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)

• ClinicalTrials.gov Identifier: NCT04111458
• Recruitment Status: Active, not recruiting
• First Posted: October 1, 2019
• Last Update Posted: May 3, 2023
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Solid Tumors, KRAS Mutation; SOS1	Drug: BI 1701963; Drug: Trametinib	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 71 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 28, 2019
• Estimated Primary Completion Date: September 29, 2023
• Estimated Study Completion Date: September 29, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: BI 1701963 monotherapy	Drug: BI 1701963; Tablet
Experimental: BI 1701963 + Trametinib	Drug: BI 1701963; Tablet; Drug: Trametinib; Tablet

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. 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) [ Time Frame: Up to 5 weeks ]
2. 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) [ Time Frame: Up to 5 weeks ]
3. Dose escalation (Part A), confirmation (Part B) and expansion (Part C) - Pharmacokinetic parameters of trametinib: Cmax (maximum measured concentration of the analyte in plasma) [ Time Frame: Up to 5 weeks ]
4. 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) [ Time Frame: Up to 5 weeks ]
5. Dose confirmation (Part B) - Pharmacokinetic parameters of BI 1701963: Cmax (maximum measured concentration of the analyte in plasma) [ Time Frame: Up to 5 weeks ]
6. 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) [ Time Frame: Up to 5 weeks ]
7. Dose confirmation (Part B) - Pharmacokinetic parameters of midazolam: Cmax (maximum measured concentration of the analyte in plasma) [ Time Frame: Up to 5 weeks ]
8. 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) [ Time Frame: Up to 5 weeks ]
9. Dose confirmation (Part B) - Number of patients with Grade ≥3 treatment-related adverse events observed during the on-treatment period [ Time Frame: Up to 3 years ]
10. Dose confirmation (Part B) and expansion (Part C) - Duration of Objective response (OR) [ Time Frame: Up to 3 years ]
11. Dose confirmation (Part B) and expansion (Part C) - Tumour shrinkage (in millimetres) [ Time Frame: Up to 3 years ]
12. Dose confirmation (Part B) and expansion (Part C) - Progression-free survival [ Time Frame: 6 months ]
13. Dose confirmation (Part B) and expansion (Part C) - Number of patients with Grade ≥3 treatment-related adverse events observed during the on-treatment period [ Time Frame: Up to 3 years ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, North Carolina

Levine Cancer Institute

Charlotte, North Carolina, United States, 28204

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

United States, Texas

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

Germany

Universitätsklinikum Frankfurt

Frankfurt am Main, Germany, 60590

Universitätsklinikum Köln (AöR)

Köln, Germany, 50937

Netherlands

Erasmus Medisch Centrum

Rotterdam, Netherlands, 3015 GD

Universitair Medisch Centrum Utrecht

Utrecht, Netherlands, 3584 CX

Sponsors and Collaborators

Boehringer Ingelheim

More Information

Additional Information:

Related Info 

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT04111458
• Other Study ID Numbers: 1432-0001; 2018-004757-24 ( EudraCT Number )
• First Posted: October 1, 2019
• Last Update Posted: May 3, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

After the study is completed and the primary manuscript is accepted for publishing, researchers can use this following link https://www.mystudywindow.com/msw/datasharing to request access to the clinical study documents regarding this study, and upon a signed "Document Sharing Agreement".

Also, Researchers can use the following link https://www.mystudywindow.com/msw/datasharing to find information in order to request access to the clinical study data, for this and other listed studies, after the submission of a research proposal and according to the terms outlined in the website.

The data shared are the raw clinical study data sets.

• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: After all regulatory activities are completed in the US and EU for the product and indication, and after the primary manuscript has been accepted for publication.
• Access Criteria: For study documents - upon signing of a 'Document Sharing Agreement'. For study data - 1. after the submission and approval of the research proposal (checks will be performed by both the independent review panel and the sponsor, including checking that the planned analysis does not compete with sponsor'
• URL: https://www.mystudywindow.com/msw/datasharing

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

Keywords provided by Boehringer Ingelheim:

SOS1

Additional relevant MeSH terms:

Neoplasms; Trametinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action