PMID- 34799399 OWN - NLM STAT- MEDLINE DCOM- 20220111 LR - 20220111 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 9 IP - 11 DP - 2021 Nov TI - Phase I study of single agent NIZ985, a recombinant heterodimeric IL-15 agonist, in adult patients with metastatic or unresectable solid tumors. LID - 10.1136/jitc-2021-003388 [doi] LID - e003388 AB - BACKGROUND: NIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors. METHODS: Single agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 microg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, in an accelerated 3+3 dose escalation trial design. IL-15 and endogenous cytokines were monitored by ELISA and multiplexed electrochemiluminescent assays. Multiparameter flow cytometry assessed the frequency, phenotype and proliferation of peripheral blood mononuclear cells. Preliminary antitumor activity was assessed by overall response rate (Response Evaluation Criteria in Solid Tumors V.1.1). RESULTS: As of March 2, 2020, median treatment duration was 7.5 weeks (range 1.1-77.1). Thirteen patients had discontinued and one (uveal melanoma) remains on treatment with stable disease. Best clinical response was stable disease (3 of 14 patients; 21%). The most frequent adverse events (AEs) were circular erythematous injection site reactions (100%), chills (71%), fatigue (57%), and fever (50%). Treatment-related grade 3/4 AEs occurred in six participants (43%); treatment-related serious AEs (SAEs) in three (21%). The per-protocol maximum tolerated dose was not reached. Pharmacokinetic accumulation of serum IL-15 in the first week was followed by significantly lower levels in week 2, likely due to more rapid cytokine consumption by an expanding lymphocyte pool. NIZ985 treatment was associated with increases in several cytokines, including interferon (IFN)-gamma, IL-18, C-X-C motif chemokine ligand 10, and tumor necrosis factor-beta, plus significant induction of cytotoxic lymphocyte proliferation (including natural killer and CD8(+) T cells), increased CD16(+) monocytes, and increased CD163(+) macrophages at injection sites. CONCLUSIONS: Subcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-gamma and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy. TRIAL REGISTRATION NUMBER: NCT02452268. CI - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. FAU - Conlon, Kevin AU - Conlon K AUID- ORCID: 0000-0002-4118-7524 AD - Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. FAU - Watson, Dionysios C AU - Watson DC AUID- ORCID: 0000-0002-9146-5641 AD - Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA. AD - University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA. FAU - Waldmann, Thomas A AU - Waldmann TA AUID- ORCID: 0000-0003-4500-6660 AD - Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. FAU - Valentin, Antonio AU - Valentin A AUID- ORCID: 0000-0002-0745-7922 AD - Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA. FAU - Bergamaschi, Cristina AU - Bergamaschi C AUID- ORCID: 0000-0003-1030-2662 AD - Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA. FAU - Felber, Barbara K AU - Felber BK AUID- ORCID: 0000-0001-8925-8128 AD - Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA. FAU - Peer, Cody J AU - Peer CJ AUID- ORCID: 0000-0001-9395-3473 AD - Clinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland, USA. FAU - Figg, William D AU - Figg WD AUID- ORCID: 0000-0003-2428-5613 AD - Clinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland, USA. FAU - Potter, E Lake AU - Potter EL AUID- ORCID: 0000-0003-4339-9800 AD - Vaccine Research Center, NIAID, Bethesda, Maryland, USA. FAU - Roederer, Mario AU - Roederer M AUID- ORCID: 0000-0001-7448-7040 AD - Vaccine Research Center, NIAID, Bethesda, Maryland, USA. FAU - McNeel, Douglas G AU - McNeel DG AUID- ORCID: 0000-0003-1471-6723 AD - Carbone Cancer Center, University of Wisconsin Madison, Madison, Wisconsin, USA. FAU - Thompson, John A AU - Thompson JA AUID- ORCID: 0000-0002-0872-7306 AD - Seattle Cancer Care Alliance, Seattle, Washington, USA. FAU - Gupta, Sumati AU - Gupta S AUID- ORCID: 0000-0001-6271-0831 AD - Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA. FAU - Leidner, Rom AU - Leidner R AUID- ORCID: 0000-0003-0788-7938 AD - Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. FAU - Wang-Gillam, Andrea AU - Wang-Gillam A AUID- ORCID: 0000-0003-0458-7614 AD - Division of Oncology, Department of Medicine, Washington University in Saint Louis, St Louis, Missouri, USA. FAU - Parikh, Nehal S AU - Parikh NS AUID- ORCID: 0000-0002-4746-1168 AD - Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA. FAU - Long, Debby AU - Long D AUID- ORCID: 0000-0003-4882-049X AD - Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA. FAU - Kurtulus, Sema AU - Kurtulus S AUID- ORCID: 0000-0002-2842-9437 AD - Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA. FAU - Ho Lee, Lang AU - Ho Lee L AUID- ORCID: 0000-0002-9684-160X AD - Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA. FAU - Chowdhury, Niladri Roy AU - Chowdhury NR AUID- ORCID: 0000-0003-0427-0879 AD - Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA. FAU - Bender, Florent AU - Bender F AUID- ORCID: 0000-0001-7407-5847 AD - Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA. FAU - Pavlakis, George N AU - Pavlakis GN AUID- ORCID: 0000-0002-4027-4036 AD - Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA george.pavlakis@nih.gov. LA - eng SI - ClinicalTrials.gov/NCT02452268 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (IL15 protein, human) RN - 0 (IL15RA protein, human) RN - 0 (Interleukin-15) RN - 0 (Receptors, Interleukin-15) RN - 0 (Recombinant Proteins) SB - IM MH - Adult MH - Aged MH - Female MH - Humans MH - Immunotherapy MH - Interleukin-15/*administration & dosage/*agonists MH - Male MH - Middle Aged MH - Neoplasm Metastasis MH - Neoplasms/*drug therapy MH - Protein Multimerization MH - Receptors, Interleukin-15/*administration & dosage MH - Recombinant Proteins/administration & dosage PMC - PMC8606766 OTO - NOTNLM OT - clinical trials as topic OT - cytokines OT - immunomodulation OT - immunotherapy OT - investigational OT - therapies COIS- Competing interests: AV, CB, BKF, and GNP report inventorship in issued patents of relevance to this work (licensed to Novartis; managed by the National Cancer Institute) and other support by Novartis during the conduct of this study. DGM and TAW report other support from Novartis during the conduct of the study. JT reports grants from Alpine Biosciences, other support from Novartis during the conduct of the study, other support from Pfizer, Five Prime, Merck, Trillium, Incyte and Xencor outside of the current work, and personal fees from Regeneron, Aveo, Neoleukin, Seattle Genetics, BJ Biosciences, and Calithera outside of the current work. SG reports other support from Novartis during the conduct of the study, other support from Bristol Myers Squibb, Rexahn, Incyte, LSK, Five Prime, Mirati, QED, Debiopharm, Merck, Pfizer, AstraZeneca, Medimmune, Clovis, and Seattle Genetics outside of the current work, and ownership of stock in Salerius Pharmaceuticals by spouse. RL reports grants and personal fees from Bristol Myers Squibb, personal fees from Merck, Oncolys, and Sanofi, and non-financial support from Clinigen outside of the current work. NSP, DL, SK, LHL, NRC and FB are, or were at the time of the work described, employees of Novartis Pharmaceuticals. KC, DCW, CJP, WF, ELP, MR and AW-G report nothing to disclose. EDAT- 2021/11/21 06:00 MHDA- 2022/01/12 06:00 PMCR- 2021/11/19 CRDT- 2021/11/20 05:37 PHST- 2021/10/22 00:00 [accepted] PHST- 2021/11/20 05:37 [entrez] PHST- 2021/11/21 06:00 [pubmed] PHST- 2022/01/12 06:00 [medline] PHST- 2021/11/19 00:00 [pmc-release] AID - jitc-2021-003388 [pii] AID - 10.1136/jitc-2021-003388 [doi] PST - ppublish SO - J Immunother Cancer. 2021 Nov;9(11):e003388. doi: 10.1136/jitc-2021-003388.