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

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат VLS-1488
  VLS-1488 tablets will be given orally.

Первичные конечные точки

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

Вторичные конечные точки (12)

• Dose Escalation: ORR as assessed by RECIST version 1.1 [Срок оценки: Up to 12 months]
• Dose Expansion: Frequency of SAEs graded according to NCI-CTCAE version 5.0 [Срок оценки: Up to 18 months]
• Dose Expansion: Frequency of Treatment-related AEs graded according to NCI-CTCAE version 5.0 [Срок оценки: Up to 18 months]
• Dose Expansion: Frequency of TEAEs graded according to NCI-CTCAE version 5.0 [Срок оценки: Up to 18 months]
• Dose Expansion: Frequency of Dose Interruptions and Permanent Treatment Discontinuations [Срок оценки: Up to 18 months]
• Dose Expansion: Area Under the Plasma Concentration-Time Curve (AUC) of Midazolam and its metabolite 1'-hydroxymidazolam [Срок оценки: Up to 18 months]
• Dose Expansion: Maximum Plasma Concentration (Cmax) of Midazolam and its metabolite 1'-hydroxymidazolam [Срок оценки: Up to 18 months]
• Dose Expansion: Evaluation of CA-125 response by Gynecologic Cancer InterGroup (GCIG) criteria (High Grade Serous Ovarian Cancer only) [Срок оценки: Up to 18 months]
• Dose Escalation & Dose Expansion: Duration of Response (DOR) as assessed by RECIST version 1.1 [Срок оценки: Up to 32 months]
• Dose Escalation & Dose Expansion: Disease Control Rate (DCR) as assessed by RECIST version 1.1 [Срок оценки: Up to 32 months]
• Dose Escalation & Dose Expansion: Progression Free Survival (PFS) as assessed by RECIST version 1.1 [Срок оценки: Up to 32 months]
• Dose Escalation & Dose Expansion: Cmax of VLS-1488 [Срок оценки: Up to 32 months]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 14 центров

• University of Southern California — Los Angeles
• Hoag Memorial Hospital — Newport Beach
• University of Colorado Cancer Center — Aurora
• Yale Cancer Center — New Haven
• Kellogg Cancer Center — Evanston
• Community Health Network — Indianapolis
• Johns Hopkins Sidney Kimmel Comprehensive Cancer Center — Baltimore
• University of Michigan — Ann Arbor
• … и ещё 6 центров

Идентификаторы

NCT: NCT05902988 · VLS-1488-2201

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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