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

Primary Purpose

Neurofibromatosis 2, Progressive Vestibular Schwannoma (VS)

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Crizotinib
Sponsored by
University of Alabama at Birmingham
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Neurofibromatosis 2

Eligibility Criteria

6 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • The University of Alabama at Birmingham (Site 700)
  • Univ of California @ Los Angeles (Site 325)
  • Children's National Medical Center (Site 775)
  • Children's HealthCare of Atlanta (Site 950)
  • Lurie Children's Hospital of Chicago (Site 350)
  • University of Chicago (Site 850)
  • Indiana University (Site 400)
  • Johns Hopkins University (Site 250)
  • Children's Hospital Boston (Site 725)
  • Mayo Clinic (Site 908)
  • Washington University - St. Louis (Site 900)
  • New York University Medical Center (Site 200)
  • Memorial Sloan Kettering Cancer Center (Site 210)
  • Cincinnati Children's Hospital Medical Center (Site 800)
  • Children's Hospital of Philadelphia (Site 750)
  • Childrens Medical Center - Univ. of Texas SW (Site 917)
  • University of Utah (Site 875)

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

Open Label Continuous Treatment

Arm 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.

Outcomes

Primary Outcome Measures

Volumetric Response Rate
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.

Secondary Outcome Measures

Full Information

First Posted
February 22, 2020
Last Updated
September 8, 2023
Sponsor
University of Alabama at Birmingham
Collaborators
Memorial Sloan Kettering Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04283669
Brief Title
Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas
Acronym
NF110
Official Title
Open-label, Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 18, 2020 (Actual)
Primary Completion Date
August 18, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Alabama at Birmingham
Collaborators
Memorial Sloan Kettering Cancer Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neurofibromatosis 2, Progressive Vestibular Schwannoma (VS)

7. Study Design

Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
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)
Allocation
N/A
Enrollment
19 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Open Label Continuous Treatment
Arm Type
Other
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Crizotinib
Intervention Description
Oral
Primary Outcome Measure Information:
Title
Volumetric Response Rate
Description
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.
Time Frame
Up to 48 Weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bruce R Korf, MD, PhD
Organizational Affiliation
University of Alabama at Birmingham
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Matthias A Karajannis, MD, MS
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Study Chair
Facility Information:
Facility Name
The University of Alabama at Birmingham (Site 700)
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
Univ of California @ Los Angeles (Site 325)
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Children's National Medical Center (Site 775)
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Children's HealthCare of Atlanta (Site 950)
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30324
Country
United States
Facility Name
Lurie Children's Hospital of Chicago (Site 350)
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
University of Chicago (Site 850)
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Indiana University (Site 400)
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Johns Hopkins University (Site 250)
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Children's Hospital Boston (Site 725)
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Mayo Clinic (Site 908)
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
56001
Country
United States
Facility Name
Washington University - St. Louis (Site 900)
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
New York University Medical Center (Site 200)
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center (Site 210)
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center (Site 800)
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229-3039
Country
United States
Facility Name
Children's Hospital of Philadelphia (Site 750)
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19096
Country
United States
Facility Name
Childrens Medical Center - Univ. of Texas SW (Site 917)
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Facility Name
University of Utah (Site 875)
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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