Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations — N??-RAS  

Lung Cancer Clinical Trial

Official title: New Therapeutic Approaches for Tumors With RAS Gene Mutations

Status Recruiting

Clinical Trial Summary

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.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Colorectal Cancer Recurrent
• Colorectal Neoplasms
• Lung Cancer
• Melanoma
• Pancreas Cancer
• Pancreatic Neoplasms
• RAS Mutation
• Refractory Cancer

• NCT number: NCT06229340
• Study type: Interventional
• Source: N.N. Petrov National Medical Research Center of Oncology
• Contact: Evgeny Imyanitov
• Phone: +79013023707
• Email: evgeny@imyanitov.spb.ru
• Status: Recruiting
• Phase: Phase 2
• Start date: October 3, 2023
• Completion date: October 1, 2026