海报库PosterKeep
PO.CT01.02 · 临床试验

雄激素受体抑制以克服AR阳性转移性TNBC的紫杉烷耐药：4CAST 1b期试验的中期结果

Androgen receptor inhibition to overcome taxane resistance in AR-positive metastatic TNBC: Interim results of the 4CAST Phase 1b trial

海报缩略图：雄激素受体抑制以克服AR阳性转移性TNBC的紫杉烷耐药：4CAST 1b期试验的中期结果
编号 CT043 展板 3 时间 4/20 09:00–12:00 区域 Section 50 主讲 Jia (Jenny) Liu, MD;PhD
分会场 First-in-Human Phase I Clinical Trials
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作者与单位 Authors & Affiliations

Jia Liu1, Rasha Cosman1, Sarah Childs2, Jordan E. Cohen3, Anthony Rodrigues1, Thomas Hansen2, Belinda E. Kiely4, Julia Chen5, Anuradha Pala2, Geeta Sandhu6, Juliet Ho7, Sandunika Warakulasuriya8, Doha Elgundi8, Hao-Wen Sim9, Robert Kent2, Chloe Martin10, Elizabeth M. Woodson11, Christine L. Chaffer12, Rachel Dear1

1The Kinghorn Cancer Centre, St Vincent's Hospital, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Garvan Institute, Sydney, Australia,2The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, Australia,3The Kinghorn Cancer Centre, St Vincent's Hospital, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Calvary Mater Hospital, Newcastle, Sydney, Australia,4Department of Medical Oncology, Campbelltown Hospital, Campbelltown, Sydney Medical School, The University of Sydney, Sydney, Australia,5School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Garvan Institute, Department of Medical Oncology, St George Hospital, Sydney, Australia,6Department of Pharmacy, St Vincent’s Hospital, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Camperdown, Sydney, Australia,7School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Camperdown, Sydney, Australia,8Department of Pharmacy, St Vincent’s Hospital, Sydney, Australia,9The Kinghorn Cancer Centre, St Vincent's Hospital, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Garvan Institute, NHMRC Clinical Trials Centre, The University of Sydney, Camperdown, Sydney, Australia,10The Kinghorn Cancer Centre, St Vincent’s Hospital, Sydney, Australia,11Kembi Therapeutics Pty Ltd, Sydney, Australia,12Garvan Institute of Medical Research, Darlinghurst, St Vincent's Healthcare, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Medicine, The Kinghorn Cancer Centre, St Vincent's Hospital Darlinghurst, Kembi Therapeutics, Sydney, Australia

摘要 Abstract

中文摘要
背景：Seviteronel（sevi）是一种口服生物可利用的CYP17,20-裂解酶抑制剂，可抑制雄激素合成并抑制雄激素受体（AR）的结合与激活。在AR+三阴性乳腺癌（TNBC）的临床前模型中，AR信号通过转录性生存程序促进化疗耐药，为AR抑制与紫杉烷联合治疗提供了理论依据。我们开展了1b期开放标签4CAST试验（NCT04947189），以评估sevi联合紫杉烷治疗在转移性乳腺癌（mBC）中的初步安全性和初步疗效，并试点一种以患者为中心的去中心化入组和参与模式，旨在减少时间毒性并改善可及性。 方法：sevi以450 mg每日一次给药，联合多西他赛（静脉注射75 mg/m2，每3周一次）或白蛋白结合型紫杉醇（静脉注射100 mg/m2，第1/8/15天，每4周一次），用于mBC患者（探索阶段）或AR+转移性TNBC患者（扩展阶段）。扩展阶段入组要求前瞻性评估的IHC上AR核或胞质表达>0%。在剂量探索阶段，主要目标是评估sevi加地塞米松联合紫杉烷治疗的单药推荐2期剂量（RP2D）的安全性。在剂量扩展阶段，主要目标是评估按RECIST v1.1的客观缓解率（ORR）。次要终点包括不良事件（AE）发生频率、缓解持续时间、总生存期以及去中心化参与（口服药物运送、远程医疗评估和本地化疗给药）的可行性。探索性分析包括血清CA15-3和睾酮水平。 结果：剂量探索：入组8名接受过多线治疗的mBC患者（2名TNBC，6名激素受体阳性），其中6名可评估剂量限制性毒性（DLT）。未观察到DLT，确认sevi 450 mg每日的RP2D。2名患者在DLT期后出现2级肺炎；其中1名此前有sacituzumab govitecan（SG）相关性肺炎。剂量扩展：入组8名AR+转移性TNBC患者；3名通过去中心化入组。截至2025年12月，6名患者可按RECIST评估。ORR为67%（4/6），包括既往接受过紫杉烷和SG的患者的缓解。AE以1级或2级为主，且归因于紫杉烷治疗。sevi相关AE主要为1级疲劳和头痛。1名患者出现3级体位性低血压，需要减量。所有患者均观察到睾酮抑制。去中心化入组和参与对研究者和参与者均可行。 结论：sevi联合紫杉烷治疗耐受性良好，在接受过多线治疗的AR+转移性TNBC（包括既往接受过紫杉烷的患者）中显示出令人鼓舞的抗肿瘤活性。这些发现支持将AR抑制作为克服化疗耐药的策略，并证明持续进行II期扩展的合理性。
查看英文原文 English abstract
Background: Seviteronel (sevi) is an orally bioavailable CYP17,20-lyase inhibitor that supresses androgen synthesis and inhibits androgen receptor (AR) binding and activation. In preclinical models of AR+ triple-negative breast cancer (TNBC), AR signalling promotes chemotherapy resistance through transcriptional survival programs providing a rationale for combined AR inhibition and taxane therapy. We conducted the Phase 1b open-label 4CAST trial (NCT04947189) to assess preliminary safety and preliminary efficacy of sevi in combination with taxane therapy in metastatic breast cancer (mBC), and to pilot a patient-centric decentralised enrolment and participation model aimed at reducing time toxicity and improving access. Methods: Sevi was administered at 450 mg once daily in combination with docetaxel (IV 75 mg/m2 q3wkly) or nab-paclitaxel (IV 100 mg/m2 D1/8/15 q4wkly) in patients with mBC (exploration phase) or AR+ metastatic TNBC (expansion phase). AR nuclear or cytoplasmic expression on IHC >0% assessed prospectively was required for eligibility in expansion. In the dose exploration phase, the primary objective was to assess the safety of the monotherapy recommended phase 2 dose (RP2D) of sevi plus dexamethasone in combination with taxane therapy. In the dose expansion phase, the primary objective was to assess the objective response rate (ORR) per RECIST v1.1. Secondary endpoints included frequency of adverse events (AE), duration of response, overall survival, and feasibility of decentralised participation (oral drug shipment, telehealth assessments, and local chemotherapy delivery). Exploratory analyses included serum CA15−3 and testosterone levels. Results: Dose exploration: Eight heavily pretreated patients with mBC (2 TNBC, 6 hormone receptor-positive) were enrolled with 6 evaluable for dose-limiting toxicity (DLT). No DLTs were observed, confirming the RP2D of sevi 450 mg daily. Two patients developed Grade 2 pneumonitis beyond the DLT period; one had prior sacituzumab govitecan (SG)-associated pneumonitis. Dose expansion: Eight AR+ metastatic TNBC patients were enrolled; 3 via decentralised enrolment. As of Dec 2025, 6 patients were RECIST-evaluable. The ORR was 67% (4/6), including responses in patients previously exposed to taxanes and SG. AEs were predominantly Grade 1 or 2 and attributable to taxane therapy. Sevi-related AEs were mainly Grade 1 fatigue and headache. One patient experienced grade 3 postural hypotension requiring dose reduction. Testosterone suppression was observed in all patients. Decentralised enrolment and participation were feasible for both investigators and participants. Conclusion: Sevi combined with taxane therapy was well tolerated and demonstrated encouraging antitumour activity in heavily pretreated AR+ metastatic TNBC, including patients with prior taxane exposure. These findings support AR inhibition as a strategy to overcome chemotherapy resistance and justify ongoing Phase II expansion.
利益披露 Disclosure
J. Liu, Taiho Therapeutics, MSD, Merck, Starpharma, Greywolf Therapeutics ), Other, Honoraria. Innovent Biologics, Starphama ), Other, Travel expenses. Abbvie, AVEO, Bayer, BMS, Carina Biotech, Covus Pharmaceuticals, Daiichi Sankyo, ImmVirx, Merus, Relay Therapeutics, Regeneron, Virocure ). R. Cosman, ETIRA, Create Medicines Other, Advisory. CSTONE, Create Medicines Travel. Create Medicines, Astra Zeneca, Roche, MSD, BMS, Genetech, BioNTech, Created Medicine, Vividion, Voronoi, BridgeBio, Incyte, Adlai Nortye, Novartis, Bohringer Ingelheim, Moderna, Tigermed ). Akesobio, Etira, Dynamicure, BeiGene, OncoC4 ). S. Childs, None.. J. E. Cohen, None.. A. Rodrigues, None.. T. Hansen, None.. B. E. Kiely, None.. J. Chen, None.. A. Pala, None.. G. Sandhu, None.. J. Ho, None.. S. Warakulasuriya, None.. D. Elgundi, None. H. Sim, AbbVie, Bristol-Myers Squibb ). Eli Lilly Australia, Servier Australia, AstraZeneca Other, Honoraria. R. Kent, None.. C. Martin, None. E. M. Woodson, Kembi Therapeutics Other, Consultant. C. L. Chaffer, Kembi Therapeutics Pty Ltd g., Board of Directors, non-salaried role), Stock. R. Dear, None.

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