RecruitingInterventionalPhase 1/Phase 2

A Phase I/II Study of VLS-1488 (an Oral KIF18A Inhibitor) in Subjects With Advanced Cancer

NCT ID: NCT05902988Sponsor: Volastra Therapeutics, Inc.Last updated: 2025-11-04

Summary

This is a first-in-human phase I/II study to examine the safety, tolerability and preliminary efficacy of VLS-1488 in subjects with advanced cancers.

Detailed description

This a first-in-human phase I/II study designed to assess the safety, tolerability and preliminary efficacy of VLS-1488 monotherapy and consists of two parts: Dose Escalation and Dose Expansion. Dose Escalation will examine the safety and tolerability of VLS-1488 in different solid tumor types at various dose levels through a series of Dose Escalation and Backfill Cohorts to identify the Maximum Tolerated Dose (MTD) and to select dose levels for Dose Expansion. The criteria for dose (de-)escalation will be based on a Bayesian Optimal Interval (BOIN) design. Dose Expansion will examine the safety, tolerability, Drug Drug Interaction (DDI) risk, Food Effect (FE) and preliminary efficacy of VLS-1488 in different tumor types and/or dose levels of interest through various expansion cohorts. VLS-1488 will be given orally in 28-day cycles. Dosing will be continued until disease progression, unacceptable toxicity, withdrawal of consent, or other stopping criteria are met.

Arms & interventions

DrugVLS-1488
VLS-1488 tablets will be given orally.

Outcome measures

Primary

Dose Escalation: Incidence of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects
Time frame: Up to 12 months
Dose Escalation: Determination of the MTD of VLS-1488
Time frame: Up to 12 months
Dose Escalation: Frequency of Serious Adverse Events (SAEs) graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0
Time frame: Up to 12 months
Dose Escalation: Frequency of Treatment-related Adverse Events (AEs) graded per NCI-CTCAE version 5.0
Time frame: Up to 12 months
Dose Escalation: Frequency of Treatment-Emergent AEs (TEAEs) graded per NCI-CTCAE version 5.0
Time frame: Up to 12 months
Dose Escalation: Frequency of Dose Interruptions and Permanent Treatment Discontinuations
Time frame: Up to 12 months
Dose Expansion: Frequency of Trigger Events (TEs)
Time frame: Up to 18 months
Dose Expansion: Objective Response Rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time frame: Up to 18 months

Secondary

Dose Escalation: ORR as assessed by RECIST version 1.1
Time frame: Up to 12 months
Dose Expansion: Frequency of SAEs graded according to NCI-CTCAE version 5.0
Time frame: Up to 18 months
Dose Expansion: Frequency of Treatment-related AEs graded according to NCI-CTCAE version 5.0
Time frame: Up to 18 months
Dose Expansion: Frequency of TEAEs graded according to NCI-CTCAE version 5.0
Time frame: Up to 18 months
Dose Expansion: Frequency of Dose Interruptions and Permanent Treatment Discontinuations
Time frame: Up to 18 months
Dose Expansion: Area Under the Plasma Concentration-Time Curve (AUC) of Midazolam and its metabolite 1'-hydroxymidazolam
Time frame: Up to 18 months
Dose Expansion: Maximum Plasma Concentration (Cmax) of Midazolam and its metabolite 1'-hydroxymidazolam
Time frame: Up to 18 months
Dose Expansion: Evaluation of CA-125 response by Gynecologic Cancer InterGroup (GCIG) criteria (High Grade Serous Ovarian Cancer only)
Time frame: Up to 18 months
Dose Escalation & Dose Expansion: Duration of Response (DOR) as assessed by RECIST version 1.1
Time frame: Up to 32 months
Dose Escalation & Dose Expansion: Disease Control Rate (DCR) as assessed by RECIST version 1.1
Time frame: Up to 32 months
Dose Escalation & Dose Expansion: Progression Free Survival (PFS) as assessed by RECIST version 1.1
Time frame: Up to 32 months
Dose Escalation & Dose Expansion: Cmax of VLS-1488
Time frame: Up to 32 months
Dose Escalation & Dose Expansion: AUC of VLS-1488
Time frame: Up to 32 months
Dose Escalation & Dose Expansion: Trough Concentration (Ctrough) of VLS-1488
Time frame: Up to 32 months
Dose Escalation & Dose Expansion: Time to Maximum Plasma Concentration (Tmax) of VLS-1488
Time frame: Up to 32 months
Dose Escalation & Dose Expansion: Ratio of Total Cholesterol to 4β-hydroxycholesterol in plasma
Time frame: Up to 32 months
Dose Escalation & Dose Expansion: Increase in the number of Phospho-Histone 3 positive tumor cells
Time frame: Up to 32 months
Dose Escalation & Dose Expansion: Frequency of Micronucleated Reticulocytes in blood
Time frame: Up to 32 months
Dose Escalation & Dose Expansion: Increase in Micronuclei in Circulating Tumor Cells
Time frame: Up to 32 months

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy volunteers: No

Key Inclusion Criteria: * All Parts: Age ≥ 18 years, ECOG Performance Status ≤ 1, at least 1 site of measurable disease evaluable by CT scan or MRI per RECIST 1.1, able to take oral medication without alteration * Dose Escalation: No available therapeutic options to provide clinically meaningful benefits in the following tumor types: High Grade Serous Ovarian Cancer, Squamous Non -Small Cell Lung Cancer, Triple Negative Breast Cancer, Gastric Adenocarcinoma (not EBV+), Colorectal, Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma, Gastroesophageal Junction, Bladder (transitional cell), Head and Neck Squamous Cell Carcinomas (not nasopharynx, sinonasal or lip), Ovarian Carcinosarcoma, CN-high Endometrial/Uterine * Dose Expansion: Must have been previously treated with several lines of standard of care treatment specified in the protocol in the following tumor types: High Grade Serous Ovarian Cancer, Squamous Non-Small Cell Lung Cancer, Triple Negative Breast Cancer, Gastric Adenocarcinoma (not EBV+), Colorectal, Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma, Head and Neck Squamous Cell Carcinomas (not nasopharynx, sinonasal or lip), CN-high Endometrial/Uterine Key Exclusion Criteria: * MSI-H, dMMR, POLE gene hotspot mutated, or known hypermutator phenotype * Previously received KIF18A inhibitor * Current CNS metastases or leptomeningeal disease * Cardiac parameters: MI or stroke ≤ 1 year, unstable angina/PE/DVT/CABG ≤ 6 months, NYHA Class ≥ II, LVEF \< 50% * Inability to comply with concomitant medication restrictions with respect to strong inhibitors and inducers of CYP3A, and clinical inhibitors of MDR1 (P-gp) and BCRP * Any clinically significant ascites or pleural effusions at time of enrollment, or any therapeutic paracentesis or thoracentesis within 28 days of planned first dose of study drug * Bowel obstruction or GI perforation within 6 months of planned first dose of study drug