Related Experiment Video
Updated: Sep 23, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
First-in-man, first-in-class phase I study with the monopolar spindle 1 kinase inhibitor S81694 administered
Patrick Schöffski1, Ahmad Awada2, Anne-Marie de la Bigne3
1Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
Background:
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.
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/m2/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/m2 dose level. Three first cycle DLTs included G3 anaemia (4 mg/m2 dose), G4 hypertension (20 mg/m2), G3 fatigue (135 mg/m2). 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/m2 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/m2/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.
Trial Registration:
EudraCT number: 2014-002023-10; ISRCTN registry ISRCTN35641359.
Insights
S81694, a monopolar spindle 1 kinase inhibitor, was evaluated for safety in solid tumor patients. The study identified a safe dosing schedule up to 135 mg/m²/week, with common side effects including fatigue and anemia.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- S81694 targets monopolar spindle 1 kinase, a protein crucial for proliferating cells.
- The CL1-81694-001 trial was the first human study to assess S81694 dosing in solid tumor patients.
Purpose of the Study:
- To determine the safety and tolerability of S81694 in adult patients with solid tumors.
- To establish dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase II dose (RP2D).
Main Methods:
- Dose-escalation study of single-agent S81694 in cohorts of at least 3 patients.
- S81694 administered as a 1-hour infusion on days 1, 8, and 15 of a 28-day cycle.
- 38 patients treated with doses ranging from 4 to 135 mg/m²/week.
Main Results:
- 144 cycles administered; common adverse events (AEs) included fatigue (57.9%), anemia (44.7%), and nausea (31.6%).
- Mild hematological toxicity observed; Grade 3 anemia and neutropenia occurred at higher doses.
- Maximum tolerated dose (MTD) was not reached; one complete response (renal cell carcinoma) and stable disease in 13 patients were noted.
Conclusions:
- S81694 can be safely administered as a single agent up to 135 mg/m²/week in adult solid tumor patients.
- The recommended phase II dose (RP2D) was not defined due to planned combination therapy with cytotoxic agents based on preclinical data.
More Related Videos
08:17A Human Peripheral Blood Mononuclear Cell PBMC Engrafted Humanized Xenograft Model for Translational Immuno-oncology I-O Research
Published on: August 15, 2019
07:10Orthotopic Xenografting of Human Luciferase-Tagged Malignant Peripheral Nerve Sheath Tumor Cells for in vivo Testing of Candidate Therapeutic Agents
Published on: March 7, 2011