Abstract 2668
Background
Tumors with low argininosuccinate synthetase 1 (ASS1) expression have impaired arginine synthesis and are dependent on extracellular arginine for survival. Pegzilarginase (AEB1102) is a pegylated, recombinant, cobalt-substituted human arginase I that depletes plasma arginine. MTD was previously reported as 0.33 mg/kg weekly (AACR 2018). Here we update the preliminary safety and activity of monotherapy pegzilarginase in uveal (UM) and cutaneous (CM) melanoma cohorts of an ongoing Phase 1 study (NCT02561234).
Methods
Adult patients (pts) with metastatic UM or CM were eligible after prior standard treatments. IV pegzilarginase was administered at the MTD. Primary objective was safety (CTCAE v4.03); additional endpoints included PK, PD, tumor ASS1 expression, and preliminary anti-tumor activity (RECIST 1.1).
Results
At analysis, 16 pts with melanoma (11 UM, 5 CM) received pegzilarginase in cohort expansions. 5 dose-escalation pts with UM (3) or CM (2) were also treated at MTD. For the 21 pts with UM or CM treated at MTD, treatment-related AEs (TRAE) in > 10% pts included fatigue, nausea, diarrhea, vomiting, decreased appetite, dizziness, gait disturbance, muscular weakness, and tremor. No Grade ≥4 TRAEs were observed, and Grade 3 TRAEs were reported by one pt each: asthenia, failure to thrive, and hypophosphatemia. Median weeks on pegzilarginase was 5.9 (range 0 [1 dose] to 17.1 weeks). Pegzilarginase depleted plasma arginine from a median of 58 µM at baseline to a median of 4 µM at 72 hours post-dose (n = 12). In 13 pts with week 8 response assessment, 6 had stable disease. 13 pts with UM or CM had prior IO therapy; 7 had PD as best response to last prior therapy. 10/16 tumors showed no or low ASS1 expression.
Conclusions
The safety, PD, and activity profile of pegzilarginase at the MTD continues to support weekly administration with a margin for dose adjustment. Given very poor outcomes in pts with advanced UM and CM, pre-clinical data showing enhanced effects of pegzilarginase when combined with PD-L1 inhibition, and the observation of stable disease this trial, further development of pegzilarginase in combination with anti-PD-L(1) therapy is warranted for these tumors.
Clinical trial identification
NCT02561234.
Legal entity responsible for the study
Aeglea Biotherapeutics.
Funding
Aeglea Biotherapeutics.
Editorial Acknowledgement
Abstract was prepared by Aeglea Biotherapeutics.
Disclosure
R.J. Sullivan: Consultant: Novartis, Merck, Amgen, Syndax, Replimmune, Array Biopharma. D. Davar: Corporate-sponsored research (clinical trial support): Merck and Bristol-Myers Squibb. H. Lara-Guerra, S.E. Alters, S. Eckert, S.W. Rowlinson, J.E. Wooldridge: Full-time employee: Stock options: Aeglea Biotherapeutics. S. Ferrati: Full-time employee: Aeglea Biotherapeutics. R.D. Carvajal: Consulting: BMS, Castle Biosciences, Foundation Medicine, Immunocore, Incyte, Merck, Roche/Genentech advisory board: Aura Biosciences, Chimeron, Rgenix. All other authors have declared no conflicts of interest.
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