Status and phase
Conditions
Treatments
About
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.
Full 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.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
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.
Must have documented RAS (KRAS, HRAS, NRAS) mutation identified within the last 5 years by a local test on tumor tissue.
More than 2 lines of standard drug antitumor therapy in the anamnesis.
Must have disease progression as defined by RECIST version 1.1 criteria
Appropriate hematologic and liver function:
For women of childbearing potential: consent to abstinence (abstain from heterosexual intercourse) or use at least two forms of effective contraception with an ineffectiveness rate < 1% per year during treatment.
Patients with asymptomatic new or advanced brain metastases (active brain metastases) are eligible to participate if the treating physician determines that localized treatment is not required.
Exclusion criteria
Exit criteria:
Primary purpose
Allocation
Interventional model
Masking
20 participants in 3 patient groups
Loading...
Central trial contact
Liliya Baboshkina; Evgeny Imyanitov
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal