biosciences, Abbisko, Abbvie, ABL Bio ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Boehringer Ingelheim, Celldex, Celgene, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MacroGenics, Incyte, Jacobio, Jounce, Kolltan, Loxo/Bayer, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Navire, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, RasCal, Regeneron, Rgenix, Ribon, Samumed, Sapience, Silicon, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, Vegenics, and Xencor, royalties from Wolters Kluwer, and travel funding from Bristol-Myers Squibb, EMD Serono, Fujifilm, Millennium, and Sarah Cannon Research Institute. CG has no conflict of interest to report. SJ is an employee of HCA Healthcare and Sarah Cannon Research Institute, and reports ownership of stock/shares in HCA. DS has no conflict of interest to report. GFabbri, CK, JEP, LS, AM are employees of, and report ownership of stock/shares in, AstraZeneca. SS was previously employed by AstraZeneca, and is currently an employee of GlaxoSmithKline. PS is an employee of AstraZeneca, and reports ownership of stock/shares in AstraZeneca and Eli Lilly. JC is an employee of AstraZeneca. HB is an employee of, and reports ownership of stock/shares in, HCA Healthcare and Sarah Cannon Research Institute, and reports non-compensated consulting for Daiichi Sankyo, Pfizer, Bayer, GRAIL, Novartis, Vincerx Pharma, AstraZeneca and Incyte, and research grants or funds (paid to institution) from Roche/Genentech, BMS, Incyte, AstraZeneca, MedImmune, Macrogenics, Novartis, Boehringer Ingelheim, Lilly, Seattle Genetics, Merck, Agios, Jounce Therapeutics, Moderna Therapeutics, CytomX, GlaxoSmithKline, Verastem, Tesaro, BioMed Valley Discoveries, TG Therapeutics, Vertex, eFFECTOR Therapeutics, Janssen, Gilead Sciences, BioAtla, CicloMed, Harpoon Therapeutics, Arch, Arvinas, Revolution Medicine, Array BioPharma, Bayer, BIND Therapeutics, Kymab, miRNA Therapeutics, Pfizer, Takeda/Millennium, Foundation Medicine, EMD Serono, ARMO BioSciences, CALGB, Hengrui Therapeutics, Infinity Pharmaceuticals, XBiotech, Zymeworks, Coordination Pharmaceuticals, NGM Biopharmaceuticals, Gossamer Bio, Ryvu Therapeutics, BioTheryX, and Abbvie. EDAT- 2023/03/05 06:00 MHDA- 2023/05/01 06:42 PMCR- 2023/03/04 CRDT- 2023/03/04 23:37 PHST- 2022/06/17 00:00 [received] PHST- 2023/01/25 00:00 [accepted] PHST- 2023/01/18 00:00 [revised] PHST- 2023/05/01 06:42 [medline] PHST- 2023/03/05 06:00 [pubmed] PHST- 2023/03/04 23:37 [entrez] PHST- 2023/03/04 00:00 [pmc-release] AID - 10.1038/s41416-023-02185-2 [pii] AID - 2185 [pii] AID - 10.1038/s41416-023-02185-2 [doi] PST - ppublish SO - Br J Cancer. 2023 May;128(10):1906-1915. doi: 10.1038/s41416-023-02185-2. Epub 2023 Mar 4.