Advanced Solid Tumor, Chromosomal Instability, Endometrium Cancer, Head and Neck Squamous Cell Carcinoma, High Grade Serous Adenocarcinoma of Ovary, Ovarian Carcinosarcoma, Squamous Non-small-cell Lung Cancer, Triple Negative Breast Cancer, Uterine Carcinosarcoma, Uterine Serous Carcinoma
Conditions
Keywords
KIF18A Inhibitor, HGSOC, TNBC, HNSCC, sqNSCLC
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.
Interventions
DRUGVLS-1488
VLS-1488 tablets will be given orally.
Sponsors
Volastra Therapeutics, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame |
|---|---|
| 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: ORR as assessed by RECIST version 1.1 | Up to 12 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 |
| Dose Escalation & Dose Expansion: Trough Concentration (Ctrough) of VLS-1488 | Up to 32 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 |
Countries
United States
Contacts
Primary ContactVolastra Therapeutics, Inc.
Outcome results
None listed