Plasma cytokine profiles and survival outcomes in the 1801 phase 1/2 clinical trial of 9-ING-41 (elraglusib) in patients with advanced cancer.

person Taylor Weiskittel Mayo Clinic, Rochester, MN info_outline Taylor Weiskittel, Kelsey Huntington, Benedito A. Carneiro, Ludimila Cavalcante, Devalingam Mahalingam, Francis J. Giles, Pamela N. Munster, Wafik S. El-Deiry, Hu Li, Andrew Paul Mazar

Authors person Taylor Weiskittel Mayo Clinic, Rochester, MN info_outline Taylor Weiskittel, Kelsey Huntington, Benedito A. Carneiro, Ludimila Cavalcante, Devalingam Mahalingam, Francis J. Giles, Pamela N. Munster, Wafik S. El-Deiry, Hu Li, Andrew Paul Mazar Organizations Mayo Clinic, Rochester, MN, Brown University, Providence, RI, Legorreta Cancer Center, Brown University, Providence, RI, Winship Cancer Institute of Emory University, Atlanta, GA, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, DTC, Chicago, IL, University of California, San Francisco, San Francisco, CA, Mayo Clinic College of Medicine, Rochester, MN, Actuate Therapeutics, Inc., Lake Forest, IL Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Actuate Therapeutics Inc. Background: 9-ING-41 (elraglusib) is a novel inhibitor of GSK-3β that has shown early signs of clinical benefit in a phase 1/2 clinical trial (ACT1801; NCT03678883). Early data support a multi-modal mechanism of action for elraglusib that targets both the tumor and immune system. Thus, the discovery and validation of biomarkers of drug sensitivity to elraglusib is a high priority. Here, we take inspiration from the literature on checkpoint inhibitor therapy and explore the potential of cytokines to predict elraglusib clinical response. Methods: Peripheral plasma samples from 59 patients enrolled in the 1801 phase 1/2 trial of elraglusib were assayed for 40 circulating cytokine levels. Patients advanced solid tumors refractory to standard treatments and received either elraglusib (1.0-15.0 mg/kg) as a single agent or in combination with other chemotherapies. Samples were taken from time points prior to elraglusib administration (pre-dose), after cycle 1, or after cycle 2. Each cytokine time point combination was used to stratify patients into high and low categories using an optimal cut-point determined using maximally selected rank statistics. Kaplan Meier and Cox Proportional Hazards analysis was used to determine the efficacy of each cytokine as a biomarker. The change in cytokine values between pre-dose and cycle 1 or pre-dose and cycle 2 was evaluated in a similar manner. Results: A total of 142 samples spanning eight different tumor histologies were collected and analyzed. A total of 240 cytokine-timepoint combinations were evaluated, and 53 significantly stratified patients by overall survival (p-value < 0.05). Of those, 35 showed that higher levels of the given cytokine correlated with a survival benefit and 18 a survival decrease. Notable among the cytokines demonstrating survival benefits were Granzyme B at Cycle 1 Day 4 (HR: 9.54, p-value:0.015) and TGF β at Cycle 1 Day 4 (HR: 8.48, p-value:0.0063). Strong hazard ratios were also observed for cytokines that correlated with survival decreases including TRAIL-R2 at Cycle 1 Day 2 (HR: 9.56e-02, p-value:0.0001), and IL-10 at Cycle 1 Day 4 (HR: 8.77e-02, p-value:0.007). Delta between timepoints was also able to stratifying patients by overall survival. Conclusions: Plasma cytokine profiling is a promising approach for discovery and validation of biomarkers prognostic for elraglusib clinical benefit. Numerous cytokines measured pre-dose stratified patients into significant survival groups suggesting a potential strategy for patient enrichment in clinical trials of elraglusib. These initial findings are being expanded by 1) increasing the cohort to accommodate histology specific investigations; 2) examining which cytokines are elraglusib response-specific versus drug-agnostic; and 3) combining cytokines in multivariate and machine learning models for optimal predictive capacity. Clinical trial information: NCT03678883.

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