Clinical trial NCT05902988: A Phase I/II Study of VLS-1488 in Subjects With Advanced Cancer
Official title: A Phase I/II Study of VLS-1488 (an Oral KIF18A Inhibitor) in Subjects With Advanced Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: 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
Keywords: KIF18A Inhibitor
Lead sponsor: Volastra Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2023-06-15
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Dose Escalation: Incidence of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects
timeFrame: Up to 12 months
measure: Dose Escalation: Determination of the MTD of VLS-1488
timeFrame: Up to 12 months
measure: 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
timeFrame: Up to 12 months
measure: Dose Escalation: Frequency of Treatment-related Adverse Events (AEs) graded per NCI-CTCAE version 5.0
timeFrame: Up to 12 months
measure: Dose Escalation: Frequency of Treatment-Emergent AEs (TEAEs) graded per NCI-CTCAE version 5.0
timeFrame: Up to 12 months
measure: Dose Escalation: Frequency of Dose Interruptions and Permanent Treatment Discontinuations
timeFrame: Up to 12 months
measure: Dose Expansion: Frequency of Trigger Events (TEs)
timeFrame: Up to 18 months
measure: Dose Expansion: Objective Response Rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
timeFrame: Up to 18 months
Secondary outcomes:
measure: Dose Escalation: ORR as assessed by RECIST version 1.1
timeFrame: Up to 12 months
measure: Dose Expansion: Frequency of SAEs graded according to NCI-CTCAE version 5.0
timeFrame: Up to 18 months
measure: Dose Expansion: Frequency of Treatment-related AEs graded according to NCI-CTCAE version 5.0
timeFrame: Up to 18 months
measure: Dose Expansion: Frequency of TEAEs graded according to NCI-CTCAE version 5.0
timeFrame: Up to 18 months
measure: Dose Expansion: Frequency of Dose Interruptions and Permanent Treatment Discontinuations
timeFrame: Up to 18 months
measure: Dose Expansion: Area Under the Plasma Concentration-Time Curve (AUC) of Midazolam and its metabolite 1'-hydroxymidazolam
timeFrame: Up to 18 months
measure: Dose Expansion: Maximum Plasma Concentration (Cmax) of Midazolam and its metabolite 1'-hydroxymidazolam
timeFrame: Up to 18 months
measure: Dose Expansion: Evaluation of CA-125 response by Gynecologic Cancer InterGroup (GCIG) criteria (High Grade Serous Ovarian Cancer only)
timeFrame: Up to 18 months
measure: Dose Escalation & Dose Expansion: Duration of Response (DOR) as assessed by RECIST version 1.1
timeFrame: Up to 32 months
measure: Dose Escalation & Dose Expansion: Disease Control Rate (DCR) as assessed by RECIST version 1.1
timeFrame: Up to 32 months
measure: Dose Escalation & Dose Expansion: Progression Free Survival (PFS) as assessed by RECIST version 1.1
timeFrame: Up to 32 months
measure: Dose Escalation & Dose Expansion: Cmax of VLS-1488
timeFrame: Up to 32 months
measure: Dose Escalation & Dose Expansion: AUC of VLS-1488
timeFrame: Up to 32 months
measure: Dose Escalation & Dose Expansion: Trough Concentration (Ctrough) of VLS-1488
timeFrame: Up to 32 months
measure: Dose Escalation & Dose Expansion: Time to Maximum Plasma Concentration (Tmax) of VLS-1488
timeFrame: Up to 32 months
measure: Dose Escalation & Dose Expansion: Ratio of Total Cholesterol to 4β-hydroxycholesterol in plasma
timeFrame: Up to 32 months
measure: Dose Escalation & Dose Expansion: Increase in the number of Phospho-Histone 3 positive tumor cells
timeFrame: Up to 32 months
measure: Dose Escalation & Dose Expansion: Frequency of Micronucleated Reticulocytes in blood
timeFrame: Up to 32 months
measure: Dose Escalation & Dose Expansion: Increase in Micronuclei in Circulating Tumor Cells
timeFrame: Up to 32 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Evanston
country: United States
facility: Kellogg Cancer Center
state: Illinois
city: Indianapolis
country: United States
facility: Community Health Network
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: START Midwest
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Cincinatti
country: United States
facility: The Christ Hospital
state: Ohio
city: Providence
country: United States
facility: Women & Infants Hospital
state: Rhode Island
city: Houston
country: United States
facility: M.D. Anderson Cancer Center
state: Texas
city: Milwaukee
country: United States
facility: Froedtert & the Medical College of Wisconsin
state: Wisconsin
Study officials:
References: