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Comments

BI 1701963 is a pan-KRAS inhibitor (“pan”: aimed to block signaling of all KRAS mutations)
Unlike other KRAS inhibitors currently in clinical trials, this pan-KRAS inhibitor aims to hit all the most prevalent KRAS mutant alleles, by targeting SOS1 as well as G12C. SOS1 is a protein that turns KRAS from an “off” to “on” state.
For solid cancers with a KRAS mutation, including CRC in the dose escalation part (first part of the trial)
BI 1701963 monotherapy and in combination with MEK inhibitor (Trametinib)
Key inclusion criteria:
-measurable disease (at least one target lesion)
-prior treatment with a RAS-targeting agent is not allowed

Inclusion 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

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) 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