Schöffski Patrick, Awada Ahmad, de la Bigne Anne-Marie, Felloussi Zakia, Burbridge Mike, Cantero Frederique, Colombo Riccardo, Maruzzelli Sara, Ammattatelli Katia, de Jonge Maja, Aftimos Philippe, Dumez Herlinde, Sleijfer Stefan
Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
Clinical Trials Conduct Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
Eur J Cancer. 2022 Jul;169:135-145. doi: 10.1016/j.ejca.2022.04.001. Epub 2022 May 11.
S81694 is an inhibitor of monopolar spindle 1 kinase, a target expressed in proliferating cells. CL1-81694-001 was the first-in-human study aiming at identifying a safe dosing schedule in solid tumour patients.
This trial was based on inter-individual dose-escalation of single agent S81694 in cohorts of ≥3 patients to assess the safety and tolerability and determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose (RP2D), with S81694 given on days 1,8,15 of a 28-day cycle as 1-h infusion.
38 patients were treated at doses ranging from 4 to 135 mg/m/week; 144 cycles were administered (median 2/patient; range 1-32 cycles). Patients discontinued treatment for disease progression (78.9%), adverse events (AE; 18.4%) or withdrawal of consent (2.6%). Treatment modifications occurred in 22 patients (57.9%; 49 cycles). Common treatment-emergent AEs were fatigue (22 patients;57.9%), anaemia (17;44.7%) and nausea (12;31.6%). Haematological toxicity was mild, with Grade 3 anaemia observed in three patients and neutropenia mainly seen at the 135 mg/m dose level. Three first cycle DLTs included G3 anaemia (4 mg/m dose), G4 hypertension (20 mg/m), G3 fatigue (135 mg/m). MTD was not reached due to premature discontinuation of enrolment based on a sponsor decision. Among 35 patients evaluable for response, one (renal cell carcinoma) had a complete response, one (hepatocellular carcinoma) had a transient decrease of target lesions and 13 had stable disease. Seven patients remained on study for ≥6 cycles, two at the 135 mg/m dose.
S81694 can be administered safely as a single agent in adults with solid tumours on days 1,8,15 of a 28-day cycle up to a dose of 135 mg/m/week without reaching MTD. The RP2D was not defined due to the prioritization of the use of S81694 in combination with cytotoxic agents, based on emerging preclinical data.
EudraCT number: 2014-002023-10; ISRCTN registry ISRCTN35641359.
S81694是单极纺锤体1激酶的抑制剂，该靶点在增殖细胞中表达。CL1-81694-001是一项首次人体研究，旨在确定实体瘤患者的安全给药方案。
本试验基于对≥3例患者组成的队列进行单药S81694的个体间剂量递增，以评估安全性和耐受性，并确定剂量限制毒性（DLT）、最大耐受剂量（MTD）和推荐的II期剂量（RP2D），S81694在28天周期的第1、8、15天给药，静脉输注1小时。
38例患者接受了4至135mg/m/周剂量的治疗；共进行了144个周期（中位值为2个周期/患者；范围为1-32个周期）。患者因疾病进展（78.9%）、不良事件（AE；18.4%）或撤回同意（2.6%）而停止治疗。22例患者（57.9%；49个周期）出现治疗调整。常见的治疗中出现的AE包括疲劳（22例患者；57.9%）、贫血（17例；44.7%）和恶心（12例；31.6%）。血液学毒性较轻，3例患者出现3级贫血，中性粒细胞减少主要出现在135mg/m剂量水平。3例第一周期的DLT包括3级贫血（4mg/m剂量）、4级高血压（20mg/m）、3级疲劳（135mg/m）。由于申办方决定提前停止入组，未达到MTD。在35例可评估疗效的患者中，1例（肾细胞癌）完全缓解，1例（肝细胞癌）靶病灶短暂缩小，13例病情稳定。7例患者持续研究≥6个周期，2例接受135mg/m剂量。
S81694作为单药在实体瘤成人患者中可在28天周期的第1、8、15天安全给药，剂量高达135mg/m/周，未达到MTD。基于新出现的临床前数据，由于优先考虑将S81694与细胞毒性药物联合使用，因此未确定RP2D。
欧洲药品管理局临床试验编号：2014-002023-10；国际标准随机对照试验编号ISRCTN35641359。
