Clinical trial NCT04886804: Beamion LUNG-1: A Study to Test Different Doses of Zongertinib in People With Different Types of Advanced Cancer (Solid Tumours With Changes in the HER2 Gene)
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Neoplasm Metastasis
Non-Small Cell Lung Cancer
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2021-05-14
Enrollment: 554
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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 (ECOG) score of 0, 1 or 2 (ECOG=2 only for Cohorts 6 and 7) .
* 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) 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.

Additional inclusion criteria for Phase Ib - Cohort 6 only

* Non-squamous NSCLC Patient with documented HER2 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.
* Patient without active brain metastases or patient with active brain metastases who are not eligible for immediate local therapy, as per investigator evaluation.
* Patient who is not eligible for any other recruiting cohort.

Additional inclusion criteria for Phase Ib - Cohort 7 only

* Non-squamous NSCLC patient with documented HER2 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.
* Patient without active brain metastases or patient with active brain metastases who are not eligible for immediate local therapy, as per investigator evaluation.
* Patient who is not eligible for any other recruiting cohort.

Additional inclusion criteria for Phase Ib - Cohort 8 only

* Treatment naïve for NSCLC
* NSCLC (adenocarcinoma or squamous) patient with documented HER2 mutation in the tyrosine kinase domain (TKD) or non-squamous NSCLC with a documented HER2 mutation in the non tyrosine kinase domain (non TKD) as per local lab results

Further inclusion criteria apply.

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
* Previous treatment with zongertinib.
* 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

Primary outcomes:
measure: Phase Ia: Maximum Tolerated Dose (MTD)
timeFrame: At the end of Cycle 1 (each cycle is 21 days).
measure: Phase Ia: Number of patients with Dose Limiting Toxicities (DLTs) in the MTD evaluation period
timeFrame: At the end of Cycle 1 (each cycle is 21 days).
measure: Phase Ib - Cohorts 1, 2 and 5 : Objective response (OR) as assessed by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohorts 3, 6, 7, and 8: Objective response according to RECIST 1.1 by investigator assessment
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib: Cohort 4: Objective response according to Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
Secondary outcomes:
measure: Phase Ia: Number of patients experiencing DLTs during the entire treatment period
timeFrame: From the start of the trial treatment until end of month 8, up to 8 months.
measure: Phase Ia: Maximum measured concentration of zongertinib in plasma (Cmax)
timeFrame: On day 1 and on day 15 of Cycle 1 (each cycle is 21 days).
measure: Phase Ia: Area under the concentration-time curve of zongertinib in plasma (AUC0-t2)
timeFrame: On day 1 and on day 15 of Cycle 1 (each cycle is 21 days).
measure: Phase Ib - Cohorts 1, 2 and 5: Duration of objective response (DoR) according to RECIST 1.1
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohorts 1, 2 and 5: Disease control (DC)
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohorts 1, 2 and 5: Progression-free survival (PFS)
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: 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
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: 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
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohorts 1, 2 and 5: Objective response according to RECIST 1.1 criteria as assessed by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohorts 1, 2 and 5: Disease control according to RECIST 1.1 criteria as assessed by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohorts 3, 6, 7 and 8: Duration of objective response according to RECIST 1.1 by investigator assessment
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohorts 3, 6, 7 and 8: Disease control according to RECIST 1.1 as assessed by the investigator
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohorts 3, 6, 7 and 8: Progression-free survival according to RECIST 1.1 as assessed by the investigator
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohorts 3, 6, 7 and 8: Objective response according to RANO-BM criteria as assessed by the investigator for patients with CNS lesions at baseline
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohorts 3, 6, 7 and 8: Disease control according to RANO-BM criteria as assessed by the investigator for patients with CNS lesions at baseline
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohort 4: Duration of objective response (DoR) according to RANO-BM by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohort 4: Disease control (DC) according to RANO-BM by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohort 4: Progression-free survival (PFS) according to RANO-BM as assessed by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohort 4: DoR according to RECIST 1.1 by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohort 4: DC according to RECIST 1.1 by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohort 4: PFS according to RECIST 1.1 as assessed by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohort 4: OR according to RECIST 1.1 by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohort 4: Duration of OR according to RECIST 1.1 by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - Cohort 4: PFS according to RECIST 1.1 by central independent review
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - All cohorts: Overall survival (OS), defined as time from first treatment administration until death from any cause
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: Phase Ib - All Cohorts: Number of patients experiencing DLTs during the entire treatment period
timeFrame: From the start of the trial treatment until end of month 12, up to 12 months.
measure: 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
timeFrame: Baseline and on Day 1 of Cycle 5 (each cycle is 21 days).
measure: 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
timeFrame: Baseline and on Day 1 of Cycle 5 (each cycle is 21 days).
measure: Phase Ib - All Cohorts: Change from baseline to Day 1 of Cycle 5 in EORTC item List 46 (IL46) score
timeFrame: Baseline and on Day 1 of Cycle 5 (each cycle is 21 days).
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Beverly Hills
country: United States
facility: Precision NextGen Oncology
state: California
city: Duarte
country: United States
facility: City of Hope-Duarte-56419
state: California
city: Huntington Beach
country: United States
facility: City of Hope - Seacliff
state: California
city: Irvine
country: United States
facility: City of Hope-Irvine-69674
state: California
city: Los Angeles
country: United States
facility: Valkyrie Clinical Trials
state: California
city: Orange
country: United States
facility: University of California Irvine
state: California
city: Sacramento
country: United States
facility: University of California Davis
state: California
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital-Fort Lauderdale-57892
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute
state: Georgia
city: Honolulu
country: United States
facility: Hawaii Cancer Care - Honolulu
state: Hawaii
city: New York
country: United States
facility: Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Nashville
country: United States
facility: Sarah Cannon Research Institute-Nashville-48456
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Macquarie Park
country: Australia
facility: Macquarie University
state: New South Wales
city: Linz
country: Austria
facility: KH der Barmherzigen Schwestern Linz
city: Anderlecht/Brussels-Capital
country: Belgium
facility: Brussels - HOSP Jules Bordet
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Changchun
country: China
facility: Jilin Province Cancer Hospital
city: Changchun
country: China
facility: The First Hospital of Jilin University
city: Fuzhou
country: China
facility: Fujian Cancer Hospital
city: Guangzhou
country: China
facility: Guangdong Provincial People's Hospital
city: Hangzhou
country: China
facility: The First Affiliated Hospital, Zhejiang University
city: Hangzhou
country: China
facility: Zhejiang Cancer Hospital
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
city: Nanning
country: China
facility: The Affiliated Cancer Hospital, Guangxi Medical University
city: Shanghai
country: China
facility: Shanghai Chest Hospital
city: Wuhan
country: China
facility: Wuhan Union Hospital
city: Wuhan
country: China
facility: Tongji Hospital Affiliated Tongji Medical College Huazhong University of S & T
city: Xiamen
country: China
facility: First Affiliated Hospital of Xiamen University
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
city: Bron
country: France
facility: HOP Louis Pradel
city: Lyon
country: France
facility: CTR Leon Berard
city: Marseille
country: France
facility: HOP Timone
city: Paris
country: France
facility: INS Curie
city: Rennes
country: France
facility: HOP Pontchaillou
city: Villejuif
country: France
facility: INS Gustave Roussy
city: Augsburg
country: Germany
facility: Universitätsklinikum Augsburg
city: Dresden
country: Germany
facility: Technische Universität Dresden
city: Gießen
country: Germany
facility: Justus-Liebig Universität Gießen
city: Köln
country: Germany
facility: Universitätsklinikum Köln (AöR)
city: Oldenburg
country: Germany
facility: Pius-Hospital, Oldenburg
city: Hong Kong
country: Hong Kong
facility: Prince of Wales Hospital-Hong Kong-20715
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center
city: Tel Hashomer
country: Israel
facility: The Chaim Sheba Medical Center Tel HaShomer
city: Candiolo (TO)
country: Italy
facility: Istituto Di Candiolo
city: Napoli
country: Italy
facility: Istituto Nazionale IRCCS Tumori Fondazione Pascale
city: Parma
country: Italy
facility: Azienda Ospedaliera Unversitaria di Parma
city: Chiba, Kashiwa
country: Japan
facility: National Cancer Center Hospital East
city: Ehime, Matsuyama
country: Japan
facility: Shikoku Cancer Center
city: Hiroshima, Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Osaka, OsakaSayama
country: Japan
facility: Kindai University Hospital
city: Osaka, Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Shizuoka, Hamamatsu
country: Japan
facility: Hamamatsu University Hospital
city: Tokyo, Chuo-ku
country: Japan
facility: National Cancer Center Hospital
city: Cheongju-si
country: Korea, Republic of
facility: Chungbuk National University Hospital
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Amsterdam
country: Netherlands
facility: Nederlands Kanker Instituut
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum (LUMC)
city: Porto
country: Portugal
facility: Hospital CUF Porto
city: Singapore
country: Singapore
facility: National University Hospital-Singapore-22806
city: Singapore
country: Singapore
facility: National Cancer Centre Singapore
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: L'Hospitalet de Llobregat
country: Spain
facility: Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Malaga
country: Spain
facility: Hospital Virgen de la Victoria
city: Valencia
country: Spain
facility: Hospital Clínico de Valencia
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Solna
city: London
country: United Kingdom
facility: The Royal Marsden Hospital, Chelsea
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: Sutton
country: United Kingdom
facility: The Royal Marsden Hospital, Sutton
Study officials:
References: