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

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.

SUBMITTER: Zibelman M

PROVIDER: S-EPMC10374608 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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

Zibelman Matthew M MacFarlane Alexander W AW Costello Kimberly K McGowan Thomas T O'Neill John J Kokate Rutika R Borghaei Hossein H Denlinger Crystal S CS Dotan Efrat E Geynisman Daniel M DM Jain Angela A Martin Lainie L Obeid Elias E Devarajan Karthik K Ruth Karen K Alpaugh R Katherine RK Dulaimi Essel Al-Saleem EA Cukierman Edna E Einarson Margret M Campbell Kerry S KS Plimack Elizabeth R ER

Nature communications 20230727 1

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 onl ...[more]

PMID: 37500647

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Project description:PurposeCopanlisib in combination with immune checkpoint inhibitors demonstrated synergy and favorable antitumor immune responses in preclinical models. This study evaluated copanlisib plus nivolumab in adults with advanced solid tumors.Patients and methodsIn this phase Ib, nonrandomized, open-label, dose-escalation study, patients received intravenous nivolumab 240 mg (day 15 of cycle 1 and days 1 and 15 of subsequent cycles) plus intravenous copanlisib (45 or 60 mg on days 1, 8, and 15 of each cycle) in 28-day cycles. The primary objective was to determine the MTD and/or recommended phase II dose of copanlisib plus nivolumab. Secondary objectives were safety, tolerability, and efficacy. Exploratory objectives included evaluation of potentially predictive biomarkers.ResultsOverall, 16 patients were treated [copanlisib: 45 mg (n = 5); 60 mg (n = 11)]. The most common cancer types at baseline were bladder (25.0%) and oropharyngeal (18.8%) cancers. No dose-limiting toxicities were observed; copanlisib 60 mg was deemed the recommended phase II dose in combination with nivolumab 240 mg. Grade 3 and 4 treatment-emergent adverse events were reported in 56.3% and 12.5% of patients, respectively; one grade 5 event was reported (unrelated to treatment). Overall, 18.8% of patients achieved a partial response. Evaluations of potential biomarkers did not correlate with response, but copanlisib-modulated biomarker changes were observed before nivolumab administration and were consistent and dose-dependent.ConclusionsNo new safety concerns were identified with this combination, and preliminary efficacy indicated an antitumor effect. Data supported an immunomodulatory effect of copanlisib, suggesting that this combination may enhance the efficacy of immune checkpoint inhibitors.SignificanceThe combination of copanlisib and nivolumab was well tolerated and showed antitumor effects in patients with advanced solid tumors. The number of circulating myeloid-derived suppressive cells decreased 24 to 48 hours after treatment with copanlisib. Further investigation of copanlisib and nivolumab is warranted as a novel strategy to enhance the efficacy of checkpoint inhibitors.

Project description:BackgroundGlutamate signaling activates MAPK and PI3K/AKT pathways in tumor cells. Treatment with riluzole, a glutamate release inhibitor, has been previously shown to be safe in melanoma patients and produced biologic effects, but did not lead to radiographic responses, possibly due to poor pharmacokinetic properties. Therefore, we conducted a phase Ib trial to determine the safety and tolerability of the combination of the riluzole prodrug troriluzole (BHV-4157, trigriluzole) and the PD-1 antibody nivolumab in patients with advanced solid tumors.MethodsPatients with advanced or refractory solid tumors and measurable disease per RECIST 1.1 were treated with increasing doses of troriluzole using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Troriluzole monotherapy was orally self-administered for a 14-day lead-in period followed by continuation of troriluzole in combination with nivolumab 240 mg IV every 2 weeks. Endpoints included safety, pharmacokinetics (PK) and efficacy.ResultsWe enrolled 14 patients with advanced solid tumors (melanoma = 3, NSCLC = 3, renal cell carcinoma = 2, bladder/urothelial = 2, ovarian cancer = 1, adenoid cystic carcinoma = 1, pleural mesothelial = 1, head and neck cancer = 1). Eleven patients had cancer progression on prior therapy with PD-1 or PD-L1 agent. Patients received troriluzole total daily doses from 140 to 560 mg (divided). The most common treatment-related adverse events (TRAE) occurring in ≥ 5 patients (> 35%) were transaminitis and increased lipase. DLT (dose-limiting toxicity) occurred in 3 patients: (1) grade 3 anorexia, (2) grade 3 fatigue and, (3) grade 3 atrial fibrillation. Six patients were treated at the MTD (maximum tolerated dose). No subjects discontinued treatment due to AEs. One response occurred (7%), which was a partial response in a subject who had PD-1 refractory disease. The 6-month PFS rate was 21%. PK data showed that the prodrug troriluzole was efficiently cleaved into riluzole by 2-h post-dosing in all dose cohorts tested.ConclusionThe combination of troriluzole and nivolumab was safe and well-tolerated. The MTD of troriluzole was determined to be 420 mg total daily dose. The observed antitumor activity, primarily disease stabilization, is of interest in patients with PD-1 resistant tumors. Trial Registration ClinicalTrials.gov Identifier NCT03229278.

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

Publications

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

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