Abemaciclib for Neurofibroma

Overseen By Brigitte C Widemann, M.D.

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test abemaciclib, a cancer treatment, to determine a safe and tolerable dose for atypical neurofibromas, nerve-related tumors linked to NF1, a genetic disorder. Currently, surgery is the only treatment for these tumors. The trial seeks participants aged 12 and older with NF1 and one or more atypical neurofibromas that cannot or will not be surgically removed. Participants will take abemaciclib capsules twice daily and attend regular visits for health checks, including MRI and PET scans. The goal is to assess whether abemaciclib can effectively and safely treat these tumors without surgery. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this potentially groundbreaking therapy.

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.

Is there any evidence suggesting that abemaciclib is likely to be safe for humans?

Research has shown that abemaciclib, a drug already approved for some breast cancers, is being tested for safety in treating atypical neurofibromas. The MONARCH trials found that abemaciclib is generally safe for people. Common side effects included diarrhea, tiredness, and a drop in white blood cells, but these were often manageable with dose adjustments or additional care.

Most side effects in these studies were mild to moderate, indicating a good safety profile. This ongoing research aims to find a safe and tolerable dose specifically for atypical neurofibromas. Researchers will closely monitor participants for any side effects, ensuring their safety remains a top priority throughout the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for neurofibromas, which often involve surgery or radiation, Abemaciclib is unique because it is an oral medication that targets specific proteins involved in cell division. This targeted approach allows it to interfere directly with the cancer cell cycle, potentially stopping tumor growth more effectively. Researchers are excited about Abemaciclib because its mechanism of action could offer a less invasive and more precise treatment option for patients with neurofibromas, potentially leading to better outcomes with fewer side effects.

What evidence suggests that abemaciclib might be an effective treatment for neurofibroma?

Studies have shown that abemaciclib can block certain proteins called CDK4/6, which help cells grow and divide. By blocking these proteins, abemaciclib may slow or stop the growth of atypical neurofibromas, tumors related to the genetic condition NF1. This trial will investigate abemaciclib's effectiveness for atypical neurofibromas, with one arm focusing on dose escalation to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and another arm assessing the objective response rate at the RP2D. Early research suggests that combining CDK4/6 inhibitors with other treatments can enhance their effectiveness against tumors. Although direct evidence of abemaciclib's effectiveness for atypical neurofibromas is limited, its success with similar tumors is promising. Researchers hope abemaciclib could offer a non-surgical way to manage these tumors. ^{1 3 4 6 7}

Who Is on the Research Team?

Brigitte C Widemann, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04750928

Cyclin-Dependent Kinase (CDK)4/6 Inhibitor Abemaciclib ... Effect of abemaciclib on CDK4/6 target inhibition, Measurement of phosphorylated Retinoblastoma (pRB) in tumor biopsy samples, after Day 7 of Cycle 1 ; Effect of ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11060649/

Combined CDK4/6 and ERK1/2 inhibition enhances anti- ... Combined CDK4/6 and ERK1/2 inhibition enhances anti-tumor activity in NF1-associated plexiform neurofibroma

3. clinicalstudies.info.nih.gov clinicalstudies.info.nih.gov/protocoldetails.aspx?id=21-C-0011&&query=Neurofibromatosis%20Type

Protocol Details 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 ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03130439?term=AREA%5BBasicSearch%5D(LY2835219)&rank=10&tab=results

Study Results | Abemaciclib for Patients With ... See Delay Results Type in the Results Data ... These trials gather additional information about a drug's safety, efficacy, or optimal use.

5. asco.org asco.org/abstracts-presentations/ABSTRACT411840

A multicenter, open-label, single-arm phase 1/2 study to ... A multicenter, open-label, single-arm phase 1/2 study to evaluate the safety and efficacy of FCN-159 in pediatric participants with neurofibromatosis type 1.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2017/208716Orig1s000MultidisciplineR.pdf

208716Orig1s000 - accessdata.fda.gov safety results in the two registration trials MONARCH 1 and MONARCH 2. Overall, the clinical pharmacology evidence supported the rationale ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2017/208716Orig1s000RiskR.pdf

208716Orig1s000 - accessdata.fda.gov The safety profile of abemaciclib for the proposed indications is based on safety data from the Phase 3. MONARCH 2 study and the Phase 2 MONARCH ...