Abstract CT111: Pharmacokinetic and pharmacodynamic evaluation of NXP800, a novel GCN2 activator, in a first in human clinical trial
Authors: Pacey Simon , Leung Ching , Rodney Simon , DosReis Ana Filipa Palma , Ruddle Ruth , Tall Matthew , Swales Karen , Poele Robert te , Workman Paul , Marsolini Diane , Sardone Megan , Poradosu Enrique , Shemesh Shay , Banerji Udai 
Published: April 2024

Abstract
Background NXP800 is an oral, small molecule that activates the integrated stress response through activation of the kinase GCN2. The drug causes growth inhibition and regression in various preclinical models, including ARID1A mutated ovarian and endometrial xenograft and cholangiocarcinoma PDX models.
Methods We describe results of the dose-defining dose escalation cohort and the toxicity-pharmacokinetics and pharmacodynamic evaluation in a first-in-human phase I trial of NXP800. 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%. Toxicity was assessed using NCI.CTC.V5. Detailed sampling of blood for pharmacokinetic analysis and blood for mRNA and protein analysis in peripheral blood mononuclear cells was conducted on C1D-3 to -7 (run in prior to continuous dosing) and C2D1. Two schedules (once per day [QD] and twice per day [BID] and a dose range of 50 to 150 mg/day were evaluated.
Results Eighteen patients were treated: 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. The most common treatment emergent adverse events (more than 20% of patients) were nausea, vomiting, diarrhea, fatigue, decreased appetite, AST increase and thrombocytopenia. All these side effects were grade 1-2 except grade 3 nausea and grade 3 diarrhea reported in one patient each and grade 3 thrombocytopenia in 2 patients. The MTD for the QD schedule was 100 mg (DLTp=26%), no doses in the BID schedule had estimated DLTp of &lt;33%. The average Cmax at 50 mg and 75 mg OD was 190 nM and 384 nM during the run-in and 495 nM and 656 nM in cycle 2 reached by 3 hours. ATF4 protein in PBMCs was elevated in 57% and 80% of patients during run in and Cycle 2 respectively, 6 hours after 50 mg and 75 mg treatment. The mRNA biomarkers in blood most consistently elevated included ATF4 transcriptional targets NUPR1, ULBP1 and TRIB3 at 2 - 24 hours after 50 mg and 75 mg treatment. Further, mRNA levels for these biomarkers were elevated in post-treatment biopsy samples in one of the two patients tested. It is envisaged that NXP800 will need to be dosed continuously and although the protocol defined MTD at 28 days at 100 mg QD, it was decided to take a dose of range of 50 mg and 75 mg OD which caused biomarker modulation, forward for further evaluation.
Conclusions A tolerable dose/schedule of continuous dosing of NXP800 has been established with biomarker modulation in blood. Patients will be randomized to two dose levels 50 and 75 mg/day in a QD schedule to evaluate response in a population of ARID1A mutated, platinum-resistant, clear cell ovarian cancer (NCT05226507).
Citation Format: Simon Pacey, Ching Leung, Simon Rodney, Ana Filipa Palma DosReis, Ruth Ruddle, Matthew Tall, Karen Swales, Robert te Poele, Paul Workman, Diane Marsolini, Megan Sardone, Enrique Poradosu, Shay Shemesh, Udai Banerji. Pharmacokinetic and pharmacodynamic evaluation of NXP800, a novel GCN2 activator, in a first in human clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT111.