A Phase 2 interventional study of Leflunomide and The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab in RAS Mutation, Ras (Kras or Nras) Gene Mutation and Colorectal Cancer Recurrent, sponsored by N.N. Petrov National Medical Research Center of Oncology. Recruiting at 1 site in Russian Federation. Open to participants aged 18 Years to 85 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-01-29.
Sponsored by N.N. Petrov National Medical Research Center of Oncology · Phase 2, Interventional, and Basic science
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.
Mutations in the RAS gene are a common cause for the development of many tumors.
It is of practical interest to study the potential efficacy of several drugs registered for the treatment of other diseases, which may also be able to affect various parts of the RAS pathway.
Leflunomide, with its active metabolite , inhibits the enzyme dihydroorotate dehydrogenase (DHODH). DHODH plays an essential role in the biosynthesis of pyrimidine, which is particularly important for the growth of RAS mutant cells.
Tumors with KRAS, NRAS, and HRAS mutations are characterized by increased MEK kinase activity. The combination of MEK inhibitor + hydroxychloroquine ± bevacizumab is able to affect MEK kinase activity by direct inhibition as well as regulation of autophagy, which is controlled in this case by the antimalarial drug hydroxychloroquine.
The use of bevacizumab is appropriate because there is evidence of its efficacy in the treatment of patients with colorectal cancer, including colorectal cancer with mutations in the KRAS gene.
5,599 studies on the registry are indexed under Colorectal Neoplasms; 1,459 are open to participants now.
This study's planned enrollment of 20 is below the median of 77 across 4,123 interventional studies indexed under Colorectal Neoplasms.
Browse Colorectal Neoplasms studies →N.N. Petrov National Medical Research Center of Oncology is the lead sponsor of 26 studies on the registry; 15 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Appropriate hematologic and liver function:
Exclusion Criteria:
Exit criteria:
Leflunomide
Drug: Leflunomide
Combination of MEK Inhibitor and Hydroxychloroquine ( Plaquenil)
Drug: The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab
standard therapy
100 mg daily for 3 days at the loading dose, then 20 mg daily at the standard dose.
Use 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
Time frame: at the end of 2 cycles of treatment (each cycle is 28 days)
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.
Time frame: at the end of 2 cycles of treatment (each cycle is 28 days)
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.
Time frame: at the end of 2 cycles of treatment (each cycle is 28 days)
Overall survival
Overall survival was defined as the time from start treatment to subsequent death, measured in weeks and months.
Time frame: up to 3 years
Plan to share: No
No publications or documents are linked to this record.
Eligibility is decided by the study team. Share this record with your doctor or contact the team directly.
Contact study teamGet an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
N.N. Petrov National Medical Research Center of Oncology