2391 - A phase 1 study of Sym021, an anti-PD-1 antibody (Ab), alone and in combination with Sym022 (anti-LAG-3) or Sym023 (anti-TIM-3)

Background

Although anti-PD-(L)1 Abs are becoming standard of care for various cancers, combinations with other agents are being studied to improve the activity further. Sym021 is a high affinity, chicken-derived, humanized, effector-function silenced anti-PD-1 IgG1 Ab. Preclinical models demonstrate that Sym021 combined with Abs targeting other checkpoints (e.g., Sym022 an anti-lymphocyte activation gene 3 [LAG-3] Ab, Sym023 an anti-T-cell immunoglobulin mucin 3 [TIM-3] Ab) result in enhanced immunostimulatory and antitumor activity. We present here a first in human study of Sym021 alone and in combination with Sym022 or Sym023.

Methods

Safety, tolerability, and preliminary activity of Sym021 were evaluated on an every 2 week schedule at doses of 1, 3, and 10 mg/kg in patients (pts) with advanced solid tumor malignancies or lymphomas. Pre- and post-dosing blood samples were collected for assessment of PK profile, immunogenicity, and target engagement (ex vivo immune modulation). Based on these analyses, fixed dose Sym021 (3 mg/kg) was selected for further evaluation with increasing doses of Sym022 (0.3-10 mg/kg) or Sym023 (0.3-20 mg/kg) in combination arms of the trial.

Results

17 pts (median 61 years) received escalating doses of Sym021. Treatment-related adverse events (TRAEs; 21 total) occurred in 9 pts. Two pts discontinued treatment for grade (G) 3 autoimmune AEs considered dose-limiting toxicities (colitis at 10 mg/kg; arthritis at 3 mg/kg). Remaining TRAEs were G1-2; no G4 AEs or treatment-related deaths were observed. TRAEs in > 1 pt were fatigue and hypothyroidism (3 pts each). The PK profile was consistent with other monoclonal IgG1 Abs. Immune modulation as measured by ex vivo IL-2 release was observed in 11 of 13 evaluated pts. Two confirmed responses occurred (microsatellite stable gastric carcinoma [complete response at 10 mg/kg]; lacrimal gland ductal carcinoma [partial response at 3 mg/kg]).

Conclusions

Sym021 alone was well tolerated and demonstrated both immune modulation and antitumor activity. Evaluation of single agent dose-escalation trials of Sym022 and Sym023 and of the Sym021/Sym022 and Sym021/Sym023 combination arms are ongoing. Results from these studies will be presented.

Clinical trial identification

NCT03311412.

Editorial acknowledgement

Legal entity responsible for the study

Symphogen A/S.

Funding

Symphogen A/S.

Disclosure

A. Spreafico: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Oncorus; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Janssen Oncology. F. Janku: Research grant / Funding (institution): Novartis, ; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): BioMed Valley Discoveries; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Agios; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Piqur; Advisory / Consultancy, Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Asana; Research grant / Funding (institution): Upsher-Smith Laboratories; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: IFM Therapeutics; Advisory / Consultancy: Synlogic; Advisory / Consultancy: Deciphera; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Trovagene; Advisory / Consultancy: Immunomet. J.A. Rodon: Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Novartis ; Advisory / Consultancy, Research grant / Funding (institution): Spectrum Pharmaceuticals; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): BioAtla; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): GenMab; Research grant / Funding (institution): CytomX; Research grant / Funding (institution): Kelun-Biotech; Research grant / Funding (institution): Takeda-Millenium; Research grant / Funding (institution): Glaxosmithkline; Research grant / Funding (institution): Ipsen; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Orion Pharmaceuticals; Advisory / Consultancy: Servier Pharmaceuticals; Advisory / Consultancy: Peptomyc; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme; Advisory / Consultancy, Travel / Accommodation / Expenses: Kelun Pharmaceutical/Klus Pharma; Advisory / Consultancy: Roche Pharmaceuticals. A.W. Tolcher: Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Adagene; Advisory / Consultancy, Research grant / Funding (institution): ADC Therapeutics; Advisory / Consultancy: Agenus; Advisory / Consultancy: Aro Biotx; Advisory / Consultancy, Research grant / Funding (institution): Ascentage; Advisory / Consultancy: Aximmune; Advisory / Consultancy: Bayer; Advisory / Consultancy: Bioinvent; Advisory / Consultancy: Birdie; Advisory / Consultancy: Boston Medical (Syneos); Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Forbius; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Immunome; Advisory / Consultancy: Immunomet; Advisory / Consultancy: Mekanistic; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy, Research grant / Funding (institution): Symphogen; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Jazz Pharmaceuticals; Advisory / Consultancy: NBE Therapeutics; Advisory / Consultancy: Nuvalent; Advisory / Consultancy: Pelican; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Ridgeway; Advisory / Consultancy: Scitemex; Speaker Bureau / Expert testimony: Sesen (formerly Eleven BIO); Advisory / Consultancy: Syneos; Research grant / Funding (institution): Aminex; Research grant / Funding (institution): Asana; Research grant / Funding (institution): Arrys; Research grant / Funding (institution): Birdie; Research grant / Funding (institution): Cstone; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Inhibrx; Research grant / Funding (institution): Innate; Research grant / Funding (institution): Kiromic; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Naturewise; Research grant / Funding (institution): Nextcure; Research grant / Funding (institution): Nitto Biopharma; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Tizona; Research grant / Funding (institution): Zymeworks. S.R. Chandana: Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Advisory / Consultancy: Lilly; Research grant / Funding (institution): Novocure Ltd; Research grant / Funding (institution): ALX Oncology; Research grant / Funding (institution): Forty Seven Inc; Research grant / Funding (institution): INhibRx; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Livzon; Research grant / Funding (institution): Forbius; Research grant / Funding (institution): Formation Biologics; Research grant / Funding (institution): Northern Biologics. M. Oliva: Honoraria (self): BMS; Honoraria (self): Merck; Research grant / Funding (institution): Symphogen. S. Musalli: Full / Part-time employment: Symphogen A/S. L. Knauss: Advisory / Consultancy, Full / Part-time employment: Symphogen A/S. M. Kragh: Shareholder / Stockholder / Stock options, Full / Part-time employment: Symphogen A/S. L. Alifrangis: Full / Part-time employment: Symphogen A/S. C. Fröhlich: Full / Part-time employment: Symphogen A/S. M.C. Melander: Full / Part-time employment: Symphogen A/S. T. Blondal: Full / Part-time employment: Symphogen. M.W. Pedersen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Symphogen A/S. J. Lantto: Shareholder / Stockholder / Stock options, Full / Part-time employment: Symphogen. D. Wood: Advisory / Consultancy: Symphogen; Advisory / Consultancy: Forbius; Advisory / Consultancy: Prism Pharma; Spouse / Financial dependant: Karyopharm. P.I. Nadler: Advisory / Consultancy, Leadership role: Forbius; Advisory / Consultancy: Symphogen A/S; Advisory / Consultancy: Karyopharm; Spouse / Financial dependant: Prism Pharma. I.D. Horak: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Symphogen A/S. L.L. Siu: Advisory / Consultancy, Research grant / Funding (institution): Merck ; Advisory / Consultancy, Research grant / Funding (institution): Pfizer ; Advisory / Consultancy, Research grant / Funding (institution): Celgene ; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy: Morphosys ; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: GeneSeeq ; Advisory / Consultancy: Loxo; Advisory / Consultancy: Oncorus; Advisory / Consultancy, Research grant / Funding (institution): Symphogen; Advisory / Consultancy: Seattle Genetics; Research grant / Funding (self): Novartis; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Amgen. N. Lakhani: Research grant / Funding (institution): ALX Therapeutics; Research grant / Funding (institution): Amgen/Pfizer; Research grant / Funding (institution): Ascentage; Research grant / Funding (institution): Apexian; Research grant / Funding (institution): Asana Bioscience; Research grant / Funding (institution): Formation Biologics; Research grant / Funding (institution): Beigene Cerulean; Research grant / Funding (institution): Constellation; Research grant / Funding (institution): CytomX/Compugen; Research grant / Funding (institution): Forty Seven; Research grant / Funding (institution): Innovent Biologics; Research grant / Funding (institution): InhibRx/Incyte; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Jounce/Coordination; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Livzon/TaiRx; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Northern Biologics; Research grant / Funding (institution): Regeneron.