Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations (NТО-RAS)

January 19, 2024 updated by: Baboshkina Liliya Sergeevna, N.N. Petrov National Medical Research Center of Oncology

New Therapeutic Approaches for Tumors With RAS Gene Mutations

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

20

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Russian Federation
      • Saint Petersburg, Russian Federation
        • Recruiting
        • Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint Petersburg, Russian Federation
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Non-Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group 1
Leflunomide
Drug: Leflunomide
100 mg daily for 3 days at the loading dose, then 20 mg daily at the standard dose.
Experimental: Group 2
Combination of MEK Inhibitor and Hydroxychloroquine ( Plaquenil)
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.
No Intervention: historical control group
standard therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective response rate
Time Frame: at the end of 2 cycles of treatment (each cycle is 28 days)
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
at the end of 2 cycles of treatment (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assessment of patients' quality of life
Time Frame: at the end of 2 cycles of treatment (each cycle is 28 days)
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.
at the end of 2 cycles of treatment (each cycle is 28 days)
Progression-free survival (PFS)
Time Frame: at the end of 2 cycles of treatment (each cycle is 28 days)
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.
at the end of 2 cycles of treatment (each cycle is 28 days)
Overall survival
Time Frame: up to 3 years
Overall survival was defined as the time from start treatment to subsequent death, measured in weeks and months.
up to 3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

N.N. Petrov National Medical Research Center of Oncology

Investigators

  • Study Director: Evgeny Imyanitov, N.N. Petrov NMRC of Oncology

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 3, 2023

Primary Completion (Estimated)

October 1, 2026

Study Completion (Estimated)

October 1, 2026

Study Registration Dates

First Submitted

December 21, 2023

First Submitted That Met QC Criteria

January 19, 2024

First Posted (Estimated)

January 29, 2024

Study Record Updates

Last Update Posted (Estimated)

January 29, 2024

Last Update Submitted That Met QC Criteria

January 19, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • LS01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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