A Phase I/II Study of VLS-1488 in Subjects With Advanced Cancer
Study Details
Study Description
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Dose Escalation: Dose Escalation Cohorts 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
VLS-1488 tablets will be given orally.
|
Experimental: Dose Escalation: Backfill Cohorts 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
VLS-1488 tablets will be given orally.
|
Experimental: Dose Expansion: Exploration Cohorts 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
VLS-1488 tablets will be given orally.
|
Experimental: Dose Expansion: Development Cohorts 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
VLS-1488 tablets will be given orally.
|
Outcome Measures
Primary Outcome Measures
- 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
- 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]
Eligibility Criteria
Criteria
Key Inclusion Criteria:
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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
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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
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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:
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MSI-H, dMMR, POLE gene hotspot mutated, or known hypermutator phenotype
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Previously received KIF18A inhibitor
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Current CNS metastases or leptomeningeal disease
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Cardiac parameters: MI or stroke ≤ 1 year, unstable angina/PE/DVT/CABG ≤ 6 months, NYHA Class ≥ II, LVEF < 50%
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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
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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
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Bowel obstruction or GI perforation within 6 months of planned first dose of study drug
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Volastra Therapeutics, Inc.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- VLS-1488-2201