Journal
EUROPEAN JOURNAL OF CANCER
Volume 169, Issue -, Pages 135-145Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2022.04.001
Keywords
Phase I; S81694; MPS1; Spindle assembly checkpoint inhibitor; Monopolar spindle 1 kinase
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Funding
- Institut de Recherche Internationale Servier, Suresnes (France)
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S81694 can be safely administered as a single agent in adults with solid tumors at a dose of up to 135 mg/m(2)/week on days 1,8,15 of a 28-day cycle, without reaching the MTD.
Background: S81694 is an inhibitor of monopolar spindle 1 kinase, a target ex-pressed in proliferating cells. CL1-81694-001 was the first-in-human study aiming at identifying a safe dosing schedule in solid tumour patients. Patients and methods: 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. Results: 38 patients were treated at doses ranging from 4 to 135 mg/m(2)/week; 144 cycles were administered (median 2/patient; range 1-32 cycles). Patients discontinued treatment for dis-ease 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(2) dose level. Three first cycle DLTs included G3 anaemia (4 mg/m(2) dose), G4 hypertension (20 mg/m(2)), G3 fatigue (135 mg/m(2)). 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(2) dose. Conclusions: 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(2)/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. (C) 2022 The Author(s). Published by Elsevier Ltd.
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