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

Trial Summary

What is the purpose of 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 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.

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.

What data supports the effectiveness of the drug Trastuzumab Deruxtecan + Azenosertib for stomach cancer?

Trastuzumab deruxtecan has been shown to be effective in treating advanced HER2-positive gastric cancer, improving response and overall survival compared to standard chemotherapy in clinical trials. It is also effective in treating HER2-positive breast cancer, suggesting its potential benefit in other HER2-expressing cancers. ^{1 2 3 4 5}

What safety information is available for Trastuzumab Deruxtecan in humans?

Trastuzumab Deruxtecan has been shown to be generally safe in humans, with common side effects including nausea, fatigue, and decreased appetite. However, it carries warnings for serious lung issues (interstitial lung disease/pneumonitis) and potential harm to unborn babies, so careful monitoring is required. ^{3 4 5 6 7}

What makes the drug Trastuzumab Deruxtecan + Azenosertib unique for stomach cancer?

Trastuzumab Deruxtecan is a unique drug because it is an antibody-drug conjugate that specifically targets HER2-positive cancer cells, delivering a potent chemotherapy agent directly to these cells, which can improve effectiveness and reduce side effects compared to traditional chemotherapy. It has shown significant effectiveness in patients with advanced HER2-positive gastric cancer who have already undergone other treatments. ^{3 4 5 6 8}

Research Team

Funda Meric-Bernstam, MD

Principal Investigator

University of Texas MD Anderson Cancer Center LAO

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 (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]

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]

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]

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]

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]

References

1. England 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. [2023]

2. United States 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. [2023]

3. France pubmed.ncbi.nlm.nih.gov

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

4. France pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. [2023]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan: First Approval. [2020]

6. England 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. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. [2021]