PO.CT01.01 · 临床试验
巨噬细胞激活型抗CD24抗体PHST001在晚期/转移性实体瘤患者中的1期研究初步结果
Initial results from a phase 1 study of PHST001, a macrophage activating anti-CD24 antibody, in patients with advanced/metastatic solid tumors
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摘要 Abstract
中文摘要
背景：巨噬细胞是肿瘤中最丰富的免疫细胞，可吞噬肿瘤细胞并促进广泛的抗肿瘤免疫。然而，吞噬作用可被巨噬细胞检查点（也称为"别吃我"信号）阻断。其中一种信号是CD24，它通过与Siglec-10结合来抑制巨噬细胞对肿瘤细胞的吞噬。CD24在许多肿瘤中表达升高，并与不良临床预后相关。PHST001是一种高亲和力抗CD24 IgG4抗体，可阻断CD24，在多种体外和体内临床前模型中强效诱导巨噬细胞对肿瘤细胞的吞噬。
方法：PHST001-101是一项PHST001在复发/难治性、晚期/转移性实体瘤成人患者中的首次人体剂量递增研究（NCT06840886）。这项1期研究由1a期单药剂量递增和1b期PHST001联合化疗组成。在1a期，患者以每3周一次静脉输注方式，在9个剂量水平之一以及选定剂量水平的回填队列中接受PHST001。本研究的主要目的是评估PHST001的安全性和耐受性。
结果：截至2026年1月27日，43例患者在1a期于7个剂量水平（0.1 mg/kg至9 mg/kg）接受了治疗。无患者出现剂量限制性毒性，无患者因治疗相关不良事件（TRAE）停用PHST001或死亡。大多数TRAE为一过性且为1/2级。最常见的TRAE（>10%）包括乏力（21%）、中性粒细胞计数减少（19%）、恶心（14%）和寒战（12%）。发生于1例以上患者的3/4级TRAE包括中性粒细胞减少（12%）和低血压（5%）。中性粒细胞减少无症状，无并发感染，并在≤7天内缓解。PK分析显示PHST001具有良好的线性PK特征，暴露量随剂量比例增加，无靶点介导的药物处置。从2 mg/kg起达到高达95%的外周受体占有率（RO），PK/RO建模提示在4 mg/kg时肿瘤内RO≥50%。在28例至少进行了一次RECIST评估的患者中，最佳客观缓解包括13例患者（46%）病情稳定和15例患者（54%）疾病进展（PD）。5例患者肿瘤体积缩小，包括1例在PD后继续治疗后出现缩小的患者；均在剂量≥4 mg/kg下。药效学变化包括血清肿瘤标志物和ctDNA下降，以及与巨噬细胞/髓系细胞激活相关的细胞因子和趋化因子升高。将展示更多数据，包括来自更高剂量水平的数据。
结论：PHST001在迄今评估的剂量下耐受性良好，TRAE以低级别和可逆为主。PHST001的PK特征证实了良好的暴露和持续的靶点结合。临床活性信号正在更高剂量水平出现。目前正在1b期探索与其他疗法（如化疗）的联合。
查看英文原文 English 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 ).
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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.
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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.
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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 ).
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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.
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