Abstract | BACKGROUND: METHODS: This phase I/Ib study had two dose-escalation arms: single-agent NIZ985 administered subcutaneously thrice weekly (TIW, 2 weeks on/2 weeks off) or once weekly (QW, 3 weeks on/1 week off), and NIZ985 TIW or QW administered subcutaneously plus spartalizumab (400 mg intravenously every 4 weeks (Q4W)). The dose-expansion phase investigated NIZ985 1 µg/kg TIW/ spartalizumab 400 mg Q4W in patients with anti-PD-1-sensitive or anti-PD-1-resistant tumor types stratified according to approved indications. The primary objectives were the safety, tolerability, and the maximum tolerated doses (MTDs) and/or recommended dose for expansion (RDE) of NIZ985 for the dose-expansion phase. RESULTS: As of February 17, 2020, 83 patients (median age: 63 years; range: 28-85) were treated in dose escalation (N=47; single-agent NIZ985: n=27; NIZ985/ spartalizumab n=20) and dose expansion (N=36). No dose-limiting toxicities occurred nor was the MTD identified. The most common treatment-related adverse event (TRAE) was injection site reaction (primarily grades 1-2; single-agent NIZ985: 85% (23/27)); NIZ985/ spartalizumab: 89% [50/56]). The most common grade 3-4 TRAE was decreased lymphocyte count (single-agent NIZ985: 7% [2/27]; NIZ985/ spartalizumab: 5% [3/56]). The best overall response was stable disease in the single-agent arm (30% (8/27)) and partial response in the NIZ985/ spartalizumab arm (5% [3/56]; melanoma, pancreatic cancer, gastric cancer). In dose expansion, the disease control rate was 45% (5/11) in the anti-PD-1-sensitive and 20% (5/25) in the anti-PD-1-resistant tumor type cohorts. Pharmacokinetic parameters were similar across arms. The transient increase in CD8+ T cell and natural killer cell proliferation and induction of several cytokines occurred in response to the single-agent and combination treatments. CONCLUSIONS: NIZ985 was well tolerated in the single-agent and NIZ985/ spartalizumab regimens. The RDE was established at 1 µg/kg TIW. Antitumor activity of the combination was observed against tumor types known to have a poor response to ICIs. TRIAL REGISTRATION NUMBER: NCT02452268.
|
Authors | Rom Leidner, Kevin Conlon, Douglas G McNeel, Andrea Wang-Gillam, Sumati Gupta, Robert Wesolowski, Monica Chaudhari, Nadia Hassounah, Jong Bong Lee, Lang Ho Lee, Jessica A O'Keeffe, Nancy Lewis, George N Pavlakis, John A Thompson |
Journal | Journal for immunotherapy of cancer
(J Immunother Cancer)
Vol. 11
Issue 10
(10 2023)
ISSN: 2051-1426 [Electronic] England |
PMID | 37907221
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
|
Copyright | © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. |
Chemical References |
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Antineoplastic Agents
- Immune Checkpoint Inhibitors
- Interleukin-15
- spartalizumab
|
Topics |
- Humans
- Middle Aged
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
(therapeutic use)
- Antineoplastic Agents
- Immune Checkpoint Inhibitors
(therapeutic use)
- Interleukin-15
(therapeutic use)
- Melanoma
(drug therapy)
- Neoplasms, Second Primary
(drug therapy)
- Adult
- Aged
- Aged, 80 and over
|