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Combination of MEK Inhibitor and Hydroxychloroquine ( Plaquenil)

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.

The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab

Evgeny Imyanitov

Liliya Baboshkina

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.

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

New Therapeutic Approaches for Tumors With RAS Gene Mutations

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

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 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 was defined as the time from start treatment to subsequent death, measured in weeks and months.

N.N. Petrov National Medical Research Center of Oncology

Oncologist

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations	NCT06229340	RAS Mutation Ras (Kras or Nr... Colorectal Canc... Pancreas Cancer Lung Cancer Melanoma Refractory Canc...	Leflunomide The combination...	18 Years - 85 Years	N.N. Petrov National Medical Research Center of Oncology
Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations	NCT06229340	RAS Mutation Ras (Kras or Nr... Colorectal Canc... Pancreas Cancer Lung Cancer Melanoma Refractory Canc...	Leflunomide The combination...	18 Years - 85 Years	N.N. Petrov National Medical Research Center of Oncology
Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations	NCT06229340	RAS Mutation Ras (Kras or Nr... Colorectal Canc... Pancreas Cancer Lung Cancer Melanoma Refractory Canc...	Leflunomide The combination...	18 Years - 85 Years	N.N. Petrov National Medical Research Center of Oncology

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