What side effects are associated with this type of intervention?

Common treatments for melanoma, particularly enzyme inhibitors like binimetinib and encorafenib, often cause side effects such as skin rash, diarrhea, fatigue, and nausea. More severe side effects can include liver toxicity, heart issues, and eye problems. These side effects are typical of targeted therapies that inhibit specific enzymes involved in tumor growth.

What prior FDA approvals exist?

The FDA has approved several enzyme inhibitors for the treatment of melanoma, particularly those targeting the BRAF and MEK pathways. Notable approvals include vemurafenib and dabrafenib, both BRAF inhibitors, and trametinib, a MEK inhibitor. These drugs have shown efficacy in treating BRAF V600 mutation-positive melanoma. The combination of BRAF and MEK inhibitors, such as dabrafenib with trametinib, has also been approved to improve outcomes by targeting different points in the same pathway. These treatments are similar to the investigational combination of binimetinib and encorafenib, which are being studied for their potential to inhibit tumor growth by blocking specific enzymes needed for cell proliferation.

What other types of research exist?

Promising alternatives to Binimetinib and Encorafenib for melanoma patients include: 1) Pembrolizumab and Nivolumab (PD-1 inhibitors), which have shown significant efficacy in melanoma treatment. 2) Combination therapies like Ipilimumab (CTLA-4 inhibitor) with Nivolumab. 3) Targeted therapies such as Dabrafenib and Trametinib for patients with BRAFV600E mutations. These treatments have demonstrated effectiveness in clinical trials and are expected to remain relevant in 2024.

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Kinase Inhibitor

Binimetinib + Encorafenib for Melanoma

Q: What is the mechanism of action of this treatment?

The most common treatments for melanoma, particularly those involving enzyme inhibition, include BRAF and MEK inhibitors like binimetinib and encorafenib. These drugs work by targeting specific enzymes that are involved in the growth and proliferation of melanoma cells. BRAF inhibitors block the activity of the mutated BRAF protein, which is present in about half of melanomas and drives tumor growth. MEK inhibitors, on the other hand, target the MEK enzyme, which is part of the same signaling pathway as BRAF. By inhibiting these enzymes, these treatments can effectively slow down or stop the growth of melanoma cells. This is crucial for melanoma patients as it can lead to better control of the disease, potentially prolonging survival and improving quality of life.

Phase 2

Recruiting

Led By Isabella C Glitza

Research Sponsored by M.D. Anderson Cancer Center

Eligibility Criteria Checklist

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

Must have

Age >= 18 years at the time of informed consent

Presence of BRAFV600 mutation in tumor tissue previously determined by a local assay (including immunohistochemistry [IHC]) at any time prior to Screening or during Screening

Must not have

Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, the following: History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to screening Congestive heart failure requiring treatment (New York Heart Association grade >= 2) A left ventricular ejection fraction (LVEF) < 50% as determined by multigated acquisition (MUGA) or echocardiogram (ECHO) History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia) Baseline Fridericia's correction formula (QTcF) interval >= 480 msec. Can be repeated up to three times to confirm Concurrent neuromuscular disorder (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) Impairment of gastrointestinal function or disease which may significantly alter the absorption of study treatment (e.g., uncontrolled nausea, vomiting or diarrhea; malabsorption syndrome; small bowel resection). Known history of acute or chronic pancreatitis History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease Use of herbal supplements, medications or foods that are moderate or strong inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 =< 1 week prior to the start of study treatment History of a thromboembolic event < 12 weeks prior to starting study treatment. Examples of thromboembolic events include transient ischemia attack, cerebrovascular accident, deep vein thrombosis or pulmonary embolism. Catheter-related venous thrombosis is not considered a thromboembolic event for this trial even if < 12 weeks prior to starting study treatment. Note: Patients with either deep vein thrombosis or pulmonary emboli that do not result in hemodynamic instability are allowed to enroll as long as they are stable, asymptomatic and on stable anticoagulants for at least 2 weeks. Additionally, patients with thromboembolic events related to indwelling catheters or other procedures may be enrolled Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection NOTE: Patients with laboratory evidence of cleared HBV or HCV infection may be enrolled NOTE: Patients with no prior history of HBV infection who have been vaccinated against HBV and who have a positive antibody against hepatitis B surface antigen as the only evidence of prior exposure may enroll Pregnancy or breastfeeding or patients who plan to become pregnant during the duration of the study Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 3 years

Awards & highlights

No Placebo-Only Group

Summary

This trial studies how well binimetinib and encorafenib work in patients with melanoma that has spread to the brain. These medications may help stop cancer growth by blocking important enzymes. The trial focuses on patients with a specific mutation (BRAFV600) whose cancer has spread to critical areas. Encorafenib and binimetinib are FDA-approved for treating metastatic melanoma with BRAFV600 mutations.

Who is the study for?

Adults with metastatic melanoma that has spread to the brain, including those who have previously received FDA-approved BRAF inhibitors. Participants must have a specific BRAFV600 mutation and be in good enough health as determined by certain lab parameters. Pregnant or breastfeeding individuals are excluded, as well as those with significant heart conditions, infections, gastrointestinal impairments, or a history of certain blood clots.

What is being tested?

The trial is testing binimetinib and encorafenib's effectiveness on melanoma that has reached the central nervous system. These drugs aim to halt tumor growth by inhibiting key enzymes. The study includes patients who've had prior treatments and those new to these medications.

What are the potential side effects?

Potential side effects may include fatigue, skin reactions, vision changes due to eye problems like retinal vein occlusion (RVO), liver enzyme elevations indicating potential liver damage, muscle pain or weakness from neuromuscular issues, high blood pressure, bleeding events and clotting disorders.

Eligibility Criteria

Inclusion Criteria

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

Select...

I am 18 years old or older.

Select...

My tumor has the BRAFV600 mutation.

Select...

Your blood tests need to show specific levels for things like white blood cells, hemoglobin, and platelets. Your liver and kidney function also need to be within certain limits. If you can become pregnant, you need to have a negative pregnancy test and agree to use birth control during the study. You also need to be able to keep up with your doctor visits and treatment plan.

Select...

I have brain metastases but no leptomeningeal disease.

Select...

I can take care of myself but might not be able to do heavy physical work.

Select...

I have a brain tumor between 0.5 and 3 cm that is getting worse.

Select...

My cancer has spread to the lining of my brain or spinal cord, confirmed by scans or tests.

Select...

My diagnosis of melanoma is confirmed through tissue examination.

Select...

I am taking 4 mg or less of dexamethasone daily for LMD, or just enough for adrenal insufficiency.

Select...

I have melanoma with a BRAF V600 mutation and it has spread to my brain.

Exclusion Criteria

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

Select...

I do not have significant heart issues, recent serious heart events, uncontrolled heart rhythm problems, severe eye conditions, recent major blood clots, certain infections like active hepatitis B or C, and I am not pregnant or planning to become pregnant during the study.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 3 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 3 years for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Incidence of adverse events (AEs)

Secondary study objectives

Disease control rate

Duration of response (DOR)

Extracranial response rate

+2 more

Side effects data

From 2022 Phase 3 trial • 702 Patients • NCT02928224

78%

Diarrhoea

68%

Dermatitis acneiform

59%

Nausea

54%

Fatigue

51%

Vomiting

51%

Dry Skin

43%

Pyrexia

43%

Anaemia

41%

Decreased appetite

38%

Abdominal pain

38%

Constipation

35%

Dyspnoea

32%

Vision blurred

30%

Blood creatine increased

30%

Blood creatine phosphokinase increased

24%

Arthralgia

24%

Myalgia

24%

Skin fissures

22%

Back Pain

22%

Dizziness

19%

Malaise

19%

Urinary tract infection

19%

Headache

19%

Aspartate aminotransferase increased

16%

Asthenia

16%

Stomatitis

16%

Oedema peripheral

16%

PPE syndrome

16%

Hypomagnesaemia

16%

Rash maculo-papular

16%

Palmar-planar erythrodysaesthesia

16%

Chills

16%

Paronychia

16%

Rash pustular

16%

Alanine aminotransferase increased

16%

Dysgeusia

16%

Peripheral sensory neuropathy

14%

Cough

14%

Abdominal pain upper

14%

Infusion-related reaction

14%

Ejection fraction decreased

14%

Dry eye

11%

Trichiasis

11%

Pollakiuria

11%

Vitreous floaters

11%

Dyspepsia

11%

Hypoalbuminaemia

11%

Hypertension

11%

Tumour Pain

Rhinitis allergic

Infusion related reaction

Hypokalaemia

Visual impairment

Macular oedema

Hypertrichosis

Iron deficiency

Nasopharyngitis

Weight decreased

Flank pain

Proteinuria

Rash

Pruritus

Pain in extremity

Blood bilirubin increased

Rhinnorrhoea

Hypotension

Pleural effusion

Restless legs syndrome

Musculoskeletal pain

Nervous system disorder

Wound

Trichomegaly

Infection

Hypocalcaemia

Hypophosphataemia

Rectal haemorrhage

Anal haemorrhage

Ascites

Colitis

Abdominal pain lower

Nail disorder

Pruritus generalised

Bone pain

Musculoskeletal chest pain

Chorioretinopathy

Urinary incontinence

Insomnia

Gastroesophageal reflux disease

Abdominal distension

Eczema

Cystitis

Renal failure

Conjunctivitis

Syncope

Dehydration

Dry Mouth

Skin hyperpigmentation

Muscle spasms

Erythema

Retinal detachment

Pulmonary embolism

Dysphonia

Haematuria

Blood creatinine increased

Depression

Palpitations

Rectal hemorrhage

Tumour pain

Melanocytic naevus

Large intestinal ulcer hemorrhage

Upper respiratory tract infection

Urinary tract infection bacterial

Large intestinal ulcer

Kidney infection

Epistaxis

Hyperkeratosis

Streptococcal infection

Alopecia

Skin papilloma

Large intestine perforation

Bacterial sepsis

Cholangitis

Urinary tract obstruction

Confusional state

Device occlusion

Back pain

Rhabdomyolysis

Colon cancer

Sepsis

Acute kidney injury

Large intestine ulcer

Neutropenia

Bacteria sepsis

Hydronephrosis

Neuropathy peripheral

Abdominal abscess

Hyperglycaemia

100%

80%

60%

40%

20%

Study treatment Arm

Combined Safety Lead-in

Phase 3: Triplet Arm

Phase 3: Doublet Arm

Phase 3: Control Arm

Awards & Highlights

No Placebo-Only Group

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

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (encorafenib, binimetinib)Experimental Treatment3 Interventions

Patients receive encorafenib PO QD and binimetinib PO BID on day 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Binimetinib

2018

Completed Phase 3

~1250

Encorafenib

2022

Completed Phase 3

~970

0 / 11Eligibility 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 most common treatments for melanoma, particularly those involving enzyme inhibition, include BRAF and MEK inhibitors like binimetinib and encorafenib. These drugs work by targeting specific enzymes that are involved in the growth and proliferation of melanoma cells. BRAF inhibitors block the activity of the mutated BRAF protein, which is present in about half of melanomas and drives tumor growth. MEK inhibitors, on the other hand, target the MEK enzyme, which is part of the same signaling pathway as BRAF. By inhibiting these enzymes, these treatments can effectively slow down or stop the growth of melanoma cells. This is crucial for melanoma patients as it can lead to better control of the disease, potentially prolonging survival and improving quality of life.

Involution of eruptive melanocytic nevi on combination BRAF and MEK inhibitor therapy.