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Immunotherapy of cancer

5220 - CA-170, a first in class oral small molecule dual inhibitor of immune checkpoints PD-L1 and VISTA, demonstrates tumor growth inhibition in pre-clinical models and promotes T cell activation in Phase 1 study

Date

11 Sep 2017

Session

Immunotherapy of cancer

Topics

Cancers in Adolescents and Young Adults (AYA);  Immunotherapy

Presenters

John Powderly

Citation

Annals of Oncology (2017) 28 (suppl_5): v403-v427. 10.1093/annonc/mdx376

Authors

J. Powderly1, M.R. Patel2, J.J. Lee3, J. Brody4, F. Meric-Bernstam5, E. Hamilton6, S. Ponce Aix7, J. Garcia-Corbacho8, Y. Bang9, M. Ahn10, S.Y. Rha11, K. Kim12, M. Gil Martin13, H. Wang14, A. Lazorchak14, T. Wyant14, A. Ma14, S. Agarwal14, D. Tuck14, A. Daud15

Author affiliations

  • 1 Medical Oncology, Carolina BioOncology Institute, 28078 - Huntersville/US
  • 2 Oncology, Sarah Cannon Research Institute (Nashville, TN); Florida Cancer Specialists & Research Institute, 34232-6422 - Sarasota/US
  • 3 Division Of Hematology-oncology, Department Of Medicine, University of Pittsburgh School of Medicine, PA 15261 - Pitsburgh/US
  • 4 Oncology, vIcahn School of Medicine at Mount Sinai, New York/US
  • 5 Medical Oncology, University of Texas MD Anderson Cancer Centre, Houston/US
  • 6 Medical Oncology, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 37203 - Nashville/US
  • 7 Oncology/hematology, University Hospital 12 De Octubre, 28041 - Madrid/ES
  • 8 Oncology Department, Hospital Clinic y Provincial de Barcelona, 8036 - Barcelona/ES
  • 9 Internal Medicine, Seoul National University Hospital, 110-744 - Seoul/KR
  • 10 Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, 135-710 - Seoul/KR
  • 11 Medical Oncology, Yonsei University College of Medicine, 120-752 - Seoul/KR
  • 12 Department Of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 138-736 - Seoul/KR
  • 13 Medical Oncology, Institut Català d'Oncologia (ICO)-Hospitalet, Barcelona/ES
  • 14 Clinical Research, Curis, Inc, 02421 - Lexington/US
  • 15 Medical Oncology/hematology, University of California San Francisco UCSF, 94143 - San Francisco/US
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Resources

Abstract 5220

Background

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.

Methods

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.

Results

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.

Conclusions

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).

Clinical trial identification

NCT02812875

Legal entity responsible for the study

Curis Inc

Funding

Curis Inc

Disclosure

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.

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