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

ConditionsClinical Stage III Gastric Cancer AJCC v8Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8Clinical Stage IV Gastric Cancer AJCC v8Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8Locally Advanced Gastric CarcinomaLocally Advanced Gastroesophageal Junction AdenocarcinomaLocally Advanced Malignant Solid NeoplasmMetastatic Gastric CarcinomaMetastatic Gastroesophageal Junction AdenocarcinomaMetastatic Malignant Solid NeoplasmUnresectable Gastric CarcinomaUnresectable Gastroesophageal Junction AdenocarcinomaUnresectable Malignant Solid Neoplasm
Trial statusRecruiting
Trial phasePhase 1
Trial typeInterventional
Biological sexAll
Age18+
SponsorNational Cancer Institute (NCI)

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

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

Disqualifiers

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)

Trial design

Design model

Sequential

Treatments tested in this trial

  • Azenosertib

    Drug

    Given PO

  • Biopsy Procedure

    Procedure/Surgery

    Undergo biopsy

  • Biospecimen Collection

    Procedure/Surgery

    Undergo collection of blood samples

  • Computed Tomography

    Procedure/Surgery

    Undergo CT

  • Echocardiography Test

    Procedure/Surgery

    Undergo ECHO

  • Magnetic Resonance Imaging

    Procedure/Surgery

    Undergo MRI

  • Multigated Acquisition Scan

    Procedure/Surgery

    Undergo MUGA

  • Trastuzumab Deruxtecan

    Biological/Vaccine

    Given IV

Treatment groups

48 Participants
are divided into 3 treatment groups
Group A: Dose escalation (T-DXd, azenosertib)Experimental treatment 7 interventions
Group B: Dose expansion, Cohort 1 (T-DXd, azenosertib)Experimental treatment 8 interventions
Group C: Dose expansion, Cohort 2 (T-DXd, azenosertib)Experimental treatment 8 interventions

Trial outcomes

Primary outcomes

1

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.

Time frame
Up to completion of dose-escalation
2

Recommended phase 2 dose

Time frame
Up to completion of dose-escalation
3

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.

Time frame
Up to completion of dose-escalation
4

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).

Time frame
Up to 30 days after the last administration of study intervention

Secondary outcomes

1

Objective response rate (ORR)

ORR will be the percentage of patients with measurable disease who have complete response (CR) or partial response (PR), as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR will be estimated with a 95% CIs.

Time frame
Up to 3 years
2

Progression free survival (PFS)

Disease progression will be assessed by RECIST version 1.1. PFS will be estimated using the product-limit estimator of Kaplan-Meier. PFS will be reported for the patient population as a whole as well as for the gastric cancer/gastroesophageal junction patients in the expansion.

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

Duration of response

Duration of response will be estimated using the product-limit estimator of Kaplan-Meier.

Time frame
From initial response (CR or PR) to the first date of documented disease progression or death, assessed up to 3 years
4

Pharmacodynamic effects in the tumor

Two-sample t-test (or Wilcoxon rank sum test) or Chi-square test will be used to compare pharmacodynamic markers between the two expansion cohorts.

Time frame
Up to 3 years

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

National Cancer Institute (NCI)

Lead sponsor

Source ClinicalTrials.gov
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