PO.CT01.01 · 临床试验

Initial results from a phase 1 study of PHST001, a macrophage activating anti-CD24 antibody, in patients with advanced/metastatic solid tumors

编号 CT130 展板 22 时间 4/20 02:00–05:00 区域 Section 51 主讲 Raphael Rousseau, MD;PhD

分会场 Phase 0 and First-in-Human Phase I Clinical Trials

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作者与单位

Stephane Champiat¹, Ulka Vaishampayan², Michael Cecchini³, Oliver Dorigo⁴, Anthony El-Khoueiry⁵, Gina Fleming⁶, Niharika Mettu⁷, Michael J. Dennis⁸, Elizabeth Davis⁹, Susan Luebbe¹⁰, Jen Cao¹⁰, Roy Maute¹⁰, Raphael Rousseau¹⁰, Kyriakos Papadopoulos¹¹

¹Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX,²University of Michigan, Ann Arbor, MI,³Yale School of Medicine, New Haven, CT,⁴Stanford Women's Cancer Center and Stanford Cancer Institute, Stanford, CA,⁵University of Southern California, Norris Comprehensive Cancer Center,, Los Angeles, CA,⁶University of Chicago Medicine, Chicago, IL,⁷Duke Cancer Center, Durham, NC,⁸Dana-Farber Cancer Institute, Boston, MA,⁹Vanderbilt University Medical Center, Nashville, TN,¹⁰Pheast Therapeutics Inc., Palo Alto, CA,¹¹South Texas Accelerated Research Therapeutics (START), San Antonio, TX

摘要 Abstract

Background: Macrophages are the most abundant immune cell in tumors and can phagocytose tumor cells and promote broad anti-tumor immunity. However, phagocytosis can be blocked by macrophage checkpoints, also known as ‘don't eat me' signals. One such signal is CD24 which inhibits macrophage phagocytosis of tumor cells via binding to Siglec-10. CD24 expression is elevated in many tumors and associated with poor clinical prognosis. PHST001 is a high affinity anti-CD24 IgG4 antibody that blocks CD24, potently inducing macrophage phagocytosis of tumor cells in a wide range of in vitro and in vivo preclinical models. Methods: PHST001-101 is a first-in-human, dose escalation study of PHST001 in adult patients with relapsed/refractory, advanced/metastatic solid tumors (NCT06840886). This Phase 1 study is composed of a Phase 1a monotherapy dose escalation and a Phase 1b combining PHST001 with chemotherapy. In Phase 1a, patients received PHST001 at 1 of 9 dose levels and in backfill cohorts at select dose levels via IV infusion every 3 weeks. The primary objective of this study is to assess the safety and tolerability of PHST001. Results: As of 27 Jan 2026, 43 patients have been treated in Phase 1a at 7 dose levels (0.1 mg/kg to 9 mg/kg). No patients have experienced a dose limiting toxicity and no patients have discontinued PHST001 or died due to a treatment-related adverse event (TRAE). Most TRAEs are transient and Grade 1/2. The most common TRAEs (> 10%) include fatigue (21%), neutrophil count decreased (19%), nausea (14%), and chills (12%). Grade 3/4 TRAEs occurring in more than one patient include neutropenia (12%) and hypotension (5%). Neutropenia has been asymptomatic with no concurrent infections and resolves in ≤ 7 days. PK analysis shows a favorable and linear PK profile of PHST001 with dose proportional increase in exposure and no target mediated drug disposition. Peripheral receptor occupancy (RO) of up to 95% is achieved starting at 2 mg/kg and PK/RO modeling suggests ≥ 50% RO in the tumor at 4 mg/kg. In 28 patients with at least one RECIST assessment, best objective responses include 13 patients (46%) with stable disease and 15 patients (54%) with progressive disease (PD). 5 patients had a decrease in tumor size including 1 patient with a decrease after being treated beyond PD; all at doses ≥ 4 mg/kg. Pharmacodynamic changes include decreases in serum tumor markers and ctDNA, as well as elevations in cytokines and chemokines associated with macrophage/myeloid cell activation. Additional data, including from higher dose levels, will be presented. Conclusions: PHST001 is well tolerated at doses evaluated to date with TRAEs being predominantly low grade and reversible. The PK profile of PHST001 confirms favorable exposure with sustained target engagement. Signals of clinical activity are emerging at higher dose levels. Combination with other therapies, such as chemotherapy, are currently being explored in Phase 1b.

利益披露 Disclosure

S. Champiat, Abbvie; Amgen; AstraZeneca; Boehringer Ingelheim; Bolt Biotherapeutics; Centessa Pharmaceuticals; Cytovation; Eisai; Exelixis; GlaxoSmithKline; Imcheck Therapeutics; Immunocore; Kumquat Biosciences ). Marengo; Molecular Partners Ag; Merck; OncoC4; Ose Immunotherapeutics; Owkin; Pheast; Pierre Fabre; Replimune; Roche; Sanofi Aventis; Seagen; Sotio A.S; Transgene; Trutino Biosciences ). Amgen; Astellas; AstraZeneca; Bristol Myers Squibb; Eisai; Genmab; Janssen; Merck KGaA; Merck; Novartis; Roche;Servier Other, Speaker. AccessTrial; Alderaan Biotechnology; Amgen; AstraZeneca; Aummune; Avacta; Bayer; Beigene; BioNTech; Celanese; Compugen; Domain Therapeutics; Ellipses Pharma; GE Health; Genmab; Guardant Health Other, Advisory Board/Consulting. Immunicom, Inc.; Mariana Oncology; Mima Health; Nanobiotix; Nextcure; NetCancer; Oncovita; Pharma Mar; Pierre Fabre; Replimune; Seagen; Takeda; Tatum Bioscience; Tollys; UltraHuman8 Other, Advisory Board/Consulting. Amgen; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; Merck; Ose Immunotherapeutics; Roche; Sotio Travel. Avacta Stock. U. Vaishampayan, Pheast ). M. Cecchini, Seattle Genetics; Taiho; Regeneron; Incendia Therapeutics; Agenus; Elevate Oncology; LoxoLilly; AstraZeneca; Daiichi Sankyo; Beigene; Arcus; Modifi Bio; Incyte; Abbvie; Parabalis; Wren Therapeutics Other, Honoraria. BainCapital; Cybrexa; Exelixis Other, Honoraria. O. Dorigo, Bioclipse; EMD Serono; Novartis; AstraZeneca; MilleniumPharma; Clovis Oncology; IMV Inc.; Pheast ). PSI CRO DeutschlandGmbH; Eisai; PACT; Agenus; Epsila Bio; R-Pharm U.S.; Clovis Oncology; IMV Inc. Other, Personal fees. A. El-Khoueiry, Affimed, Pheast; Astrazeneca; Auransa; Fulgent Genetics; Astex Pharmaceuticals ). Roche/Genentech; Eisai; Merck; Bristol Myers Squibb; Exelixis; Qurient; Terumo; Elevar; Senti Biosciences; Agenus, Exelixis, Astrazeneca; Jazz Other, Personal fees. Affimed Therapeutics Travel. G. Fleming, Merck; Plexxion; AstraZeneca; Astela; K group beta; Pfizer; Artios; Blueprint; Duality Bio; Sanofi; PHEAST; systimmune ). N. Mettu, Merck; Amgen; Leap; Adanate; Sapience; Jazz; Seagen; Revolution Medicine; PMV Pharmaceuticals; Pfizer; Biohaven; BioNTech; Medilink; MOMA Therapeutics ). M. J. Dennis, Dr. Reddy's Laboratories; Coherus Oncology; Corbus Pharmaceuticals Other, Consulting. E. Davis, Cogent; Inhibrx; PharmaMar; NuMab; Servier; Mirati; Pheast; Loxo ). Deciphera; Aadi Other, Consulting. S. Luebbe, Pheast Employment. J. Cao, Pheast Employment. R. Maute, Pheast Employment, g., Board of Directors, non-salaried role). R. Rousseau, Pheast Therapeutics Employment. K. Papadopoulos, Basilea; Bicycle Therapeutics; Turning Point Therapeutics Other, Consulting. 3D Medicines; Abbvie; ADC Therapeutics; Amgen; Anheart Therapeutics; AstraZeneca; Bayer; Bicycle Therapeutics; Biontech; CytomX ). Daiichi Sankyo; Debiopharm Group; F-star; Incyte; Jounce Therapeutics; Kezar Life Sciences; Lilly; Linnaeus Therapeutics; MabSpace Biosciences ). Merck; Mersana; Mirati Therapeutics; Monte Rosa Therapeutics; Pfizer; PharmaMar; Regeneron; Revolution Medicines; Sensei Biotherapeutics ). Storm Therapeutics; Syros Pharmaceuticals; Tempest Therapeutics; Treadwell Therapeutics ).

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