NCT06229340

Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations

New Therapeutic Approaches for Tumors With RAS Gene Mutations

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Sponsor: N.N. Petrov National Medical Research Center of Oncology · Academic / Other
• Sex: All
• Age: 18 Years – 85 Years
• Healthy volunteers: Accepted

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.

Detailed 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.

Conditions

• RAS Mutation
• Ras (Kras or Nras) Gene Mutation
• Colorectal Cancer Recurrent
• Pancreas Cancer
• Lung Cancer
• Melanoma
• Refractory Cancer

Interventions

Type	Name	Description
DRUG	Leflunomide	100 mg daily for 3 days at the loading dose, then 20 mg daily at the standard dose.
DRUG	The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab	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.

Timeline

• Start date: 2023-10-03
• Primary completion: 2026-10-01
• Completion: 2026-10-01
• First posted: 2024-01-29
• Last updated: 2024-01-29

Locations

1 site across 1 country: Russia