A Phase I/II Study of VLS-1488 (an Oral KIF18A Inhibitor) in Subjects With Advanced Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 200
- 试验地点
- 14
- 主要终点
- Dose Expansion: Objective Response Rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: VLS-1488 (Drug)
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.
干预措施: VLS-1488 (Drug)
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.
干预措施: VLS-1488 (Drug)
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.
干预措施: VLS-1488 (Drug)
结局指标
主要结局
Dose Expansion: Objective Response Rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
时间窗: Up to 18 months
Dose Escalation: Incidence of Dose Limiting Toxicities (DLTs) in DLT-evaluable subjects
时间窗: Up to 12 months
Dose Escalation: Determination of the MTD of VLS-1488
时间窗: 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
时间窗: Up to 12 months
Dose Escalation: Frequency of Treatment-related Adverse Events (AEs) graded per NCI-CTCAE version 5.0
时间窗: Up to 12 months
Dose Expansion: Frequency of Trigger Events (TEs)
时间窗: Up to 18 months
Dose Escalation: Frequency of Treatment-Emergent AEs (TEAEs) graded per NCI-CTCAE version 5.0
时间窗: Up to 12 months
Dose Escalation: Frequency of Dose Interruptions and Permanent Treatment Discontinuations
时间窗: Up to 12 months
次要结局
- Dose Escalation & Dose Expansion: Trough Concentration (Ctrough) of VLS-1488(Up to 32 months)
- Dose Expansion: Area Under the Plasma Concentration-Time Curve (AUC) of Midazolam and its metabolite 1'-hydroxymidazolam(Up to 18 months)
- Dose Escalation & Dose Expansion: Time to Maximum Plasma Concentration (Tmax) of VLS-1488(Up to 32 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 Expansion: Maximum Plasma Concentration (Cmax) of Midazolam and its metabolite 1'-hydroxymidazolam(Up to 18 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 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 Escalation & Dose Expansion: Cmax 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 Expansion: Frequency of Dose Interruptions and Permanent Treatment Discontinuations(Up to 18 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)