Zongertinib + Trastuzumab Combinations for HER2+ Breast Cancer

Recruiting at 57 trial locations

Overseen By Boehringer Ingelheim

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Boehringer Ingelheim

Must be taking: Zongertinib

Must not be taking: QT prolonging drugs

Disqualifiers: Uncontrolled hypertension, Heart failure, others

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

Compensation: Varies

Number of Visits: Unknown

582 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is open to adults aged 18 years and older with different types of HER2+ cancer that has spread and cannot be removed by surgery. People can take part in this study if their tumours show HER2 aberrations and previous treatment was not successful. The purpose of this study is to find a suitable dose of zongertinib that people with different types of HER2+ cancer that has spread can tolerate best when taken together with trastuzumab deruxtecan (T-DXd), with trastuzumab emtansine (T-DM1), or with trastuzumab and capecitabine. Another purpose is to check whether zongertinib alone and in combination with other treatments can make tumours shrink. Zongertinib inhibits HER2. HER2 causes cancer cells to grow. In this study, participants receive treatment in cycles. Study participants are treated with zongertinib alone or in combination with other treatments. This study has 2 parts. In Part 1, participants in different groups receive increasing doses of zongertinib. In Part 2, participants are put into different groups by chance. Each group receives a different dose of zongertinib. Every participant has an equal chance of being in each group. During the study, the participants visit the study site regularly. In this study, researchers want to find the highest dose of zongertinib that participants can tolerate when taken together with other treatments. To find this out, researchers look at certain severe health problems that a number of participants have. The doctors regularly check the size of the tumour with imaging methods (CT/MRI) during the study. The doctors also regularly check participants' health and take note of any unwanted effects

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on medications known to prolong the QT interval (a heart rhythm measure), you may need to stop them, as these are part of the exclusion criteria.

What data supports the effectiveness of the drug combination Zongertinib + Trastuzumab for HER2+ breast cancer?

Trastuzumab deruxtecan has shown effectiveness in patients with advanced HER2-positive breast cancer, with a majority responding to the treatment and a median response duration of 20.7 months. It has been approved in the USA for patients with HER2-positive metastatic breast cancer who have received prior treatments, based on the results of the phase 2 DESTINY-Breast01 trial. ^{1 2 3 4 5}

Is the combination of Zongertinib and Trastuzumab safe for humans?

Trastuzumab deruxtecan (Enhertu) has been shown to have a generally manageable safety profile in patients with HER2-positive breast cancer, though it can cause some common side effects like blood and stomach issues. It also has a warning for lung-related problems, so careful monitoring is needed. ^{2 4 6 7 8}

What makes the drug Zongertinib + Trastuzumab combinations unique for HER2+ breast cancer?

This drug combination is unique because it includes trastuzumab deruxtecan, a next-generation antibody-drug conjugate that targets HER2-positive cancer cells with a potent chemotherapy agent, potentially overcoming resistance seen in previous treatments like trastuzumab emtansine. ^{3 4 5 9 10}

Eligibility Criteria

Adults aged 18+ with HER2+ metastatic breast or gastric cancer that's spread and can't be surgically removed. Participants must have tried other treatments without success, have at least one measurable tumor, and an ECOG score of 0 or 1 indicating they are fully active or restricted in physically strenuous activity but ambulatory.

Inclusion Criteria

I am fully active or have some restrictions but can still care for myself.

My cancer is HER2 positive and has spread to other parts of my body.

I have signed the consent form for this trial.

Exclusion Criteria

Women who are pregnant, nursing, or who plan to become pregnant or nurse during the trial or within 7 months after the last dose of trial treatment with T-DXd or T-DM1

I have no other cancers needing treatment now, except for certain treated skin, cervical, or ductal cancers.

Mean resting corrected QT interval (QT interval corrected for heart rate by Fridericia´s formula (QTcF)) >470 msec

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Phase Ib)

Participants receive increasing doses of zongertinib in combination with T-DXd or T-DM1 to determine the maximum tolerated dose

3 weeks

Regular visits for monitoring and dose adjustments

Dose Optimization (Phase II)

Participants are randomized to receive different doses of zongertinib in combination with T-DXd or T-DM1 to optimize dosing

up to 50 months

Regular visits for health checks and imaging

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 48 weeks

Treatment Details

Interventions

• Trastuzumab deruxtecan
• Trastuzumab emtansine
• Zongertinib

Trial Overview The trial is testing the drug Zongertinib combined with either Trastuzumab Deruxtecan (T-DXd) or Trastuzumab Emtansine (T-DM1) to find a tolerable dose and see if it shrinks tumors in HER2+ cancers. It has two parts: increasing doses of Zongertinib (Part 1), then random groups receiving different doses (Part 2).

Participant Groups

Group I: Phase Ib - Cohort K: zongertinib + trastuzumab Experimental Treatment 2 Interventions

Dose escalation (Phase Ib)

Group II: Phase Ib - Cohort G: zongertinib + trastuzumab + capecitabine Experimental Treatment 3 Interventions

Dose escalation (Phase Ib)

Group III: Phase Ib - Cohort C: zongertinib + Trastuzumab deruxtecan Experimental Treatment 2 Interventions

Dose escalation (Phase Ib)

Group IV: Phase Ib - Cohort B: zongertinib + Trastuzumab deruxtecan Experimental Treatment 2 Interventions

Dose escalation (Phase Ib)

Group V: Phase Ib - Cohort A: zongertinib + Trastuzumab emtansine Experimental Treatment 2 Interventions

Dose escalation (Phase Ib)

Group VI: Phase II - Cohort J: zongertinib + trastuzumab Experimental Treatment 2 Interventions

Dose optimization (Phase II).

Group VII: Phase II - Cohort J-ext: zongertinib + trastuzumab Experimental Treatment 2 Interventions

Extension Phase II

Group VIII: Phase II - Cohort I: zongertinib Experimental Treatment 1 Intervention

Dose optimization (Phase II).

Group IX: Phase II - Cohort I-ext: zongertinib Experimental Treatment 1 Intervention

Extension Phase II

Group X: Phase II - Cohort H: zongertinib + trastuzumab + capecitabine Experimental Treatment 3 Interventions

Dose optimization (Phase II).

Group XI: Phase II - Cohort F: zongertinib + Trastuzumab deruxtecan Experimental Treatment 2 Interventions

Dose optimization (Phase II).

Group XII: Phase II - Cohort E: zongertinib + Trastuzumab deruxtecan Experimental Treatment 2 Interventions

Dose optimization (Phase II).

Group XIII: Phase II - Cohort D: zongertinib + Trastuzumab emtansine Experimental Treatment 2 Interventions

Dose optimization (Phase II).

Trastuzumab deruxtecan is already approved in United States, European Union, Japan for the following indications:

Approved in United States as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma
• Unresectable or metastatic HER2-low breast cancer
• Unresectable or metastatic HER2-positive solid tumors

Approved in European Union as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

Approved in Japan as Enhertu for:

• Unresectable or metastatic HER2-positive breast cancer
• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma

Who Is Running the Clinical Trial?

Boehringer Ingelheim

Lead Sponsor

Trials

2,566

Recruited

16,150,000+

Findings from Research

In a phase 2 study involving 184 patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab emtansine, trastuzumab deruxtecan demonstrated a significant response rate of 60.9%, with a median response duration of 14.8 months.

While trastuzumab deruxtecan showed promising efficacy, it was associated with notable adverse effects, including interstitial lung disease in 13.6% of patients, highlighting the need for careful monitoring of pulmonary symptoms during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. Modi, S., Saura, C., Yamashita, T., et al.[2021]

In the phase 3 DESTINY-Breast02 trial involving 608 patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan significantly improved median progression-free survival to 17.8 months compared to 6.9 months for treatment of physician's choice, demonstrating its efficacy in a population with limited treatment options.

While trastuzumab deruxtecan had a higher incidence of treatment-emergent adverse events, including nausea and interstitial lung disease, it still showed a favorable benefit-risk profile, indicating its potential as a viable treatment option for patients resistant to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. André, F., Hee Park, Y., Kim, SB., et al.[2023]

In a study of 22 patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan (T-DXd) showed a median progression-free survival of 9.7 months and an objective response rate of 61.9%, indicating its efficacy as a treatment option.

T-DXd was particularly effective in patients with heterogeneous or reduced HER2 expression, achieving partial responses in patients who did not respond to the previous treatment with ado-trastuzumab emtansine (T-DM1), highlighting its potential to overcome resistance in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer. Nakajima, H., Harano, K., Nakai, T., et al.[2022]

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 study involving 27 patients with HER2-positive metastatic breast cancer who had progressed on previous therapies, the combination of ado-trastuzumab emtansine (T-DM1) and neratinib showed promising efficacy, with 63% of evaluable patients achieving an objective response.

The recommended phase II dose for this combination was established as T-DM1 at 3.6 mg/kg and neratinib at 160 mg/d, with manageable safety profiles, although some patients experienced grade 3 toxicities like diarrhea and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10. Abraham, J., Montero, AJ., Jankowitz, RC., et al.[2020]

In the DESTINY-Breast03 trial, trastuzumab deruxtecan (T-DXd) demonstrated superior progression-free survival and overall survival compared to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer, while maintaining quality of life (QoL) throughout treatment.

Patients receiving T-DXd experienced a median time to first hospitalization that was three times longer than those on T-DM1, indicating better overall health management and fewer hospital visits during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. Curigliano, G., Dunton, K., Rosenlund, M., 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]

In the DESTINY-Breast03 trial involving 524 patients with HER2-positive metastatic breast cancer, trastuzumab deruxtecan significantly improved median progression-free survival to 28.8 months compared to 6.8 months for trastuzumab emtansine, indicating its superior efficacy.

Trastuzumab deruxtecan also demonstrated a favorable safety profile, with similar rates of severe adverse events compared to trastuzumab emtansine, although it was associated with a higher incidence of interstitial lung disease (15% vs. 3%), suggesting careful monitoring is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Hurvitz, SA., Hegg, R., Chung, WP., et al.[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 (DS-8201a) is an innovative antibody-drug conjugate that combines a monoclonal anti-HER2 antibody with a cytotoxic agent, showing promising results in heavily pretreated HER2-positive breast cancer patients, with a 60% overall response rate and 97% disease control reported in a phase 2 trial.

The FDA has granted accelerated approval for DS-8201a for advanced or unresectable HER2-positive breast cancer after at least two prior HER2-targeting treatments, highlighting its potential as a new treatment option for patients with limited alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trastuzumab Deruxtecan (DS-8201a): The Latest Research and Advances in Breast Cancer. Andrikopoulou, A., Zografos, E., Liontos, M., et al.[2021]

References

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

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

2. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer. [2022]

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

Trastuzumab Deruxtecan: First Approval. [2020]

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

Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. [2023]

7. France pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. [2023]

9. 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]

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

Trastuzumab Deruxtecan (DS-8201a): The Latest Research and Advances in Breast Cancer. [2021]