A Study to Test Different Doses of BI 1810631 in People With Different Types of Advanced Cancer (Solid Tumours With Changes in the HER2 Gene)

Study Overview
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Brief Summary
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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 BI 1810631 the participants can tolerate. Once this dose is found, it will be used in the second study part to tests whether BI 1810631 can make tumours shrink. In this study, BI 1810631 is given to people for the first time. Participants take BI 1810631 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 BI 1810631.

Official Title
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BEAMION-Lung 1: An Open Label, Phase I Dose Escalation Trial, With Dose Confirmation and Expansion, of BI 1810631 as Monotherapy in Patients With Advanced or Metastatic Solid Tumors With HER2 Aberrations

Conditions
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Neoplasm Metastasis, Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: BI 1810631


Participation Criteria
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Eligibility Criteria
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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 109/L (≥ 1.5 x 103/μL) (≥ 1500/mm3); haemoglobin ≥ 9.0 g/dL (≥ 90 g/L) (≥ 5.6 mmol/L); platelets ≥ 100 x 109/L (100 x 103/μL) (100 x 103/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 3A4 (CYP3A4) inhibitors Treatment with strong Cytochrome P450 3A (CYP3A) inducers Further exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ia - Dose escalation part<br>Consecutive cohorts of patients treated with escalating doses of BI 1810631 monotherapy. | Drug: BI 1810631<br>* BI 1810631<br>|
| Experimental: Phase Ib - Dose expansion part: Cohort 1<br> | Drug: BI 1810631<br>* BI 1810631<br>|
| Experimental: Phase Ib - Dose expansion part: Cohort 2<br> | Drug: BI 1810631<br>* BI 1810631<br>|
| Experimental: Phase Ib - Dose expansion part: Cohort 3<br> | Drug: BI 1810631<br>* BI 1810631<br>|
| Experimental: Phase Ib - Dose expansion part: Cohort 4<br> | Drug: BI 1810631<br>* BI 1810631<br>|
| Experimental: Phase Ib - Dose expansion part: Cohort 5<br> | Drug: BI 1810631<br>* BI 1810631<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 
| 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). | 
| 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. | 
| 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. | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 
| Phase Ia: Maximum measured concentration of BI 1810631 in plasma (Cmax) |  | On day 1 and on 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) |  | 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 | 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 
| 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). | 
| 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). | 
| 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). |