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), with trastuzumab and capecitabine, with zanidatamab, or with mFOLFOX6 (with or without trastuzumab). 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.
Patients ≥18 years of age or over the legal age of consent in countries where that is greater than 18 years at the time of signature of the informed consent form (ICF)
Cohorts A to K and Cohort O: Documented Human epidermal growth factor receptor 2 overexpressing and/or amplified (HER2+), metastatic breast cancer (mBC) or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma (mGEAC).
Cohorts L (L-ext), M, and N (metastatic colorectal cancer (mCRC)): Documented Human epidermal growth factor receptor 2 (HER2) overexpression/amplification according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) gastric cancer guidelines and according to the result of local testing.
For dose optimization and justification (Phase II): Patient must provide tumor tissue from locations not radiated prior to biopsy, if possible, collected through archival tissue
Any small molecule HER2 inhibitor in the palliative setting in Cohorts D, E, F, H, L, L-ext, M, and N. In Cohort D allowed in up to 15 patients in each dose level (DL).
T-DXd in Cohorts E and F. In Cohort E allowed in up to 15 patients in each DL.
trastuzumab emtansine (T-DM1) in the palliative setting in Cohort D and H. In Cohort H allowed in up to 15 patients in each DL.
Capecitabine in Cohort D and H. In Cohort D allowed in up to 15 patients in each DL
Sequential
Zongertinib
DrugZongertinib
Trastuzumab deruxtecan
DrugTrastuzumab deruxtecan
Trastuzumab emtansine
DrugTrastuzumab emtansine
Trastuzumab
DrugHerceptin®
Capecitabine
DrugXeloda®
mFOLFOX6
DrugmFOLFOX6
zanidatamab
Drugzanidatamab
18
Treatment groupsSee each treatment group below.
Dose escalation (Phase Ib): Occurrence of dose-limiting toxicities (DLTs) in the maximum tolerated dose (MTD) evaluation period
The MTD evaluation period is defined as the first 21 days of the first treatment cycle for Cohorts A, B, C, G, K, and O. The MTD evaluation period is defined as the first 28 days after the first administration of any trial medication for Cohorts M and N.
Dose optimization and justification (Phase II): Objective response (OR)
Objective response (OR) is defined as the best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST 1.1 from the date of treatment start until the earliest date of disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, or treatment discontinuation as assessed by investigator review.
Dose escalation (Phase Ib): Objective response (OR)
Dose escalation (Phase Ib): Occurrence of dose-limiting toxicities (DLTs) during the entire treatment period
Dose escalation (Phase Ib): Maximum measured concentration of zongertinib (at steady state) (Cmax,(ss))
For cycle 2 only.
Dose escalation (Phase Ib): Area under the concentration-time curve of zongertinib over the time interval from 0 to 4h at steady state (AUC0-4h,ss)
For cycle 2 only.
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