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

• ClinicalTrials.gov Identifier: NCT04886804
• Recruitment Status: Recruiting
• First Posted: May 14, 2021
• Last Update Posted: May 14, 2024
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Tracking Information

• First Submitted Date: May 4, 2021
• First Posted Date: May 14, 2021
• Last Update Posted Date: May 14, 2024
• Actual Study Start Date: June 22, 2021
• Estimated Primary Completion Date: December 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 12, 2023)

• Phase Ia: Maximum Tolerated Dose (MTD) [ Time Frame: At the end of Cycle 1 (each cycle is 21 days). ]
  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.
• Phase Ia: Number of patients with Dose Limiting Toxicities (DLTs) in the MTD evaluation period [ Time Frame: At the end of Cycle 1 (each cycle is 21 days). ]
• Phase Ib - Cohorts 1, 2 and 5 : Objective response (OR) as assessed by central independent review [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
  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.
• Phase Ib - Cohort 3: Objective response according to RECIST 1.1 by investigator assessment [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib: Cohort 4: Objective response according to Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) by central independent review [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]

Original Primary Outcome Measures (submitted: May 12, 2021)

• Phase Ia: Maximum Tolerated Dose (MTD) [ Time Frame: At the end of Cycle 1 (each cycle is 21 days) ]
  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.
• Phase Ia: Number of patients with Dose Limiting Toxicities (DLTs) in the MTD evaluation period [ Time Frame: At the end of Cycle 1 (each cycle is 21 days) ]
• Phase Ib: Objective response (OR) [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months ]
  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 as assessed by the Investigator, 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.

Current Secondary Outcome Measures (submitted: March 4, 2024)

• Phase Ia: Number of patients experiencing DLTs during the entire treatment period [ Time Frame: From the start of the trial treatment until end of month 8, up to 8 months. ]
• Phase Ia: Maximum measured concentration of zongertinib in plasma (Cmax) [ Time Frame: On day 1 and on day 15 of Cycle 1 (each cycle is 21 days). ]
• Phase Ia: Area under the concentration-time curve of zongertinib in plasma (AUC0-t2) [ Time Frame: On day 1 and on day 15 of Cycle 1 (each cycle is 21 days). ]
• Phase Ib - Cohorts 1, 2 and 5: Duration of objective response (DoR) according to RECIST 1.1 [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
  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.
• Phase Ib - Cohorts 1, 2 and 5: Disease control (DC) [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
  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.
• Phase Ib - Cohorts 1, 2 and 5: Progression-free survival (PFS) [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
  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.
• 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 [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• 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 [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 3: Duration of objective response according to RECIST 1.1 by investigator assessment [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 3: Disease control according to RECIST 1.1 as assessed by the investigator [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 3: Progression-free survival according to RECIST 1.1 as assessed by the investigator [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 3: Objective response according to RANO-BM criteria as assessed by the investigator for patients with CNS lesions at baseline [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 3: Disease control according to RANO-BM criteria as assessed by the investigator for patients with CNS lesions at baseline [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 4: Duration of objective response (DoR) according to RANO-BM by central independent review [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 4: Disease control (DC) according to RANO-BM by central independent review [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 4: Progression-free survival (PFS) according to RANO-BM as assessed by central independent review [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 4: OR according to RECIST 1.1 by central independent review [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 4: Duration of OR according to RECIST 1.1 by central independent review [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 4: DC according to RECIST 1.1 by central independent review [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - Cohort 4: PFS according to RECIST 1.1 as assessed by central independent review [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• Phase Ib - All Cohorts: Number of patients experiencing DLTs during the entire treatment period [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]
• 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 [ Time Frame: Baseline and on Day 1 of Cycle 5 (each cycle is 21 days). ]
• 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 [ Time Frame: Baseline and on Day 1 of Cycle 5 (each cycle is 21 days). ]
• Phase Ib - All Cohorts: Change from baseline to Day 1 of Cycle 5 in EORTC item List 46 (IL46) score [ Time Frame: Baseline and on Day 1 of Cycle 5 (each cycle is 21 days). ]
• Phase Ib - All cohorts: Overall survival (OS), defined as time from first treatment administration until death from any cause [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months. ]

Original Secondary Outcome Measures (submitted: May 12, 2021)

• Phase Ia: Number of patients experiencing DLTs during the entire treatment period [ Time Frame: From the start of the trial treatment until end of month 8, up to 8 months ]
• Phase Ia: Maximum measured concentration of BI 1810631 in serum (Cmax) [ Time Frame: At day 1, at day 8 and at day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase Ia: Area under the concentration-time curve of BI 1810631 in plasma (AUC0-t2) [ Time Frame: At day 1, at day 8 and at day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase Ib: Duration of objective response (DoR) [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months ]
  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.
• Phase Ib: Disease control (DC) [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months ]
  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 by the Investigator, from 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.
• Phase Ib: Duration of disease control (DoDC) [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months ]
  DoDC is defined as the time from first treatment administration until the earliest of disease progression or death, among patients with disease control.
• Phase Ib: Progression-free survival (PFS) [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months ]
  PFS is defined as the time from first treatment administration until tumor progression according to RECIST version 1.1 as assessed by the Investigator, or death from any cause, whichever occurs earlier.
• Phase Ib: Number of patients experiencing DLTs during the entire treatment period [ Time Frame: From the start of the trial treatment until end of month 12, up to 12 months ]
• Phase Ib: Maximum measured concentration of BI 1810631 in serum (Cmax ) [ Time Frame: At day 1 of Cycle 1 (each cycle is 21 days) ]
• Phase Ib: Area under the concentration-time curve of BI 1810631 in plasma (AUC0-t2 (,ss)) [ Time Frame: From day 1 to day 3 of Cycle 1 (each cycle is 21 days) ]
• Phase Ib: Maximum measured concentration of BI 1810631 in serum at steady state (Cmax,ss) [ Time Frame: At day 15 of Cycle 1 (each cycle is 21 days) ]
• Phase Ib: Area under the concentration-time curve of BI 1810631 in plasma at steady state (AUC0-t2,ss) [ Time Frame: From day 15 to day 16 of Cycle 1 (each cycle is 21 days) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Neoplasm Metastasis
• Non-Small Cell Lung Cancer

Intervention

Drug: zongertinib

zongertinib

Other Name: BI 1810631

Study Arms

• Experimental: Phase Ia - Dose escalation part
  Consecutive cohorts of patients treated with escalating doses of BI 1810631 monotherapy.
  Intervention: Drug: zongertinib
• Experimental: Phase Ib - Dose expansion part: Cohort 1
  Intervention: Drug: zongertinib
• Experimental: Phase Ib - Dose expansion part: Cohort 2
  Intervention: Drug: zongertinib
• Experimental: Phase Ib - Dose expansion part: Cohort 3
  Intervention: Drug: zongertinib
• Experimental: Phase Ib - Dose expansion part: Cohort 4
  Intervention: Drug: zongertinib
• Experimental: Phase Ib - Dose expansion part: Cohort 5
  Intervention: Drug: zongertinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 12, 2023): 371
• Original Estimated Enrollment (submitted: May 12, 2021): 96
• Estimated Study Completion Date: December 31, 2027
• Estimated Primary Completion Date: December 31, 2025 (Final data collection date for primary outcome measure)

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 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Boehringer Ingelheim; 1-800-243-0127; clintriage.rdg@boehringer-ingelheim.com

Contact: Additional US locations available on demand. Please contact for options.; 1-800-243-0127

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

Administrative Information

• NCT Number: NCT04886804
• Other Study ID Numbers: 1479-0001; 2020-004563-47 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

Plan Description

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents, except for the following exclusions:

1. studies in products where Boehringer Ingelheim is not the license holder;
2. studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials;
3. studies conducted in a single center or targeting rare diseases (because of limitations with anonymization).

For more details refer to: https://www.mystudywindow.com/msw/datasharing

• Current Responsible Party: Boehringer Ingelheim
• Original Responsible Party: Same as current
• Current Study Sponsor: Boehringer Ingelheim
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Boehringer Ingelheim
• Verification Date: May 2024