PO.CTP01.01 · 进行中的临床试验
CTPS2表达缺失暴露出对选择性CTPS1抑制的合成致死易感性：dencatistat（STP938）的1期剂量爬坡研究及在生物标志物筛选队列中的安全性扩展
Lack of CTPS2 expression exposes synthetic lethal vulnerability to selective CTPS1 inhibition: A phase 1 dose escalation study of dencatistat (STP938) with safety expansion in biomarker selected cohorts
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摘要 Abstract
中文摘要
背景：嘧啶合成是癌症中的一个治疗易感靶点，但对其进行抑制会对正常细胞产生毒性。差异化靶向CTP合酶1（CTPS1）而不影响CTPS2同工酶，是一种在淋巴系统肿瘤中的治疗策略，该策略得到人类遗传学研究的支持，有可能避免毒性；然而，在上皮性肿瘤中CTPS2活性可能起到代偿作用。CTPS2蛋白表达缺失是25%实体瘤的特征，预计会暴露出对CTPS1抑制的合成致死易感性。Dencatistat（STP938）是一种首创（first in class）的口服CTPS1抑制剂，相对CTPS2具有>1,300倍的选择性。在临床前研究中，CTPS2表达被确认为CTPS1抑制应答的关键调控因素，且dencatistat在CTPS2阴性卵巢癌的体内模型中诱导了肿瘤消退。
研究设计：本研究采用标准的3+3期1a剂量爬坡设计，鼓励患者内剂量爬坡，随后进行1b期安全性扩展。剂量爬坡研究正在招募已用尽标准治疗的高级别晚期肿瘤受试者（不包括血液系统肿瘤、唾液腺肿瘤及任何组织的低级别肿瘤）。此外，肿瘤缺乏CTPS2表达（经中心实验室免疫组化检测）的高级别浆液性卵巢癌受试者在剂量爬坡期间有资格回填（backfill）进入已清除的队列。推荐2期剂量（RP2D）将基于安全性、耐受性、靶点结合及早期临床疗效迹象来确定。1b期安全性扩展研究将招募CTPS2阴性的卵巢癌、肺癌或子宫内膜癌受试者，他们将在RP2D下接受治疗。适用标准纳入标准；ECOG体能状态评分>2（法国1a期为>1）或活动性/有症状的CNS转移的患者不符合条件。本研究的主要目的是评估单药dencatistat的安全性和耐受性，并确定用于进一步开发的RP2D。次要目的包括评估药代动力学特性和初步临床活性。探索性终点包括评估靶点结合、与应答相关的分子特征以及药物代谢产物的测定。本研究于2024年9月在英国、法国和美国开放入组，目前处于剂量爬坡阶段（NCT06297525）。1b期研究预计于2026年年中启动，并将纳入西班牙的更多中心。
查看英文原文 English abstract
Background: Pyrimidine synthesis is a therapeutic vulnerability in cancer but inhibition results in toxicity to normal cells. Differential targeting of CTP synthase 1 (CTPS1), sparing the CTPS2 isoenzyme, is a therapeutic strategy in lymphoid cancers, supported by human genetic studies, that can potentially avoid toxicity; however, CTPS2 activity may compensate in epithelial tumours. Loss of CTPS2 protein expression characterises 25% of solid tumours and is predicted to expose a synthetic lethal vulnerability to CTPS1 inhibition. Dencatistat (STP938) is a first in class oral CTPS1 inhibitor showing >1,300-fold selectivity over CTPS2. In preclinical studies, CTPS2 expression was confirmed as a key modulator of response to CTPS1 inhibition, and dencatistat induced tumour regression in an in vivo model of CTPS2 negative ovarian cancer.
Study design: The study comprises a standard 3+3 phase 1a dose escalation design, in which intra-patient dose escalation is encouraged, followed by a phase 1b safety expansion. The dose escalation study is recruiting participants with high grade advanced tumours who have exhausted standard of care therapy (excluding haematological cancers, salivary gland tumours and low grade tumours of any tissue). In addition, participants with high grade serous ovarian cancer whose tumours lack expression of CTPS2 (per central laboratory testing by immunohistochemistry) are eligible for backfill into cleared cohorts during dose escalation. The recommended phase 2 dose (RP2D) will be nominated based on safety, tolerability, target engagement and early signs of clinical efficacy. The phase 1b safety expansion study will recruit participants with CTPS2 negative ovarian, lung or endometrial cancer who will receive treatment at the RP2D. Standard inclusion criteria apply; patients with ECOG performance score >2 (>1 for phase 1a in France) or active/symptomatic CNS metastases are not eligible. The primary objectives of the study are to evaluate the safety and tolerability of single agent dencatistat and to determine the RP2D for further development. Secondary objectives comprise evaluation of pharmacokinetic properties and preliminary clinical activity. Exploratory endpoints include evaluation of target engagement, molecular features associated with response, and determination of drug metabolites. The study opened to enrolment in the UK, France and USA in September 2024 and is currently in dose escalation (NCT06297525). The phase 1b study is expected to commence mid-2026 and will include additional centres in Spain.
利益披露 Disclosure
D. M. Graham,
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AstraZeneca ).
Bristol-Myers Squibb ).
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Genmab ).
Takeda ).
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Eisai ).
Janssen ).
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D. Sommerhalder,
Texas Oncology, NEXT Oncology Employment, Stock.
Syneos Gift.
Guidepoint ).
AbbVie, Acrivon Therapeutics, ADC Therapeutics, Alentis Therapeutics, Aprea Therapeutics, Ascentage Pharma Group, Astellas, AstraZeneca, Avenzo Therapeutics, Axion Bio Inc, Biomea Fusion, Boehringer ).
BJ Bioscience, BioNTech, Bristol-Myers Squibb, Compugen, Day One Biopharma, Dewpoint Therapeutics Inc, Dicerna/Novo Nordisk, Dren Bio Inc., DualityBio Inc, Erasca Inc, Exelixis, Fate Therapeutics ).
Gilead Sciences, GlaskoSmithKline, Haihe Pharmaceutical, Iconovir Bio, Ideaya Biosciences, Immuneering, Impact Therapeutics, Incendia, Ipsen, Kura Oncology, MediLink Therapeutics ).
Mirati Therapeutics, ModeX Therapeutics, Monopteros Therapeutics, Navire Pharma Inc, Nimbus Therapeutics, NGM Biopharmaceuticals, Normunity Inc, OBI Pharma, OncoResponse Inc, Pfizer ).
ProteinQure, Revolution Medicines, Step Pharmaceuticals, Sutro Biopharma, Symphogen, Systimmune, Tachyon Therapeutics, Teon Therapeutics, Tyligand Bioscience, VelaVigo Pharma Co ).
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D. Orr, None.
R. Miller,
MSD, GSK, AstraZeneca, Ellipses, Clovis Oncology, Abbvie, Pharma& ).
GSK, AstraZeneca, Eisai, Pharma&, MSD, Abbvie and Clovis Oncology, Pharma& Gift.
AstraZeneca, MSD , Pharma& and GSK Travel.
MSD and GSK ).
N. Makani, None.
D. O'Malley,
AbbVie, Advaxis, Agenus,Inc, Alkermes, Aravive, Inc., Arcus Biosciences, Inc., AstraZeneca, BeiGene USA,Inc., Boston Biomedical, Bristol Myers Squibb, Clovis Oncology, Deciphera Pharma ).
Eisai, EMD Serono, Inc., Exelixis, Genentech Inc, Genmab, GlaxoSmithKline, GOG Foundation, Hoffmann-La Roche Inc, ImmunoGen, Inc, Incyte Corporation, IOVANCE Biotherapeutics ).
Karyopharm, Leap Therapeutics, Inc., Ludwig Institute for Ca, Merck & Co, Merck Sharp & Dohme Corp., Mersana Therapeutics,Inc., NCI, Novartis, NovoCure, NRG Oncology ).
OncoC4, Inc., OncoQuest Inc., Pfizer Inc, Precision Therapeutics, Inc., Prelude Therapeutics, Regeneron Pharmaceuticals, Inc, RTOG, Rubius Therapeutics, Seattle Genetics (SeaGen) ).
Sutro Biopharma, SWOG, TESARO, Verastem, Inc ).
AbbVie, AstraZeneca, Corcept Therapeutics, Duality Bio, Eli Lilly, GlaxoSmithKline, GOG Foundation, Merck & Co, Merck Sharp & Dohme Corp., Regeneron Pharmaceuticals, Inc, Verastem, Inc, Zentalis ).
I. Winer,
Jazz Pharmaceuticals ).
P. A. Beer,
Step Pharma Employment, Stock Option.
K. Smith,
Step Pharma Employment, Stock Option.
M. Higgins,
Step Pharma Employment, Stock Option.
J. R. Hawse, None..
X. Wang, None.
S. J. Weroha,
Abbvie ).
Novartis, Genentech, Tesaro, KIYATEC, Atossa Therapeutics ).
Kiyatec Patent.
Merck Travel.
C. Massard,
AEC Partner, Biomunex Pharmaceuticals, Biotrial Paris, Bristol-Myer Squibb, Daiichi Sankyo, Faron Pharmaceuticals Ltd, Lilly France, MabQuest, MSD, Netcancer, Orion Corporation, Pfizer, Roche, Servie ).
P. Roxburgh,
GSK, MSD, AbbVie, MSD, Johnson and Johnson, Roche ).
Starpharma, Eisai, astra Zeneca, Bayer, Artios, Immunocore, Immutep, Sierra, mersana, iovance, nucana, PsiOxus, Replimune, Forma Therapeutics, StepPharma ).