Crizotinib for Acoustic Neuroma

(NF110 Trial)

No longer recruiting at 25 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests crizotinib, a pill, to determine its effectiveness for individuals with neurofibromatosis type 2 (NF2) who have a growing vestibular schwannoma, a type of ear nerve tumor. Participants will take crizotinib daily in 28-day cycles for up to 12 cycles or until the disease progresses or side effects become too severe. The trial aims to assess whether the medication can slow tumor growth, as monitored by MRI scans. This trial may suit those with NF2 and progressive ear tumors that have increased by at least 20% over the past 18 months. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research has shown that crizotinib, a drug under study for treating acoustic neuroma in individuals with Neurofibromatosis Type 2 (NF2), is already approved for certain lung cancers, providing some safety information. Crizotinib blocks proteins that promote tumor growth. In past studies, most participants tolerated crizotinib well. Common side effects included nausea, diarrhea, and vision changes, which were usually manageable. Serious side effects were less common and could involve liver problems and changes in heart rhythm.

The trial's advanced stage indicates earlier safety tests succeeded, suggesting crizotinib has demonstrated a certain level of safety in humans. Ongoing trials continue to confirm this and monitor for new issues. Always consult a healthcare provider to weigh the benefits and risks before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Crizotinib is unique because it targets a specific genetic pathway involved in the growth of tumors associated with Neurofibromatosis Type 2 (NF2), which is different from the standard of care that often involves surgery or radiation. This drug, taken orally, works by inhibiting certain enzymes crucial for tumor cell growth, offering a non-invasive option that could potentially slow down or shrink the tumors. Researchers are excited about crizotinib because it offers hope for better management of vestibular schwannomas without the risks associated with surgical interventions.

What evidence suggests that crizotinib might be an effective treatment for acoustic neuroma?

Research has shown that crizotinib, a drug that blocks certain proteins, can help stop the growth of tumors linked to Neurofibromatosis Type 2 (NF2). In lab and animal studies, it effectively halted the spread of the cells that form these tumors. Early tests also demonstrated that crizotinib reduces tumor growth, making it a promising treatment for this condition. In this trial, participants with progressive vestibular schwannoma will receive crizotinib as an open-label continuous treatment. Overall, these studies provide strong evidence that crizotinib can effectively manage growing vestibular schwannomas in people with NF2. ^{1 2 6 7 8}

Who Is on the Research Team?

Girish Dhall, MD

Principal Investigator

University of Alabama at Birmingham

Matthias A Karajannis, MD, MS

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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 (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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04283669

NCT04283669 | Phase 2 Clinical Trial of Crizotinib for ... Patients who complete 12 cycles of treatment without disease progression, but within the following 24 weeks show subsequent disease progression (defined as >20% ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5342359/

Crizotinib inhibits NF2-associated schwannoma through ... We identified crizotinib, a MET and ALK inhibitor, as a potent inhibitor of NF2-null Schwann cell proliferation in vitro and tumor growth in vivo.

3. mskcc.org mskcc.org/cancer-care/clinical-trials/21-028

A Phase II Study of Crizotinib for Children and Adults ... The purpose of this study is to assess the safety and effectiveness of the drug crizotinib in children and adults with neurofibromatosis type 2 (NF2) and ...

4. uab.edu uab.edu/nfconsortium/clinical-trials/crizotinib

NF110: Crizotinib Study - Neurofibromatosis Consortium Crizotinib (Xalkori®), a small molecule kinase inhibitor, reduces NF2 schwannoma cell growth and tumor formation in preclinical schwannoma models via inhibition ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7881257/

New developments in neurofibromatosis type 2 and vestibular ... For example, crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinase, can enhance schwannoma radiosensitivity in the mouse ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04374305

Study Details | NCT04374305 | Innovative Trial for ... This is a multi-arm phase II platform-basket screening study designed to test multiple experimental therapies simultaneously in patients with NF2-related ...

7. withpower.com withpower.com/clinical-trials/for-acoustic-neuroma

Top Acoustic Neuroma Clinical Trials | Power This trial tests crizotinib, an oral medication, in patients with NF2 and growing vestibular schwannoma tumors. The drug works by blocking proteins that help ...

8. cancerci.biomedcentral.com cancerci.biomedcentral.com/articles/10.1186/s12935-023-02940-8

The genetic landscape and possible therapeutics of ... NF2 is a mixed neuro-cutaneous genetic disease predisposing to the development of multiple benign tumors throughout the lifetime. The ...