1070TiP - A phase Ia/Ib dose-escalation/expansion study of NPX887 in subjects with solid tumor malignancies known to express HHLA2/B7-H7

Background

HHLA2/B7-H7 is a B7 family member which suppresses T and NK cell activation through an inhibitory receptor, KIR3DL3, and stimulates activation through a distinct receptor, TMIGD2. B7-H7 is expressed on tumor cells of many histologic subtypes and is frequently associated with poor prognosis. As B7-H7 expression is independent of PD-L1 expression, this may represent a novel checkpoint axis for therapeutic targeting. NPX887 is an ADCC-enhanced monoclonal antibody (IgG1) directed against B7-H7 which blocks the interaction with KIR3DL3 while sparing interaction with TMIGD2.

Trial design

NPX887 is being studied in a phase 1a/1b study in solid tumor malignancies where B7-H7 is known to be expressed. The primary objective is evaluation of the safety and tolerability in phase 1a and preliminary efficacy in phase 1b. Secondary objectives include characterization of pharmacokinetics (PK), pharmacodynamics (PD) (including dose-dependent changes in the tumor microenvironment reflective of T/NK cell activation or proliferation), and immunogenicity of NPX887. Dose escalation follows a Bi3+3 design to permit backfill of cohorts cleared for safety during ongoing dose escalation to better characterize PK/PD relationships. Three expansion cohorts are planned, including clear cell renal cell carcinoma, PD-L1-negative lung adenocarcinoma, and colorectal carcinoma. Dose expansion follows a multi-arm, 2-stage (MATS) design with an initial dose explored for estimation of efficacy (Part 1b) followed by randomization to more than one dose (Part 1c) if indicated. Key eligibility criteria in Phase 1a include histologic diagnosis of tumor types known to express B7-H7, refractory metastatic or locally advanced disease and the absence of autoimmune disease or history of colitis or pneumonitis. Phase 1b participants will be required to have had or be intolerant to standard therapies for their disease. B7-H7 expression will be assessed by IHC from archival tissue and fresh biopsies to assess correlation with pharmacodynamic and clinical activity. A validated, clinical trial assay for B7-H7 will be used for prospective selection of participants in phase 1b.

Clinical trial identification

NCT06240728.

Editorial acknowledgement

Legal entity responsible for the study

NextPoint Therapeutics.

Funding

NextPoint Therapeutics.

Disclosure

H. Cheng: Financial Interests, Personal, Advisory Board: Jessen, G1 therapeutic, AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca. I.I. Rodriguez Rivera: Financial Interests, Personal, Advisory Board: Syneos, Telix Pharmaceuticals; Financial Interests, Institutional, Full or part-time Employment: Next Oncology; Financial Interests, Personal, Stocks/Shares: Next Oncology; Non-Financial Interests, Principal Investigator: Omega Therapeutics, Poseida Therapeutics, Werewolf Therapeutics, Merck KGaA, Amgen, Vincerx Pharma, Transcenta Therapeutics, NextPoint Therapeutics, BeiGene, Boundless Bio, Inc. D.F. McDermott: Financial Interests, Personal, Advisory Board: Pfizer, Merck, BMS, Alkermes, Iovance, werewolf therapeutics, Calithera, Eisai; Financial Interests, Personal, Advisory Board, Scientific Advisory Board Members: Cullinan; Financial Interests, Institutional, Coordinating PI: BMS. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; Financial Interests, Personal, Other, Consulting or Advisory Role/Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med, Regeneron, Loxo, Alkermes, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, Arrivent Biopharma. Y. Ged: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Eisai, Exelixis. J. Liu: Financial Interests, Personal, Full or part-time Employment: Cytel. Y. Ji: Financial Interests, Personal, Financially compensated role: Cytel. M. Rausch: Financial Interests, Personal, Full or part-time Employment: Nextpoint Therapeutics; Financial Interests, Personal, Stocks/Shares: Nextpoit Therapeutics. Y. Hashambhoy-Ramsay: Financial Interests, Personal, Full or part-time Employment, full time as a translational scientist: NextPoint Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares,: NextPoint Therapeutics, Inc.; Other, employed from 2017 - 2023: Jounce Therapeutics. K. Kis-Toth: Financial Interests, Institutional, Full or part-time Employment: NextPoint Therapeutics; Financial Interests, Institutional, Stocks/Shares: NextPoint Therapeutics; Non-Financial Interests, Institutional, Proprietary Information: NextPoint Therapeutics. L. Gandhi: Financial Interests, Personal, Officer: NextPoint. A. Naing: Financial Interests, Personal, Advisory Board: CTI, Deka Biosciences, Janssen Biotech, NGM Bio, PsiOxus Therapeutics, Immune-Onc Therapeutics, STCube Pharmaceuticals, OncoSec Keynote 695, Genome & Company, CytomX Therapeutics, Nouscom, Merck Sharp & Dohme Crop, Servier, Lynx Health, AbbVie, PsiOxus; Financial Interests, Institutional, Invited Speaker: AKH Inc., ASCO Direct Oncology Highlights, European Society for Medical Oncology; Financial Interests, Personal, Invited Speaker: Lynx Group, Society for Immunotherapy of Cancer, Korean Society of Medical Oncology, Scripps Cancer Care Symposium, CME Outfitters; Financial Interests, Institutional, Coordinating PI: NCI, EMD Serono; Financial Interests, Personal, Local PI: MedImmune, Healios Onc. Nutrition, Atterocor/Millendo; Financial Interests, Institutional, Local PI: Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Eli Lilly, Kymab PsiOxus, Arcus Biosciences, NeoImmuneTech, Immune-Onc Therapeutics, Surface Oncology, Monopteros Therapeutics, BioNTech Se, Seven & Eight Biopharma, SOTIO Biotech AG; Other, Travel and Accommodation: ARMO BioSciences, NeoImmune Tech, NGM BioPharmaceuticals.