Crizotinib for Acoustic Neuroma

(NF110 Trial)

Recruiting at 23 trial locations

Overseen By Matthias Karajannis, MD, MS

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alabama at Birmingham

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Cardiac disease, Severe infections, Others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 48 weeks

19 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests crizotinib, an oral medication, in patients with NF2 and growing vestibular schwannoma tumors. The drug works by blocking proteins that help the tumor grow.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications that affect the metabolism of the study drug, crizotinib. This includes drugs that are potent CYP3A4 inhibitors or inducers, as well as certain other medications with narrow therapeutic indices. It's important to discuss your current medications with the study team to determine if any need to be stopped.

What data supports the effectiveness of the drug Crizotinib for treating Acoustic Neuroma?

Crizotinib has shown effectiveness in controlling brain metastases in patients with ALK-positive non-small cell lung cancer, suggesting it may have potential benefits for other brain-related conditions like Acoustic Neuroma. ^{1 2 3 4 5}

Is crizotinib generally safe for humans?

Crizotinib, also known as Xalkori, has been used safely in humans for conditions like ALK-positive lung cancer and myofibroblastic tumors. Common side effects include vision problems, nausea, and swelling, but serious side effects are rare. In studies, most side effects were mild to moderate, and no serious adverse events were observed in healthy volunteers. ^{1 6 7 8 9}

How does the drug Crizotinib differ from other treatments for acoustic neuroma?

Crizotinib is unique because it is a small-molecule inhibitor that targets specific proteins (ALK and c-MET tyrosine kinases) and has shown effectiveness in controlling brain metastases in lung cancer, although its ability to penetrate the central nervous system is limited. This mechanism of action may offer a novel approach for treating acoustic neuroma, a condition with limited standard treatment options. ^{1 4 5 10 11}

Research Team

Girish Dhall, MD

Principal Investigator

University of Alabama at Birmingham

Matthias A Karajannis, MD, MS

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for children and adults over 6 years old with Neurofibromatosis Type 2 (NF2) and growing vestibular schwannomas. Participants must have stable neurologic symptoms, meet specific health criteria, not be on certain drugs or treatments that could interfere, and women of childbearing age must use effective birth control.

Inclusion Criteria

I can care for myself but may need occasional help.

My neurological symptoms have been stable for at least a week.

I have been diagnosed with neurofibromatosis 2 according to NIH, Manchester criteria, or a genetic test.

Exclusion Criteria

I am taking medication that is sensitive to changes in my body's enzyme levels.

I haven't had radiation on the tumor I want to study in the last year or any radiation in the last 4 weeks.

Prior treatment with any investigational drug within the preceding 4 weeks

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive crizotinib orally in continuous 28-day cycles for up to 12 cycles (48 weeks) until disease progression or unacceptable toxicity

48 weeks

MRI and audiology assessments at the end of every 3rd cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Re-treatment

Eligible participants may receive re-treatment for up to 48 additional weeks if disease progression occurs within 24 weeks after completing initial treatment

48 weeks

Treatment Details

Interventions

• Crizotinib

Trial Overview The trial tests Crizotinib, an oral medication given in continuous 28-day cycles up to a maximum of 12 cycles. It aims to see if it can stop the growth of tumors in patients with NF2 until either the disease progresses further or side effects become too severe.

Participant Groups

Group I: Open Label Continuous Treatment Experimental Treatment 1 Intervention

Subjects with Neurofibromatosis Type 2 (NF2) and progressive vestibular schwannoma (VS) will be treated with crizotinib administered orally. Crizotinib will be taken continuously until disease progression or unacceptable toxicity, in continuous treatment cycles of 28 days each, for a maximum of 12 cycles. Clinical response will be assessed by MRI (volumetrics, primary objective) and audiology at the end of every 3rd cycle. Subjects with volumetric tumor progression will be taken off protocol. Patients who complete 12 cycles of treatment without disease progression, but within the following 24 weeks show subsequent disease progression (defined as \>20% increase in target tumor volume compared to off-treatment volume), will be eligible for re-treatment on study for up to 48 additional weeks, provided they still meet study eligibility criteria.

Crizotinib is already approved in United States, European Union, Japan, Canada for the following indications:

Approved in United States as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in European Union as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in Japan as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Approved in Canada as Xalkori for:

• Non-small cell lung cancer (NSCLC) with ALK rearrangements

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Memorial Sloan Kettering Cancer Center

Collaborator

Trials

1,998

Recruited

602,000+

Findings from Research

Crizotinib (Xalkori) has been approved by the FDA for treating recurrent or refractory ALK-positive myofibroblastic tumors in both adults and children aged one year and older, highlighting its efficacy in this specific cancer type.

Common side effects include vision disorders and nausea in adults, while pediatric patients may experience a broader range of effects such as vomiting, diarrhea, and abdominal pain, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Indication for Cancer Drug Crizotinib. Aschenbrenner, DS.[2023]

Crizotinib is an effective treatment for adults with ALK-rearranged non-small-cell lung cancer, but managing its common side effects is essential for maintaining treatment continuity and achieving optimal survival rates.

While some side effects like visual disturbances and bradycardia are generally mild, serious cardiac and liver-related adverse events require careful monitoring, particularly for QT interval prolongation and liver function, to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ALK-rearranged non-small cell lung cancers: how best to optimize the safety of crizotinib in clinical practice? Girard, N., Audigier-Valette, C., Cortot, AB., et al.[2018]

Crizotinib, an ALK inhibitor, has been established as a new standard of care for advanced ALK-positive non-small cell lung cancer (NSCLC) due to its significant efficacy and favorable safety profile observed in phase I, II, and III trials.

Most adverse events associated with crizotinib are mild to moderate, and with proper monitoring and supportive care, dose interruptions can often be avoided, allowing patients to continue benefiting from the treatment even after initial disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of crizotinib therapy for ALK-rearranged non-small cell lung carcinoma: an expert consensus. Cappuzzo, F., Moro-Sibilot, D., Gautschi, O., et al.[2018]

Crizotinib has an oral bioavailability of about 43%, and while a high-fat meal slightly decreases its absorption, this effect is not clinically significant, indicating that it can be taken with food without major concerns.

In two phase I clinical studies involving healthy volunteers, crizotinib was found to be safe, with no serious adverse events reported and only mild side effects, such as diarrhea, suggesting it is well-tolerated in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjects. Xu, H., O'Gorman, M., Boutros, T., et al.[2018]

Alectinib, a next-generation ALK inhibitor, has shown significant antitumor activity against brain metastases in mouse models of ALK-positive non-small-cell lung cancer, suggesting it may be effective for patients with crizotinib-resistant tumors.

In a reported case, alectinib was highly effective in treating brain metastases that did not respond to crizotinib, highlighting its potential as a valuable treatment option in this challenging scenario.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid response of brain metastases to alectinib in a patient with non-small-cell lung cancer resistant to crizotinib. Ajimizu, H., Kim, YH., Mishima, M.[2019]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Clinical impact of crizotinib on central nervous system progression in ALK-positive non-small lung cancer. [2022]

2. Germany pubmed.ncbi.nlm.nih.gov

Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. [2022]

3. India pubmed.ncbi.nlm.nih.gov

Clinical data from the real world: Efficacy analysis of ceritinib (450mg) in ALK-rearrangement non-small-cell lung cancer patients with brain metastases in China. [2022]

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

Clinical data from the real world: efficacy of Crizotinib in Chinese patients with advanced ALK-rearranged non-small cell lung cancer and brain metastases. [2022]

5. China pubmed.ncbi.nlm.nih.gov

Clinical efficacy of crizotinib in Chinese patients with ALK-positive non-small-cell lung cancer with brain metastases. [2020]

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

New Indication for Cancer Drug Crizotinib. [2023]

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

ALK-rearranged non-small cell lung cancers: how best to optimize the safety of crizotinib in clinical practice? [2018]

8. Ireland pubmed.ncbi.nlm.nih.gov

Management of crizotinib therapy for ALK-rearranged non-small cell lung carcinoma: an expert consensus. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Evaluation of crizotinib absolute bioavailability, the bioequivalence of three oral formulations, and the effect of food on crizotinib pharmacokinetics in healthy subjects. [2018]

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

Rapid response of brain metastases to alectinib in a patient with non-small-cell lung cancer resistant to crizotinib. [2019]

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

Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases. [2022]