Using Leflunomide or a Combination of Drugs for Patients with RAS Mutations

New Therapeutic Approaches for Tumors With RAS Gene Mutations

This study is testing if leflunomide alone or in combination with other drugs can help patients with RAS mutations who haven't had success with standard cancer treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years to 85 Years
• Sex: All
• Sponsor: N.N. Petrov National Medical Research Center of Oncology (Academic / other)
• Drugs / interventions: bevacizumab
• Locations: 1 site (Saint Petersburg)
• Trial ID: NCT06229340 on ClinicalTrials.gov

What this trial studies

This study investigates the efficacy of leflunomide and a combination of a MEK inhibitor with hydroxychloroquine, with or without bevacizumab, in patients who have RAS mutations and have not responded to standard treatments. The approach focuses on targeting the RAS signaling pathway, which is often activated in various cancers, including colorectal, pancreatic, and lung cancers. By utilizing existing drugs that may affect the RAS pathway, the study aims to improve therapeutic outcomes for patients with advanced malignancies. Participants will be closely monitored for disease progression and treatment response.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with metastatic cancer and documented RAS mutations who have failed multiple lines of standard therapy.

Not a fit: Patients without RAS mutations or those who have not progressed after standard treatments may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could provide new treatment options for patients with RAS mutations who have limited alternatives.

How similar studies have performed: Other studies have explored targeting the RAS pathway with various agents, showing promise, but this specific combination approach is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Patient is able to provide informed consent and sign approved consent forms to participate in the study.
2. Patient age is at least 18 years old.
3. Performance status Eastern Cooperative Oncology Group (ECOG) 0-2.
4. Histologically confirmed metastatic metastatic disease stage 4.
5. Must have documented RAS (KRAS, HRAS, NRAS) mutation identified within the last 5 years by a local test on tumor tissue.
6. More than 2 lines of standard drug antitumor therapy in the anamnesis.
7. Must have disease progression as defined by RECIST version 1.1 criteria
8. Appropriate hematologic and liver function:

   * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1500/μL)
   * Lymphocyte count ≥ 0.5 x 109/L (500/μL)
   * Platelet count ≥ 100 x 109/L (100,000/μL) without transfusion
   * Hemoglobin ≥ 90 g/L without transfusion.
   * Creatinine clearance ≥ 40 mL/min
   * Serum albumin ≥ 25 g/L (2.5 g/dL)
   * Serum bilirubin ≤ 1.5 x HGH, with the following exception:
   * Patients with known Gilbert's disease or liver metastases: serum bilirubin level ≤ 3 x IUH
   * AST, ALT, and alkaline phosphate ≤ 2.5 x HGN;

10\. 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.

11\. 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:

1. Age over 85 years.
2. Рresence of acute or active chronic infections.
3. Impaired renal and hepatic function; - left ventricular ejection fraction (LVEF) \< 45%
4. Known history of acute or chronic hepatitis B or C due to known potential hepatotoxicity of leflunomide.
5. History of allergic reactions associated with compounds similar in chemical or biological composition to leflunomide or teriflunomide or other drugs in the combination.
6. Uncontrolled intercurrent disease, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmias, or mental illness/social situations that limit study compliance.
7. Patients should not be pregnant or breastfeeding due to the potential for teratogenic effects and side effects of planned chemotherapeutic regimens.
8. History of retinal disease (retinal tear, exudate, hemorrhage) or retinal vein occlusion, central serous retinopathy or retinal pigment epithelium detachment, or current risk factors for ROS (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).

Exit criteria:

1. Refusal to continue participation in the study.
2. Intolerable toxicity.
3. Progression according to RECIST 1.1 and IRECIST criteria or clinically significant (in the opinion of the physician) progression requiring a change in anticancer treatment.
4. Non-compliance with IND procedures.

Where this trial is running

Saint Petersburg

• Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint Petersburg, Russian Federation — Saint Petersburg, Russia (Recruiting)

Study contacts

• Study coordinator: Evgeny Imyanitov

Conditions RAS Mutation; Ras Gene Mutation; Colorectal Cancer Recurrent; Pancreas Cancer; Lung Cancer; Melanoma; Refractory Cancer; Colorectal Cancer