Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors

Recruiting now · Phase 1

Conditions studied: 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, 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, Unresectable Gastric Carcinoma, Unresectable Gastroesophageal Junction Adenocarcinoma, Unresectable Malignant Solid Neoplasm

In brief

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 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.

Key facts

Study ID

NCT06364410

Run by

National Cancer Institute (NCI)

People needed

48

Starts

2025-02-03

Expected to finish

2027-07-08

Last updated by the study team

2026-06-17

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• In the dose escalation, patients must have a histologically documented locally advanced, unresectable, or metastatic solid tumor that has progressed following at least one prior line of treatment in the metastatic setting or has no satisfactory alternative treatment option and all of the following:
• HER2 expression by immunohistochemistry (IHC) (1+, 2+, or 3+) or HER2 amplification by in situ hybridization (ISH) or next generation sequencing (NGS) (on any Clinical Laboratory Improvements Amendments [CLIA] platform on tissue), AND
• T-DXd (DS-8201a)-naive disease
• In the dose expansion, patients must have histologically documented locally advanced, unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer that has progressed following at least one prior line of treatment in the metastatic setting and have all of the following:
• HER2 expression by IHC (1+, 2+, or 3+) or HER2 amplification by ISH or NGS (on any CLIA platform on tissue), AND
• T-DXd (DS-8201a)-naive disease
• Received prior trastuzumab-based treatment, if eligible for such treatment
• For the dose escalation and dose expansion, patients can have evaluable or measurable disease
• Potential trial participants should have recovered from clinically significant adverse events (AEs) of their most recent therapy/intervention prior to enrollment
• Age ≥ 18 years. Because no dosing or AE data are currently available on the use of T-DXd (DS-8201a) in combination with azenosertib (ZN-c3) in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (Karnofsky ≥ 70%). Both T-DXd (DS-8201a) and azenosertib (ZN-c3) have fatigue as an adverse effect. Due to the overlapping adverse effect, the performance status cannot be less restrictive
• Absolute neutrophil count ≥ 1.5 × 10\^9/L (within 7 days of study treatment initiation)
• No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
• No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
• Hemoglobin > 9.0 g/dL (within 7 days of study treatment initiation)
• No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
• No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
• Platelets ≥ 100 × 10\^9/L (within 7 days of study treatment initiation)
• No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
• No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
• Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is ≤ 3 × institutional ULN (within 7 days of study treatment initiation)
• No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
• No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
• Aspartate aminotransferase (AST [serum glutamic-oxaloacetic transaminase (SGOT)])/alanine aminotransferase (ALT [serum glutamate pyruvate transaminase (SGPT)]) ≤ 3 × institutional ULN. In the presence of liver metastases, AST or ALT up to 5 × institutional ULN is permitted (within 7 days of study treatment initiation)
• No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment

You may not qualify if…

• As azenosertib (ZN-c3) is a substrate of CYP3A4, use of prescription or non-prescription drugs known to be moderate or strong inhibitors or inducers of CYP3A4 are prohibited with the exception of moderate or strong inhibitors or inducers of CYP3A4 that are part of the prophylactic antiemetic regimen. Chloroquine/hydroxychloroquine are metabolized by CYP3A4 and therefore, should be prohibited. For patients who have received prior moderate or strong inhibitors or inducers of CYP3A4, the required washout period is approximately 5 half-lives prior to study treatment initiation
• Patients who are receiving any other investigational agents
• Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to the study drugs
• Patients who have a history of severe hypersensitivity reactions to other monoclonal antibodies (mAbs)
• Patients with clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy
• Patients who require supplemental oxygen for activities of daily living
• Pregnant women are excluded from this study because T-DXd (DS-8201a) and azenosertib (ZN-c3) have the potential risk for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with T-DXd (DS-8201a) and azenosertib (ZN-c3), breastfeeding should be discontinued if the mother is treated with T-DXd (DS-8201a) or azenosertib (ZN-c3)
• Patients with history of non-infectious pneumonitis/interstitial lung disease (ILD), current ILD, or where suspected ILD cannot be ruled out by imaging at screening
• Patients with active infections requiring treatment (antibiotic, antifungal, or antiviral) at the time of study treatment initiation are not eligible. Patients who have completed such treatment and whose infection is controlled/resolved (and afebrile) for at least 7 days before cycle 1 day 1 are eligible
• Patients with history of malabsorption syndrome or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills
• Patients with current signs or symptoms of bowel obstruction including sub-occlusive disease related to underlying disease
• Patients with a medical history of myocardial infarction within 6 months before enrollment, symptomatic congestive heart failure (New York Heart Association class IIb to IV), and/or troponin levels consistent with myocardial infarction as defined according to the manufacturer 28 days prior to enrollment
• Patients with clinically significant corneal disease
• Patients with a pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screening assessment)
• Patients with history of Torsades de Pointes unless all risk factors that contributed to Torsades de Pointes have been corrected
• Based on an average of triplicate 12-lead electrocardiogram (ECG), patients with a mean resting corrected QT (QTc) interval using Fridericia formula of > 470 msec for both males and females at screening or a history of congenital long QT syndrome will be excluded
• Patients with prior treatment with a WEE1 inhibitor (dose escalation and dose expansion)
• Patients with prior treatment with T-DXd (DS-8201a) or other topoisomerase inhibitors (dose escalation and dose expansion)
• Patients with uncontrolled intercurrent illness
• Patients with prior allogeneic organ transplantation including allogeneic stem cell transplantation
• Patients with clinically significant chronic gastrointestinal disorder with diarrhea as a major symptom; ≥ grade 2 diarrhea at baseline. Please contact the protocol principal investigator (PI) for any patient with more than two episodes of diarrhea per day averaged over at least a 7-day period at time of screening to determine whether the diarrhea would be considered clinically significant
• Patients with spinal cord compression

Where it is running

• UT MD Anderson Cancer Center — Houston, Texas, United States (enrolling)

Full record on ClinicalTrials.gov

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