RAS MutationPhase 2NТО-RASNCT06229340
Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations
A Phase 2 study testing Leflunomide and The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab in people with RAS Mutation and Ras (Kras or Nras) Gene Mutation, run by N.N. Petrov National Medical Research Center of Oncology at 1 site in Russia.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 85 yearsHealthy volunteers can take part
- Conditions the study is for
- RAS Mutation, Ras (Kras or Nras) Gene Mutation, Colorectal Cancer Recurrent
- What is being tested?
- Leflunomide and The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteRussia
- Study dates
- 3 Oct 2023to 1 Oct 2026
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 85 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
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- 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:
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
Russia1 site, 1 recruiting
- Recruiting
Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, Saint Petersburg, Russian Federation
Saint Petersburg
Liliya Baboshkina, +79869932745, lilya_baboshkina@mail.ru
About this study
Official title: 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.
Read the 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.
- Conditions
- RAS Mutation, Ras (Kras or Nras) Gene Mutation, Colorectal Cancer Recurrent, Pancreas Cancer, Lung Cancer, Melanoma
- Being tested
- Leflunomide, The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab
- Keywords
- RAS Mutation, Ras (Kras or Nras) Gene Mutation, Colorectal Cancer, Pancreas Cancer, Melanoma, Lung Cancer, Refractory Cancer
- Medical subject headings
- Pancreatic Neoplasms, Lung Neoplasms, Melanoma, Neoplasms, Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LeflunomideDrug
100 mg daily for 3 days at the loading dose, then 20 mg daily at the standard dose.
The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumabDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Group 1 | Experimental | Leflunomide Receives: Drug: Leflunomide |
| Group 2 | Experimental | Combination of MEK Inhibitor and Hydroxychloroquine ( Plaquenil) Receives: Drug: The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab |
| historical control group | No intervention | standard therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: at the end of 2 cycles of treatment (each cycle is 28 days)
Secondary outcomes (3)
Assessment of patients' quality of life
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.
Measured: at the end of 2 cycles of treatment (each cycle is 28 days)
Progression-free survival (PFS)
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.
Measured: at the end of 2 cycles of treatment (each cycle is 28 days)
Overall survival
Overall survival was defined as the time from start treatment to subsequent death, measured in weeks and months.
Measured: up to 3 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jan 2024
- Study start3 Oct 2023
- Primary completion1 Oct 2026 (estimated)
- Study completion1 Oct 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for RAS MutationStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- N.N. Petrov National Medical Research Center of Oncology
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Baboshkina Liliya Sergeevna, N.N. Petrov National Medical Research Center of Oncology
- Investigators
- Evgeny Imyanitov, Study director, N.N. Petrov NMRC of Oncology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06229340
- Sponsor's protocol ID
- LS01
- Acronym
- NТО-RAS
- Status last verified
- Jan 2024
- First submitted
- 21 Dec 2023
- Last updated
- 29 Jan 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Jan 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- New Therapeutic Approaches for Tumors With RAS Gene Mutations
- ClinicalTrials.gov ID
- NCT06229340
- Acronym / sponsor ID
- NТО-RAS / LS01
- Conditions
- RAS Mutation, Ras (Kras or Nras) Gene Mutation, Colorectal Cancer Recurrent, Pancreas Cancer, Lung Cancer, Melanoma
- Keywords
- RAS Mutation, Ras (Kras or Nras) Gene Mutation, Colorectal Cancer, Pancreas Cancer, Melanoma, Lung Cancer, Refractory Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 20 participants (estimated)
- Lead sponsor
- N.N. Petrov National Medical Research Center of OncologyUniversity, hospital or other
- Study start
- 3 Oct 2023 (actual)
- Primary completion
- 1 Oct 2026 (estimated)
- Study completion
- 1 Oct 2026 (estimated)
- First posted
- 29 Jan 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Group 1 | Experimental | Drug: LeflunomideLeflunomide |
| Group 2 | Experimental | Drug: The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumabCombination of MEK Inhibitor and Hydroxychloroquine ( Plaquenil) |
| historical control group | No intervention | –standard therapy |
Who may qualify
- Ages
- 18 to 85 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- 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.
Key exclusion criteria (13 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Leflunomide100 mg daily for 3 days at the loading dose, then 20 mg daily at the standard dose. | Drug | Group 1 |
| The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumabUse 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. | Drug | Group 2 |
Primary outcome
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
3 secondary outcomes
Assessment of patients' quality of life
Time frame: 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)
Overall survival
Time frame: up to 3 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jan 2024.
- Individual participant dataSharing planned: No
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RecruitingPhase 3
Study of Zoldonrasib + Chemo of Investigator's Choice vs Placebo + Chemo of Investigator's Choice as First-line Treatment in Metastatic KRAS G12D-mutated Pancreatic Adenocarcinoma ( RASolute 305 )
Pancreatic Cancer, Pancreatic Cancer Metastatic
RecruitingPhase 2
A Phase 2 Study of VS-7375 in Patients With KRAS G12D-Mutated Pancreatic Cancer
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RecruitingPhase 3
Study of Zoldonrasib (RMC-9805) Plus Daraxonrasib (RMC-6236) Versus Gemcitabine and Nab-Paclitaxel as First-Line Treatment in Metastatic KRAS G12D-Mutated Pancreatic Adenocarcinoma
Pancreatic Cancer, Pancreatic Cancer Metastatic
Not yet recruitingPhase 1/2
A Phase Ib/II Study of GFH276 in Combination With Chemotherapy (± Bevacizumab) or Cetuximab in Patients With RAS-mutant Metastatic Colorectal Cancer
CRC
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Evgeny Imyanitov study director
N.N. Petrov NMRC of Oncology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Leflunomide and The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab in people with RAS Mutation and Ras (Kras or Nras) Gene Mutation, run by N.N. Petrov National Medical Research Center of Oncology at 1 site in Russia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 29 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Russia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Evgeny Imyanitov (+79013023707, evgeny@imyanitov.spb.ru), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective response rate (time frame: at the end of 2 cycles of treatment (each cycle is 28 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jan 2024.