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

NCT06229340 | Recruiting Phase 2

• 1 other identifier: LS01
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Objective response rate

  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 Outcomes (3)

• Assessment of patients' quality of life

  at the end of 2 cycles of treatment (each cycle is 28 days)

• Progression-free survival (PFS)

  at the end of 2 cycles of treatment (each cycle is 28 days)

• Overall survival

  up to 3 years

Study Arms (3)

Group 1

EXPERIMENTAL

Leflunomide

Drug: Leflunomide

Group 2

EXPERIMENTAL

Combination of MEK Inhibitor and Hydroxychloroquine ( Plaquenil)

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

historical control group

NO INTERVENTION

standard therapy

Interventions

Leflunomide DRUG

100 mg daily for 3 days at the loading dose, then 20 mg daily at the standard dose.

Group 1

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

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.

Group 2

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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:

You may not qualify if:

• Age over 85 years.
• Рresence of acute or active chronic infections.
• Impaired renal and hepatic function; - left ventricular ejection fraction (LVEF) \< 45%
• Known history of acute or chronic hepatitis B or C due to known potential hepatotoxicity of leflunomide.
• History of allergic reactions associated with compounds similar in chemical or biological composition to leflunomide or teriflunomide or other drugs in the combination.
• 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.
• Patients should not be pregnant or breastfeeding due to the potential for teratogenic effects and side effects of planned chemotherapeutic regimens.
• 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:
• Refusal to continue participation in the study.
• Intolerable toxicity.
• 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.
• Non-compliance with IND procedures.

Sponsors & Collaborators

• N.N. Petrov National Medical Research Center of Oncology: lead

Study Sites (1)

Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint Petersburg, Russian Federation

Saint Petersburg, Russia

RECRUITING

MeSH Terms

Conditions

Pancreatic Neoplasms; Lung Neoplasms; Melanoma; Neoplasms; Colorectal Neoplasms

Interventions

Leflunomide; Bevacizumab

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Evgeny Imyanitov

  N.N. Petrov NMRC of Oncology

  STUDY DIRECTOR

Central Study Contacts

Evgeny Imyanitov

CONTACT

+79013023707; evgeny@imyanitov.spb.ru

Liliya Baboshkina

CONTACT

+79869932745; lilya_baboshkina@mail.ru

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Oncologist

Study Record Dates

• First Submitted: December 21, 2023
• First Posted: January 29, 2024
• Study Start: October 3, 2023
• Primary Completion (Estimated): October 1, 2026
• Study Completion (Estimated): October 1, 2026
• Last Updated: January 29, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

RU (1)