Trastuzumab Deruxtecan + Azenosertib for Stomach Cancer

Recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Pulmonary disorders, Severe hypersensitivity, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 31

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the safest and most effective dose of a new drug combination for individuals with certain advanced or hard-to-treat stomach cancers and other tumors that are inoperable. The treatment combines azenosertib, which increases cancer cells' sensitivity to treatment, with trastuzumab deruxtecan, a drug that targets and kills HER2-positive cancer cells. This trial may suit individuals with HER2-positive gastric or gastroesophageal cancer that has spread or cannot be surgically removed, especially if previous treatments have failed. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use drugs that are moderate or strong inhibitors or inducers of CYP3A4, except for those in the anti-nausea regimen. If you've used such drugs, a washout period (time without taking these medications) of about 5 half-lives is required before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that trastuzumab deruxtecan is usually well-tolerated by patients with gastric cancer. In several studies, patients have managed the generally manageable side effects. In contrast, azenosertib is a newer treatment, and researchers are still exploring its safety. This trial is in its early stages and primarily aims to assess the safety of this combination and identify potential side effects. Since trastuzumab deruxtecan is already used for other types of cancer, there is some confidence in its safety. However, using it with azenosertib is new, so researchers are carefully monitoring for any issues. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Trastuzumab Deruxtecan and Azenosertib for stomach cancer because it represents a novel approach to treatment. Unlike traditional therapies that primarily focus on chemotherapy, this combo uses Trastuzumab Deruxtecan, an antibody-drug conjugate, to target cancer cells directly and deliver a potent anti-cancer drug right to the tumor site. Azenosertib, on the other hand, is a new compound that could potentially enhance the effectiveness of Trastuzumab Deruxtecan by disrupting cancer cell division. Together, these treatments promise a more targeted and possibly more effective strategy against stomach cancer than current standard options, such as chemotherapy alone.

What evidence suggests that this trial's treatments could be effective for stomach cancer?

Research has shown that trastuzumab deruxtecan, also known as Enhertu®, can extend the lives of people with advanced HER2-positive stomach cancers. In studies, patients lived about three months longer than those receiving standard chemotherapy. This drug targets cancer cells directly and delivers chemotherapy to them. In this trial, participants will receive a combination of trastuzumab deruxtecan and azenosertib. Azenosertib blocks a protein called Wee1, which can increase cancer cells' sensitivity to treatment. Combining azenosertib with trastuzumab deruxtecan may enhance the treatment's effectiveness by boosting its ability to kill cancer cells. ^{3 6 7 8 9}

Who Is on the Research Team?

Funda Meric-Bernstam, MD

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with HER2-positive and cyclin E amplified gastric or gastroesophageal junction cancer, as well as other HER2-positive solid tumors that are advanced, metastatic, or unresectable. Participants must have recovered from previous therapy side effects and have an adequate performance status.

Inclusion Criteria

I have never been treated with T-DXd (DS-8201a).

My cancer has CCNE1 amplification.

I have never been treated with T-DXd (DS-8201a).

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Dose Escalation

Patients receive T-DXd intravenously and azenosertib orally in a dose-escalation study to determine the maximum tolerated dose

21-day cycles

Multiple visits per cycle for treatment and monitoring

Dose Expansion

Patients are assigned to cohorts to receive T-DXd and azenosertib with expanded dosing schedules

21-day cycles

Multiple visits per cycle for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

Up to 3 years

Follow-up at 30 days, then every 3 months in years 1 and 2, and every 6 months in year 3

What Are the Treatments Tested in This Trial?

Interventions

• Azenosertib
• Trastuzumab Deruxtecan

Trial Overview The trial tests the safety and optimal dose of azenosertib combined with trastuzumab deruxtecan in treating certain cancers. Azenosertib inhibits Wee1 protein to enhance tumor cell vulnerability, while trastuzumab deruxtecan targets and kills HER2 positive cancer cells.

How Is the Trial Designed?

Group I: Dose expansion, Cohort 2 (T-DXd, azenosertib) Experimental Treatment 7 Interventions

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.

Group II: Dose expansion, Cohort 1 (T-DXd, azenosertib) Experimental Treatment 8 Interventions

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.

Group III: Dose escalation (T-DXd, azenosertib) Experimental Treatment 7 Interventions

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. 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.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In the DESTINY-Gastric02 trial involving 79 patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer, trastuzumab deruxtecan demonstrated a confirmed objective response rate of 42% after a median follow-up of 10.2 months, indicating its efficacy as a second-line therapy.

While trastuzumab deruxtecan showed promising results, it was associated with some serious adverse events, including two treatment-related deaths due to interstitial lung disease or pneumonitis, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan in patients in the USA and Europe with HER2-positive advanced gastric or gastroesophageal junction cancer with disease progression on or after a trastuzumab-containing regimen (DESTINY-Gastric02): primary and updated analyses from a single-arm, phase 2 study. Van Cutsem, E., di Bartolomeo, M., Smyth, E., et al.[2023]

Trastuzumab deruxtecan (Enhertu®) has been shown to significantly improve progression-free survival in adults with unresectable or metastatic HER2-positive breast cancer compared to the previous standard treatment, trastuzumab emtansine, in a pivotal phase 3 trial.

The treatment has a generally manageable safety profile, although it is associated with common adverse events like hematological and gastrointestinal disorders, and requires careful monitoring for interstitial lung disease (ILD)/pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. Nie, T., Blair, HA.[2023]

Trastuzumab deruxtecan (ENHERTU®) is an innovative treatment that combines an antibody targeting HER2 with a DNA topoisomerase I inhibitor, specifically designed for HER2-expressing solid tumors, including various types of cancer.

It received accelerated approval in the USA based on the promising results from the phase 2 DESTINY-Breast01 trial, which focused on patients with advanced HER2-positive breast cancer who had already undergone multiple treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. Keam, SJ.[2020]

Trastuzumab deruxtecan (Enhertu®) has been shown to be significantly more effective than standard chemotherapy in improving overall survival and achieving objective responses in adults with advanced HER2-positive gastric or gastro-oesophageal junction adenocarcinoma, based on results from the phase II DESTINY-Gastric01 trial.

The treatment is generally well-tolerated, with common side effects including nausea and fatigue, but it does carry important safety warnings for interstitial lung disease and embryo-foetal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Gastric or Gastro-Oesophageal Junction Adenocarcinoma. Kang, C.[2023]

In a phase 1 trial involving 115 patients with HER2-positive breast cancer previously treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a manageable safety profile, with 59.5% of patients achieving a confirmed objective response.

Despite some serious treatment-emergent adverse events, including cases of interstitial lung disease and pneumonitis, the preliminary efficacy results suggest that trastuzumab deruxtecan is a promising treatment option, warranting further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Tamura, K., Tsurutani, J., Takahashi, S., et al.[2020]

Trastuzumab deruxtecan (T-DXd) demonstrated clinical activity in patients with HER2-low gastric or gastroesophageal junction adenocarcinoma, showing a confirmed objective response rate of 26.3% in cohort 1 and 9.5% in cohort 2, with many patients experiencing reduced tumor size.

The treatment was generally well-tolerated, with no drug-related deaths reported, although some patients experienced significant adverse events like anemia and decreased neutrophil counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Anti-Human Epidermal Growth Factor Receptor 2 Treatment-Naive Patients With Human Epidermal Growth Factor Receptor 2-Low Gastric or Gastroesophageal Junction Adenocarcinoma: Exploratory Cohort Results in a Phase II Trial. Yamaguchi, K., Bang, YJ., Iwasa, S., et al.[2023]

In a phase 1 trial involving 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer, trastuzumab deruxtecan demonstrated a manageable safety profile, with the most common serious side effects being anemia and decreases in blood cell counts, but no drug-related deaths were reported.

The treatment showed promising preliminary activity, with 43.2% of patients achieving a confirmed objective response, indicating its potential effectiveness in patients who had previously been treated with trastuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Shitara, K., Iwata, H., Takahashi, S., et al.[2020]

In a phase 2 trial involving 187 patients with HER2-positive advanced gastric cancer, trastuzumab deruxtecan showed a significantly higher objective response rate of 51% compared to 14% for standard chemotherapy, indicating its superior efficacy.

Patients treated with trastuzumab deruxtecan also experienced longer overall survival (median 12.5 months) compared to those receiving chemotherapy (median 8.4 months), although notable side effects included myelosuppression and interstitial lung disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. Shitara, K., Bang, YJ., Iwasa, S., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06364410

Study Details | NCT06364410 | Testing the Combination of ... Giving azenosertib in combination with trastuzumab deruxtecan may be safe, tolerable, and/or more effective in treating patients with locally advanced, ...

2. daiichisankyo.com daiichisankyo.com/files/news/pressrelease/pdf/202503/20250303_E.pdf

"ENHERTU® (Trastuzumab Deruxtecan) DESTINY- ... “The results of DESTINY-Gastric04 show that second-line treatment with ENHERTU can extend survival compared with a chemotherapy-based regimen ...

3. enhertuhcp.com enhertuhcp.com/en/gastric/efficacy/efficacy-data

Efficacy Data | ENHERTU® (fam-trastuzumab deruxtecan-nxki) Learn about median overall survival, progression-free survival, confirmed objective response, duration of response, and tumor response for patients on ...

4. asco.org asco.org/about-asco/press-center/news-releases/trastuzumab-deruxtecan-can-help-some-people-with-advanced-gastric-cancers-live-about-3-months-longer

Trastuzumab Deruxtecan Can Help Some People With ... Second-line treatment with trastuzumab deruxtecan (Enhertu®) can help people with advanced HER2-positive gastric cancers that have grown during first-line ...

5. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK617426/

Pharmacoeconomic Review - Trastuzumab Deruxtecan ... Clinician groups commented that trastuzumab deruxtecan would likely be the new standard of care for second-line treatment of metastatic HER2-positive gastric or ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06364410?cond=gastric%20cancer&intr=enhertu&rank=10

Study Details | Testing the Combination of the Anticancer ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

7. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-02982

Testing the Combination of the Anticancer Drugs ... Giving azenosertib in combination with trastuzumab deruxtecan may be safe, tolerable, and/or more effective in treating patients with locally advanced, ...

8. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2024-1566.html

Phase 1 study of trastuzumab deruxtecan (DS-8201a) in ... This phase I trial tests the safety, side effects, and best dose of azenosertib in combination with trastuzumab deruxtecan in treating patients with HER2- ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8205906/

Discovery and development of trastuzumab deruxtecan ... Phase 1 and 2 gastric cancer trials. The safety profile of T-DXd in patients with GC is generally manageable; safety and tolerability results for the T-DXd ...