Abstract B044: Results of a phase 1 dose escalation clinical trial of NXP800, a novel GCN2 activator, in patients with advanced or metastatic solid tumors
Authors: Banerji Udai , Pacey Simon , Finkelstein Karen , Rodney Simon , DosReis Ana Filipa Palma , Codaccipisanelli Giovanni , Sloan Mark , Raynaud Florence I , Ruddle Ruth , Swales Karen , Tall Matthew , Shemesh Shay , Marsolini Diane , Sardone Megan , Hay Justin , Bliss Robin , Poradosu Enrique , Workman Paul 
Published: December 2023

Abstract
Background: NXP800 is an antineoplastic, oral, small molecule discovered in a phenotypic screen for inhibitors of the heat shock factor 1 stress response. In a panel of human carcinoma cell lines NXP800 induced the expression of genes associated with activation of the integrated stress response (ISR). Orthogonal experimental approaches revealed that activation of the kinase GCN2 was required for ISR activation by NXP800. In tumor samples from ARID1a-mutated ovarian carcinoma xenografts, treatment with NXP800 resulted in substantial tumor growth inhibition and tumor regressions. Induction of the ISR effector ATF4 was observed. Here we present data on the safety, pharmacokinetics and pharmacodynamics of NXP800 from the dose escalation phase 1 trial in patients with advanced or metastatic solid tumors.
Methods: This is a first-in-human, open label, dose escalation and expansion Phase 1 study in patients with advanced solid tumors (Part A, all comers) and ovarian cancer (Part B).Dose escalation was guided by a Bayesian modified continual reassessment method that targeted a dose-limiting toxicity DLT probability (DLTp) closest to 30% but &lt;33%.The primary objective of the dose escalation was to identify a dose and dosing schedule for Part B, in which the clinical activity of NXP800 is being evaluated in patients with platinum resistant,ARID1a-mutated ovarian carcinoma.
Results: Eighteen patients were treated in Part A: at baseline, the median age was 65 years (range 42-77), 9 (50%) were female and 14/18 (78%) had an ECOG score of 1. Two schedules (once per day [QD] and twice per day [BID] and a dose range of 50 to 150 mg/day were evaluated. The most common (incidence &gt;20%) non-laboratory, treatment emergent adverse events (TEAEs) were vomiting, nausea, diarrhea, fatigue, and decreased appetite, all reported as Grade 1-2 except for nausea and diarrhea that were reported as Grade 3 in one patient each. The most common laboratory TEAEs were thrombocytopenia and aspartate aminotransferase increase, all reported as Grade 1-2 except in two patients in whom thrombocytopenia was reported as Grade 3. Two Grade 4 TEAEs that were considered unrelated to study drug and no Grade 5 TEAEs were reported. The DLT for the QD schedule was 150 mg/day, with an estimated Dose Limiting Toxicity Probability (DLTp) of 34% (no doses in the BID schedule had estimated DLTp of &lt;33%). The maximum tolerated dose was 100 mg/day (DLTp=26%). Model-based simulations demonstrated that NXP800 exposures obtained following 50, 75 and 100 mg QD were comparable to the drug exposure achieved in xenograft model of ARID1a-mutated ovarian carcinoma. ATF4 protein and ISR genes were induced in peripheral blood mononuclear cell samples obtained from patients treated with NXP800.
Conclusion: The NXP800 doses and dosing schedules selected for Part B are 50 and 75 mg/day in a QD schedule. At these dose levels, NXP800 was tolerable, achieved relevant systemic exposure levels and induced ISR PD biomarkers. Part B is open for enrollment of patients with platinum resistant, ARID1a-mutated ovarian carcinoma.
Citation Format: Udai Banerji, Simon Pacey, Karen Finkelstein, Simon Rodney, Ana Filipa Palma DosReis, Giovanni Codaccipisanelli, Mark Sloan, Florence I Raynaud, Ruth Ruddle, Karen Swales, Matthew Tall, Shay Shemesh, Diane Marsolini, Megan Sardone, Justin Hay, Robin Bliss, Enrique Poradosu, Paul Workman. Results of a phase 1 dose escalation clinical trial of NXP800, a novel GCN2 activator, in patients with advanced or metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B044.