Clinical Trial 23835

• Overview

  Study Title:

  Beamion BCGC-1: A Phase Ib dose escalation and Phase II dose optimization, randomized, open-label, multicenter trial of oral zongertinib (BI 1810631) alone or in combination with other agents for the treatment of patients with advanced HER2+ metastatic breast cancer (mBC), metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma (mGEAC), or metastatic colorectal cancer (mCRC)

  Summary:

  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.

  Objective:

  Primary objectives: Dose escalation (Phase Ib): To characterize the safety, tolerability, and the dose-toxicity curve of zongertinib: * in combination with T-DM1 in patients with HER2+ mBC (Cohort A) * in combination with T-DXd in patients with HER2+ mBC (Cohort B) * in combination with T-DXd in patients with mGEAC (Cohort C) * in combination with capecitabine and trastuzumab in patients with HER2+ mBC (Cohort G) * in combination with trastuzumab in patients with HER2+ mBC (Cohort K) *in combination with mFOLFOX6 in patients with HER2+ mCRC (Cohort M) *in combination with trastuzumab and mFOLFOX6 in patients with HER2+ mCRC (Cohort N) *in combination with zanidatamab in patients with HER2+ mBC (Cohort O) by assessing escalating dose levels with overdose control to achieve the primary objective of determining the maximum tolerated doses (MTDs) and/or doses for further development per cohort. To evaluate the number of patients with dose-limiting toxicities (DLTs) within the MTD evaluation period per dose level. 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. The MTD is to be determined by the dose escalation committee (DEC) based on the totality of data. It may be chosen as the highest dose with less than 25% risk of the true DLT rate being equal to or above 33% during the MTD evaluation period based on the Bayesian Logistic Regression Model (BLRM) with overdose control (escalation with overdose control [EWOC]) for the trial. The primary characterization of the primary objective will be based on the initial dose administered to the patient during the MTD evaluation period and the strategy for handling intercurrent events will be a combined composite and principal stratum approach where some intercurrent events are considered as outcome and some define the population consisting of patients who are able to adhere to the assigned treatment regimen and trial schedule. Dose optimization and justification (Phase II): To assess the anti-tumor activity of zongertinib in the following settings, to assist in the selection of optimal dose for further clinical development: * in combination with T-DM1 in patients with HER2+ mBC (Cohort D) * in combination with T-DXd in patients with HER2+ mBC (Cohort E) * in combination with T-DXd in patients with HER2+ mGEAC (Cohort F) * in combination with capecitabine and trastuzumab in patients with HER2+ mBC (Cohort H) * as a monotherapy in patients with HER2+ mBC (Cohort I, I-ext) * in combination with trastuzumab in patients with HER2+ mBC (Cohort J, J-ext) * in combination with trastuzumab in patients with HER2+ mCRC (Cohort L, L-ext) The primary endpoint is the proportion of patients with objective response (OR) by RECIST version 1.1 as assessed by investigator review in the intent-to-treat population. The summary measure of OR will include all treated patients regardless of breaks from trial treatment but will exclude the effects of any subsequent anti-cancer therapy started before progression. Secondary objectives: To characterize the pharmacokinetic properties of zongertinib when given as a monotherapy or in combination (all trial parts) To further evaluate preliminary efficacy, safety, and the risk-benefit profile of zongertinib monotherapy and zongertinib in combination: with trastuzumab with or without capecitabine, with zanidatamab, with mFOLFOX6 with or without trastuzumab, with T-DXd, or with T-DM1 (all trial parts) To evaluate patient reported outcomes (PROs) (dose optimization)

• Treatments

  Therapies:

  ADC consisting of a humanized anti-HER2 mAb.; Chemotherapy (NOS); Humanized IgG1-bispecific antibody; Tyrosine kinase inhibitor (TKI) that selectively targets and blocks the HER2 receptor; monoclonal antibody

  Medications:

  Herceptin (Trastuzumab); T-DM1 (); T-Dxd (); Trastuzumab (); Xeloda (capecitabine); Zanidatamab (); Zongertinib (); capecitabine (); rhuMAb HER2 (Trastuzumab)

• Inclusion Criteria

  Key Inclusion criteria:
  • 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.
  • Presence of at least one measurable lesion according to RECIST 1.1.
  • Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
  • Adequate organ function based on laboratory values Further inclusion criteria apply.

• Exclusion Criteria

  Key Exclusion criteria:
  • Presence of uncontrolled and/or symptomatic brain metastases, or leptomeningeal disease.
  • Mean resting corrected QT interval (QT interval corrected for heart rate by Fridericia´s formula (QTcF)) >470 msec.
  • Any factors that increase the risk of QT interval corrected for heart rate (QTc) prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, personal or family history of long QT syndrome or unexplained sudden death under 40 years-of-age.
  • Ejection fraction > History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening Further exclusion criteria apply.

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