Zongertinib + Trastuzumab Combinations for HER2+ Breast Cancer
Recruiting in Palo Alto (17 mi)
+50 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Boehringer Ingelheim
Must be taking: Zongertinib
Must not be taking: QT prolonging drugs
Disqualifiers: Uncontrolled hypertension, Heart failure, others
No Placebo Group
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.
12345Is 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.
24678What 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.
345910Eligibility 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.
+5 more
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
+4 more
Trial 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
Participant Groups
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).
13Treatment groups
Experimental Treatment
Group I: Phase Ib - Cohort K: zongertinib + trastuzumabExperimental Treatment2 Interventions
Dose escalation (Phase Ib)
Group II: Phase Ib - Cohort G: zongertinib + trastuzumab + capecitabineExperimental Treatment3 Interventions
Dose escalation (Phase Ib)
Group III: Phase Ib - Cohort C: zongertinib + Trastuzumab deruxtecanExperimental Treatment2 Interventions
Dose escalation (Phase Ib)
Group IV: Phase Ib - Cohort B: zongertinib + Trastuzumab deruxtecanExperimental Treatment2 Interventions
Dose escalation (Phase Ib)
Group V: Phase Ib - Cohort A: zongertinib + Trastuzumab emtansineExperimental Treatment2 Interventions
Dose escalation (Phase Ib)
Group VI: Phase II - Cohort J: zongertinib + trastuzumabExperimental Treatment2 Interventions
Dose optimization (Phase II).
Group VII: Phase II - Cohort J-ext: zongertinib + trastuzumabExperimental Treatment2 Interventions
Extension Phase II
Group VIII: Phase II - Cohort I: zongertinibExperimental Treatment1 Intervention
Dose optimization (Phase II).
Group IX: Phase II - Cohort I-ext: zongertinibExperimental Treatment1 Intervention
Extension Phase II
Group X: Phase II - Cohort H: zongertinib + trastuzumab + capecitabineExperimental Treatment3 Interventions
Dose optimization (Phase II).
Group XI: Phase II - Cohort F: zongertinib + Trastuzumab deruxtecanExperimental Treatment2 Interventions
Dose optimization (Phase II).
Group XII: Phase II - Cohort E: zongertinib + Trastuzumab deruxtecanExperimental Treatment2 Interventions
Dose optimization (Phase II).
Group XIII: Phase II - Cohort D: zongertinib + Trastuzumab emtansineExperimental Treatment2 Interventions
Dose optimization (Phase II).
Trastuzumab deruxtecan is already approved in United States, European Union, Japan, Australia 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
🇦🇺 Approved in Australia as Enhertu for:
- Unresectable or metastatic HER2-positive breast cancer
- Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Iowa Hospitals & Clinics PARENTIowa City, IA
Valkyrie Clinical TrialsLos Angeles, CA
University of California IrvineOrange, CA
Sharp Memorial HospitalSan Diego, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Boehringer IngelheimLead Sponsor
References
Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. [2021]Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.
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]In the single-arm, phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan showed robust activity in patients with HER2-positive metastatic breast cancer who were refractory or resistant to trastuzumab emtansine; a population with scarce effective treatments. In DESTINY-Breast02, we aimed to compare the efficacy and safety of trastuzumab deruxtecan with treatment of physician's choice in this patient population.
Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer. [2022]The previous second-line treatment for HER2-positive metastatic breast cancer were ado-trastuzumab emtansine (T-DM1); however, its activity is decreased in tumors with heterogenous, reduced, or loss of HER2 expression. Trastuzumab deruxtecan (T-DXd) has recently been developed as a novel antibody-drug conjugate to overcome resistance to T-DM1. However, clinical evidence on its ability to overcome this resistance is limited.
Trastuzumab Deruxtecan: First Approval. [2020]Trastuzumab deruxtecan (ENHERTU®), a HER2-directed antibody and DNA topoisomerase I inhibitor conjugate, is being developed for the treatment of HER2-expressing solid tumours, including breast cancer, gastric cancer, colorectal cancer and non-small cell lung cancer by Daiichi Sankyo Company Ltd in collaboration with AstraZeneca. Based primarily on the results of the phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan was recently approved in the USA under accelerated approval for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. This article summarizes the milestones in the development of trastuzumab deruxtecan leading to this first approval.
Safety and Efficacy of T-DM1 Plus Neratinib in Patients With Metastatic HER2-Positive Breast Cancer: NSABP Foundation Trial FB-10. [2020]Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer eventually develop resistance to dual-antibody therapy with trastuzumab plus pertuzumab. Mechanisms of resistance have not been well elucidated. We evaluated the safety, tolerability, and efficacy of ado-trastuzumab emtansine (T-DM1) plus neratinib in patients who progressed on trastuzumab plus pertuzumab.
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]In the DESTINY-Breast03 clinical trial, trastuzumab deruxtecan (T-DXd) showed superior progression-free survival and overall survival versus trastuzumab emtansine (T-DM1) and manageable safety in patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer. Here, patient-reported outcomes (PROs) are reported along with hospitalization data.
Trastuzumab Deruxtecan: A Review in Unresectable or Metastatic HER2-Positive Breast Cancer. [2023]Trastuzumab deruxtecan (Enhertu®) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate approved in several countries, including the USA and those of the EU, for adults with unresectable or metastatic HER2-positive breast cancer who have previously received at least one prior anti-HER2-based regimen. In a pivotal phase 3 trial in this setting, intravenous trastuzumab deruxtecan demonstrated prolonged progression-free survival compared with trastuzumab emtansine (previously the recommended second-line therapy in this indication). Trastuzumab deruxtecan had a generally manageable safety and tolerability profile. Common treatment-related adverse events included haematological and gastrointestinal disorders. Interstitial lung disease (ILD)/pneumonitis is associated with a regulatory warning and requires careful monitoring. In conclusion, trastuzumab deruxtecan is a valuable new treatment option for HER2-positive breast cancer, having been shown to be effective with a generally manageable safety and tolerability profile in adults with unresectable or metastatic disease who have received one or more prior anti-HER2-based regimens.
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]An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine.
Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. [2020]Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanised anti-HER2 antibody, cleavable peptide-based linker, and potent topoisomerase I inhibitor payload. A phase 1, non-randomised, open-label, multiple-dose study was done to assess the safety, tolerability, and activity of trastuzumab deruxtecan in HER2-expressing, advanced solid tumours. The dose escalation (part 1) has previously been reported and the recommended doses for expansion of 5·4 mg/kg or 6·4 mg/kg were established. In this Article, we report the safety and preliminary activity results from this phase 1 trial in all patients with HER2-positive advanced-stage breast cancer with previous trastuzumab emtansine treatment who received trastuzumab deruxtecan at the recommended doses for expansion.
Trastuzumab Deruxtecan (DS-8201a): The Latest Research and Advances in Breast Cancer. [2021]The development of antibody-drug conjugates composed of a cytotoxic agent and a monoclonal antibody carrier offers an important alternative to classic chemotherapy strategies. Trastuzumab deruxtecan (DS-8201a) is a next-generation antibody-drug conjugate composed of a monoclonal anti-HER2 antibody and a topoisomerase I inhibitor, an exatecan derivative (DX-8951f). DS-8201a resulted in favorable outcomes in HER2-positive heavily pretreated breast cancer patients and also had a promising efficacy in patients with HER2-negative/low-expressing disease, whose options are limited. Interestingly, a recently published phase 2 trial (NCT03248492) reported 60% overall response and 97% disease control in patients with HER2-positive disease previously treated with multiple regimens, including trastuzumab emtansine. On the basis of recent clinical trials, the US Food and Drug Administration granted accelerated approval to DS-8201a in advanced or unresectable HER2-positive breast cancer pretreated with at least two HER2-targeting treatment lines. We review all preclinical and clinical data of DS-8201a regarding breast cancer.