Clinical trial NCT04111458: 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)
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Solid Tumors, KRAS Mutation; SOS1
Keywords: SOS1
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2019-10-01
Enrollment: 71
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Dose escalation (Part A) - Maximum tolerated dose (MTD) based on number of dose-limiting toxicities (DLTs)
timeFrame: 4 weeks
measure: Dose confirmation (Part B) - Number of patients with DLTs during the on-treatment period
timeFrame: Up to 3 years
measure: Dose confirmation (Part B) and expansion (Part C) - Objective response
timeFrame: Up to 3 years
Secondary outcomes:
measure: 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)
timeFrame: Up to 5 weeks
measure: 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)
timeFrame: Up to 5 weeks
measure: Dose escalation (Part A), confirmation (Part B) and expansion (Part C) - Pharmacokinetic parameters of trametinib: Cmax (maximum measured concentration of the analyte in plasma)
timeFrame: Up to 5 weeks
measure: 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)
timeFrame: Up to 5 weeks
measure: Dose confirmation (Part B) - Pharmacokinetic parameters of BI 1701963: Cmax (maximum measured concentration of the analyte in plasma)
timeFrame: Up to 5 weeks
measure: 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)
timeFrame: Up to 5 weeks
measure: Dose confirmation (Part B) - Pharmacokinetic parameters of midazolam: Cmax (maximum measured concentration of the analyte in plasma)
timeFrame: Up to 5 weeks
measure: 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)
timeFrame: Up to 5 weeks
measure: Dose confirmation (Part B) - Number of patients with Grade ≥3 treatment-related adverse events observed during the on-treatment period
timeFrame: Up to 3 years
measure: Dose confirmation (Part B) and expansion (Part C) - Duration of Objective response (OR)
timeFrame: Up to 3 years
measure: Dose confirmation (Part B) and expansion (Part C) - Tumour shrinkage (in millimetres)
timeFrame: Up to 3 years
measure: Dose confirmation (Part B) and expansion (Part C) - Progression-free survival
timeFrame: 6 months
measure: Dose confirmation (Part B) and expansion (Part C) - Number of patients with Grade ≥3 treatment-related adverse events observed during the on-treatment period
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute-Nashville-48456
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Frankfurt am Main
country: Germany
facility: Universitätsklinikum Frankfurt
city: Köln
country: Germany
facility: Universitätsklinikum Köln (AöR)
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum-ROTTERDAM-50697
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
Study officials:
References: