A Study to Test Different Doses of BI 1701963 Alone and Combined With Trametinib in Patients With Different Types of Advanced Cancer (Solid Tumours With KRAS Mutation)

Study Overview
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Brief Summary
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This is a study in adults with advanced cancer (solid tumours) in whom previous chemotherapy was not successful. Only people who have a tumour with a KRAS mutation can participate in the study. A KRAS mutation makes cancer grow faster. The study tests 2 medicines called BI 1701963 and trametinib. BI 1701963 prevents reactivation of KRAS. In this study, BI 1701963 is given to humans for the first time. Trametinib is an approved medicine (MEK inhibitor). The purpose of this study is to find out the highest dose of BI 1701963 alone and in combination with trametinib the participants can tolerate. Another purpose is to check whether BI 1701963 in combination with trametinib is able to make tumours shrink. Participants can stay in the study as long as they benefit from treatment and can tolerate it. During this time, they get tablets of BI 1701963 and trametinib once daily. The doctors regularly monitor the size of the tumour. Doctors also regularly record any unwanted effects and check participants' health.

Official Title
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A Phase I Open-label Dose Escalation Trial of BI 1701963 as Monotherapy and in Combination With Trametinib in Patients With KRAS Mutated Advanced or Metastatic Solid Tumours

Conditions
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Solid Tumors, KRAS Mutation; SOS1

Intervention / Treatment
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* Drug: BI 1701963
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: All parts Previously-identified activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation in tumour tissue or blood prior to screening At least one target lesion that can be measured per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Adequate organ function Age ≥18 years of age, or over the legal age of consent as required by local legislation. Signed and dated written informed consent in accordance with GCP and local legislation prior to admission to the trial. Women of childbearing potential who are not surgically sterilized must have a negative serum pregnancy test completed during the Screening period Further inclusion criteria apply Monotherapy and combination therapy dose escalation and monotherapy dose confirmation part - Documented disease progression despite appropriate prior standard therapies or for whom no standard therapy exists for their tumour type and disease stage Combination dose confirmation and expansion cohort Pathologically confirmed diagnosis of adenocarcinoma of the lung. Patients with mixed histology are eligible if adenocarcinoma is the predominant histology. Locally advanced stage IIIb or metastatic stage IV Non-small cell lung cancer (NSCLC) Patients must have received both chemotherapy and immunotherapy Exclusion criteria: All parts Previous anticancer chemotherapy within 3 weeks of the first administration of trial drug. Previous treatment with RAS, Mitogen-activated protein kinase (MAPK) or Son of sevenless 1 (SOS1) targeting agents Major surgery performed within 4 weeks prior to start of treatment Uncontrolled hypertension, congestive heart failure NYHA classification of ≥3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to start of treatment Left ventricular ejection fraction (LVEF) <50 % Congenital long QT prolongation syndrome Mean resting corrected QT interval (QTcF) >470 msec Leptomeningeal carcinomatosis Presence or history of uncontrolled or symptomatic brain metastases Known pre-existing interstitial lung disease Known active hepatitis B infection (defined as presence of Hep B sAg and/or Hep B Deoxyribonucleic acid (DNA)), active hepatitis C infection (defined as presence of Hep C Ribonucleic acid (RNA)) Active infectious disease Any history or presence of uncontrolled gastrointestinal disorders that could affect the intake and/or absorption of the trial drug History of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) Further exclusion criteria apply Combination part - Hypersensitivity to any of the excipients listed in the current Summary of Product Characteristics (SmPC)/Package insert (PI) of trametinib

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: BI 1701963 monotherapy<br> | Drug: BI 1701963<br>* Tablet<br>|
| Experimental: BI 1701963 + Trametinib<br> | Drug: BI 1701963<br>* Tablet<br>Drug: Trametinib<br>* Tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation (Part A) - Maximum tolerated dose (MTD) based on number of dose-limiting toxicities (DLTs) |  | 4 weeks | 
| Dose confirmation (Part B) - Number of patients with DLTs during the on-treatment period |  | Up to 3 years | 
| Dose confirmation (Part B) and expansion (Part C) - Objective response |  | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation (Part A), confirmation (Part B) and expansion (Part C) - Pharmacokinetic parameters of BI 1701963: Cmax (maximum measured concentration of the analyte in plasma) |  | Up to 5 weeks | 
| Dose escalation (Part A), confirmation (Part B) and expansion (Part C) - Pharmacokinetic parameters of BI 1701963: AUCτ (area under the concentration-time curve over a uniform dosing interval τ) |  | Up to 5 weeks | 
| Dose escalation (Part A), confirmation (Part B) and expansion (Part C) - Pharmacokinetic parameters of trametinib: Cmax (maximum measured concentration of the analyte in plasma) |  | Up to 5 weeks | 
| Dose escalation (Part A), confirmation (Part B) and expansion (Part C) - Pharmacokinetic parameters of trametinib: AUCτ (area under the concentration-time curve over a uniform dosing interval τ) |  | Up to 5 weeks | 
| Dose confirmation (Part B) - Pharmacokinetic parameters of BI 1701963: Cmax (maximum measured concentration of the analyte in plasma) |  | Up to 5 weeks | 
| Dose confirmation (Part B) - Pharmacokinetic parameters of BI 1701963: AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) |  | Up to 5 weeks | 
| Dose confirmation (Part B) - Pharmacokinetic parameters of midazolam: Cmax (maximum measured concentration of the analyte in plasma) |  | Up to 5 weeks | 
| Dose confirmation (Part B) - Pharmacokinetic parameters of midazolam: AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point) |  | Up to 5 weeks | 
| Dose confirmation (Part B) - Number of patients with Grade ≥3 treatment-related adverse events observed during the on-treatment period |  | Up to 3 years | 
| Dose confirmation (Part B) and expansion (Part C) - Duration of Objective response (OR) |  | Up to 3 years | 
| Dose confirmation (Part B) and expansion (Part C) - Tumour shrinkage (in millimetres) |  | Up to 3 years | 
| Dose confirmation (Part B) and expansion (Part C) - Progression-free survival |  | 6 months | 
| Dose confirmation (Part B) and expansion (Part C) - Number of patients with Grade ≥3 treatment-related adverse events observed during the on-treatment period |  | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SOS1