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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

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...

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Published in:Molecular cancer therapeutics 2023-12, Vol.22 (12_Supplement), p.B044-B044
Main 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
Format: Article
Language:English
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Summary: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 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
ISSN:1538-8514
1538-8514
DOI:10.1158/1535-7163.TARG-23-B044