A Study to Test How Well Different Doses of BI 3706674 Are Tolerated by People With Advanced Cancer in the Stomach and Oesophagus

Study Overview
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Brief Summary
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This study is open to adults with advanced cancer in the stomach and oesophagus. This is a study for people for whom previous treatment was not successful or no treatment exists. In this study, BI 3706674 is given to humans for the first time. The purpose of this study is to find a suitable dose of BI 3706674 that people with advanced cancer can tolerate when taken alone. Another purpose is to check whether BI 3706674 can make tumours shrink. BI 3706674 blocks growth signals and may prevent the tumour from growing. Participants take BI 3706674 as a tablet when starting treatment. Different doses of BI 3706674 are tested during this study. If there is benefit for the participants and if they can tolerate it, the treatment is given up to the maximum duration of the study. During this time, participants visit the study site regularly. The total number of visits depends on how they respond to and tolerate the treatment. Doctors record any unwanted effects and regularly check the general health of the participants.

Official Title
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Open-label Dose-finding Trial to Explore Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of BI 3706674 Given Orally as Monotherapy in Patients With Unresectable Metastatic KRAS Wild Type Amplified Gastric, Oesophageal, and Gastroesophagealjunction Adenocarcinoma

Conditions
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Solid Tumor, KRAS Mutation

Intervention / Treatment
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* Drug: BI 3706674


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with pathologically confirmed diagnosis of locally advanced or metastatic gastric adenocarcinoma (GAC), oesophageal adenocarcinomas (EAC), and gastroesophageal junction adenocarcinoma (GEJAC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type (wt) amplification and documented disease progression despite at least 1 line of prior therapy. KRAS status will be confirmed retrospectively for those with a known KRAS status or determined prospectively (dose confirmation and expansion) if KRAS status is unknown, using archival tissue (if available) or a fresh biopsy. Dose escalation (Part A) only: Patients with advanced or metastatic relapsed or refractory solid tumours of any histology with KRAS wt amplification or harbouring a KRAS G12V mutation who have exhausted treatment options known to prolong survival for their disease. Detection of KRAS status by a local test is allowed for enrolment but will be retrospectively confirmed. Patients who have failed conventional treatment or for whom no therapy of proven efficacy exists or who are not eligible for established treatment options. Dose confirmation (Part B) only: Patient is willing and able to undergo mandatory pre- and on-treatment low risk tumour biopsies. Patients with a high risk for biopsy complications can be included without undergoing pre- and on-treatment tumour biopsy as long as archival tumour tissue is available for confirmation of KRAS status. At least one target lesion that can be measured per RECIST version 1.1 (radiated lesions do not qualify as target lesions unless there has been demonstrated progression of the lesion after completion of radiotherapy) Dose escalation (Part A) only: Patients with no lesions measurable per RECIST version 1.1 may be included if agreed between Sponsor and investigator. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All toxicities related to previous anti-cancer therapies have resolved ≤ CTCAE Grade 1 prior to trial treatment administration (except for alopecia and peripheral neuropathy which must be ≤ CTCAE Grade 2 and amenorrhea/menstrual disorders which can be any grade). Life expectancy ≥3 months at the start of treatment in the opinion of the investigator. Age ≥18 years of age, or over the legal age of consent as required by local legislation. Further inclusion criteria apply. Exclusion Criteria: Previous anti-cancer chemotherapy within 3 weeks of the first administration of trial drug. Previous anti-cancer hormonal treatment or anti-cancer immunotherapy within 2 weeks of the first administration of trial drug. Previous treatment with rat sarcoma (RAS), mitogen-activated protein kinases (MAPKs) or son of sevenless homolog 1 (SOS1) targeting agents. Presence of cardiovascular abnormalities such as uncontrolled hypertension (defined as systolic blood pressure ≥140 and/or diastolic blood pressure ≥90 millimetre of mercury (mmHg)), congestive heart failure New York Heart Association (NYHA) classification of ≥ III or IV, unstable angina or poorly controlled arrhythmia. History of myocardial infarction, stroke, or pulmonary embolism within 6 months prior to randomisation. Left ventricular ejection fraction (LVEF) <50%. Congenital or family history of long QT prolongation syndrome. Mean resting corrected QT interval (QTcF) >470 msec. Radiotherapy within 2 weeks prior to start of treatment, except as follows: Palliative radiotherapy to regions other than the chest is allowed if completed at least 2 weeks prior to randomisation. Single dose palliative radiotherapy for symptomatic metastasis within 2 weeks prior to randomisation may be allowed but must be discussed with the Sponsor. 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: Part A (Phase Ia): Dose escalation<br> | Drug: BI 3706674<br>* BI 3706674<br>|
| Experimental: Part B (Phase Ib): Dose confirmation<br> | Drug: BI 3706674<br>* BI 3706674<br>|
| Experimental: Part C (Phase Ib): Dose expansion<br> | Drug: BI 3706674<br>* BI 3706674<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Occurrence of dose limiting toxicities (DLTs) in the maximum tolerated dose (MTD) evaluation period |  | up to 28 days | 
| Part B: Occurrence of drug-related adverse events (AEs) ≥ Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 during the on-treatment period |  | up to 3.5 years | 
| Part C: Objective response (OR) based on central assessment | OR is defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), where BOR is determined according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 from first treatment administration until the earliest of disease progression, death, or last evaluable tumour assessment before start of subsequent anticancer therapy, loss to follow-up or withdrawal of consent. | up to 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Occurrence of DLTs during the on-treatment period |  | up to 3.5 years | 
| Part B: Occurrence of DLTs during the on-treatment period |  | up to 3.5 years | 
| Part B: OR based on central assessment | OR is defined as best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), where BOR is determined according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 from first treatment administration until the earliest of disease progression, death, or last evaluable tumour assessment before start of subsequent anticancer therapy, loss to follow-up or withdrawal of consent. | up to 3.5 years | 
| Part B: Duration of objective response (DOR) | DOR is defined as the time from first documented CR or PR until the earliest of disease progression or death among patients with objective response. | up to 3.5 years | 
| Part B: Tumour shrinkage | Tumour shrinkage is defined as the difference between the minimum post-baseline sum of diameters of target lesions (long axis for non-nodal lesions, short axis for nodal lesions) and the baseline sum of diameters of the same set of target lesions. | up to 3.5 years | 
| Part B: Progression-free survival (PFS) | PFS is defined as the time from first treatment administration until tumour progression according to RECIST version 1.1 or death from any cause, whichever occurs earlier. | up to 3.5 years | 
| Part C: Duration of objective response |  | up to 3.5 years | 
| Part C: Tumour shrinkage |  | up to 3.5 years | 
| Part C: Progression-free survival (PFS) |  | up to 3.5 years | 
| All trial parts: Maximum measured concentration (Cmax) of BI 3706674 evaluated after the first dose in Cycle 1 |  | up to 28 days | 
| All trial parts: Area under the plasma concentration-time curve over a uniform dosing interval τ (AUCτ) of BI 3706674 evaluated after the first dose in Cycle 1 |  | up to 28 days | 
| Maximum measured concentration of BI 3706674 evaluated at steady state on Cycle 2 Day 1 (Cmax,ss) |  | From Day 1 of Cycle 2 (each cycle is 28 days) up to 3.5 years | 
| All trial parts: Area under the plasma concentration-time curve over a uniform dosing interval τ of BI 3706674 evaluated at steady state on Cycle 2 Day 1 (AUCτ,ss) |  | From Day 1 of Cycle 2 (each cycle is 28 days) up to 3.5 years | 
| All trial parts: Occurrence of AEs during the on-treatment period |  | up to 3.5 years |