Selumetinib + APG-115 for Neurofibromatosis

(MEKMDM2 Trial)

Overseen By Rachel E Reed, MS

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AeRang Kim

Must not be taking: Immunosuppressants, Herbal supplements

Disqualifiers: Other cancer, Major surgery, Hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

45 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial requires that you stop taking any other anti-cancer therapies and certain herbal supplements or medications that affect specific liver enzymes at least 14 days before starting the study. If you are on immunosuppressive medications, you must stop them 14 days prior to the study, with some exceptions for low-dose or specific types of steroids.

What data supports the effectiveness of the drug Selumetinib for treating neurofibromatosis?

Selumetinib has been shown to be effective in treating children with neurofibromatosis type 1 who have inoperable plexiform neurofibromas, with a 66% response rate in a clinical trial. Many patients experienced improvements in symptoms and functional impairments, and the benefits were considered favorable compared to the risks. ^{1 2 3 4 5}

Is the combination of Selumetinib and APG-115 safe for humans?

Selumetinib has been approved for use in children with neurofibromatosis type 1 and has known side effects like eye, heart, muscle, stomach, and skin issues, which are common for its drug class. Safety data for APG-115 (Alrizomadlin) specifically in combination with Selumetinib is not provided, but Selumetinib's safety has been evaluated in various trials. ^{1 2 3 4 6}

What makes the drug Selumetinib unique for treating neurofibromatosis?

Selumetinib is unique because it is an oral drug specifically approved for children with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas, and it works by targeting the MAPK pathway, which is involved in cell growth and division. It has shown a significant response rate in reducing tumor size and improving symptoms, making it a novel option for patients with limited treatment choices. ^{1 2 3 5 7}

What is the purpose of this trial?

This is a phase 0/1/2, multi-site study to evaluate the MEK inhibitor Selumetinib with the MDM2 Inhibitor APG-115 in patients with Neurofibromatosis Type 1 and pre-malignant and malignant peripheral nerve sheath tumors

Research Team

AeRang Kim, MD, PhD

Principal Investigator

Children's National Research Institute

Eligibility Criteria

This trial is for patients with Neurofibromatosis Type 1 (NF1) and those who have benign or malignant tumors on their peripheral nerves. Participants should meet specific health criteria not detailed here.

Inclusion Criteria

My cancer has worsened after chemotherapy, and surgery is planned.

My blood, liver, kidney, and heart are functioning within normal ranges.

Fertile men and women of childbearing potential must agree to use an effective method of birth control

Exclusion Criteria

I have had cancer before, but it fits the exceptions.

I have eye conditions.

Currently pregnant or breastfeeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Determine the safety, tolerability, pharmacokinetics, and recommended doses of selumetinib and APG-115

15 months

Treatment Part B

Determine the clinical benefit of selumetinib and APG-115 by evaluating tumor response by imaging

28 months

Treatment Part C

Evaluate the percent apoptosis and tumor proliferation in resected tumor tissue after exposure to selumetinib and APG-115

12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Treatment Details

Interventions

• APG-115
• Selumetinib

Trial Overview The study tests the combination of two drugs, Selumetinib (a MEK inhibitor) and APG-115 (an MDM2 inhibitor), to see how they work together in treating NF1-related nerve tumors.

Participant Groups

Group I: APG-115 and Selumetinib Experimental Treatment 2 Interventions

There is only one arm. It is combination therapy of APG-115 and Selumetinib.

Who Is Running the Clinical Trial?

AeRang Kim

Lead Sponsor

Trials

3

Recruited

50+

Children's National Research Institute

Collaborator

Trials

227

Recruited

258,000+

Findings from Research

A Phase I study involving 24 healthy male volunteers evaluated a new granule formulation of selumetinib, showing that its absorption is comparable to the existing capsule form, making it a potential alternative for younger patients or those who have difficulty swallowing capsules.

The study found that the granule formulation was well-tolerated with low incidence of mild adverse events, and participants rated its palatability positively, indicating they would be willing to take it again.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib. Cohen-Rabbie, S., Mattinson, A., So, K., et al.[2022]

Selumetinib (KOSELUGO) was approved by the FDA for treating pediatric patients aged 2 and older with inoperable plexiform neurofibromas, showing a 66% overall response rate in a trial of 50 patients, with many experiencing significant symptom relief for at least 12 months.

While selumetinib is effective, it carries risks typical of MEK inhibitors, including potential ocular, cardiac, and gastrointestinal side effects, but the overall benefit-risk assessment is considered favorable for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma. Casey, D., Demko, S., Sinha, A., et al.[2022]

Selumetinib, a MEK inhibitor, has shown significant efficacy in treating plexiform neurofibromas in patients with neurofibromatosis type 1, with 68% of 50 symptomatic patients experiencing a partial response and a median tumor volume reduction of 27.9%.

The treatment demonstrated a favorable safety profile, with manageable adverse effects, and resulted in an 84% estimated progression-free survival at 3 years, marking it as the first FDA-approved therapy for inoperable plexiform neurofibromas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas. Anderson, MK., Johnson, M., Thornburg, L., et al.[2022]

In a clinical trial, the MEK inhibitor selumetinib showed promising results, inducing partial responses in 70% of children with neurofibromatosis type 1 and inoperable plexiform neurofibromas.

The treatment demonstrated a high progression-free survival rate of 84% after 3 years, indicating its potential efficacy in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selumetinib Shrinks Tumors in Neurofibromatosis. [2021]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Selumetinib: First Approval. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

A Phase I, Open-label, Randomized, Crossover Study of the Relative Bioavailability of Capsule and Granule Formulations of Selumetinib. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Selumetinib for plexiform neurofibromas in neurofibromatosis type 1: a single-institution experience. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Selumetinib Shrinks Tumors in Neurofibromatosis. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Selumetinib in Japanese pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas: An open-label, phase I study. [2023]