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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

2668 - Initial cohort expansion results of sustained arginine depletion with Pegzilarginase in melanoma patients in a Phase 1 advanced solid tumor trial

Date

21 Oct 2018

Session

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology

Topics

Clinical Research

Tumour Site

Melanoma

Presenters

Bartosz Chmielowski

Citation

Annals of Oncology (2018) 29 (suppl_8): viii442-viii466. 10.1093/annonc/mdy289

Authors

B. Chmielowski1, M. Gordon2, E.I. Buchbinder3, R.J. Sullivan4, J.V. Cohen4, B.D. Curti5, D. Davar6, J. Homsi7, K.M. Komatsubara8, H. Lara-Guerra9, S.E. Alters10, S. Ferrati10, S. Eckert11, S.W. Rowlinson10, J.E. Wooldridge9, A. Ribas1, R.D. Carvajal8

Author affiliations

  • 1 Department Of Medicine, Jonsson Comprehensive Cancer Center at UCLA, 90095-1781 - Los Angeles/US
  • 2 Medical Oncology, HonorHealth Virginia G Piper Cancer Care Network, Scottsdale/US
  • 3 Melanoma, Dana-Farber Cancer Institute, Boston/US
  • 4 Hematology/oncology, Massachusetts General Hospital, 2114 - Boston/US
  • 5 Oncology And Hematology, Providence Cancer Institute, Portland/US
  • 6 Medicine, University of Pittsburgh, Pittsburgh/US
  • 7 Internal Medicine, UT Southwestern Medical Center, Dallas/US
  • 8 Hematology/oncology, Herbert Irving Comprehensive Cancer Center, New York/US
  • 9 Medical, Aeglea Biotherapeutics, 78746-5759 - Austin/US
  • 10 Translational Research, Aeglea Biotherapeutics, 78746-5759 - Austin/US
  • 11 Biometrics, Aeglea Biotherapeutics, 78746-5759 - Austin/US
More

Resources

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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