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Clinical Trial Summary

This phase I trial tests the safety, side effects, and best dose of azenosertib in combination with trastuzumab deruxtecan in treating patients with HER2-positive and cyclin E amplified gastric or gastroesophageal junction cancer and other HER2-positive solid tumors that have spread to nearby tissue or lymph nodes (locally advanced), that have spread from where it first started (primary site) to other places in the body (metastatic), or that cannot be removed by surgery (unresectable). Azenosertib is in a class of medications called kinase inhibitors. It inhibits a protein called Wee1. Inhibition of the Wee1 protein can make tumor cells more vulnerable to chemotherapy drugs, leading to tumor cell death. Trastuzumab deruxtecan is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Giving azenosertib in combination with trastuzumab deruxtecan may be safe, tolerable, and/or more effective in treating patients with locally advanced, metastatic, or unresectable HER2-positive gastric, gastroesophageal junction, or other solid tumors, compared to just trastuzumab deruxtecan alone.


Clinical Trial Description

PRIMARY OBJECTIVE: I. To evaluate the safety and tolerability of trastuzumab deruxtecan (T-DXd; DS-8201a) in combination with azenosertib (ZN-c3) in human epidermal growth factor receptor 2 (HER2)-expressing/amplified solid tumors. SECONDARY OBJECTIVES: I. To observe and record the antitumor activity of the T-DXd (DS-8201a) and azenosertib (ZN-c3) combination. II. To assess the pharmacodynamic effects of T-DXd (DS-8201a) in combination with azenosertib (ZN-c3). III. To assess predictors of response and acquired resistance to the T-DXd (DS-8201a) and azenosertib (ZN-c3) combination. OUTLINE: This is a dose-escalation study of azenosertib followed by a dose-expansion study. DOSE ESCALATION: Patients receive T-DXd intravenously (IV) over 30-90 minutes on day 1 of each cycle and azenosertib orally (PO) once daily (QD) on days 1-5, 8-12, and 15-19 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) and collection of blood samples at screening and on study and undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. DOSE EXPANSION: Patients are assigned to 1 of 2 cohorts. COHORT 1: Patients receive T-DXd IV over 30-90 minutes on day 1 of each cycle and azenosertib PO QD on days 8-12 and 15-19 of cycle 1 and days 1-5, 8-12, and 15-19 in subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO or MUGA and collection of blood samples at screening and on study and undergo CT or MRI throughout the trial. Patients also undergo biopsy at screening and on study. COHORT 2: Patients receive treatment as in the dose escalation arm. Patients also undergo ECHO or MUGA and collection of blood samples at screening and on study and undergo CT or MRI throughout the trial. Patients also undergo biopsy at screening and on study. After completion of study treatment, patients are followed up at 30 days and then every 3 months in years 1 and 2 and every 6 months in year 3. ;


Study Design


Related Conditions & MeSH terms

  • Adenocarcinoma
  • Carcinoma
  • Clinical Stage III Gastric Cancer AJCC v8
  • Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IV Gastric Cancer AJCC v8
  • Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Esophageal Neoplasms
  • Locally Advanced Gastric Carcinoma
  • Locally Advanced Gastroesophageal Junction Adenocarcinoma
  • Locally Advanced Malignant Solid Neoplasm
  • Metastatic Gastric Carcinoma
  • Metastatic Gastroesophageal Junction Adenocarcinoma
  • Metastatic Malignant Solid Neoplasm
  • Neoplasms
  • Stomach Neoplasms
  • Unresectable Gastric Carcinoma
  • Unresectable Gastroesophageal Junction Adenocarcinoma
  • Unresectable Malignant Solid Neoplasm

NCT number NCT06364410
Study type Interventional
Source National Cancer Institute (NCI)
Contact
Status Not yet recruiting
Phase Phase 1
Start date August 30, 2024
Completion date March 31, 2026

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