There is a huge variety of nucleotide substitutions that activate RAS. The search for new "universal" drugs for the RAS pathway that either interfere with RAS upregulation upstream in the signaling pathway or offset the consequences of RAS activation is important for improving therapeutic outcomes for patients with refractory malignancies.
The use of leflunomide or the combination of MEK inhibitor + hydroxychloroquine ± bevacizumab is promising for patients with mutations in RAS cascade genes who have failed all existing treatment standards.
Patient is able to provide informed consent and sign approved consent forms to participate in the study.
Patient age is at least 18 years old.
Performance status Eastern Cooperative Oncology Group (ECOG) 0-2.
Histologically confirmed metastatic metastatic disease stage 4.
Age over 85 years.
Рresence of acute or active chronic infections.
Impaired renal and hepatic function; - left ventricular ejection fraction (LVEF) < 45%
Known history of acute or chronic hepatitis B or C due to known potential hepatotoxicity of leflunomide.
Crossover
Leflunomide
Drug100 mg daily for 3 days at the loading dose, then 20 mg daily at the standard dose.
The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab
DrugUse of one of the possible MEK-inhibitor options: Trametinib 2 mg once daily orally; Cobimetinib 60 mg on days 1-21, break 7 days, cycle 28 days orally; Binimetinib 45 mg 2 times a day daily orally. + Hydroxychloroquine 600 mg 2 times a day daily orally. ± Bevacizumab 7.5 mg/m² every 3 weeks intravenously.
Objective response rate
Objective response rate was assigned for a subject if the subject displayed either complete response (CR) or partial response (PR) per RECIST version 1.1
Assessment of patients' quality of life
European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. It consisted of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact. The EORTC QLQ-C30 GHS/QoL score ranges from 0 to 100; High score indicates better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL.
Progression-free survival (PFS)
Progression-free survival was defined as the time from start treatment to subsequent confirmed progression per RECIST version 1.1, or death (whichever occurred first), measured in weeks and months. For PFS assessment clinical progression (i.e., treatment discontinuation due to progression of disease) was also considered as an event.
Overall survival
Overall survival was defined as the time from start treatment to subsequent death, measured in weeks and months.
Click on the lead sponsor to view all of their trials.
