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Simon Pacey

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    P2.06 - Mesothelioma (ID 170)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Mesothelioma
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.06-07 - Phase 1 Study of CA-170: First-in-Class Small Molecule Targeting VISTA/PD-L1 in Patients with Malignant Pleural Mesothelioma (ID 2341)

      10:15 - 18:15  |  Author(s): Simon Pacey

      • Abstract


      In contrast to PD-L1, VISTA is expressed in up to 90% of malignant pleural mesothelioma (MPM) patients with strong expression on infiltrating lymphocytes and on mesothelioma cells. Recent work also found that expression of VISTA in epithelioid MPM is strikingly higher than in other solid tumors. PD-1 and PD-L1 immune checkpoint inhibitors (ICI) have shown modest activity in ≥2nd line MPM which has fueled interest in novel targets, such as VISTA. Many genes associated with VISTA signaling are proliferative and may help drive cancer, providing strong rationale for inhibitors blocking VISTA. VISTA and PD-1 are independent immune checkpoints negatively regulating T-cell function. VISTA is expressed on immune and tumor cells and implicated in resistance to ICI. Preclinical studies show that dual blockade of VISTA and PD-L1 can be synergistic. CA-170, a small molecule inhibitor of VISTA and PD-L1, has demonstrated anti-tumor activity in multiple in vivo models including syngeneic models that do not respond to anti-PD-1 treatment. Phase 1/2 trialsof CA-170 monotherapy showed that CA-170 has a favorable safety profile with preliminary signs of anti-tumor activity in PD-1 malignancies. Pharmacological activity, as measured by immune-modulating effects, was observed across a wide dose range. Development of CA-170 is on-going with evaluation of BID doses in VISTA expressing tumors, such as MPM.


      CA-170-101 is a Phase 1 dose finding study in advanced solid tumors and lymphomas. Selected dose levels can be expanded with additional patients in tumor types of interest. Two pharmacologically active doses, 200 and 1200 mg BID, were selected to further expand with MPM patients to better understand CA-170 activity in this high VISTA-expressing tumor type. As of April 2019, 12 patients with MPM have been enrolled; 8 have completed the 21-day safety evaluation period without DLT. Objectives: tolerability and RP2D (primary), anti-tumor activity (PFS and ORR, secondary) and exploratory biomarkers and PD effects. Key eligibility: histologically confirmed epithelioid, ≥1 prior therapy including pemetrexed-platinum doublet, no prior ICI, measurable disease, paired tumor biopsies if medically feasible, ECOG 0-1, life expectancy >3 months, and adequate organ function. Clinical trial: NCT02812875.


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