Study of Axitinib in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT02129647
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arm: 1
• Duration (Months): 58.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if the study drug, AXITINIB, has any effect on tumors found in patients with Neurofibromatosis Type 2 (NF2).

Condition or Disease	Intervention/Treatment	Phase
Neurofibromatosis Type 2; Vestibular Schwannomas	Drug: Axitinib	Phase 2

Detailed Description

NF2 is a condition that mainly affects the skin and nervous system. It causes non-cancerous tumors to grow on the nerves around a person's body. Some signs of NF2 include a gradual loss of hearing and tumors growing on the skin, the brain and the spinal cord, which can lead to complications.

AXITINIB is an oral drug (taken by mouth) that is approved by the United States Food and Drug Administration (FDA) for the treatment of other types of tumors. However, in this research study, AXITINIB is considered investigational because it is not approved by the FDA for treatment of NF2. Much is known regarding how well it is tolerated (handled), but investigators do not know if it is effective in treating NF2.

This research study will test whether AXITINIB may shrink tumors commonly found in patients with NF2 or stop them from growing. This will help to decide if AXITINIB should be used to treat NF2 patients in the future. AXITINIB is a drug that has been used to treat various forms of cancer. It has not been studied for the treatment of tumors in NF2 patients. Investigators have selected AXITINIB for this clinical trial in patients with NF2 and NF2-related tumors because a very similar drug, bevacizumab, can shrink Vestibular Schwannomas (VS) in some NF2 patients.

Pfizer, Inc., the manufacturer of the study drug, AXITINIB, will provide the AXITINIB being used in this study.

Primary Objective: To estimate the objective volumetric response rates to axitinib in adult NF2 patients with VS.

Secondary Objectives: To assess the toxicity of axitinib given daily in patients with NF2 and to examine the association of objective measures of response on MRI, i.e. volumetric tumor analysis with clinical measures of response, i.e. (audiogram), as well as quality of life assessments (NFTI-QOL). In addition, response in non-VS tumors, such as other schwannomas and meningiomas, may be explored.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Axitinib in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas
• Study Start Date: Apr 1, 2014
• Actual Primary Completion Date: Feb 5, 2019
• Actual Study Completion Date: Feb 5, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Axitinib 5 mg axitinib orally twice daily, with increase to 7 mg orally twice daily and 10 mg orally twice daily after 2 and 4 weeks, respectively, provided no adverse reactions (i.e., not exceeding grade 2 toxicities) and normotensive and not receiving antihypertension medications. Axitinib will be given continuously in 28-day cycles until disease progression or unacceptable toxicity.

Drug: Axitinib; Other Names: Inlyta

Outcome Measures

Primary Outcome Measures

1. Expression Levels of p-S6 Based Immunohistochemistry (Histoscore) [10 days]

   The histoscore is given as the sum of the percentage of staining multiplied by an ordinal value corresponding to the intensity level (0 = none, 1 = weak, 2 = moderate, 3 = strong). With 4 intensity levels, the resulting score ranged from 0 (no staining in the tumor) to 300 (diffuse intense staining of the tumor).

2. Expression Levels of p-ERK Based Immunohistochemistry (Histoscore) [10 days]

   The histoscore is given as the sum of the percentage of staining multiplied by an ordinal value corresponding to the intensity level (0 = none, 1 = weak, 2 = moderate, 3 = strong). With 4 intensity levels, the resulting score ranged from 0 (no staining in the tumor) to 300 (diffuse intense staining of the tumor).

3. Expression Levels of p-AKT Based Immunohistochemistry (Histoscore) [10 days]

   The histoscore is given as the sum of the percentage of staining multiplied by an ordinal value corresponding to the intensity level (0 = none, 1 = weak, 2 = moderate, 3 = strong). With 4 intensity levels, the resulting score ranged from 0 (no staining in the tumor) to 300 (diffuse intense staining of the tumor).

4. Pre-Operative Everolimus Blood Levels [Baseline]

5. Post-Operative Everolimus Blood Levels [10 days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria

• Age ≥18 years

• Meets clinical diagnostic criteria for NF2

• At least one volumetrically measurable and ≥1 cc NF2-related VS (histological confirmation not required)

• MRI evidence of progression (either as >2 mm increase in maximum linear diameter on conventional MRI, or a >20%volume increase by 3D volumetrics) over the past ≤18 months, OR progressive hearing loss, defined as a decline in word recognition score below the 95% critical difference interval from baseline score related to VS (i.e., not due to prior interventions such as surgery or radiation)

• Karnofsky performance status (PS) 60-100%. Note: Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

• Adequate bone marrow function as shown by: absolute neutrophil count ≥1.5 x 10^{9/L, Platelets ≥100 x 10}9/L, Hb >9 g/dL

• Adequate liver function as shown by:

• serum bilirubin ≤1.5 x upper limit of normal (ULN)

• ALT and AST ≤2.5x ULN

• INR ≤1.5. (anticoagulation with low molecular weight heparin is allowed if on a stable dose for >2 weeks at time of enrollment.)

• Adequate renal function: serum creatinine ≤1.5 x ULN

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

• Any neurologic deficits must be stable for ≥1 week

• Able to provide signed informed consent Exclusion criteria

• Patients currently receiving medical anticancer therapies or who have received medical anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, antibody based therapy, etc.)

• Radiation therapy to a study target tumor within 1 year prior to enrollment, or any radiation therapy within 4 weeks prior to enrollment.

• Patients who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study

• Prior treatment with bevacizumab or other agents targeting vascular endothelial growth factor (VEGF) or VEGF receptor

• Prior treatment with any investigational drug within the preceding 4 weeks

• Unstable or rapidly progressive disease, including patients who require glucocorticoids for symptomatic control of brain or spinal tumors

• Treatment with strong CYP3A4 enzyme inhibitors or inducers, including but not limited to ketoconazole, itraconazole, ritonavir, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital and St. John's wort

• Requirement of therapeutic anticoagulant therapy with oral vitamin K antagonists; low-dose anticoagulants for maintenance of patency of central venous access devise or prevention of deep venous thrombosis is allowed; therapeutic use of low molecular weight heparin (or similar parenteral drug) for venous-thromboembolic disease is allowed.

• Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.

• 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 diffusion capacity of lung for carbon monoxide (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 axitinib (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

• Patients with an active bleeding diathesis

• 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 8 weeks after the last dose of study drug, by both sexes. (Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to administration of axitinib)

• Male patient whose sexual partner(s) are women of child bearing potential, who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment

• History of noncompliance to medical regimens

• Patients unwilling to or unable to comply with the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NYU Langone Medical Center	New York	New York	United States	10016

Sponsors and Collaborators

• NYU Langone Health

Investigators

• Principal Investigator: Theodore Nicolaides, MD, NYU Langone Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 18, 2019

More Information

Publications

None provided.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT02129647
• Other Study ID Numbers: 14-00004
• First Posted: May 2, 2014
• Last Update Posted: Dec 1, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by NYU Langone Health: Neurofibromatosis Type 2; Vestibular Schwannomas; Axitinib
• Additional relevant MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurilemmoma; Neuroma, Acoustic; Neurofibromatosis 2; Axitinib

Study Results

Participant Flow

Arm/Group Title	Axitinib
Arm/Group Description	5 mg axitinib orally twice daily, with increase to 7 mg orally twice daily and 10 mg orally twice daily after 2 and 4 weeks. Axitinib will be given continuously in 28-day cycles until disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	13
COMPLETED	10
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Axitinib
Arm/Group Description	5 mg axitinib orally twice daily, with increase to 7 mg orally twice daily and 10 mg orally twice daily after 2 and 4 weeks. Axitinib will be given continuously in 28-day cycles until disease progression or unacceptable toxicity.
Overall Participants	13
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	39
Sex: Female, Male (Count of Participants)
Female	9 69.2%
Male	4 30.8%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Expression Levels of p-S6 Based Immunohistochemistry (Histoscore)
Description	The histoscore is given as the sum of the percentage of staining multiplied by an ordinal value corresponding to the intensity level (0 = none, 1 = weak, 2 = moderate, 3 = strong). With 4 intensity levels, the resulting score ranged from 0 (no staining in the tumor) to 300 (diffuse intense staining of the tumor).
Time Frame	10 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Axitinib
Arm/Group Description	5 mg axitinib orally twice daily, with increase to 7 mg orally twice daily and 10 mg orally twice daily after 2 and 4 weeks. Axitinib will be given continuously in 28-day cycles until disease progression or unacceptable toxicity.
Measure Participants	10
Median (Full Range) [score]	90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		10 tissue matched historical controls were analyzed. The Median (Full Range) of the histoscore was 122 (60 to 265)

2. Primary Outcome

Title	Expression Levels of p-ERK Based Immunohistochemistry (Histoscore)
Description	The histoscore is given as the sum of the percentage of staining multiplied by an ordinal value corresponding to the intensity level (0 = none, 1 = weak, 2 = moderate, 3 = strong). With 4 intensity levels, the resulting score ranged from 0 (no staining in the tumor) to 300 (diffuse intense staining of the tumor).
Time Frame	10 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Axitinib
Arm/Group Description	5 mg axitinib orally twice daily, with increase to 7 mg orally twice daily and 10 mg orally twice daily after 2 and 4 weeks. Axitinib will be given continuously in 28-day cycles until disease progression or unacceptable toxicity.
Measure Participants	10
Median (Full Range) [score]	180

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		10 tissue matched historical controls were analyzed. The Median (Full Range) of the histoscore was 135 (100 to 240)

3. Primary Outcome

Title	Expression Levels of p-AKT Based Immunohistochemistry (Histoscore)
Description	The histoscore is given as the sum of the percentage of staining multiplied by an ordinal value corresponding to the intensity level (0 = none, 1 = weak, 2 = moderate, 3 = strong). With 4 intensity levels, the resulting score ranged from 0 (no staining in the tumor) to 300 (diffuse intense staining of the tumor).
Time Frame	10 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Axitinib
Arm/Group Description	5 mg axitinib orally twice daily, with increase to 7 mg orally twice daily and 10 mg orally twice daily after 2 and 4 weeks. Axitinib will be given continuously in 28-day cycles until disease progression or unacceptable toxicity.
Measure Participants	10
Median (Full Range) [score]	42

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Axitinib
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		10 tissue matched historical controls were analyzed. The Median (Full Range) of the histoscore was 12 (0 to 100)

4. Primary Outcome

Title	Pre-Operative Everolimus Blood Levels
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

No controls - Given that only a single surgery is generally performed to resect meningiomas and schwannomas without prior biopsy, obtaining matched control of pre and post treatment samples from the same tumor was not feasible. The study team therefore relied on matched archival control tissue for comparisons of other outcome measures; Everolimus blood levels not being one of them.

Arm/Group Title	Axitinib
Arm/Group Description	5 mg axitinib orally twice daily, with increase to 7 mg orally twice daily and 10 mg orally twice daily after 2 and 4 weeks. Axitinib will be given continuously in 28-day cycles until disease progression or unacceptable toxicity.
Measure Participants	10
Median (Full Range) [ng/ml]	17.4

5. Primary Outcome

Title	Post-Operative Everolimus Blood Levels
Time Frame	10 days

Outcome Measure Data

Analysis Population Description

No controls - Given that only a single surgery is generally performed to resect meningiomas and schwannomas without prior biopsy, obtaining matched control of pre and post treatment samples from the same tumor was not feasible. The study team therefore relied on matched archival control tissue for comparisons of other outcome measures; Everolimus blood levels not being one of them.

Arm/Group Title	Axitinib
Arm/Group Description	5 mg axitinib orally twice daily, with increase to 7 mg orally twice daily and 10 mg orally twice daily after 2 and 4 weeks. Axitinib will be given continuously in 28-day cycles until disease progression or unacceptable toxicity.
Measure Participants	10
Median (Full Range) [ng/ml]	9.4

Adverse Events

Time Frame	10 days
Arm/Group Title	Axitinib
Arm/Group Description	5 mg axitinib orally twice daily, with increase to 7 mg orally twice daily and 10 mg orally twice daily after 2 and 4 weeks. Axitinib will be given continuously in 28-day cycles until disease progression or unacceptable toxicity.
All Cause Mortality
	Axitinib
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Serious Adverse Events
	Axitinib
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Other (Not Including Serious) Adverse Events
	Axitinib
	Affected / at Risk (%)	# Events
Total	6/10 (60%)
Gastrointestinal disorders
Mucositis	3/10 (30%)	3
General disorders
nausea	1/10 (10%)	1
Fatigue	1/10 (10%)	1
Skin and subcutaneous tissue disorders
Rash	1/10 (10%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.