Programmed-death 1 (PD-1) and V-domain Ig suppressor of T-cell activation (VISTA) are independent immune checkpoints that inhibit T cell function. Preclinical studies demonstrated that dual blockade of these checkpoints can be synergistic. CA-170 is an oral small molecule antagonist of PD-L1 and VISTA, currently undergoing Phase (Ph) 1 clinical testing.
Pre-clinically, CA-170 inhibition of PD-L1 or VISTA-mediated suppression of T cell function was tested in vitro using human, monkey, or mouse cells. In vivo anti-tumor activity was examined in multiple syngeneic mouse models. Pts with advanced solid tumors or lymphomas, age ≥ 18, ECOG ≤1 and adequate organ function are treated with escalating doses of oral CA-170 daily during Ph 1a. Ph 1b dose expansion will enrich enrollment for selected pt population possibly responsive to this novel inhibitor. Primary objectives: safety, maximum tolerated dose and recommended Phase 2 dose. Secondary objectives: pharmacokinetics and anti-tumor activity. Exploratory endpoints: biomarkers and pharmacodynamic (PD) effects in periphery and tumor tissues.
CA-170 rescues in vitro T cell effector function with activity comparable to that of PD-1 or VISTA blocking antibodies. Oral CA-170 inhibits the growth of mouse syngeneic tumors (B16 melanoma, CT26 and MC38 colon carcinoma), enhances peripheral T cell activation, and promotes the activation of tumor infiltrating CD8+ T cells in vivo. In humans, a total of 19 patients have been treated across 6 dose levels (50 - 800 mg). No dose limiting toxicity has been observed. CA-170 exhibits generally dose proportional plasma exposure with T1/2 of ∼ 4-9.5 hours. Evidence of peripheral T cell activation was observed with an increased proportion of circulating CD8+ and CD4+ T cells expressing activation markers, CD69 and CD134, following oral dosing.
These pre-clinical and preliminary clinical PD data warrant the continued clinical development of CA-170, the first oral, small molecule immune checkpoint antagonist for the treatment of advanced cancers. Dose escalation is currently ongoing (NCT02812875).
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J. Powderly: Employment BioCytics Consult Bristol-Myers Squibb; Genentech; AstraZeneca; Curis Stock BioCytics; Lion Biotech; Juno; Bluebird; Kite; Ziopharm; Carolina Funding Bristol-Myers Squibb; Genentech; AstraZeneca; EMD; Macrogeneics; Lilly; Incyte; TopAlliance; Seattle Genetics; Abbvie; Corvus; Curis. M.R. Patel: Honoraria and Speaker\'s Bureau Medivation, Genentech; Exelixis; Bristol-Myers Squibb; Gilead; Guardant Health. J.J. Lee: Consulting/Advisory role Genentech Research Funding Merck. J. Brody: Consulting/Advisory role Gilead; Teva; Pharmacyclics; Bristol-Myers Squibb; Corvus; Merck; Celledex; Novartis; Janssen Research funding Acerta; Merck; Celgene. E. Hamilton: Consulting Pfizer; Genentech; Flatiron health; Cascadian. H. Wang, A. Lazorchak, T. Wyant, A. Ma, S. Agarwal, D. Tuck: Employment/stock Curis. A. Daud: Consulting or Advisory Role Oncosec, Merck, GSK Stock/Ownership Oncosec Honoraria EMD Serono; Inovio Pharmaceuticals Research Funding Merck/Schering Plough; GSK; Pfizer; Genentech/Roche; Oncosec. All other authors have declared no conflicts of interest.