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

NCT06364410 | Recruiting Phase 1 FDA Drug

• 3 other identifiers: NCI-2024-0298210554UM1CA186688
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief 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 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.

Conditions

Clinical Stage III Gastric Cancer AJCC v8; Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8; Locally Advanced Malignant Solid Neoplasm; Metastatic Malignant Solid Neoplasm; Unresectable Malignant Solid Neoplasm; Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8; Clinical Stage IV Gastric Cancer AJCC v8; Locally Advanced Gastric Carcinoma; Locally Advanced Gastroesophageal Junction Adenocarcinoma; Metastatic Gastric Carcinoma; Metastatic Gastroesophageal Junction Adenocarcinoma; Unresectable Gastric Carcinoma; Unresectable Gastroesophageal Junction Adenocarcinoma

Outcome Measures

Primary Outcomes (4)

• Maximum tolerated dose

  A Bayesian optimal interval design will be used to determine the maximum tolerated dose of the T-DXd (DS-8201a) and azenosertib (ZN-c3) combination.

  Up to completion of dose-escalation

• Recommended phase 2 dose

  Up to completion of dose-escalation

• Incidence of dose limiting toxicities (DLTs)

  DLTs will be defined as the below based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

  Up to completion of dose-escalation

• Incidence of adverse events (AEs)

  The incidence of AEs of the T-DXd (DS-8201a) and azenosertib (ZN-c3) combination, including but not limited to treatment-emergent adverse events, serious adverse events, deaths, and clinical laboratory abnormalities, will be assessed by the NCI CTCAE version 5.0. AEs will be tabulated by grade and by relationship to the study drugs. The proportion of patients who discontinue study treatment due to AEs and the unacceptable toxicity rate will be estimated with a 95% confidence intervals (CIs).

  Up to 30 days after the last administration of study intervention

Secondary Outcomes (5)

• Objective response rate (ORR)

  Up to 3 years

• Progression free survival (PFS)

  From study treatment initiation to the date of disease progression, assessed up to 3 years

• Duration of response

  From initial response (CR or PR) to the first date of documented disease progression or death, assessed up to 3 years

• Pharmacodynamic effects in the tumor

  Up to 3 years

• Predictors of response and acquired resistance

  Up to 3 years

Study Arms (3)

Dose escalation (T-DXd, azenosertib)

EXPERIMENTAL

Patients receive T-DXd IV over 30-90 minutes on day 1 of each cycle and azenosertib PO QD on days 1-5, 8-12, and 15-19 or on days 2-5, 9-12 and 16-19 or on days 2-5 and 9-12 of each cycle. 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.

Drug: Azenosertib; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Echocardiography Test; Procedure: Magnetic Resonance Imaging; Procedure: Multigated Acquisition Scan; Biological: Trastuzumab Deruxtecan

Dose expansion, Cohort 1 (T-DXd, azenosertib)

EXPERIMENTAL

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 or days 9-12 and 16-19 or days 9-12 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.

Drug: Azenosertib; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Echocardiography Test; Procedure: Magnetic Resonance Imaging; Procedure: Multigated Acquisition Scan; Biological: Trastuzumab Deruxtecan

Dose expansion, Cohort 2 (T-DXd, azenosertib)

EXPERIMENTAL

Patients receive T-DXd IV over 30-90 minutes on day 1 of each cycle and azenosertib PO QD on days 1-5, 8-12, and 15-19 of each cycle. 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.

Drug: Azenosertib; Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Echocardiography Test; Procedure: Magnetic Resonance Imaging; Procedure: Multigated Acquisition Scan; Biological: Trastuzumab Deruxtecan

Interventions

Azenosertib DRUG

Given PO

Also known as: Wee1 Inhibitor ZN-c3, ZN c3, ZN-c3, ZNc3

Dose escalation (T-DXd, azenosertib); Dose expansion, Cohort 1 (T-DXd, azenosertib); Dose expansion, Cohort 2 (T-DXd, azenosertib)

Biopsy Procedure PROCEDURE

Undergo biopsy

Also known as: Biopsy, BIOPSY_TYPE, Bx

Dose expansion, Cohort 1 (T-DXd, azenosertib); Dose expansion, Cohort 2 (T-DXd, azenosertib)

Biospecimen Collection PROCEDURE

Undergo collection of blood samples

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Dose escalation (T-DXd, azenosertib); Dose expansion, Cohort 1 (T-DXd, azenosertib); Dose expansion, Cohort 2 (T-DXd, azenosertib)

Computed Tomography PROCEDURE

Undergo CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Dose escalation (T-DXd, azenosertib); Dose expansion, Cohort 1 (T-DXd, azenosertib); Dose expansion, Cohort 2 (T-DXd, azenosertib)

Echocardiography Test PROCEDURE

Undergo ECHO

Also known as: EC, Echocardiography

Dose escalation (T-DXd, azenosertib); Dose expansion, Cohort 1 (T-DXd, azenosertib); Dose expansion, Cohort 2 (T-DXd, azenosertib)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Dose escalation (T-DXd, azenosertib); Dose expansion, Cohort 1 (T-DXd, azenosertib); Dose expansion, Cohort 2 (T-DXd, azenosertib)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA

Also known as: Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNV Scan, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning

Dose escalation (T-DXd, azenosertib); Dose expansion, Cohort 1 (T-DXd, azenosertib); Dose expansion, Cohort 2 (T-DXd, azenosertib)

Trastuzumab Deruxtecan BIOLOGICAL

Given IV

Also known as: DS-8201, DS-8201a, Enhertu, Fam-trastuzumab Deruxtecan-nxki, T-DXd, WHO 10516

Dose escalation (T-DXd, azenosertib); Dose expansion, Cohort 1 (T-DXd, azenosertib); Dose expansion, Cohort 2 (T-DXd, azenosertib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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)

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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

MeSH Terms

Conditions

Stomach Neoplasms; Neoplasm Metastasis

Interventions

Biopsy; Specimen Handling; Magnetic Resonance Spectroscopy; trastuzumab deruxtecan

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical

Study Officials

• Funda Meric-Bernstam

  University of Texas MD Anderson Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 12, 2024
• First Posted: April 15, 2024
• Study Start: February 3, 2025
• Primary Completion (Estimated): July 8, 2027
• Study Completion (Estimated): July 8, 2027
• Last Updated: April 13, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

US (1)