Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas (NF110)

• ClinicalTrials.gov Identifier: NCT04283669
• Recruitment Status: Active, not recruiting
• First Posted: February 25, 2020
• Last Update Posted: September 11, 2023
• Sponsor: University of Alabama at Birmingham
• Collaborator: Memorial Sloan Kettering Cancer Center
• Information provided by (Responsible Party): Bruce Korf, MD, University of Alabama at Birmingham

Tracking Information

• First Submitted Date: February 22, 2020
• First Posted Date: February 25, 2020
• Last Update Posted Date: September 11, 2023
• Actual Study Start Date: February 18, 2020
• Estimated Primary Completion Date: August 18, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 22, 2020)

Volumetric Response Rate [ Time Frame: Up to 48 Weeks ]

estimate the best objective volumetric response rates (i.e. maximum tumor shrinkage) to crizotinib in NF2 patients with VS during up to 12 cycles (48 weeks) of treatment.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas
• Official Title: Open-label, Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas
• Brief Summary: 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.
• Detailed Description: 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.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

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.

Masking: None (Open Label)
Primary Purpose: Other

Condition

• Neurofibromatosis 2
• Progressive Vestibular Schwannoma (VS)

Intervention

Drug: Crizotinib

Oral

Study Arms

Open Label Continuous Treatment

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.

Intervention: Drug: Crizotinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: February 22, 2020): 19
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: August 18, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Participants must meet the following criteria on screening examination to be eligible to participate in the study:

Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling National Institute of Health (NIH) criteria or Manchester criteria, or by detection of a causative mutation in the NF2 gene.

The NIH criteria include presence of:

• Bilateral vestibular schwannomas, OR
• First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR
• Two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity.

The Manchester criteria include presence of:

• Bilateral vestibular schwannomas, OR First-degree relative with NF2 and EITHER unilateral eighth nerve mass OR - Two of the following: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity OR
• Unilateral vestibular schwannoma AND any two of: neurofibroma, meningioma, glioma, schwannoma, juvenile posterior subcapsular lenticular opacity, OR
• Multiple meningiomas (two or more) AND unilateral vestibular schwannoma OR
• Any two of: schwannoma, glioma, neurofibroma, cataract.

Patients must have progressive and measurable disease, defined as at least one VS with the following qualities:

• ≥ 0.75 ml (on volumetric analysis) that can be accurately measured by contrast-enhanced cranial MRI scan with fine cuts through the internal auditory canal (1 mm slices, no skip)
• MRI evidence of progression over the past 18 months (defined as ≥20% annualized increase in volume)

Age ≥ 6 years on day 1 of treatment.

Life expectancy of greater than 1 year.

Lansky/Karnofsky performance status ≥ 60

Organ and marrow function as defined below:

• Absolute neutrophil count ≥ 1,500/ μl
• Platelets ≥ 100,000/ μl
• Total bilirubin within ≤ 1.5 X institutional upper limit of normal
• AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal
• Patients must have a creatinine clearance or radioisotope GFR ≥60ml/min/1.73 ≥60ml/min/1.73 m2 or a normal serum creatinine based on age/gender described in the table below:
• Age: 6 to < 10 years with a Maximum Serum Creatinine (mg/dL) of 1 for Male and 1 for Female
• Age: 10 to < 13 years with a Maximum Serum Creatinine (mg/dL) of 1.2 for Male and 1.2 for Female
• Age: 13 to < 16 years with a Maximum Serum Creatinine (mg/dL) of 1.5 for Male and 1.4 for Female
• Age: ≥ 16 years with a Maximum Serum Creatinine (mg/dL) of 1.7 for Male and 1.4 for Female

The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.

Fully recovered from acute toxic effects of any prior chemotherapy, biological modifiers or radiotherapy

Any neurologic deficits must be stable for ≥1 week

Patient or parent/legal guardian must be able to provide signed informed consent and assent (as applicable for minors)

Exclusion Criteria:

Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.

Patients currently receiving medical anticancer therapies or who have received medical anticancer therapies within 4 weeks of the start of study drug (including chemotherapy and molecular targeted agents), as these may interfere with the study drug

Monoclonal antibody treatment and/or agents with prolonged half-lives: At least three half-lives must have elapsed from the last dose prior to enrollment

Radiation therapy to a study target tumor within 1 year prior to enrollment, or any radiation therapy within 4 weeks prior to enrollment, as these may interfere with our ability to assess response to study drug

Prior treatment with any investigational drug within the preceding 4 weeks, as they may interfere with the study drug

Unstable or rapidly progressive disease, including patients who require glucocorticoids for symptomatic control of brain or spinal tumors, as this would represent a high risk for inability to comply with the study requirements

Use of drugs or foods that are known potent CYP3A4 inhibitors, including but not limited to ketoconazole, itraconazole, miconazole, clarithromycin, erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice, as this would interfere with study drug metabolism

Use of drugs that are known potent CYP3A4 inducers, including but not limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, tipranavir, ritonavir, and St. John's wort, as this would interfere with study drug metabolism

Use of drugs that are CYP3A4 substrates with narrow therapeutic indices, including but not limited to pimozide, aripiprazole, triazolam, dihydroergotamine, ergotamine, astemizole, cisapride, terfenadine and halofantrine, as this would interfere with study drug metabolism

Ongoing cardiac dysrhythmias of CTCAE grade ≥2, uncontrolled atrial fibrillation of any grade or prolonged QTc interval (>480 msec), as patients with these conditions would be expected to have an increased risk for cardiac toxicity related to study drug

Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

• symptomatic congestive heart failure of New York heart Association Class III or IV
• unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
• severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 90% or less at rest on room air
• active (acute or chronic) or uncontrolled severe infections liver disease, such as cirrhosis or severe hepatic impairment (Child-Pugh class C)

Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of crizotinib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Adequate contraception must be used throughout the trial and for 90 days after the last dose of study drug, as the effects of crizotinib on an unborn fetus are not known. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to administration of crizotinib.

Male patients whose sexual partner(s) are women of child bearing potential, who are not willing to use adequate contraception during the study and for 90 days after the last dose of study drug.

History of significant noncompliance to medical regimens that would jeopardize compliance with study therapy

Patients unwilling to or unable to comply with the study protocol

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04283669
• Other Study ID Numbers: IRB-300003645; W81XWH-17-2-0037 ( Other Grant/Funding Number: CDMRP of the Dept. of Defense, US Army )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Bruce Korf, MD, University of Alabama at Birmingham
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Alabama at Birmingham
• Original Study Sponsor: Same as current
• Collaborators: Memorial Sloan Kettering Cancer Center

Investigators

• Study Director: Bruce R Korf, MD, PhD; University of Alabama at Birmingham
• Study Chair: Matthias A Karajannis, MD, MS; Memorial Sloan Kettering Cancer Center

• PRS Account: University of Alabama at Birmingham
• Verification Date: September 2023