PMID- 33037117 OWN - NLM STAT- MEDLINE DCOM- 20211005 LR - 20211005 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 8 IP - 2 DP - 2020 Oct TI - Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors. LID - 10.1136/jitc-2020-001095 [doi] LID - e001095 AB - BACKGROUND: MEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors. PATIENTS AND METHODS: Eligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005-0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response. RESULTS: From November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade >/=3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease >/=8 weeks. CONCLUSION: IT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations. TRIAL REGISTRATION NUMBER: NCT02556463. CI - (c) Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Siu, Lillian AU - Siu L AD - Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre, Toronto, Ontario, Canada lillian.siu@uhn.ca. FAU - Brody, Joshua AU - Brody J AD - Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, United States. FAU - Gupta, Shilpa AU - Gupta S AD - Department of Hematology and Oncology, Cleveland Clinic, Cleveland, Ohio, United States. FAU - Marabelle, Aurelien AU - Marabelle A AUID- ORCID: 0000-0002-5816-3019 AD - Drug Development Department, Gustave Roussy, Villejuif, France. FAU - Jimeno, Antonio AU - Jimeno A AD - Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Denver, Colorado, United States. FAU - Munster, Pamela AU - Munster P AD - Department of Medicine (Hematology/Oncology), University of California San Francisco, San Francisco, California, United States. FAU - Grilley-Olson, Juneko AU - Grilley-Olson J AD - Division of Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States. FAU - Rook, Alain H AU - Rook AH AD - Department of Dematology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States. FAU - Hollebecque, Antoine AU - Hollebecque A AD - Drug Development Department, Gustave Roussy, Villejuif, France. FAU - Wong, Rebecca K S AU - Wong RKS AD - Radiation Medicine Program, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada. FAU - Welsh, James W AU - Welsh JW AD - Division of Radiation Oncology, Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States. FAU - Wu, Yuling AU - Wu Y AD - AstraZeneca, Gaithersburg, Maryland, USA. FAU - Morehouse, Christopher AU - Morehouse C AD - AstraZeneca, Gaithersburg, Maryland, USA. FAU - Hamid, Oday AU - Hamid O AD - AstraZeneca, Gaithersburg, Maryland, USA. FAU - Walcott, Farzana AU - Walcott F AD - AstraZeneca, Gaithersburg, Maryland, USA. FAU - Cooper, Zachary A AU - Cooper ZA AUID- ORCID: 0000-0003-1059-0940 AD - AstraZeneca, Gaithersburg, Maryland, USA. FAU - Kumar, Rakesh AU - Kumar R AD - AstraZeneca, Gaithersburg, Maryland, USA. FAU - Ferte, Charles AU - Ferte C AD - AstraZeneca, Gaithersburg, Maryland, USA. FAU - Hong, David S AU - Hong DS AD - Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. LA - eng SI - ClinicalTrials.gov/NCT02556463 GR - UL1 TR003167/TR/NCATS NIH HHS/United States PT - Journal Article PT - Multicenter Study PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (Antibodies, Monoclonal) RN - 0 (Heterocyclic Compounds, 3-Ring) RN - 0 (Stearic Acids) RN - 16598XQ2BT (MEDI9197) RN - 28X28X9OKV (durvalumab) SB - IM MH - Animals MH - Antibodies, Monoclonal/pharmacology/*therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/pharmacology/*therapeutic use MH - Female MH - Heterocyclic Compounds, 3-Ring/pharmacology/*therapeutic use MH - Humans MH - Male MH - Mice MH - Neoplasms/*drug therapy/*radiotherapy MH - Palliative Care MH - Stearic Acids/pharmacology/*therapeutic use PMC - PMC7549442 OTO - NOTNLM OT - CD8-positive t-lymphocytes OT - Th1-Th2 balance OT - combination OT - drug therapy OT - immunotherapy OT - radioimmunotherapy COIS- Competing interests: LS reports consultant fees for Merck, Pfizer, Celgene, AstraZeneca, MorphoSys, Roche, GeneSeeq, Loxo, Oncorus, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi; grant/research funding (for institution) from Novartis, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks, and Avid. Her spouse reports stocks in Agios. JB reports grant/research funding (for institution) from Merck, Bristol-Myers Squibb, Acerta Pharma, Genentech, Kite/Gilead, Celldex Therapeutics, Celgene. SG reports grant/research funding (for institution) from Bristol-Myers Squibb; personal fees from Bristol-Myers Squibb, Exelixis, Merck, AstraZeneca, and Janssen. AM is the principal investigator of clinical trials for Roche/Genentech, Bristol-Myers Squibb, Merck, MSD, Pfizer, Lytix Pharma, Eisai, AstraZeneca, Chugai, and Tesaro; reports scientific/advisory board fees from GlaxoSmithKline, AstraZeneca, Merck Serono, eTheRNA, Lytix Biopharma, Kyowa, Novartis, Bristol-Myers Squibb, Symphogen, Genmab, Amgen, Biothera, Nektar, Tesaro, OncoSec, Pfizer, Seattle Genetics, AstraZeneca, Servier, Gritstone Oncology, Molecular Partners, Bayer, Partner Therapeutics, Sanofi, Pierre Fabre, Redx Pharma, OSE Immunotherapeutics, Medicxi; speakers' bureau fees from Roche/Genentech, Bristol-Myers Squibb, Merck, MSD, Merck Serono, AstraZeneca, Amgen, Sanofi, Servier; consultant fees from Roche, Pierre Fabre, Onxeo, Eisai, Bayer, Genticel, Rigontec, Daiichi Sankyo, IMAXIO, Sanofi, BioNTech, Molecular Partners, Pillar Partners, and BPI; patent holder: anti-CD81 (Stanford University); research support from Merus; and research grants (for institution) from Bristol-Myers Squibb, Boehringer Ingelheim, MSD Avenir, and PRTK INCa. AJ reports grant/research funding (for institution) from Bristol-Myers Squibb, Merck Serono, Pfizer, AstraZeneca, Holy Stone Healthcare, Moderna, Iovance, Roche, and Squeeze Therapeutics. PM reports consultant fees from HUYA Bioscience International; leadership roles with Alessa Therapeutics; a patent/royalty/IP with Alessa Therapeutics; honoraria from AtlasMedX, CStone Pharmaceuticals, Xynomic Pharmaceuticals (to institution) McVeigh, Epigene, and Celgene; research funding (to institution) from: Merck, Pfizer, Novartis, GlaxoSmithKline, OncoMed, Celgene, Intellikine, Onconova Therapeutics, Nektar, Sanofi, Merrimack, Roche/Genentech, OncoSec, Bristol-Myers Squibb, Plexxikon, Piramal Life Science, Andes Biotechnologies, Immune Design, and BioMarin. AH reports consultant fees from Amgen, AstraZeneca (to institution), Gritstone Oncology, Incyte (to institution), Lilly, Spectrum Pharmaceuticals (to institution), and Debiopharm Group (to institution); travel/accommodation/expenses from Amgen, Servier, Lilly, AstraZeneca, Roche, and Incyte; other from AbbVie, Agios, Amgen, argenx, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, AVEO, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai, Clovis Oncology, Daiichi Sankyo, Debiopharm Group, Eisai, Exelixis, FORMA Therapeutics, GamaMabs Pharma, Genentech, GlaxoSmithKline, H3 Biomedicine, Innate Pharma, Janssen-Cilag, Kyowa, Loxo, Lytix Biopharma, Menarini, Merck, Merrimack, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar, Octimet, OncoEthix, Onyx, Orion Pharma GmbH, Oryzon Genomics, Pfizer, Pierre Fabre, Roche/Genentech, Sanofi/Aventis, Taiho Pharmaceutical, Tesaro, Xencor, Roche, Servier, Lilly; and honoraria from Merck Serono. JW reports grant/research funding (for institution) from Bristol-Myers Squibb, Merck, Nanobiotix, Mavupharma, and Checkmate Pharmaceuticals; scientific/advisory board fees from Alpine Immune Sciences, Mavupharma, Merck, OncoResponse, and Reflection; consultant fees from AstraZeneca, MolecularMatch, and Nanobiotix; stocks/shares in Checkmate Pharmaceuticals and Reflection; and business ownership of Healios. DSH reports grant/research funding (for institution) from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, Loxo, Merck, Mirati, Mirna, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, Turning Point Therapeutics; travel/accommodations/expenses from Loxo, Mirna, Genmab, AACR, ASCO, and SITC; consultant/advisory fees from Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD; and other ownership interests with MolecularMatch (Advisor), OncoResponse (Founder), Presagia Inc (Advisor). YW, CM, OH, FW, ZC, RK, and CF are current or former employees of and stockholders in AstraZeneca. EDAT- 2020/10/11 06:00 MHDA- 2021/10/06 06:00 PMCR- 2020/10/09 CRDT- 2020/10/10 05:28 PHST- 2020/08/23 00:00 [accepted] PHST- 2020/10/10 05:28 [entrez] PHST- 2020/10/11 06:00 [pubmed] PHST- 2021/10/06 06:00 [medline] PHST- 2020/10/09 00:00 [pmc-release] AID - jitc-2020-001095 [pii] AID - 10.1136/jitc-2020-001095 [doi] PST - ppublish SO - J Immunother Cancer. 2020 Oct;8(2):e001095. doi: 10.1136/jitc-2020-001095.