Malignancies harboring BRAF mutations with impaired kinase activity Solid tumors D03 C43 C26 C73 C50 C56 C16 C44 C24 C22
Conditions
Interventions
Group 1: Dosing Schedule:
Dose allocation takes place upon registration in the study for the entire duration of max. 12 cycles or until relapse/progression,
unacceptable toxicity, death , whatever occ
Sponsors
Universitätsklinikum FreiburgKlinik für Innere Medizin IHämatologie, Onkologie und StammzelltransplantationHugstetter Str. 55 · 79106 Freiburg
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: Male or female patients aged =18 years without upper age limit; 2. Metastatic malignancy 3. Patients must have received standard therapy or have no standard therapy available. Or, in the opinion of investigator have been considered ineligible for a particular form of standard therapy on medical grounds. 4. BRAF mutation with impaired kinase activity (according to Brummer laboratory at Medical Center – University of Freiburg) 5. BRAF mutation with sensitivity to sorafenib in vitro (according to Brummer laboratory at Medical Center – University of Freiburg) 6. At least one lesion that can be measured by CT, PET-CT, or MRI according to RECIST 1.1 7. Adequate hepatic function with - AST and ALT < 3 ULN AND - Total bilirubin < 1.5 x ULN. Patient with Gilberts syndrome and in whom total bilirubin elevations are accompanied by elevated indirect bilirubin are eligible. Calculated creatinine clearance = 50 mL/min by the Cockcroft-Gault- Equation 9. Patient is able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels 10. Written informed consent obtained according to international guidelines and local laws 11. Ability to understand the nature of the trial and the trial related procedures and to comply with them
Exclusion criteria
Exclusion criteria: Finding of a strongly activating BRAF mutation (according to Brummer laboratory at Medical Center – University of Freiburg) 2. Life expectancy 2 5. Patients with known positivity for HIV, Hepatitis B or Hepatitis C at the time of screening 6. Uncontrolled bacterial, viral or fungal infection 7. Radiation therapy, major surgery, other locoregional therapy, within 4 weeks prior to the first dose of study drug 8. Serious cardiovascular disease (e.g. manifest heart failure, coronary heart disease, uncontrolled hypertension) 9. Any serious disease interfering with a regular therapy according to the study protocol 10. Patients who have received sorafenib in the past 11. Patient with a known history of aneurysms 12. History of retinal vein occlusion (RVO) 13. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression 14. Ongoing interstitial lung disease or pneumonitis, which requires treatment/medication 15. Known hypersensitivity to the active substances or any of the excipients 16. Participation in any other interventional clinical trial within the last 30 days before the start of this trial; simultaneous participation in registry and diagnostic trials is allowed 17. Patient without legal capacity who is unable to understand the nature, significance and consequences of the trial; 18. Concurrent treatment with anticancer therapy (other than IMPs) 19. Concomitant use of strong Cytochrome P450 3A4 inducers 20. For female patient: current or planned pregnancy, nursing period 21. Failure to use one of the following safe methods of contraception: hormonal contraception in combination with a mechanical method of contraception, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, sexual abstinence
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Determination of the maximum tolerated dose (MTD) of trametinib in combination with sorafenib and the recommended Phase II dose (RP2D) for the extension part of the study | — |
Secondary
| Measure | Time frame |
|---|---|
| - Characterization of safety and compatibility in the extension part. - To provide a preliminary estimate of the efficacy of sorafenib and trametinib in advanced malignant diseases involving a BRAF mutation with impaired BRAF kinase activity - Characterization of novel mutations with unknown BRAF activation status. - To demonstrate target inhibition in mutations with unknown BRAF activation status. | — |
Countries
Germany
Contacts
Public ContactLena Illert
Klinikum rechts der Isar der Technische Universität München, Klinik und Poliklinik für Innere Medizin III
Outcome results
None listed