What side effects are associated with this type of intervention?

The most common treatments for Neurofibromatosis, particularly those involving MEK inhibitors like Selumetinib, are associated with several side effects. These include gastrointestinal issues such as nausea, vomiting, and diarrhea, as well as fatigue and skin rashes. Additionally, patients may experience elevated liver enzymes, indicating potential liver toxicity, and hematologic effects such as decreased neutrophil counts and anemia. These side effects are generally manageable but require monitoring and supportive care.

What prior FDA approvals exist?

Selumetinib, a MEK inhibitor, has been approved by the FDA for the treatment of Neurofibromatosis type 1 (NF1) with symptomatic, inoperable plexiform neurofibromas. This approval marks a significant advancement as it is one of the first targeted therapies for NF1. Other treatments under investigation include mTOR inhibitors like everolimus, which have shown promise in clinical trials for managing tumors associated with Neurofibromatosis type 2 (NF2). Bevacizumab, an anti-angiogenic agent, has also been studied for its efficacy in reducing tumor size in NF2-related vestibular schwannomas.

What other types of research exist?

Promising alternatives to Selumetinib for Neurofibromatosis patients include other MEK inhibitors such as Trametinib and Cobimetinib, which have shown efficacy in various tumor types. Additionally, mTOR inhibitors like Everolimus and targeted therapies such as Bevacizumab are being explored for their potential benefits in treating Neurofibromatosis-related tumors.

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Kinase Inhibitor

Selumetinib for Plexiform Neurofibroma

Phase 1

Waitlist Available

Research Sponsored by AstraZeneca

Eligibility Criteria Checklist

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

Must have

Male and female participants aged ≥ 12 to < 18 years at the time of signing the informed consent

Participants must have a BSA ≥ 1.3 and ≤ 2.5 m2

Must not have

Participants who have previously been treated with a MEKi (including selumetinib) and either discontinued treatment or required a dose reduction due to toxicity

Have any unresolved chronic toxicity associated with previous therapy for NF1-PN: Gastrointestinal toxicity of CTCAE Grade 1 or higher; Have any other unresolved chronic toxicity with CTCAE Grade ≥ 2, except hair changes (such as alopecia or hair lightening)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose (cycle 1 day 8 of each treatment period 1, 2 and 3); each treatment period 1 and 2 has 1 cycle (each cycle is 28 days). if needed, treatment period 3 will be started approximately 5 cycles later.

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing how well selumetinib works when taken with a low-fat meal in adolescents with NF1 who have tumors that can't be removed by surgery. The goal is to see if eating a low-fat meal affects how the body absorbs the medication and if it helps reduce stomach-related side effects. Selumetinib is being investigated for its effectiveness in treating NF1-associated tumors, with previous studies showing promising positive results in patients.

Who is the study for?

Adolescents aged 12-17 with Neurofibromatosis Type 1 (NF1) and inoperable Plexiform Neurofibromas (PN), who have symptoms or risk of complications. They must not have had recent major surgery, abnormal eye conditions, significant heart disease, poor liver or kidney function, previous MEKi treatment issues, unresolved toxicity from past treatments for NF1-PN, or any life-threatening illness.

What is being tested?

The trial is testing the drug Selumetinib to see how taking it with a low-fat meal affects its absorption and gastrointestinal side effects in young patients. The goal is to find an effective dose that can be taken with food while maintaining safety and efficacy.

What are the potential side effects?

Selumetinib may cause gastrointestinal issues like nausea or diarrhea when taken without food. Other potential side effects include skin changes, vision problems due to optic nerve damage, fatigue, rash, muscle pain and heart dysfunction.

Eligibility Criteria

Inclusion Criteria

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

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I am between 12 and 17 years old.

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My body surface area is between 1.3 and 2.5 square meters.

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I have NF1 with inoperable PN and meet another NF1 diagnostic criterion.

Exclusion Criteria

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

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I stopped or lowered my MEKi treatment due to side effects.

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I have ongoing side effects from previous NF1-PN treatment, but no severe stomach issues.

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I may have a brain tumor or another cancer needing chemo or radiation.

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I have a serious heart condition as listed in the study details.

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My liver tests are within normal limits, except for Gilbert syndrome.

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My kidney function is reduced, with specific creatinine levels based on my age.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose (cycle 1 day 8 of each treatment period 1, 2 and 3); each treatment period 1 and 2 has 1 cycle (each cycle is 28 days). if needed, treatment period 3 will be started approximately 5 cycles later.

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose (cycle 1 day 8 of each treatment period 1, 2 and 3); each treatment period 1 and 2 has 1 cycle (each cycle is 28 days). if needed, treatment period 3 will be started approximately 5 cycles later.

This trial's timeline: 3 weeks for screening, Varies for treatment, and at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 hours post-dose (cycle 1 day 8 of each treatment period 1, 2 and 3); each treatment period 1 and 2 has 1 cycle (each cycle is 28 days). if needed, treatment period 3 will be started approximately 5 cycles later. for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Assessing change of Gastrointestinal toxicity diary: Modified Bristol Stool Form Scale for Children (mBSFS-C)

Assessing change of Gastrointestinal toxicity diary: Nausea and Vomiting Symptom Rating Scale (adapted from the Children's Cancer and Leukaemia Group)

Gastrointestinal Adverse Events graded by CTCAE Ver 5.0 (Grade 1 to 5)

+3 more

Secondary study objectives

Adverse events(AEs) graded by CTCAE Version 5.0

Area under the concentration-time curve from time zero to time of last measurable concentration (AUClast) of selumetinib and N-desmethyl selumetinib

Maximum Peak plasma concentration (Cmax) of selumetinib and N-desmethyl selumetinib

+2 more

Side effects data

From 2012 Phase 2 trial • 37 Patients • NCT01085214

75%

Diarrhea

50%

Fatigue

47%

Anemia

47%

Rash acneiform

44%

Hypoalbuminemia

44%

Edema, limbs

39%

Aspartate aminotransferase increased

33%

Neutrophil count decreased

33%

White blood cell decreased

31%

Nausea

31%

Vomiting

28%

Platelet count decreased

25%

CPK increased

25%

Hypomagnesemia

22%

Hypertension

19%

Hypophosphatemia

19%

Hyponatremia

19%

Hypocalcemia

19%

Edema, face

17%

Dry skin

17%

Alanine aminotransferase increased

14%

Skin and subcutaneous tissue disorders - Other

14%

Hypokalemia

14%

Creatinine increased

14%

Back pain

14%

Dyspnea

14%

Lymphocyte count decreased

11%

Pain

11%

Fever

11%

Localized edema

11%

Peripheral sensory neuropathy

11%

Hyperkalemia

11%

Dizziness

11%

Abdominal pain

Anorexia

Hypoglycemia

Acute kidney injury

Death, NOS

Periorbital edema

Skin hypopigmentation

Pain in extremity

Cough

Insomnia

Alkaline phosphatase increased

Dry mouth

Sepsis

Hypernatremia

Metabolism and nutrition disorders - Other

Blood and lymphatic system disorders - Other

Renal and urinary disorders - Other

Hypercalcemia

Dehydration

Musculoskeletal and connective tissue disorder - Other, Rhabdomyolysis

Chills

Hypotension

Myalgia

Arthralgia

Upper respiratory infection

Headache

Sinusitis

Generalized muscle weakness

Gastrointestinal disorders - Other

Gastroesophageal reflux disease

Vaginal inflammation

Confusion

Pruritus

Febrile neutropenia

Flu like symptoms

Hepatic failure

Skin infection

Fall

Fracture

Skin and subcutaneous tissue disorders - Other, Angular cheilitis, unilateral

Adult respiratory distress syndrome

Renal and urinary disorders - Other, Acute renal failure

INR increased

100%

80%

60%

40%

20%

Study treatment Arm

AZD6244 (Selumetinib) Treatment

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: selumetinib single armExperimental Treatment1 Intervention

This is a sequential study consisting of a screening period lasting up to 28 days, a 28 day (1 cycle) treatment period (T1) in a fed state, a 7 day washout period, a further 1 cycle treatment period (T2) in a fasted state and an extension to T2 until results from the primary analysis are available. During Treatment Period 1 and 2 all participants will receive selumetinib (25 mg/m2 bid). If a third treatment period (T3) is required, participants will enter a 7 day washout period followed by a treatment period in a fed state at an adjusted dose for 3 cycles.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Selumetinib

2010

Completed Phase 2

~2080

0 / 9Eligibility 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 Neurofibromatosis, particularly those similar to Selumetinib, include MEK inhibitors like Selumetinib and mTOR inhibitors like Everolimus. MEK inhibitors work by blocking the MEK1/2 proteins in the MAPK/ERK pathway, which is often overactive in Neurofibromatosis type 1 and 2, leading to tumor growth. By inhibiting this pathway, MEK inhibitors can reduce tumor size and growth. mTOR inhibitors, on the other hand, target the mTOR pathway, which is involved in cell growth and proliferation. Inhibiting this pathway can also help control tumor growth. These mechanisms are crucial for Neurofibromatosis patients as they offer targeted approaches to manage tumor growth and associated symptoms, potentially improving quality of life and reducing the need for surgical interventions.

Clinical, genetic and pharmacological data support targeting the MEK5/ERK5 module in lung cancer.Targeted Approaches Applied to Uncommon Diseases: A Case of Salivary Duct Carcinoma Metastatic to the Brain Treated with the Multikinase Inhibitor Neratinib.Novel multi-targeted ErbB family inhibitor afatinib blocks EGF-induced signaling and induces apoptosis in neuroblastoma.