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

Sponsor

University of Alabama at Birmingham (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT04283669

Collaborator

Memorial Sloan Kettering Cancer Center (Other)

Enrollment

Locations

Arm

70.4

Anticipated Duration (Months)

1.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Condition or Disease	Intervention/Treatment	Phase
Neurofibromatosis 2 Progressive Vestibular Schwannoma (VS)	Drug: Crizotinib	Phase 2

Detailed Description

Study Design

Study Type:

Interventional

Anticipated Enrollment :

19 participants

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.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

Official Title:

Open-label, Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas

Actual Study Start Date :

Feb 18, 2020

Anticipated Primary Completion Date :

Aug 18, 2025

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Other: 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.	Drug: Crizotinib Oral

Arm

Intervention/Treatment

Other: Open Label Continuous Treatment

Drug: Crizotinib

Oral

Outcome Measures

Primary Outcome Measures

Volumetric Response Rate [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Alabama at Birmingham (Site 700)	Birmingham	Alabama	United States	35294
2	Univ of California @ Los Angeles (Site 325)	Los Angeles	California	United States	90027
3	Children's National Medical Center (Site 775)	Washington	District of Columbia	United States	20010
4	Children's HealthCare of Atlanta (Site 950)	Atlanta	Georgia	United States	30324
5	Lurie Children's Hospital of Chicago (Site 350)	Chicago	Illinois	United States	60611
6	University of Chicago (Site 850)	Chicago	Illinois	United States	60637
7	Indiana University (Site 400)	Indianapolis	Indiana	United States	46202
8	Johns Hopkins University (Site 250)	Baltimore	Maryland	United States	21287
9	Children's Hospital Boston (Site 725)	Boston	Massachusetts	United States	02115
10	Mayo Clinic (Site 908)	Minneapolis	Minnesota	United States	56001
11	Washington University - St. Louis (Site 900)	Saint Louis	Missouri	United States	63110
12	New York University Medical Center (Site 200)	New York	New York	United States	10016
13	Memorial Sloan Kettering Cancer Center (Site 210)	New York	New York	United States	10065
14	Cincinnati Children's Hospital Medical Center (Site 800)	Cincinnati	Ohio	United States	45229-3039
15	Children's Hospital of Philadelphia (Site 750)	Philadelphia	Pennsylvania	United States	19096
16	Childrens Medical Center - Univ. of Texas SW (Site 917)	Dallas	Texas	United States	75235
17	University of Utah (Site 875)	Salt Lake City	Utah	United States	84132

Sponsors and Collaborators

University of Alabama at Birmingham
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