What is the mechanism of action of this treatment?

The RAF/MEK/ERK signaling pathway is essential for cell division and survival, and its dysregulation is commonly associated with cancer. RAF kinase inhibitors, like lifirafenib, inhibit RAF proteins, preventing the activation of downstream MEK and ERK proteins. MEK inhibitors, such as mirdametinib, directly inhibit MEK proteins, blocking the pathway further. This dual inhibition can effectively reduce tumor cell proliferation and growth, making it a promising treatment strategy for patients with solid tumors.

What side effects are associated with this type of intervention?

Treatments for solid tumors that target the RAF/MEK/ERK signaling pathway, such as RAF kinase inhibitors (e.g., lifirafenib) and MEK inhibitors (e.g., mirdametinib), commonly cause side effects including skin rash, diarrhea, fatigue, and hypertension. Additionally, MEK inhibitors may lead to peripheral edema and ocular toxicity. Both drug classes can also pose risks of cardiotoxicity, requiring careful patient monitoring.

What prior FDA approvals exist?

The FDA has approved several treatments targeting the RAF/MEK/ERK signaling pathway for solid tumors. Notably, dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) have been approved for the treatment of BRAF V600E-mutated melanoma. This combination has shown significant efficacy in targeting the RAF/MEK/ERK pathway, similar to the investigational combination of BGB-283 (lifirafenib) and PD-0325901 (mirdametinib). These approvals underscore the therapeutic potential of targeting this pathway in various solid tumors.

What other types of research exist?

Promising alternatives to the combination of BGB-283 (lifirafenib) and PD-0325901 (mirdametinib) for solid tumors include: 1) Dabrafenib plus Trametinib, which targets BRAFV600E mutations and has shown efficacy in various solid tumors. 2) FGFR inhibitors like Infigratinib and Futibatinib, which have shown promising results in cholangiocarcinoma and other FGFR-altered tumors. 3) Immune checkpoint inhibitors such as anti-PD-1/PD-L1 therapies, which have shown efficacy in various solid tumors and are being explored in combination with other targeted therapies.

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Kinase Inhibitor

Lifirafenib + Mirdametinib for Cancer

Phase 1

Recruiting

Research Sponsored by BeiGene

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Eastern Cooperative Oncology Group performance status of less than or equal to 1

Advanced or metastatic, unresectable tumors (other than patients with tumors of the brain or central nervous system) who have experienced disease progression

Must not have

Hemorrhage or bleeding event at NCI-CTCAE v5.0 Grade 3 or higher within 28 days of first dose

LVEF less than 50%

Timeline

Screening 3 weeks

Treatment Varies

Follow Up approximately 2 years from date of the participants enrollment

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a combination of two experimental drugs, lifirafenib and mirdametinib, in people with tumors. The goal is to see if these drugs can work together to stop or slow down tumor growth by blocking signals that cancer cells need to grow.

Who is the study for?

Adults with advanced solid tumors who can provide a tumor sample and consent, have a life expectancy over 12 weeks, measurable disease per RECIST 1.1, good performance status (ECOG ≤1), adequate organ function, and agree to use contraception can join. Exclusions include CNS metastasis, certain heart conditions, abnormal QT interval on ECG, active liver disease or infections like HIV/Hepatitis B/C.

What is being tested?

The trial is testing the combination of two drugs: Lifirafenib (BGB-283) and Mirdametinib (PD-0325901) in adults with various types of advanced solid tumors. It's designed to assess safety and how the body processes these drugs.

What are the potential side effects?

Potential side effects may include typical reactions seen with cancer treatments such as fatigue, nausea, skin rash or other allergic reactions. Specific risks related to Lifirafenib or Mirdametinib will be monitored based on their known profiles.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I can carry out all my self-care but cannot do heavy physical work.

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My cancer has spread, cannot be surgically removed, and is getting worse.

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I am a male who is either vasectomized or agrees to use contraception.

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I can provide previous tumor samples or agree to a new biopsy.

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I am at least 18 years old or of legal age in my area to consent.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I haven't had severe bleeding in the last 28 days.

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My heart's pumping ability is below normal.

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My cancer has spread to my brain.

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I haven't had major surgery or serious injuries in the last 4 weeks and don't expect to need major surgery during the study.

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I had to stop taking certain cancer drugs due to severe side effects.

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I have not received a live vaccine in the last 4 weeks, except for flu and COVID-19 shots.

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I have a severe illness that is not under control.

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I do not have an active or known history of significant liver disease.

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I have an eye condition that could lead to central vision loss.

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I have a history of bleeding disorders, including Von Willebrand disease.

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I cannot swallow pills.

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I have a parathyroid disorder or had cancer-related high calcium levels.

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I have a history of glaucoma.

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I am not taking any strong medications that affect liver enzymes.

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I haven't had radiation or certain cancer treatments in the last 4 weeks.

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I am HIV positive.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ approximately 2 years from date of the participants enrollment

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~approximately 2 years from date of the participants enrollment

This trial's timeline: 3 weeks for screening, Varies for treatment, and approximately 2 years from date of the participants enrollment for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Adverse Events and Serious Adverse Events

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Group I: Part B: ExpansionExperimental Treatment2 Interventions

Approximately 20 participants with NRAS mutated solid tumors will be enrolled

Group II: Part A: Dose Escalation/Dose finding Dose Level Cohorts ranging in dose levels and dose regimens.Experimental Treatment2 Interventions

Combination doses of, Mirdametinib at once a day and lifirafenib at once a day And Mirdametinib at twice a day and lifirafenib at once a day

0 / 21Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The RAF/MEK/ERK signaling pathway is essential for cell division and survival, and its dysregulation is commonly associated with cancer. RAF kinase inhibitors, like lifirafenib, inhibit RAF proteins, preventing the activation of downstream MEK and ERK proteins. MEK inhibitors, such as mirdametinib, directly inhibit MEK proteins, blocking the pathway further. This dual inhibition can effectively reduce tumor cell proliferation and growth, making it a promising treatment strategy for patients with solid tumors.