Abemaciclib for Neurofibroma

Overseen By Amanda M Carbonell

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Strong CYP3A inhibitors

Disqualifiers: Pregnancy, Serious medical conditions, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

55 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: NF1 is a genetic disease that causes tumors called atypical neurofibromas. These tumors, which arise from nerves, can cause serious medical problems. The only treatment is surgery. Researchers want to see if a drug called abemaciclib can help. Objective: To find a safe, tolerable dose of abemaciclib for treating atypical neurofibromas. Eligibility: People ages 12 and older who have NF1 and have one or more atypical neurofibromas that cannot or will not be removed with surgery Design: Participants will be screened with: Medical history and physical exam Blood, urine, and heart tests MRI: Participants will lie in a machine that takes pictures of the body. A padding or coil will be placed around their head. They may have a contrast agent injected into a vein. Biopsy sample: A small piece of tumor will be removed using a large needle. Participants will have frequent visits during the study. These will include repeats of the screening tests as well as the following: PET scan: Participants will lie in a machine that takes pictures of the body. They will have a contrast agent injected into their arm. Questionnaires about the effects of abemaciclib on pain and quality of life Possible photographs of tumors Participants will take abemaciclib capsules orally twice daily in 28-day cycles. They will take the drug for up to 2 years. Some may be able to take it for longer. Participants will have a follow-up visit about 30 days after their last dose of the study drug. Then they will have visits every 3 months for 1 year.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you require treatment with strong CYP3A inhibitors or inducers, as these can interact with the study drug, abemaciclib.

How is the drug Abemaciclib different from other treatments for neurofibroma?

Abemaciclib is unique because it is a CDK4/6 inhibitor, which means it targets specific proteins involved in cell division, potentially offering a novel approach for treating neurofibromas compared to other treatments like MEK inhibitors or tyrosine kinase inhibitors that have been used for similar conditions. ^{1 2 3 4 5}

Research Team

Andrea M Gross, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

This trial is for individuals aged 12 or older with Neurofibromatosis Type I (NF1) and at least one inoperable tumor measuring over 3 cm. Participants must not be pregnant, agree to use effective contraception, have no severe allergies to abemaciclib, and should not require certain other medications that could interfere with the study drug.

Inclusion Criteria

I can take care of myself but may not be able to do active work.

I have a neurofibroma or plexiform neurofibroma.

My blood, liver, kidney, and heart are functioning well.

Exclusion Criteria

I have interstitial lung disease.

I have a history of fainting due to heart issues, irregular heartbeats, or sudden cardiac arrest.

I need medication that strongly affects liver enzymes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Phase 0

Participants receive abemaciclib for 7-10 days prior to tumor resection to determine pharmacodynamic effects

1-2 weeks

1 visit (in-person)

Phase I/II Treatment

Participants receive abemaciclib orally twice daily in 28-day cycles to determine the recommended Phase II dose and objective response rate

Up to 2 years

Frequent visits including MRI and toxicity monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Visits every 3 months

Treatment Details

Interventions

• Abemaciclib

Trial Overview The trial is testing the safety and tolerability of a drug called abemaciclib for treating atypical neurofibromas associated with NF1. Patients will take this medication orally twice daily in cycles of 28 days for up to two years, possibly longer.

Participant Groups

Group I: 2/ Phase II Objective Response Rate Experimental Treatment 1 Intervention

Abemaciclib orally twice daily at the RP2D

Group II: 1/ Phase I Dose Escalation Experimental Treatment 1 Intervention

Abemaciclib orally twice daily at escalating doses to determine the MTD/RP2D

Abemaciclib is already approved in United States, European Union for the following indications:

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

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]

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]

Cantharidin, a protein phosphatase 2A (PP2A) inhibitor, was found to effectively slow down the growth of malignant peripheral nerve sheath tumor (MPNST) cells in patients with neurofibromatosis type 1 (NF1).

Nifedipine, an L-type calcium channel blocker, significantly reduced local tumor growth in an animal model of MPNST, suggesting that both Cantharidin and Nifedipine could be promising candidates for further preclinical studies in treating NF1-related tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1. Semenova, G., Stepanova, DS., Deyev, SM., et al.[2018]

In a phase II clinical trial involving 19 patients with Neurofibromatosis type 1 (NF1) and progressive plexiform neurofibromas (PNs), cabozantinib demonstrated efficacy, with 42% of participants achieving a partial response, defined as a ≥20% reduction in tumor volume after 12 cycles of treatment.

Cabozantinib was associated with significant reductions in tumor pain intensity and interference in daily life, although common adverse events included gastrointestinal issues and fatigue, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. Fisher, MJ., Shih, CS., Rhodes, SD., et al.[2023]

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]

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

3. France pubmed.ncbi.nlm.nih.gov

Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1. [2018]

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

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. [2023]

5. England pubmed.ncbi.nlm.nih.gov

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