A phase 1 study of nivolumab in combination with interferon-gamma for patients with advanced solid tumors

Matthew Zibelman (), Alexander W. MacFarlane, Kimberly Costello, Thomas McGowan, John O’Neill, Rutika Kokate, Hossein Borghaei, Crystal S. Denlinger, Efrat Dotan, Daniel M. Geynisman, Angela Jain, Lainie Martin, Elias Obeid, Karthik Devarajan, Karen Ruth, R. Katherine Alpaugh, Essel Al-Saleem Dulaimi, Edna Cukierman, Margret Einarson, Kerry S. Campbell and Elizabeth R. Plimack
Additional contact information
Matthew Zibelman: Fox Chase Cancer Center
Alexander W. MacFarlane: Institute for Cancer Research
Kimberly Costello: Fox Chase Cancer Center
Thomas McGowan: Fox Chase Cancer Center
John O’Neill: Fox Chase Cancer Center
Rutika Kokate: Fox Chase Cancer Center
Hossein Borghaei: Fox Chase Cancer Center
Crystal S. Denlinger: Fox Chase Cancer Center
Efrat Dotan: Fox Chase Cancer Center
Daniel M. Geynisman: Fox Chase Cancer Center
Angela Jain: Fox Chase Cancer Center
Lainie Martin: Fox Chase Cancer Center
Elias Obeid: Fox Chase Cancer Center
Karthik Devarajan: Fox Chase Cancer Center
Karen Ruth: Fox Chase Cancer Center
R. Katherine Alpaugh: Fox Chase Cancer Center
Essel Al-Saleem Dulaimi: Fox Chase Cancer Center
Edna Cukierman: Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center
Margret Einarson: Fox Chase Cancer Center
Kerry S. Campbell: Institute for Cancer Research
Elizabeth R. Plimack: Fox Chase Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/m2, however based on a composite of safety, clinical, and correlative factors the RP2D is 50 mcg/m2. Exploratory analyses of efficacy in the phase I cohorts demonstrate one patient with a complete response, and five have achieved stable disease. Pre-planned correlative assessments of circulating immune cells demonstrate intermediate monocytes with increased PD-L1 expression correlating with IFN-γ dose and treatment duration. Interestingly, post-hoc analysis shows that IFN-γ induction increases circulating chemokines and is associated with an observed paucity of irAEs, warranting further evaluation. ClinicalTrials.gov Trial Registration: NCT02614456.

Date: 2023
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DOI: 10.1038/s41467-023-40028-z

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