Beamion BCGC-1: A Study to Find a Suitable Dose of Zongertinib Used Alone and in Combination With Other Treatments to Test Whether it Helps People With Different Types of HER2+ Cancer That Has Spread

Official 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)

Overview

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.

Interventions

• Drug Zongertinib
  Zongertinib
• Drug Trastuzumab deruxtecan
  Trastuzumab deruxtecan
• Drug Trastuzumab emtansine
  Trastuzumab emtansine
• Drug Trastuzumab
  Herceptin®
• Drug Capecitabine
  Xeloda®
• Drug mFOLFOX6
  mFOLFOX6
• Drug zanidatamab
  zanidatamab

Primary outcome measures

• Dose escalation (Phase Ib): Occurrence of dose-limiting toxicities (DLTs) in the maximum tolerated dose (MTD) evaluation period [Time frame: up to 21 days]
• Dose optimization and justification (Phase II): Objective response (OR) [Time frame: up to 50 months]

Secondary outcome measures (12)

• Dose escalation (Phase Ib): Objective response (OR) [Time frame: up to 50 months]
• Dose escalation (Phase Ib): Occurrence of dose-limiting toxicities (DLTs) during the entire treatment period [Time frame: up to 50 months]
• Dose escalation (Phase Ib): Maximum measured concentration of zongertinib (at steady state) (Cmax,(ss)) [Time frame: up to 2 days]
• 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) [Time frame: up to 2 days]
• Dose escalation (Phase Ib): Area under the concentration-time curve of zongertinib over the time interval from 0 to the last quantifiable data point at steady state (AUC0-tz,ss) [Time frame: up to 2 days]
• Dose optimization and justification (Phase II): Progression-free survival (PFS) [Time frame: up to 50 months]
• Dose optimization and justification (Phase II): Disease control (DC) [Time frame: up to 50 months]
• Dose optimization and justification (Phase II): Occurrence of treatment-emergent AEs leading to zongertinib (BI 1810631) dose reduction during the on-treatment period [Time frame: up to 50 months]
• Dose optimization and justification (Phase II): Maximum measured concentration (at steady state) (Cmax,(ss)) [Time frame: up to 50 months]
• Dose optimization and justification (Phase II): Area under the concentration-time curve over the time interval from 0 to the last quantifiable data point at steady state (AUC0-tz,ss) [Time frame: up to 50 months]
• Dose optimization and justification (Phase II): Patient-reported outcome (PRO) - PRO-CTCAE [Time frame: up to 24 weeks]
• Dose optimization and justification (Phase II): Patient-reported outcome (PRO) - EORTC IL46 [Time frame: up to 48 weeks]

Eligibility criteria

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
• History of prior treatment lines in palliative setting:

• For cohorts A, B, C, D, E, F, G, H, I, I-ext, J, J-ext, K and O documented investigator assessed progression after HER2-directed treatment for unresectable locally advanced or metastatic disease (For Cohorts D, H, I (I-ext), J (J-ext) - patients must have been pretreated with trastuzumab deruxtecan (T-DXd) and have progressed or have been intolerant to previous T-DXd).
• For cohorts L, L-ext, M and N documented progression or recurrence of disease during or following their latest line of therapy. Patients must have had at least one prior line of therapy for locally advanced unresectable disease or metastatic disease (adjuvant and neoadjuvant therapy excluded) and documented disease progression or recurrence of disease during or following their latest line of therapy. In the opinion of the Investigator, patients must be unlikely to tolerate or derive clinically meaningful benefit from further standard of care therapy known to prolong survival.
• 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

• Previous treatment with:

• 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
• 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 <50% or the lower limit of normal of the institutional standard within 28 days prior to randomization
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 26 centers

• The Oncology Institute of Hope and Innovation — Cerritos
• Ellison Medical Institute — Los Angeles
• Valkyrie Clinical Trials — Los Angeles
• University of California Los Angeles — Los Angeles
• University of California Irvine — Orange
• Sharp Memorial Hospital — San Diego
• Yale University School of Medicine — New Haven
• Helios CR Inc — Lakeland
• … and 18 more centers

Spain · 14 centers

Center list to be confirmed — check the primary protocol.

France · 11 centers

• INS Bergonie — Bordeaux
• CTR François Baclesse — Caen
• CTR Georges-François Leclerc — Dijon
• CTR Leon Berard — Lyon
• INS Paoli-Calmettes — Marseille
• HOP Tenon — Paris
• CTR Eugène Marquis — Rennes
• Institut de Cancérologie de l'Ouest — Saint-Herblain
• … and 3 more centers

United Kingdom · 10 centers

Center list to be confirmed — check the primary protocol.

China · 8 centers

• Jilin Province Cancer Hospital — Changchun
• The First Hospital of Jilin University — Changchun
• Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine — Hangzhou
• Harbin Medical University Cancer Hospital — Harbin
• Jiangsu Province Hospital — Nanjing
• Fudan University Shanghai Cancer Center — Shanghai
• Tianjin Cancer Hospital — Tianjin
• Henan Cancer Hospital — Zhengzhou

Italy · 8 centers

• Azienda Ospedaliero Universitaria delle Marche — Ancona
• Istituto Di Candiolo — Candiolo (TO)
• Istituto Scientifico Romagnolo — Meldola (FC)
• Ospedale San Raffaele S.r.l. — Milan
• Istituto Europeo di Oncologia — Milan
• Humanitas Istituto Clinico Catanese S.p.A. — Misterbianco (CT)
• Istituto Nazionale IRCCS Tumori Fondazione Pascale — Naples
• Istituto Clinico Humanitas — Rozzano

Japan · 8 centers

• Aichi Cancer Center Hospital — Aichi, Nagoya
• Tokai University Hospital — Isehara
• Hakuaikai Sagara Hospital — Kagoshima
• Kanagawa Cancer Center — Kanagawa, Yokohama
• National Cancer Center Hospital East — Kashiwa-shi
• Kyoto University Hospital — Kyoto
• Osaka International Cancer Institute — Osaka
• Japanese Foundation for Cancer Research — Tokyo, Koto-ku

South Korea · 8 centers

• CHA Bundang Medical Center — Seongnam-si
• Seoul National University Bundang Hospital — Seongnam-si
• Seoul National University Hospital — Seoul
• Severance Hospital, Yonsei University Health System — Seoul
• Asan Medical Center — Seoul
• Korea University Anam Hospital — Seoul
• The Catholic University of Korea, Seoul St.Mary's Hospital — Seoul
• … and 1 more center

Belgium · 6 centers

• Cliniques Universitaires Saint-Luc — Brussels
• Universitair Ziekenhuis Antwerpen — Edegem
• UZ Leuven — Leuven
• Hôpital Vivalia De Libramont — Libramont-Chevigny
• Centre Hospitalier Universitaire de Liège — Liège
• CHU UCL Namur — Namur

Germany · 6 centers

• Universitätsklinikum Carl Gustav Carus Dresden — Dresden
• Universitätsklinikum Erlangen — Erlangen
• Evang. Kliniken Essen-Mitte gGmbh — Essen
• Asklepios Kliniken GmbH & Co. KGaA — Hamburg
• Universitätsklinikum Mannheim GmbH — Mannheim
• Universitätsklinikum Ulm — Ulm

Publications

• Hurvitz S, Simonelli M, Yarza R, Berz D, Kitano S, Del Conte G, Acosta Eyzaguirre D, Doger de Speville Uribe BG, Maier D, Erzen D, Aykut Yazgili S, Curigliano G, Deng T, Yan M, Zhang Q, Wang X, Nakayama I, Shitara K. Beamion BCGC-1: phase Ib/II trial of zongertinib for advanced HER2-positive breast or gastroesophageal cancers. Future Oncol. 2025 Nov;21(26):3385-3393. doi: 10.1080/14796694.2025.256 PMID 41108088

Identifiers

NCT: NCT06324357 · 1479-0012

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗