PO.CT01.02 · 临床试验

SGR-3515（一种Wee1/Myt1双重抑制剂）在晚期实体瘤受试者中一项正在进行的1期研究（SGR-3515-101）的初步安全性、药代动力学和药效学

Preliminary safety, pharmacokinetics and pharmacodynamics of SGR-3515, a Wee1/Myt1 dual inhibitor from an ongoing Phase 1 study in participants with advanced solid tumors (SGR-3515-101)

编号 CT065 展板 25 时间 4/20 09:00–12:00 区域 Section 50 主讲 Stephanie Lheureux, MD;PhD

分会场 First-in-Human Phase I Clinical Trials

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作者与单位 Authors & Affiliations

Stephanie Lheureux¹, Michael K. Gibson², Kathleen N. Moore³, Wendel Naumann⁴, Mohamad Salkeni⁵, Pedro Hermida de Viveiros⁶, Deborah Doroshow⁷, David Miller⁸, Vivek Subbiah⁹, Ira Winer¹⁰, Shaoxian Sun¹¹, Peter Skrdla¹¹, Francois Lafleur¹¹, Steven Pirie-Shepherd¹¹, Sarsvat Patel¹¹, Yi Zhang¹¹, Kevin Wu¹¹, Margaret Dugan¹¹, Patricia M. LoRusso¹²

¹UHN Princess Magaret Cancer Centre, Toronto, ON, Canada,²Vanderbilt-Ingram Cancer Center, Nashville, TN,³University of Oklahoma, Oklahoma City, OK,⁴Levine Cancer Atrium Health, Wake Forest School of Medicine, Charlotte, NC,⁵Next Oncology, Fairfax, VA,⁶Northwestern University Feinberg School of Medicine, Chicago, IL,⁷Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY,⁸University of Texas Southwestern Medical Center, Dallas, TX,⁹Sarah Cannon Research Institute, Nashville, TN,¹⁰Karmanos Cancer Institute, Detroit, MI,¹¹Schrödinger, New York, NY,¹²Yale University, New Haven, CT

摘要 Abstract

中文摘要

引言：SGR-3515是一种口服小分子共抑制剂，靶向Wee1和Myt1激酶，二者在调控细胞周期中发挥关键作用，且基于临床前数据具有合成致死性。SGR-3515已显示出优于单靶点抑制的临床前抗肿瘤活性，目前正在一项1期、首次人体、剂量递增研究SGR-3515-101中于晚期实体瘤受试者中进行评估。该研究的主要目的是评估安全性、耐受性、剂量限制性毒性（DLT），以确定最大耐受剂量和推荐的2期剂量。其他目的包括评估SGR-3515的药代动力学、抗肿瘤活性和药效学。方法：受试者在28天周期中按间歇给药方案每日一次接受SGR-3515，采用BOIN剂量递增设计。前2个周期每周评估安全性，此后每2周评估一次。通过IHC检测分别测定配对肿瘤活检中pCDK1 Y15和pCDK1 T14信号的调节，以衡量对Wee1和Myt1的靶点抑制。每8周采用RECIST v1.1进行疾病评估。结果：截至2025年10月31日，33例受试者接受了7个剂量水平（15 mg-175 mg）的治疗。肿瘤组织学类型主要为卵巢癌（20例）、ER+乳腺癌（5例）和子宫癌（5例）。既往治疗线数中位数：5（范围1-10）。11例受试者仍在治疗中，22例已停药，主要因疾病进展（19例）。剂量递增正在进行中。治疗中出现的不良事件（TEAE，任意级别，≥G3）总发生率为79%、37%；治疗相关不良事件（TRAE，任意级别，≥G3）：64%、15%；无G5事件。常见TRAE（≥10%）为恶心（27%）、腹泻（21%）、乏力（18%）和中性粒细胞计数降低（15%）。4例G3 TRAE为腹泻（1）、恶心（1）、乏力（1）和肝功能检查（LFT）升高（1）。2例G4 TRAE均为中性粒细胞计数降低。药物相关严重AE为G3恶心（1）和G3 LFT升高（1）。无DLT，有1例药物相关的治疗停药，为G3 LFT升高。初步PK结果显示SGR-3515血浆暴露随剂量相关增加（15-135 mg）。在30-135 mg剂量水平的配对肿瘤活检中观察到对Wee1和Myt1的靶点抑制。初步抗肿瘤活性数据包括在所有剂量水平可评估疗效的23例受试者中有8例（35%）出现疾病稳定。在100-135 mg时，9例可评估受试者中有7例（78%）显示疾病稳定，其中6例仍在治疗中，治疗持续时间中位数：165天（范围110-292天）。结论：SGR-3515总体耐受性良好，并在肿瘤活检中显示出对Wee1和Myt1共抑制的初步证据。通过疾病稳定显示出初步抗肿瘤活性。SGR-3515-101（NCT06463340）继续入组可能从共抑制中获益的受试者。

查看英文原文 English abstract

Introduction: SGR-3515 is an oral, small molecule co-inhibitor targeting Wee1 and Myt1 kinases, which play a crucial role in regulating cell cycle and are synthetic lethal based on preclinical data. SGR-3515 has shown preclinical antitumor activity superior to single target inhibition, and is being evaluated in a Phase 1, first-in-human, dose-escalation study, SGR-3515-101, in participants with advanced solid tumors. The primary objectives of this study are to evaluate the safety, tolerability, dose-limiting toxicities (DLTs), to identify the maximum tolerated dose and recommended Phase 2 dose. Other objectives include evaluating pharmacokinetics, antitumor activity and pharmacodynamics of SGR-3515. Methods: Participants received SGR-3515 once daily on an intermittent schedule in 28-day cycles in a BOIN dose escalation design. Safety was evaluated weekly for 2 cycles, and every 2 weeks thereafter. Target inhibition of Wee1 and Myt1 in paired tumor biopsies was measured by modulation of the pCDK1 Y15 and pCDK1 T14 signal, respectively, using IHC assays. Disease assessments occurred every 8 weeks using RECIST v1.1. Results: As of 31-Oct-2025, 33 participants have been treated across 7 dose levels (15 mg-175 mg). Tumor histologies were predominantly ovarian cancer (20), ER+ breast cancer (5) and uterine cancer (5). Median lines of prior therapy: 5 (range 1-10). Eleven (11) participants remain on treatment and 22 are discontinued, mostly due to disease progression (19). Dose escalation is ongoing. The overall incidence of treatment-emergent adverse events (TEAE, any grade, ≥ G3) was 79%, 37%; treatment-related adverse events (TRAE, any grade, ≥ G3): 64%, 15%; no G5 events. Common TRAEs (≥ 10%) were nausea (27%), diarrhea (21%), fatigue (18%) and neutrophil count decreased (15%). The 4 G3 TRAEs were diarrhea (1), nausea (1), fatigue (1) and liver function tests (LFT) increased (1). The 2 G4 TRAEs were both neutrophil count decreased. Drug-related serious AEs were G3 nausea (1) and G3 LFT increased (1). There were no DLTs and 1 drug related treatment discontinuation, G3 LFT increased. Preliminary PK results demonstrated a dose-related increase in SGR-3515 plasma exposure (15-135 mg). Target inhibition of Wee1 and Myt1 was observed in paired tumor biopsies at dose levels between 30-135 mg. Preliminary antitumor activity data include stable disease in 8 of the 23 (35%) participants evaluable for efficacy across all dose levels. At 100-135 mg, 7 of the 9 (78%) evaluable participants demonstrated stable disease, 6 of which remain on treatment, median treatment duration: 165 days (range 110-292 days). Conclusion: SGR-3515 was generally well tolerated and demonstrated initial evidence of co-inhibition of Wee1 and Myt1 in tumor biopsies. Preliminary antitumor activity was demonstrated by stable disease. SGR-3515-101 (NCT06463340) continues to enroll participants that may benefit from the co-inhibition.

利益披露 Disclosure

S. Lheureux, AstraZeneca ), Other, consulting. Repare Therapeutics ), Other, consulting. GSK ), Other, consulting. Schrodinger ), Other, consulting. Merck ), consulting. Roche ), Other, consulting. Seagen ), Other, consulting. Eisai Other, consulting. Zai Lab Other, consulting. Regeneron Other, consulting. Lilly Other, consulting. AbbVie Other, consulting. Gilead Other, consulting. M. K. Gibson, None.. K. N. Moore, None. W. Naumann, Amgen Stock. Johnson & Johnson/MedTech Other, Honoraria. Merck Sharp & Dohme Other, consulting and advisory role. AstraZeneca Other, consulting and advisory role. Eisai Other, consulting and advisory role. BMS ), Other, consulting and advisory role. Seagen Other, consulting and advisory role. GSK/Tesaro ), Other, consulting and advisory role. EMD Serono Other, consulting and advisory role. Genmab Other, consulting and advisory role. Schrödinger ). M. Salkeni, Abbvie ), Other, Advisory board. Acrivon ). Aprea ). AstraZeneca ), Other, advisory board. Beigene ). Daiichi ), Other, Advisory board. Takeda ). Merck ). P. de Viveiros, Springworks/EMD Serono Other, speaker, advisory board. Deciphera/Ono Other, advisory board. Daiichi Sankyo Other, advisory board. D. Doroshow, AstraZeneca Other, consultant, advisory board. Nuvalent Other, consultant, advisory board. Boehringer Ingelheim Other, consultant, advisory board. Summit Other, consultant, advisory board. Bayer Other, consultant, advisory board. BMS Other, consultant, advisory board. Takeda Other, consultant, advisory board. D. Miller, None. V. Subbiah, Schrödinger Other, clinical trial funding. I. Winer, None.. S. Sun, None.. P. Skrdla, None.. F. Lafleur, None.. S. Pirie-Shepherd, None.. S. Patel, None.. Y. Zhang, None.. K. Wu, None.. M. Dugan, None.. P. M. LoRusso, None.

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