Mirdametinib for Neurofibromatosis

(Mirda Trial)

Overseen By Joshua Roberts

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Johns Hopkins University

Must not be taking: MEK inhibitors, Glucocorticoids

Disqualifiers: Liver disease, Glaucoma, HIV, others

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

Compensation: Varies

Number of Visits: 2

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 1/2a, open-label, non-randomized, multi-dose study of mirdametinib monotherapy in adults with NF1 and cNF. In both Phases of the study, participation in the study will comprise three periods: screening, treatment and post-study safety follow-up to be performed at the NF1 and cNF specialty center: Johns Hopkins University.

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

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently receiving certain treatments like systemic glucocorticoids or specific enzyme inducers within 14 days before the study starts.

What data supports the effectiveness of the drug Mirdametinib for treating Neurofibromatosis?

Research shows that Mirdametinib, a MEK inhibitor, has been effective in reducing the size of plexiform neurofibromas in patients with Neurofibromatosis type 1. Similar drugs like Selumetinib have shown positive results, leading to FDA approval, and Mirdametinib has also proven its efficacy in adults. ^{1 2 3 4 5}

Is Mirdametinib safe for humans?

Mirdametinib, a MEK inhibitor, has been studied for safety in patients with neurofibromatosis type 1 and inoperable plexiform neurofibromas. While specific safety data for Mirdametinib is limited, similar drugs in the same class, like selumetinib, have shown risks including eye, heart, muscle, stomach, and skin issues, but these are generally manageable. ^{1 2 3 6 7}

How is the drug Mirdametinib different from other treatments for neurofibromatosis?

Mirdametinib is a MEK inhibitor that targets a specific pathway involved in tumor growth, making it effective for treating inoperable plexiform neurofibromas in neurofibromatosis type 1. Unlike some other treatments, it has shown positive results in adults, expanding options beyond the FDA-approved selumetinib, which is primarily used in children. ^{1 2 3 5 8}

Research Team

Carlos Romo, MD

Principal Investigator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Eligibility Criteria

Adults over 18 with Neurofibromatosis type 1 (NF1) and at least 12 measurable cutaneous neurofibromas (cNF). They must have a certain level of overall health, including specific blood cell counts and performance status. Participants need to be able to undergo tumor biopsies.

Inclusion Criteria

I have at least 24 measurable skin growths, with 2 areas having at least 6 each.

My eligible neurofibromas are in the study's specified areas or can be biopsied if outside those areas.

I can carry out normal activities with minimal symptoms.

Exclusion Criteria

I have had a heart problem in the last 6 months.

I have a history of eye problems related to the retina.

I have a condition that affects how my body absorbs medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment Phase 1

Participants receive mirdametinib in multiple dose regimens to identify the recommended phase 2 dose (RP2D). Treatment is administered continuously or intermittently in 28-day cycles.

Up to 24 cycles (28 days each)

Monthly visits (in-person)

Treatment Phase 2a

Participants receive mirdametinib at the RP2D to evaluate efficacy and safety. Treatment continues until disease progression, intolerance, or completion of 24 cycles.

Up to 24 cycles (28 days each)

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment ends. The study ends 30 days after the last dose.

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Mirdametinib

Trial Overview The trial is testing Mirdametinib as a single-agent therapy for adults with NF1 and cNF. It's an open-label study, meaning both doctors and patients know what treatment is being given, conducted in multiple doses across three phases: screening, treatment, and follow-up.

Participant Groups

Group I: Phase 2 Experimental Treatment 1 Intervention

For the Phase 2 portion, treatment will be administered based on recommended RP2D from Phase 1. All participants will receive study drug until: 1. cessation of study treatment due to death, intolerance, or withdrawal of consent from the study; 2. completion of 24 cycles of treatment (unless the investigator's benefit-risk assessment supports continued treatment; 3. disease progression; or 4. Investigator's decision. Treatment period ends with the administration of the last dose. The study ends 30 days after the last dose.

Group II: Phase 1 Experimental Treatment 1 Intervention

For the Phase 1 portion, treatment will be administered continuously (Dose regimens 1, 2, 4) or intermittently (Dose regimen 3; 3 weeks on/1 week off) in 28-day cycles). All participants will receive study drug until: 1. cessation of study treatment due to death, intolerance, or withdrawal of consent from the study; 2. completion of 24 cycles of treatment (unless the investigator's benefit-risk assessment supports continued treatment); 3. participants enroll in the phase 2a portion of the study; 4. disease progression; or 5. Investigator's decision. Treatment period ends with the administration of the last dose. The study ends 30 days after the last dose

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Neurofibromatosis Therapeutic Acceleration Program

Collaborator

Trials

3

Recruited

600+

SpringWorks Therapeutics, Inc.

Industry Sponsor

Trials

14

Recruited

900+

Findings from Research

In a phase II trial involving 19 patients with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs), the MAPK/ERK kinase inhibitor mirdametinib showed a 42% partial response rate after 12 courses, indicating its efficacy in reducing tumor size.

Patients reported significant and durable decreases in pain, suggesting that mirdametinib not only affects tumor volume but also improves quality of life for those suffering from NF1-related PNs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. Weiss, BD., Wolters, PL., Plotkin, SR., 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]

Selumetinib, a MEK inhibitor, has shown a remarkable overall response rate of 68% in children with neurofibromatosis type 1 (NF1) and symptomatic inoperable plexiform neurofibromas (PNs), leading to its FDA approval in May 2020.

Other targeted therapies, including cabozantinib and mirdametinib, have also demonstrated efficacy in adults with NF1, indicating a growing range of treatment options for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review. Solares, I., Viñal, D., Morales-Conejo, M., et al.[2021]

Selumetinib, a MEK inhibitor, is the first FDA-approved targeted therapy for neurofibromatosis type 1 (NF1), showing efficacy in treating inoperable plexiform neurofibromas, which are common and problematic tumors in NF1 patients.

Research into NF1 has advanced with better understanding of genetic and signaling pathways, leading to promising developments in combination therapies and new animal models that could enhance treatment options for other NF1-related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurofibromatosis in the Era of Precision Medicine: Development of MEK Inhibitors and Recent Successes with Selumetinib. Galvin, R., Watson, AL., Largaespada, DA., et al.[2022]

A high-throughput drug sensitivity platform was used to analyze tumor cell lines from patients with Neurofibromatosis type 1 (NF1) and type 2 (NF2), revealing that NF1-associated tumors are particularly sensitive to MEK and ERK inhibitors.

The platform effectively predicted the outcomes of clinical trials for treating neurofibromas, suggesting it could be a valuable tool for developing targeted therapies for NF-related tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive pharmacological profiling of neurofibromatosis cell lines. Guo, J., Grovola, MR., Xie, H., et al.[2020]

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]

A young patient with neurofibromatosis type 1 (NF1) and recurrent glioblastoma showed a partial response to the MEK-inhibitor trametinib, but experienced significant cutaneous toxicity as a side effect.

Adding the BRAF-inhibitor dabrafenib to the treatment regimen helped alleviate the skin-related side effects, leading to a durable complete response and improved tolerance to the overall treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durable Complete Response of a Recurrent Mesencephalic Glioblastoma Treated with Trametinib and Low-Dose Dabrafenib in a Patient with Neurofibromatosis Type 1. Awada, G., Serruys, D., Schwarze, JK., et al.[2020]

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

NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. [2022]

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

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

3. England pubmed.ncbi.nlm.nih.gov

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review. [2021]

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

Neurofibromatosis in the Era of Precision Medicine: Development of MEK Inhibitors and Recent Successes with Selumetinib. [2022]

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

Comprehensive pharmacological profiling of neurofibromatosis cell lines. [2020]

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

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

7. Switzerland pubmed.ncbi.nlm.nih.gov

Durable Complete Response of a Recurrent Mesencephalic Glioblastoma Treated with Trametinib and Low-Dose Dabrafenib in a Patient with Neurofibromatosis Type 1. [2020]

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

Selumetinib Shrinks Tumors in Neurofibromatosis. [2021]