A Phase I/II Study of VLS-1488 in Subjects With Advanced Cancer

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Advanced Solid Tumor, High Grade Serous Adenocarcinoma of Ovary, Squamous Non-small-cell Lung Cancer, Triple Negative Breast Cancer, Gastric Adenocarcinoma, Colorectal Adenocarcinoma, Esophageal Squamous Cell Carcinoma, Esophageal Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Transitional Cell Carcinoma of Bladder, Head and Neck Squamous Cell Carcinoma, Ovarian Carcinosarcoma, Uterine Carcinosarcoma, Uterine Serous Carcinoma, Endometrium Cancer, Chromosomal Instability

Intervention / Treatment
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* Drug: VLS-1488


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation: Dose Escalation Cohorts<br>Subjects will be enrolled at various doses and/or schedules of VLS-1488. These Dose Escalation Cohorts will be utilized to identify the MTD and to select dose levels for Dose Expansion. | Drug: VLS-1488<br>* VLS-1488 tablets will be given orally.<br>|
| Experimental: Dose Escalation: Backfill Cohorts<br>Additional subjects may be enrolled at any dose level that does not meet de-escalation or elimination rules per the BOIN design. These Backfill Cohorts will be utilized to build additional data to support selection of doses and/or tumor types for further study in Dose Expansion. | Drug: VLS-1488<br>* VLS-1488 tablets will be given orally.<br>|
| Experimental: Dose Expansion: Exploration Cohorts<br>Subjects with a selected single tumor type will be randomized 1:1 into Exploration Cohorts at two or more dose levels of interest. A subset of subjects will have additional assessments to examine the potential for VLS-1488 to interact with other drugs and the effect of food on VLS-1488 absorption. | Drug: VLS-1488<br>* VLS-1488 tablets will be given orally.<br>|
| Experimental: Dose Expansion: Development Cohorts<br>Subjects with other tumor types will be enrolled at a single dose level of interest. These Development Cohorts will be utilized to examine the preliminary efficacy of VLS-1488 in various tumor types. | Drug: VLS-1488<br>* VLS-1488 tablets will be given orally.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KIF18A Inhibitor