Abstract 195TiP
Background
ENPP1 is a type II transmembrane protein with nucleotide pyrophosphatase, and phosphodiesterase enzymatic activities and its expression is associated with poor prognosis in cancer. ENPP1 inhibition protects cGAMP and ATP from hydrolysis and reduces adenosine levels in the TME, activates APCs and increases T-cell infiltration promoting anticancer immunity. RBS2418 is a potent oral ENPP1 inhibitor. The current study evaluates RBS2418 as monotherapy and combination with pembrolizumab (pembro), supporting preclinical data and complementary mechanism of action with the aim of generating improved anti-tumor immunity and overcoming checkpoint inhibitor resistance in the combination setting. First clinical experience with RBS2418 was within an EA IND to an advanced adrenal cancer patient where the drug was safe, well tolerated and immunologically active.
Trial Design
This is a phase 1a/b, open-label, non-randomized study in patients (pts) (≥18 years) with advanced, unresectable, recurrent or metastatic solid tumors, who have progressed on, or are ineligible for standard therapies. The study begins with dose-escalation where in a 3+3 fashion pts will receive in one cohort RBS2418 starting at 100mg bid as monotherapy and in a second cohort RBS2418 in combination with pembro (200 mg IV q3w). In the dose-escalation portion, fixed dose as the 10X OBA (OBA as the dose of RBS2418 that inhibits >90% of ENPP1 enzyme activity in human serum) or MTD will be determined, to be used in the expansion cohort which will enroll pts as monotherapy and combination therapy with pembro in tumor types where pembro is approved. The study will enroll up to 64 pts at 10 sites in the US. The primary objectives of the study are safety, tolerability, ENPP1 inhibition and cGAMP protection of RBS2418 as monotherapy and in the combination setting. Immune biomarkers predictive of anti-tumor responses will be explored as well as translational analyses will be done to explore the depth and breadth of immune activation both in tumor tissue and blood. This study is being funded by Riboscience, Llc.
Clinical trial identification
NCT05270213; Released June, 2022.
Legal entity responsible for the study
The authors.
Funding
Riboscience Llc.
Disclosure
J. Glenn: Financial Interests, Personal, Ownership Interest: Riboscience; Financial Interests, Personal, Stocks/Shares: eiger pharmaceuticals. I. Csiki: Financial Interests, Personal, Full or part-time Employment: Riboscience; Financial Interests, Personal, Stocks/Shares: Riboscience. J. Powderly: Financial Interests, Personal, Other, Consulting: Boxer Capital; Financial Interests, Personal, Invited Speaker, Consulting: Aavocyte; Financial Interests, Personal, Invited Speaker, Founder and Owner: Carolina BioOncology Institute, PLLC, BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner: BioCytics Inc.; Financial Interests, Personal, Ownership Interest, Founder and Owner of phase 1 cancer research clinic: Carolina BioOncology Institute, PLLC; Financial Interests, Personal, Other, Founder and Owner, developing intellectual property for cellular therapies: BioCytics Inc; Financial Interests, Personal and Institutional, Invited Speaker: Bristol Myers Squibb, Cullinan, Genentech/Roche, AstraZeneca/MedImmune, EMD Serono, Macrogenics, InCyte, Top Alliance BioSciience, Seattle Genetics, AbbVie, FLX Bio, Alkermes, Arcus BioSciences, Tempest Therapeutics, Calico Life Sciences, Apros, Jounce Therapeutics, Atreca, Sequenom, Repertoire Immune Medicines, Molecular Templates, I-MAB Pharma, NexCure, Xilio Therapeutics, Immune-Onc, Trethera, Zenshine Pharma, Adagene, BJ BioScience, Fate Therapeutics, Conjupro BioTherapeutics; Financial Interests, Institutional, Funding: Precision for Medicine, MT Group, STEMCELL Technologies, Replimmune, Merck, Xilis; Financial Interests, Personal and Institutional, Funding: PIOMA; Financial Interests, Personal and Institutional, Invited Speaker, Also funding for contract laboratory services: Nuvation; Other, Personal, Other, As Founder and Owner of BioCytics Inc. developing immune cellular therapy: BioCytics Inc. K. Klumpp: Financial Interests, Personal, Member of the Board of Directors: Riboscience. All other authors have declared no conflicts of interest.