A Study to Test Different Doses of Zongertinib in People With Different Types of Advanced Cancer (Solid Tumours With Changes in the HER2 Gene)

Non-Small Cell Lung Cancer Clinical Trial

Official title:

Beamion LUNG-1: An Open Label, Phase I Dose Escalation Trial, With Dose Confirmation and Expansion, of Zongertinib (BI 1810631) as Monotherapy in Patients With Advanced or Metastatic Solid Tumors With HER2 Aberrations

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04886804
• Other study ID #: 1479-0001
• Secondary ID: 2020-004563-47
• Status: Recruiting
• Phase: Phase 1
• Start date: June 22, 2021
• Est. completion date: December 31, 2027

Study information

• Verified date: June 2024
• Source: Boehringer Ingelheim
• Contact: Boehringer Ingelheim
• Phone: 1-800-243-0127
• Email: clintriage.rdg[@]boehringer-ingelheim.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The study has 2 parts. The first part is open to adults with different types of advanced cancer (solid tumours with changes in the HER2 gene) for whom previous treatment was not successful. The second part is open to people with non-small cell lung cancer with a specific mutation in the HER2 gene. The purpose of the first study part is to find the highest dose of a medicine called zongertinib the participants can tolerate. Once this dose is found, it will be used in the second study part to test whether zongertinib can make tumours shrink. In this study, zongertinib is given to people for the first time. Participants take zongertinib as tablets once a day or twice a day. The participants are in the study for as long as they benefit from and can tolerate treatment. Study doctors regularly check the participants' health and monitor the tumours. The doctors also take note of any unwanted effects that could have been caused by zongertinib.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 371
• Est. completion date: December 31, 2027
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of an advanced, unresectable and/or metastatic non-haematologic malignancy. Patient must show presence of at least one measurable lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.
• Eastern Cooperative Oncology Group score of 0 or 1.
• Availability and patient willingness to provide a sample of tumour for confirmation of the patient´s Human epidermal growth factor receptor 2 (HER2) status. This sample can be archival material obtained at any time prior to study enrollment.
• Patient willing and able to comply with the protocol requirements for tumour biopsies (biopsies from brain metastases are not allowed).
• Adequate organ function defined as all of the following:
• Absolute neutrophil count (ANC) = 1.5 x 10^9/L (= 1.5 x 10^3/µL) (= 1500/mm^3); haemoglobin = 9.0 g/dL (= 90 g/L) (= 5.6 mmol/L); platelets = 100 x 10^9/L (100 x 10^3/µL) (100 x 10^3/mm3) without the use of hematopoietic growth factors within 4 weeks of start of trial medication.
• Total bilirubin = 1.5 times the upper limit of normal (ULN), except for patients with Gilbert's syndrome: total bilirubin = 3 x ULN or direct bilirubin = 1.5 x ULN.
• Estimated Glomerular Filtration Rate (eGFR) = 50 mL/min - calculated using Chronic Kidney Disease Epidemiology (CKD-EPI) formula.
• Aspartate transaminase (AST) and alanine transaminase (ALT) = 3 x ULN if no demonstrable liver metastases, or otherwise = 5 x ULN if transaminase elevation is attributable to liver metastases.
• Alkaline Phosphatase < 5 x ULN.
• Recovered from any previous therapy-related toxicity to = Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at start of treatment (except for alopecia, stable sensory neuropathy and hypothyroidism (patients on thyroid replacement therapy) which must be = CTCAE Grade 2)
• Life expectancy of at least 12 weeks at the start of treatment in the opinion of the investigator.
• At least 18 years of age at the time of consent or over the legal age of consent in countries where that is greater than 18 years.
• Signed and dated written informed consent in accordance with International Council on Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial.
• Male or female patients. Women of childbearing potential (WOCBP)1 and men who are able to father a child must be ready and able to use highly effective methods of birth control per International Council on Harmonisation (ICH) M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. Additional inclusion criteria for Phase Ia
• Patients with a documented diagnosis of HER2 aberration: overexpression OR gene amplification OR non-synonymous somatic mutation OR gene rearrangement involving HER2 or Neuregulin 1 (NRG1)
• Patient who has failed conventional treatment or for whom no therapy of proven efficacy exists or who is not eligible for established treatment options. Patient must have exhausted, or not be a suitable candidate for, available treatment options known to prolong survival for their disease Additional inclusion criteria for Phase Ib - Cohort 1 only
• Non-squamous non-small cell lung cancer (NSCLC) patients with documented human epidermal growth factor receptor 2 (HER2) mutation in the tyrosine kinase domain (TKD) as per local lab results.
• Patient who had received, in the advanced/metastatic setting, at least one line of systemic therapy. Patients with non-squamous NSCLC harboring additionally genomic aberrations for which approved targeted therapy is available as standard of care. Additional inclusion criteria for Phase Ib - Cohort 2 only
• Non-squamous NSCLC patient with a documented HER2 mutation in the tyrosine kinase domain (TKD) as per local lab results.
• Treatment naïve for non-squamous NSCLC. Additional inclusion criteria for Phase Ib - Cohort 3 only
• NSCLC Patient with a documented HER2 mutation outside of the tyrosine kinase domain (TKD) as per local lab results or squamous NSCLC patient with mutation in the TKD as per local lab results.
• Patient who had received, in the advanced/metastatic setting, at least one line of systemic therapy. Patients with NSCLC harboring additionally genomic aberrations for which approved targeted therapy is available as standard of care. Additional inclusion criteria for Phase Ib - Cohort 4 only
• NSCLC patients with documented HER2 mutation in the TKD as per local lab results.
• NSCLC patients who are either treatment naïve or who had received any prior line of treatment, in the advanced/metastatic setting. Patients with NSCLC harboring additional genomic aberrations for which approved targeted therapy is available as standard of care.
• Patient with active brain metastases who are not eligible for immediate local therapy, as per investigator evaluation. Additional inclusion criteria for Phase Ib - Cohort 5 only
• Non-squamous NSCLC patients with documented HER2 mutation in the TKD as per local lab results.
• Patient should have received, in the advanced/metastatic setting, at least one line of systemic therapy that includes a platinum-based combination chemotherapy and should have been treated with previous HER2 directed antibody-drug conjugates (ADC) in the same advanced/metastatic setting and developed disease progression recurrence during or after completing this therapy. Patients with NSCLC harboring additional genomic aberrations for which approved targeted therapy is available as standard of care.

Exclusion Criteria:

• Major surgery (major according to the investigator's assessment) performed within 4 weeks prior to first trial treatment or planned within 6 months after screening
• Previous or concomitant malignancies other than the one treated in this trial within the last 2 years, except;
• effectively treated non-melanoma skin cancers
• effectively treated carcinoma in situ of the cervix
• effectively treated ductal carcinoma in situ
• other effectively treated malignancy that is considered cured by local treatment.
• Treatment with a systemic anti-cancer therapy or investigational drug within 21 days or 5 half-lives (whichever is shorter) of the first treatment with the study medication
• Patients who must or wish to continue the intake of restricted medication or any drug considered likely to interfere with the safe conduct of the trial
• Use of concomitant medications that are narrow therapeutic index drugs that are substrates of P-Glycoprotein (P-gp) or Breast Cancer Resistance Protein (BCRP) (e.g. digoxin, dabigatran etexilate)
• Treatment with strong Cytochrome P450 3A (CYP3A) inducers
• Previous treatment with zongertinib. For Phase Ib only: Previous treatment with any HER2 targeted treatment.
• Radiotherapy within 2 weeks prior to first study treatment, except palliative radiotherapy to regions other than the chest, which is allowed up to 1 week prior to first study treatment. Further exclusion criteria apply

Related Conditions & MeSH terms

• Neoplasm Metastasis
• Non-Small Cell Lung Cancer

Intervention

Drug:
• zongertinib
zongertinib

Locations

Country	Name	City	State
Australia	Macquarie University	Macquarie Park	New South Wales
Australia	Cabrini Malvern Hospital	Malvern	Victoria
Austria	Ordensklinikum Linz GmbH Elisabethinen	Linz
Belgium	Brussels - HOSP Jules Bordet	Anderlecht/Brussels-Capital
China	Beijing Cancer Hospital	Beijing
China	Jilin Province Cancer Hospital	Changchun
China	The First Hospital of Jilin University	Changchun
China	Fujian Cancer Hospital	Fuzhou
China	Guangdong Provincial People's Hospital	Guangzhou
China	Harbin Medical University cancer hospital	Haerbin
China	The First Affiliated Hospital, Zhejiang University	Hangzhou
China	Zhejiang Cancer Hospital	Hangzhou
China	The Affiliated Cancer Hospital, Guangxi Medical University	Nanning
China	Shanghai Chest Hospital	Shanghai
China	Tianjin Cancer Hospital	Tianjin
China	Tongji Hospital Affiliated Tongji Medical College Huazhong University of S & T	Wuhan
China	Wuhan Union Hospital	Wuhan
China	First Affiliated Hospital of Xiamen University	Xiamen
China	Henan Cancer Hospital	Zhengzhou
China	The First Affiliated Hospital of Zhengzhou Unviersity	Zhengzhou
France	HOP Louis Pradel	Bron
France	CTR Leon Berard	Lyon
France	HOP Timone	Marseille
France	INS Curie	Paris
France	HOP Pontchaillou	Rennes
France	INS Gustave Roussy	Villejuif
Germany	Universitätsklinikum Augsburg	Augsburg
Germany	Universitätsklinikum Carl Gustav Carus Dresden	Dresden
Germany	Justus-Liebig Universität Gießen	Gießen
Germany	Universitätsklinikum Köln (AöR)	Köln
Germany	Pius-Hospital, Oldenburg	Oldenburg
Hong Kong	Prince of Wales Hospital	Hong Kong
Hong Kong	Queen Mary Hospital	Hong Kong
Israel	Rambam Medical Center	Haifa
Israel	Meir Medical Center	Kfar Saba
Israel	Sourasky Medical Center	Tel Aviv
Israel	The Chaim Sheba Medical Center Tel HaShomer	Tel Hashomer
Italy	Istituto Di Candiolo	Candiolo (TO)
Italy	Istituto Nazionale IRCCS Tumori Fondazione Pascale	Napoli
Italy	Azienda Ospedaliera di Parma	Parma
Japan	National Cancer Center Hospital East	Chiba, Kashiwa
Japan	Shikoku Cancer Center	Ehime, Matsuyama
Japan	Hiroshima University Hospital	Hiroshima, Hiroshima
Japan	Sendai Kousei Hospital	Miyagi, Sendai
Japan	Osaka International Cancer Institute	Osaka, Osaka
Japan	Hamamatsu University Hospital	Shizuoka, Hamamatsu
Japan	National Cancer Center Hospital	Tokyo, Chuo-ku
Korea, Republic of	Chungbuk National University Hospital	Cheongju-si
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Severance Hospital	Seoul
Netherlands	Nederlands Kanker Instituut	Amsterdam
Netherlands	Leids Universitair Medisch Centrum (LUMC)	Leiden
Portugal	Hospital CUF Tejo	Lisboa
Portugal	Hospital CUF Porto	Porto
Singapore	National Cancer Centre Singapore	Singapore
Singapore	National University Hospital	Singapore
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Duran i Reynals	L'Hospitalet de Llobregat
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Virgen de la Victoria	Malaga
Spain	Hospital Clínico de Valencia	Valencia
Sweden	Karolinska Universitetssjukhuset Solna	Stockholm
United Kingdom	Hammersmith Hospital	London
United Kingdom	The Royal Marsden Hospital, Chelsea	London
United Kingdom	The Royal Marsden Hospital, Sutton	Sutton
United States	Precision NextGen Oncology	Beverly Hills	California
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Mary Crowley Cancer Research Center	Dallas	Texas
United States	City of Hope	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	City of Hope	Huntington Beach	California
United States	City of Hope	Irvine	California
United States	Valkyrie Clinical Trials	Los Angeles	California
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Laura & Isaac Perlmutter Cancer Center at NYU Langone Health	New York	New York
United States	University of California Irvine	Orange	California
United States	University of California Davis	Sacramento	California
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Georgetown University	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  China,  France,  Germany,  Hong Kong,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Portugal,  Singapore,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase Ia: Maximum Tolerated Dose (MTD)	Maximum tolerated dose is defined as the highest dose with less than 25% risk of the true Dose Limiting Toxicity (DLT) rate being equal to or above 33% during the MTD evaluation period in any studied regimen.	At the end of Cycle 1 (each cycle is 21 days).
Primary	Phase Ia: Number of patients with Dose Limiting Toxicities (DLTs) in the MTD evaluation period		At the end of Cycle 1 (each cycle is 21 days).
Primary	Phase Ib - Cohorts 1, 2 and 5 : Objective response (OR) as assessed by central independent review	OR is defined as best overall response of complete response (CR) or partial response (PR), where best overall response is determined according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, from the first treatment administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anticancer therapy, loss to follow-up or withdrawal of consent.	From the start of the trial treatment until end of month 12, up to 12 months.
Primary	Phase Ib - Cohort 3: Objective response according to RECIST 1.1 by investigator assessment		From the start of the trial treatment until end of month 12, up to 12 months.
Primary	Phase Ib: Cohort 4: Objective response according to Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) by central independent review		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ia: Number of patients experiencing DLTs during the entire treatment period		From the start of the trial treatment until end of month 8, up to 8 months.
Secondary	Phase Ia: Maximum measured concentration of zongertinib in plasma (Cmax)		On day 1 and on day 15 of Cycle 1 (each cycle is 21 days).
Secondary	Phase Ia: Area under the concentration-time curve of zongertinib in plasma (AUC0-t2)		On day 1 and on day 15 of Cycle 1 (each cycle is 21 days).
Secondary	Phase Ib - Cohorts 1, 2 and 5: Duration of objective response (DoR) according to RECIST 1.1	DoR is defined as the time from first documented complete response (CR) or partial response (PR) until the earliest of disease progression or death among patients with objective response as assessed by central independent review.	From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohorts 1, 2 and 5: Disease control (DC)	DC is defined as best overall response of complete response (CR) or partial response (PR) or stable disease (SD) where best overall response is defined according to RECIST version 1.1 as assessed central independent review, from first treatment administration until the earliest of disease progression, death or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up or withdrawal of consent.	From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohorts 1, 2 and 5: Progression-free survival (PFS)	PFS is defined as the time from first treatment administration until tumor progression according to RECIST version 1.1 as assessed by central independent review, or death from any cause, whichever occurs earlier.	From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohorts 1, 2 and 5: Objective response according to response assessment in neuro-oncology for brain metastases (RANO-BM) criteria as assessed by central independent review for patients with central nervous system (CNS) lesions at baseline		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohorts 1, 2 and 5: Disease control according to RANO-BM criteria as assessed by central independent review for patients with CNS lesions at baseline		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 3: Duration of objective response according to RECIST 1.1 by investigator assessment		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 3: Disease control according to RECIST 1.1 as assessed by the investigator		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 3: Progression-free survival according to RECIST 1.1 as assessed by the investigator		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 3: Objective response according to RANO-BM criteria as assessed by the investigator for patients with CNS lesions at baseline		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 3: Disease control according to RANO-BM criteria as assessed by the investigator for patients with CNS lesions at baseline		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 4: Duration of objective response (DoR) according to RANO-BM by central independent review		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 4: Disease control (DC) according to RANO-BM by central independent review		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 4: Progression-free survival (PFS) according to RANO-BM as assessed by central independent review		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 4: OR according to RECIST 1.1 by central independent review		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 4: Duration of OR according to RECIST 1.1 by central independent review		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 4: DC according to RECIST 1.1 by central independent review		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - Cohort 4: PFS according to RECIST 1.1 as assessed by central independent review		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - All Cohorts: Number of patients experiencing DLTs during the entire treatment period		From the start of the trial treatment until end of month 12, up to 12 months.
Secondary	Phase Ib - All Cohorts: Change from baseline to Day 1 of Cycle 5 in EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) physical functioning domain score		Baseline and on Day 1 of Cycle 5 (each cycle is 21 days).
Secondary	Phase Ib - All Cohorts: Change from baseline to Day 1 of Cycle 5 in Non-Small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) total score		Baseline and on Day 1 of Cycle 5 (each cycle is 21 days).
Secondary	Phase Ib - All Cohorts: Change from baseline to Day 1 of Cycle 5 in EORTC item List 46 (IL46) score		Baseline and on Day 1 of Cycle 5 (each cycle is 21 days).
Secondary	Phase Ib - All cohorts: Overall survival (OS), defined as time from first treatment administration until death from any cause		From the start of the trial treatment until end of month 12, up to 12 months.

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