Conditions: Neurofibromatosis Type 2 Vestibular Schwannomas
Keywords: Neurofibromatosis Type 2 Vestibular Schwannomas Axitinib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

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).

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.

Arms:
arm 1: 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.

Interventions: intervention 1: Axitinib
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
Phase II Study of Axitinib in Patients with Neurofibromatosis Type 2 and 
Progressive Vestibular Schwannomas 
Version Date: 4-18-2019 
PRINCIPAL INVESTIGATOR 
THEODORE NICOLAIDES, MD 
CO-INVESTIGATORS 
JEFFREY ALLEN, MD 
SHARON GARDNER, MD 
JUDITH GOLDBERG, ScD 
MATTHIAS KARAJANNIS, MD, MS (MSKCC) 
ANDREW LIN (MSKCC) 
SRIVANDANA AKSHINTALA, MBBS, MPH 
Primary/Coordinating Study Site: NYU Langone Medical Center 
Study Sub-Site: Memorial Sloan Kettering Cancer Center (MSKCC) 
NCT02129647


 
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Table of Contents 
 
1 Introduction .......................................................................................................................... 3 
1.1 Axitinib ....................................................................................................................... 3 
1.2 Neurofibromatosis Type 2 (NF2) and Study Rationale .............................................. 6 
2 Key Eligibility Criteria ......................................................................................................... 8 
3 Research Strategy ................................................................................................................. 8 
4 Endpoints/Statistical Considerations .................................................................................... 9 
5 Proposed Sample Size and Timeline for Recruitment .......................................................... 9 
6 Study Objectives ................................................................................................................. 10 
7 Investigational Plan ............................................................................................................ 10 
7.1 Study Design and Treatment .................................................................................... 10 
7.2 Study Population ...................................................................................................... 11 
7.2.1 Patient population ...................................................................................... 11 
7.2.2 Inclusion and exclusion criteria ................................................................. 11 
7.2.3 Monitoring of axitinib suspected toxicities ............................................... 14 
7.3 Treatment .................................................................................................................. 14 
7.3.1 Axitinib administration .............................................................................. 14 
7.3.2 Interruption or discontinuation of treatment .............................................. 16 
7.3.3 General criteria for dose-modification of axitinib ..................................... 17 
7.3.4 Precautions and management of specific toxicities ................................... 18 
7.3.5 Concomitant therapy .................................................................................. 21 
7.4 Visit Schedule and Assessments .............................................................................. 21 
7.4.1 Visit schedule ............................................................................................. 22 
7.4.2 Efficacy assessments ................................................................................. 22 
7.4.3 Treatment compliance ............................................................................... 23 
7.4.4 Safety assessments ..................................................................................... 23 
7.4.5 Instructions for rapid notification of serious adverse events ..................... 25 
7.4.6 Laboratory evaluations .............................................................................. 26 
8 Protocol Amendments, or Changes in Study Conduct ....................................................... 27 
9 Description of the Informed Consent Process .................................................................... 28 
10 Withdrawal from the Protocol ............................................................................................ 28  
11 Data Management and Collection ...................................................................................... 28 
 
11.1       Confidentiality ...................................................................................................... 28 
12 Data Monitoring ................................................................................................................ 29 
12.1 Monitoring Plan ...................................................................................................... 29 
12.2 Stopping Rules ........................................................................................................ 30 
13 Statistical Methods ............................................................................................................ 30 
14 References ......................................................................................................................... 31 
15 Appendix I: List of Strong CYP3A4/5 inhibitors and inducers .......................................... 33 
 


 
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1 Introduction 
1.1 Axitinib 
Axitinib is an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) 
receptors 1, 2, and 3. As of 27 August 2012, axitinib was approved in 6 countries (United States 
[US; January 2012], Switzerland [April 2012], Japan [June 2012], Canada [July 2012], 
Australia [July 2012] and Korea [August 2012]) for previously-treated patients with advanced 
renal cell carcinoma (RCC); the actual indication varies from country to country. The safety 
and efficacy of axitinib is being evaluated in patients with a variety of solid tumors, including 
in treatment-naïve patients with advanced RCC [Information from Investigator’s Brochure, 
September 2012]. 
VEGF receptors are critical components of the processes leading to the branching, extension, 
and survival of endothelial cells which form new blood vessels during angiogenesis, an absolute 
necessity for tumor growth beyond microscopic size. In nonclinical tumor mouse models, twice-
daily (BID) oral administration of axitinib demonstrated consistent and significant anti-tumor 
efficacy (marked inhibitory effect on local and distant tumor metastasis and prolonged animal 
survival). In multiple animal models, the combination of axitinib with various standard 
chemotherapies (e.g., docetaxel or carboplatin) and other antiangiogenic agents (e.g., 
bevacizumab) 
demonstrated 
improved 
benefit 
compared 
with 
single-agent 
chemotherapeutic/antiangiogenic agents. 
The nonclinical safety profile of axitinib has been well characterized through the conduct of 
single-dose and repeat-dose toxicity studies of up to 39 weeks in duration, and safety 
pharmacology, genetic toxicity, reproductive and developmental toxicity, and phototoxicity 
studies. The primary target organ toxicities were observed in the gastrointestinal, hematopoietic, 
musculoskeletal, and reproductive systems. Additionally, hemodynamic effects (elevated blood 
pressure, reduced heart rate) were identified from repeat-dosing in conscious, telemetered 
animals. Axitinib was not identified as a mutagen or clastogen, but considered an aneugen at 
area under the plasma concentration-time curve (AUC) exposure that exceeds that at the 
recommended human dose (RHD) of 5 mg BID. While axitinib has relevant ultraviolet (UV) 
absorbance with the potential to distribute to sun-exposed tissues, no phototoxicity potential 
was identified from in vitro testing in 3T3 fibroblasts. Many of the findings identified from non-
clinical safety testing are consistent with the anticipated pharmacological response to a VEGF 
receptor inhibitor, including the blood pressure changes, and effects on ovarian follicles and the 
growth plate of actively growing animals, which are reliant on angiogenesis for development. 
Fertility and developmental effects were also observed, consistent with the effects identified 
from toxicity studies on reproductive organs and role of angiogenesis in the development of a 
fetus. 
Axitinib and its metabolites were widely distributed into tissues in mice, but did not accumulate 
and were not retained for long periods of time in most tissues. The plasma protein binding was 
97%, 98%, and 99% in the mouse, dog, and human, respectively. 


 
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In humans, the median recovery of [14C] axitinib radioactivity in feces was 37.0% and in urine 
was 22.7% (total recovery = 59.7%) of the total orally administered dose (5 mg). In plasma, the 
glucuronide was the predominant metabolite and accounted for approximately 50% of the 
circulating radioactivity. The sulfoxide and unchanged parent drug accounted for approximately 
20% of the circulating radioactivity. In feces, the parent drug represented the single most 
predominant radioactive component (12% of the dose). 
As of 1 June 2012, 43 studies evaluating the safety, efficacy, and PK of axitinib have been 
completed or are ongoing. These studies include 15 Phase 1 studies in healthy subjects and 28 
studies in subjects with cancer including 1 continued access and 1 compassionate-use study. 
A study in healthy volunteers (A4061007) indicated that the mean absolute oral bioavailability 
of the drug was 58%. Interaction studies in healthy volunteers with the CYP3A4/5 inhibitor 
ketoconazole (A4061004) and CYP3A4/5 inducer rifampin (A4061026) produced a 2-fold 
increase and 79% reduction in axitinib plasma exposures, respectively. Axitinib has two major 
(non-pharmacologically active) circulating plasma metabolites, a glucuronide product and a 
sulfoxide product (A4061003). In subjects with moderate hepatic impairment (Child Pugh B), 
there was a ~2-fold increase in axitinib area under curve from zero to infinity (AUC (0-∞)) and 
a 1.3-fold increase in axitinib maximum plasma concentration (Cmax) compared to subjects with 
normal hepatic function (A4061036). No difference in axitinib plasma pharmacokinetics was 
observed between Caucasian and first-generation Japanese volunteers (n=20 each) (A4061026). 
Phase 1 studies in combination with chemotherapeutic/anticancer agents in cancer patients have 
indicated plasma pharmacokinetics of docetaxel, paclitaxel, carboplatin, capecitabine, 
gemcitabine, cisplatin, pemetrexed, oxaliplatin, 5-fluorouracil (5-FU), bevacizumab, and 
irinotecan (including its SN-38 activated metabolite) were similar in the absence and presence 
of axitinib. Likewise, axitinib plasma profiles and pharmacokinetic parameters were similar in 
the presence and absence of these co-administered chemotherapeutic/anticancer agents 
(A4061019 and A4061020). 
In ongoing clinical studies, the axitinib starting dose is 5 mg BID. Subjects who can tolerate 
axitinib with no adverse events related to axitinib above Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 2 for consecutive 2 week periods are permitted to increase 
their dose step-wise to 7 mg BID and then to a maximum of 10 mg BID, unless their blood 
pressure (BP) is >150/90 mm Hg. The dose of axitinib can be reduced to as low as 2 mg BID if 
> Grade 2 treatment-related adverse events occur. 
Overall, the adverse events reported for axitinib in clinical studies are considered manageable, 
generally reversible and expected for this class of agents. For single-agent axitinib, the most 
common adverse events (>20%) reported from 699 cancer subjects regardless of causality 
included diarrhea (397 subjects, 56.8%), fatigue (368 subjects, 52.6%), hypertension (318 
subjects, 45.5%), decrease appetite (286 subjects, 40.9%), nausea (264 subjects, 37.8%), 
dysphonia (242 subjects, 34.6%), palmar-plantar erythrodysaesthesia syndrome (202 subjects, 
28.9%), weight decreased (197 subjects, 28.2%), vomiting (166 subjects, 23.7%), constipation 
(165 subjects, 23.6%), headache (151 subjects, 21.6%), cough (149 subjects, 21.3%), arthralgia 
and dyspnea (140 subjects, 20%). Grade 3+ events occurred most frequently for hypertension 
(134 subjects, 19.2%), fatigue (90 subjects, 12.9%), and diarrhea (65 subjects, 9.3%). 


 
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Hypothyroidism and proteinuria were reported as adverse events in 122/699 subjects (17.5%) 
and 117/699 subjects (16.7 %), respectively. Hemorrhagic events (including epistaxis, 
hematuria, hemoptysis, rectal hemorrhage, cerebral hemorrhage, gastric hemorrhage, and lower 
gastrointestinal hemorrhage) were reported in 182/699 subjects (26.0%); Grade 3+ hemorrhagic 
events occurred in 13/699 subjects (1.9%), including 1 death (gastric hemorrhage). 
Arterial thromboembolic events (including cerebral infarction, cerebrovascular accident, 
embolism arterial, lacunar infarction, myocardial infarction, retinal artery occlusion, and 
transient ischemic attack) were reported in 16/699 subjects (2.3%) including 2 deaths 
(secondary to cerebrovascular accident). Venous thromboembolic events (including pulmonary 
embolism, deep vein thrombosis, retinal vein occlusion and jugular vein thrombosis) were 
reported in 21/699 subjects (3.0%) including 2 deaths (pulmonary embolism). Gastrointestinal 
perforation (including gastrointestinal perforation, large intestine perforation, and intestinal 
perforation) were reported in 5/699 subjects (0.7%) including 1 death (intestinal perforation). 
In addition to cases of gastrointestinal perforation, fistulas (including anal fistula and fistula) 
were reported in 4/699 subjects (0.6%). Reversible posterior leukoencephalopathy syndrome 
(RPLS) was reported in 3/699 subjects (0.4%). 
Axitinib has been investigated in combination with various chemotherapy regimens (e.g., 
docetaxel, carboplatin/paclitaxel, gemcitabine, capecitabine/cisplatin, gemcitabine/cisplatin, 
weekly paclitaxel, capecitabine, FOLFIRI, FOLFOX, FOLFOX + bevacizumab, and 
pemetrexed/cisplatin). In general, axitinib at a starting dose of 5 mg BID administered 
continuously has been combined with the full dose of chemotherapy. Non-hematological safety 
events have been similar to those for the single-agent axitinib and those for the chemotherapy 
regimens. Preliminary evidence of antitumor activity has been observed with axitinib as a single 
agent and in combination with chemotherapy across multiple tumor types. Plasma 
concentrations 
as 
well 
as 
pharmacokinetic 
parameters 
of 
the 
co-administered 
chemotherapeutic/anti-cancer drug were similar in the presence and absence of axitinib. 
However, a clinical study conducted with axitinib in combination with docetaxel indicated that 
the docetaxel mean plasma exposure was increased in the presence of axitinib. The plasma 
pharmacokinetics of axitinib was similar in the presence of all chemotherapeutic agents 
evaluated. 
A Phase 3 study comparing axitinib versus sorafenib in previously-treated (second-line) patients 
with advanced renal cell carcinoma (RCC) met the primary endpoint (progression- free survival 
[PFS] per blinded independent review).1 The most common (≥20%) adverse reactions observed 
following treatment with axitinib were diarrhea, hypertension, fatigue, decreased appetite, 
nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, 
vomiting, asthenia, and constipation. Based on the findings from this registrational study, as of 
27 August 2012, axitinib was approved in 6 countries (United States [US; January 2012], 
Switzerland [April 2012], Japan [June 2012], Canada [July 2012], Australia [July 2012] and 
Korea [August 2012]) for previously-treated patients with advanced renal cell carcinoma 
(RCC); the actual indication varies from country to country. A Phase 3 study comparing axitinib 
vs sorafenib in treatment-naïve (first-line) patients with advanced RCC is ongoing. A double-


 
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blind randomized Phase 2 study comparing dose titration with axitinib vs placebo in treatment- 
naïve (first-line) patients with advanced RCC is also ongoing. 
In addition, a double-blind randomized study comparing axitinib vs placebo in previously- 
treated (second-line) patients with advanced hepatocellular carcinoma (HCC) is ongoing. Phase 
1 and 2 studies are ongoing in other advanced solid tumors. Combination studies of axitinib 
with chemotherapy are being conducted in non-small cell lung cancer (NSCLC), colorectal 
cancer (CRC), and gastric cancer. 
Pediatric Studies 
The Children’s Oncology Group phase 1 study ADVL1315 (NCT02164838) for pediatric 
patients with recurrent/refractory solid tumors recently determined a recommended phase 2 
dose (RP2D) of 2.4 mg/m2 PO BID, corresponding to approximately 4mg PO BID in an average 
sized adult, or 80% of the adult standard starting dose [J Clin Oncol 34, 2016 (suppl; abstr 
10558)]. In this study, oral axitinib tablets were administered twice daily, continuously in 28-
day cycles. Dose levels 2.4 and 3.2 mg/m2/dose were evaluated using a rolling 6 design. As of 
December 11, 2015, 17 patients were enrolled with 1 ineligible (inadequate time from prior 
therapy). The median age was 14 yrs (range 5–17 yrs); 9 were male. Patients received a median 
3 prior chemotherapy regimens (range 1-8). Cancer diagnoses included soft tissue sarcomas (7), 
Ewing (2) and osteosarcoma (1), neuroblastoma (2), Wilms tumor (1), hepatoblastoma (1), 
hepatocellular carcinoma (1), medullary carcinoma (1), and epithelial-myoepithelial carcinoma 
(1). Toxicity data were available for 15 patients (6 at dose level 1, 5 at dose level 2, and 4 on an 
expanded PK cohort). One patient was inevaluable for toxicity due to inadequate drug exposure. 
DLTs occurred in 0/6 and 2/5 patients treated at dose level 1 and 2 respectively (palmar-plantar 
erythrodysesthesia syndrome (1); intratumoral hemorrhage (1)). Cycle 1 hematologic toxicities 
included grade 3 lymphopenia (1) and grade 1 or 2 anemia (4), lymphopenia (3), elevated 
hemoglobin (3), leukopenia (2), neutropenia (1), thrombocytopenia (1), and lymphocytosis (1). 
Non-hematologic toxicities included grade 1 or 2 nausea (5), hypertension (4), anorexia (3), 
creatinine elevation (2), diarrhea (2), fatigue (2), headache (2), lipase elevation (2), proteinuria 
(2), and acneiform rash (2). The most common subsequent cycle grade 3 or 4 toxicities included 
neutropenia (grade 3 (3), grade 4 (1)) and lymphopenia (grade 3 (1), grade 4 (1)). 
1.2 Neurofibromatosis Type 2 (NF2) and Study Rationale 
Neurofibromatosis type 2 (NF2) is an autosomal-dominant genetic disease with an incidence of 
approximately 1/40,000. The NF-2 gene is located on chromosome 22 and its gene product is 
named Merlin. Merlin’s function is not well understood, but it appears to act as a tumor 
suppressor. The majority of NF2 patients develop progressive hearing loss in adolescence or 
young adulthood due to unilateral or bilateral vestibular schwannomas (VS).2 Spinal tumors, 
including meningiomas, schwannomas and ependymomas, as well as intracranial tumors, 
mostly meningiomas, are also highly prevalent. NF2-related tumors, although mostly slow 
growing, cause considerable morbidity and mortality, particularly when first diagnosed at a 
young age. The available treatment options for these neoplasms, which often occur at multiple 
sites simultaneously, are non-curative and mostly limited to surgery and radiation therapy. As 


 
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a result, all NF2 patients suffer from major morbidity, mortality and significantly reduced life 
expectancy. 
Although classic chemotherapy is effective treatment for low-grade brain tumors, no such 
therapy has been validated for NF2 patients with multiple tumors for a variety of reasons. Most 
chemotherapeutic agents are mutagenic and there is reluctance to use them in patients with loss 
of tumor-suppressor function, such as NF2. Many chemotherapeutic drugs are neuro– and/or 
ototoxic, making them unsuitable for NF2 patients. No chemotherapy regimens have been 
identified to date for the most common tumors arising in NF-2 patients such as meningiomas, 
ependymomas and schwannomas. Surgery remains the mainstay of therapy for VS, but carries 
major risks including complete deafness, facial palsy, stroke and CSF leak. Medical treatment 
options for VS are therefore urgently needed.3 
Although VS and meningiomas are the hallmark of NF2, the vast majority of VS and 
meningiomas arise sporadically in non-NF2 patients. The prevalence of idiopathic VS in the 
US is roughly 3,000 new cases per year and the incidence appears to be increasing in recent 
years.4 These tumors cause unilateral hearing loss, tinnitus, imbalance and vertigo. The primary 
treatment modality for these tumors is surgical resection or radiosurgery. Surgery can be 
associated with the same complications listed above for NF2-related VS. Hence, RT is often 
offered in place of surgery. Although considered safer in idiopathic VS, long term efficacy has 
not been established and RT may complicate future procedures. Therefore, this large population 
of patients with sporadic VS may also benefit from a medical option either at initial diagnosis 
or at progression. 
 
Axitinib is an oral multi-receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial 
growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT. 
Axitinib inhibits VEGFR1/2/3, PDGFRα/β and c-KIT phosphorylation in the sub– to low 
nanomolar range.5 Axitinib is currently FDA-approved for the second-line treatment of renal 
cell carcinoma. All of the molecular targets of axitinib represent clinically and/or preclinically 
validated molecular targets for VS: 
 
VEGFR: Angiogenesis occurs in VS, and VEGFRs are expressed in these tumors.6-8 Anti-
VEGF(R)-directed therapy with bevacizumab and vandetanib normalized the vasculature of 
NF2-/- schwannoma xenografts in nude mice and decreased tumor growth.9 Clinically, VEGF-
targeted therapy with bevacizumab has been reported to lead to dramatic tumor shrinkage and 
hearing improvement in NF2 patients with VS.8,10,11 Sporadic responses of meningiomas to 
bevacizumab have been reported,12 and trials with angiogenesis inhibitors for sporadic 
meningiomas are ongoing. 
 
PDGFRβ: Schwann cells express PDGFRα and PDGFRβ.13 Signaling through these receptors 
activates the RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways, and is important for 
Schwann cell proliferation in vivo and in vitro.14-16 Overexpression of PDGFRβ has been 
observed in VS,17-19 and PDGFR inhibitors including AG1296, imatinib and nilotinib are 
effective in preventing PDGFR-driven proliferation when tested in VS in vitro models.17,20 
c-KIT: VS express activated c-KIT and are growth-inhibited by imatinib19 and nilotinib.20 


 
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In summary, the molecular target profile of axitinib makes it a promising drug candidate 
for clinical study in NF2 patients with progressive VS. Although the potency of axitinib in 
inhibiting  PDGFR and c-KIT is significantly lower than VEGFR1/2/3,5 preclinical data 
indicates accumulation of axitinib in brain tissue,5 and similarly, we have observed tumor tissue 
to plasma ratio of 4.3 +/-1.9 in human VS tissue treated with the EGFR/ErbB2 receptor tyrosine 
kinase inhibitor lapatinib (Karajannis, et. al, Neuro-Oncology 14:i19, 2012 [abstract]).  
The favorable toxicity profile and tolerability of axitinib compared to other multi-kinase 
inhibitors is advantageous for potential long-term administration in NF2. Over the past 4 years, 
we have shown that we can successfully conduct and complete single-institution Phase 2 
clinical trials in the NF2 population using molecular targeted agents including lapatinib and 
everolimus (ClinicalTrials.gov NCT00973739 and NCT01419639).21 
2 Key Eligibility Criteria 
1) Age ≥5 years 
2) Clinically (NIH or Manchester criteria) or genetically confirmed diagnosis of NF2  
3) Karnofsky (for >16 years) or Lansky (≤16 years) performance status of  ≥60 
4) Disease criteria: 
• At least one volumetrically measurable NF2-related VS (histological confirmation not 
required) 
• MRI evidence of progression over the past 18 months, OR progressive hearing loss 
5) Adequate organ system function (bone marrow, renal, hepatic) 
3 Research Strategy 
Primary Objective: To estimate the objective volumetric response rates to axitinib in pediatric 
and 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. 
Drug Dosage and Administration (adult patients, age ≥18 years): 5 mg axitinib PO BID, 
with increase to 7 mg PO BID and 10 mg BID 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. 
Drug Dosage and Administration (pediatric patients, age <18 years): 2.4 mg/m2 axitinib 
PO BID, with increase to 3.2 mg/m2 PO BID after 2 weeks, provided no adverse reactions (i.e., 
not exceeding grade 2 toxicities) and normotensive and not receiving antihypertensive 
medications. Axitinib will be given continuously in 28-day cycles using a dosing nomogram 
shown in Section 7.3.1. The maximal dose of 3.2 mg/m2 PO BID exceeds the recommended 
phase 2 dose from the pediatric phase 1 trial, with the rationale that young NF2 patients, who 


 
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are generally not pre-treated with myelotoxic chemotherapy are likely to tolerate a higher dose 
of axitinib compared to the heavily pre-treated, refractory cancer patients enrolled on the 
pediatric phase 1 study [J Clin Oncol 34, 2016 (suppl; abstr 10558)]. Similar to adult patients 
on this study, the option to escalate the dose is intended to optimize secondary target inhibition 
and therefore increase the likelihood of responses. 
Study Assessments: MRIs including volumetrics and audiograms at baseline and after every 
3rd cycle (i.e. 12 weeks). Monthly study visits including H&P, neurological examination and 
standard laboratory evaluations. Quality of life assessments (NFTI-QOL) at baseline and cycle 
6. 
Treatment Duration: Until radiographic progression or unacceptable toxicity. 
4 Endpoints/Statistical Considerations 
Volumetric tumor response by the end of cycle 12 is the primary endpoint. Response and 
progression are defined as ≥20% decrease or increase in tumor volume, respectively.22 
To evaluate the volumetric tumor response, a 2-stage Simon design will be used.23 Axitinib will 
be considered not of sufficient interest for further evaluation if the true response rate is 5% (p0) 
or less and considered active if the true response rate is 25% or greater (p1). With beta 
(probability of rejecting axitinib with true response rate 5%) set at 0.2 and alpha (probability of 
failing to reject a treatment with response probability of 25%) set at 0.05, the required sample 
size is 9 patients for stage 1 and an additional 8 patients for stage 2, (optimal and minimax 
design) . If there are no responses after the first stage is completed, axitinib will be deemed 
ineffective and the trial terminated. Recruitment will be halted after the 9th evaluable patient is 
enrolled (stage 1) until at least one response is observed during the first 12 cycles. Axitinib will 
be considered effective and of interest for further study if after successful completion of both 
stages, the cumulative number of responses is ≥3. Using this 2-stage design, the probability of 
early termination is 0.63 if the true response rate to axitinib is 5%.  
Secondary endpoints include hearing response (rise of the word recognition score above the 
95% critical difference interval from baseline) and quality of life assessments (NFTI-QOL).24 
5 Proposed Sample Size and Timeline for Recruitment 
A maximum of 17 evaluable subjects will be accrued to this study. According to our initial 
estimates, and based on our prior experience with lapatinib and everolimus phase 2 trials for 
adults and children with an average accrual rate of >2 patients per month, the expected accrual 
period was approximately 12 months. However, the widespread use of bevacizumab on clinical 
trials and off-label, has rendered a large number of NF2 patients ineligible for this study, 
resulting in slower than expected accrual. The protocol was amended to include pediatric 
patients after pediatric phase 1 data became available, to increase enrollment. 


 
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6 Study Objectives 
Primary 
• To estimate the volumetric response rates to axitinib in patients with NF2-related vestibular 
schwannomas (VS). 
Secondary 
• 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. 
7 Investigational Plan 
7.1 Study Design and Treatment 
• Multi Center, 2-stage, phase II open-label study 
• Planned treatment: Axitinib PO taken continuously until disease progression or 
unacceptable toxicity: 
o Staring dose (dose level 0): 5 mg PO twice daily (approx. 12 hours apart) for 
adult patients (≥18 years of age) and 2.4 mg/m2 axitinib PO BID for pediatric 
patients (<18 years of age). 
o Dose titration: Axitinib dose should be individually titrated up or down from the 
starting dose based on patient tolerance, as outlined in Section 7.3. 
• Response Evaluations: MRI brain and spine (with 3D volumetrics) and audiograms (if 
applicable) at baseline and after every 3rd course (cycle), i.e. every 12 weeks. Spine MRI 
will be performed only in patients with known spinal tumors with medically relevant or 
symptomatic lesions. 


 
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The overall study design is shown in the following schema: 
 
 
 
7.2 Study Population 
7.2.1 Patient population 
Minimum of 9, maximum of 17 evaluable patients (based on observed volumetric responses, 2-
stage study design, see Section 11) 
7.2.2 Inclusion and exclusion criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. Results of all baseline evaluations, which assure that 
all inclusion and exclusion criteria have been satisfied, must be reviewed by the Principal 
Investigator or his/her designee prior to enrollment of that patient. In addition, the patient must 
be thoroughly informed about all aspects of the study, including the study visit schedule and 
required evaluations and all regulatory requirements for informed consent. The written 
informed consent must be obtained from the patient (or legal guardian for minors, as applicable) 
prior to enrollment. The following criteria apply to all patients enrolled onto the study unless 
otherwise specified. 
BASELINE MRI  
AND AUDIOGRAM 
STUDY 
ENTRY 
COURSE 1–3 (12 weeks) 
of axitinib 
RESPONSE EVALUATION 
MRI AND AUDIOGRAM* 
STABLE DISEASE OR BETTER 
(PRIMARY TARGET TUMOR) 
PROGRESSIVE DISEASE 
(PRIMARY TARGET TUMOR) 
or unacceptable toxicity 
* Response evaluation after every 
 three courses until disease progression 
or unacceptable toxicity. 
Continue axitinib 
 
OFF STUDY 


 
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Inclusion criteria 
• Age ≥5 years 
• Meets clinical diagnostic criteria for NF2 or genetically conformed 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)22 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 (>16 years of age) or Lansky (≤16 years of age) 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: ANC ≥1.5 x 109/L, Platelets ≥100 x 109/L, 
Hb >9 g/dL 
• Adequate liver function as shown by: 
• serum bilirubin ≤1.5 x 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 swallow tablets 
• Able to provide signed informed consent (or consent provided by legal guardian for 
pediatric patients, as applicable) 
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 VEGF or VEGFR 


 
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• 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.  Please refer to the list in Appendix I. 
• 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 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 


 
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7.2.3 Description of the Recruitment Process 
Patients who are evaluated for NF-2 related vestibular schwannomas at the approved 
study sites may be considered potential study candidates and will be advised 
about the study by their physicians. Physicians not included as approved 
study investigators may refer their patients for enrollment on this study, and 
if the patient provides their permission, can provide the patients’ contact 
information to study team members so that they can contact the potential 
participant to discuss the study. If patients are interested in participating, 
they will be asked to provide informed consent as described in Section 8. 
7.2.4 Monitoring of axitinib suspected toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value suspected to be related to axitinib must be followed at least weekly 
until the adverse event or abnormal laboratory resolves or returns to grade 1. If a patient requires 
a dose delay of > 21 days from the intended day of the next scheduled dose, then the patient 
must be discontinued from the study. 
All interruptions or changes to study drug administration must be recorded. 
It will be documented whether or not each patient completed the clinical study. If for any patient 
either study treatment or observations were discontinued the reason will be recorded. Reasons 
that a patient may discontinue participation in a clinical study are considered to constitute one 
of the following: 
1. adverse event(s) 
2. abnormal laboratory value(s) 
3. abnormal test procedure result(s) 
4. disease progression 
5. protocol violation 
6. subject withdrew consent 
7. lost to follow-up 
8. administrative problems 
9. death 
7.3 Treatment 
7.3.1 Axitinib administration 
The study drug axitinib will be self-administered. The investigator will instruct the patient to 
take the study drug exactly as specified in the protocol. Axitinib should be administered orally 
twice daily, approximately 12 hours apart, preferably in the morning and evening, at 
approximately the same time every day with or without food. Axitinib should be swallowed 
whole with a glass of water. If the patient vomits or misses a dose, an additional dose should 
not be taken. The next prescribed dose should be taken at the usual time. 


 
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Axitinib will be provided by Pfizer, Inc. Two strengths of tablets (1 mg and 5 mg) are being 
used in the clinical program and approved for use in those countries in which axitinib (Inlyta®) 
is marketed. All tablets contain common compendial excipients and film-coating materials. The 
tablets will be packaged in appropriate packaging material and stored at room temperature. 
Axitinib PO will be taken continuously until disease progression or unacceptable toxicity, in 
continuous treatment cycles of 28 days each (maximum of 12 cycles): 
Adult patients (≥18 years of age) 
o Starting dose (dose level 0): 5 mg PO twice daily (approx. 12 hours apart) 
o Dose titration: Adult patients who tolerate axitinib with no adverse events related to 
axitinib above CTCAE Grade 2 for consecutive 2 week periods, are normotensive, and are 
not receiving anti-hypertension medication, should have their dose increased by one dose 
level until dose level +2 is reached. Axitinib dose should be individually titrated up or 
down from the starting dose based on patient tolerance: 
Dose Level 
Total dose [mg] 
BID 
5 mg tabs 
BID 
1 mg tabs 
BID 
+2 
10 
2 
 
+1 
7 
1 
2 
0 
5 
1 
 
-1 
3 
 
3 
-2 
2 
 
2 
 
Pediatric Patients (<18 years of age) 
o Starting dose (dose level 0): 2.4 mg/m2 PO twice daily (approx. 12 hours apart) 
o Dose titration: Pediatric patients who tolerate axitinib with no adverse events related to 
axitinib above CTCAE Grade 2 for2 weeks , are normotensive, and are not receiving anti-
hypertension medication, should have their dose increased by one dose level (Dose level + 
1, 3.2 mg/m2/dose). Hypertension in the pediatric patients is defined as systolic or diastolic 
BP >95th percentile for age, height, and sex. Axitinib dose should be individually titrated 
up or down from the starting dose based on patient tolerance. Dosing will be based using 
a nomogram as shown below: 


 
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Axitinib 1.8 mg/m2 BID (Dose Level -1 
BSA (m2) 
Total Daily Dose 
(mg/day) 
mg q am 
mg q pm 
0.53-0.72 
2 
1 
1 
0.73-0.97 
3 
2 
1 
0.98-1.25 
4 
2 
2 
1.26-1.52 
5 
3 
2 
1.53-1.80 
6 
3 
3 
1.81-2.08 
7 
4 
3 
   ≥2.09 
8 
4 
4 
 
Axitinib 2.4 mg/m2 BID (Dose Level 0) 
BSA (m2) 
Total Daily Dose 
(mg/day) 
mg q am 
mg q pm 
0.53-0.72 
3 
2 
1 
0.73-0.93 
4 
2 
2 
0.94-1.14 
5 
3 
2 
1.15-1.35 
6 
3 
3 
1.36-1.56 
7 
4 
3 
1.57-1.77 
8 
4 
4 
1.78-1.97 
9 
5 
4 
>1.98 
10 
5 
5 
 
Axitinib 3.2 mg/m2 BID (Dose Level +1) 
BSA (m2) 
Total Daily Dose 
(mg/day) 
mg q am 
mg q pm 
0.53-0.70 
4 
2 
2 
0.71-0.85 
5 
3 
2 
0.86-1.01 
6 
3 
3 
1.02-1.17 
7 
4 
3 
1.18-1.32 
8 
4 
4 
1.33-1.48 
9 
5 
4 
1.49-1.64 
10 
5 
5 
1.65-1.79 
11 
6 
5 
≥1.80 
12 
6 
6 
7.3.2 Interruption or discontinuation of treatment 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to keep the patient on study drug. If administration of axitinib must be 
interrupted because of unacceptable toxicity, drug dosing will be interrupted or modified 
according to rules described in Section 7.3.3. Dose Toxicity will be assessed using the NIH-
NCI 
Common 
Terminology 
Criteria 
for 
Adverse 
Events, 
version 
4.0 
(CTCAEv4.0,http://evs.nci.nih.gov/ftp1/CTCAE/). 
 


 
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7.3.3 General criteria for dose-modification of axitinib 
General criteria for dose-modification in case of suspected axitinib toxicity and re-initiation of 
axitinib treatment 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2  
 
If the toxicity is tolerable to the patient, maintain the same 
dose.If the toxicity is intolerable to patient, interrupt 
axitinib until recovery to grade ≤1. Then reintroduce 
axitinib at same dose. 
If event returns to grade 2, then  interrupt axitinib until 
recovery to grade ≤1. Then reintroduce axitinib at the 
lower dose level. 
Grade 3 
 
Interrupt axitinib until recovery to grade ≤1. Then 
reintroduce axitinib at the lower dose level. For 
pneumonitis consider the use of a short course of 
corticosteroids. 
Grade 4 
Discontinue axitinib. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75, ≥50x109/L)  
Interrupt axitinib until recovery to grade ≤1 (>75 x109/L). 
Then reintroduce axitinib at initial dose. 
If thrombocytopenia again returns to grade 2,  interrupt 
axitinib until recovery to grade ≤1. Then reintroduce 
axitinib at the lower dose level.  
Grade 3 Thrombocytopenia (platelets <50, ≥25 x10 9/L) 
Interrupt axitinib until recovery to grade ≤1 (platelets ≥75 
x109/L).  Then resume  axitinib at one dose level lower.  If 
grade 3 thrombocytopenia recurs, discontinue axitinib. 
Grade 4 Thrombocytopenia (platelets <25 x109/L) 
Discontinue axitinib. 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt axitinib until recovery to grade ≤1 (neutrophils 
≥1.5 x 109/L). Then resume axitinib at the initial dose.  If 
ANC again returns to Grade 3, hold axitinib until the 
ANC ≥1.5 x 109/L.  Then resume axitinib dosing at the 
lower dose level.  Discontinue patient from study therapy 
for a third episode of grade 3 neutropenia. 
Grade 4 Neutropenia (neutrophils <0.5 x109/L) 
Interrupt axitinib until recovery to grade ≤1 (neutrophils 
≥1.5 x 109/L). Then resume axitinib at the lower dose level. 
If grade 3 or grade 4 neutropenia occurs despite this dose 
reduction, discontinue axitinib. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt axitinib until resolution of fever and 
neutropenia to grade ≤1. Hold further axitinib until the 
ANC ≥1,500/mm3 and fever has resolved. Then resume 
axitinib at the lower dose level. If febrile neutropenia 
recurs, discontinue axitinib. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue axitinib. 
Any hematological or non-hematological toxicity requiring interruption for 
≥3 weeks 
Discontinue axitinib 
 
 


 
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7.3.4 Precautions and management of specific toxicities 
Hypertension 
In Phase 3 study A4061032 with axitinib for the treatment of patients with RCC, hypertension 
was reported in 145/359 patients (40%) receiving axitinib. Grade 3 hypertension was observed 
in 55/359 patients (15%) and Grade 4 hypertension was observed in 1/359 patients (<1%) 
receiving axitinib. Hypertensive crisis was reported in 2/359 patients (<1%). The median onset 
time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 
mmHg) was within the first month of the start of axitinib and blood pressure increases have 
been observed as early as 4 days after starting axitinib. Hypertension was managed with 
standard antihypertensive therapy. Discontinuation of axitinib treatment due to hypertension 
occurred in 1/359 patients (<1%)[Information from Investigator’s Brochure, September 2012]. 
Blood pressure should be well-controlled prior to initiating axitinib. Patients should be 
monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In 
the case of persistent hypertension despite use of anti-hypertensive medications, the axitinib 
dose should be reduced. For patients who develop severe hypertension, temporarily interrupt 
axitinib treatment and restart at a lower dose once the patient is normotensive (see Section 
7.3.3). If axitinib is interrupted, patients receiving antihypertensive medications should be 
monitored for hypotension. 
Thyroid dysfunction 
In Phase 3 study A4061032 with axitinib for the treatment of patients with RCC, 
hypothyroidism was reported in 69/359 patients (19%) receiving axitinib. Hyperthyroidism was 
reported in 4/359 patients (1%). In patients who had thyroid stimulating hormone (TSH) <5 
μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) 
receiving axitinib. 
Thyroid function will be monitored before initiation of, and periodically throughout, treatment 
with axitinib. Hypothyroidism and hyperthyroidism should be treated according to standard 
medical practice to maintain euthyroid state. 
Arterial thromboembolic events 
In Phase 3 study A4061032 with axitinib for the treatment of patients with RCC, Grade 3/4 
arterial thromboembolic events were reported in 4/359 patients (1%) receiving axitinib. The 
most frequent arterial thromboembolic event was transient ischemic attack (1%). Fatal 
cerebrovascular accident was reported in 1/359 patients (<1%). 
In monotherapy studies with axitinib, arterial thromboembolic events (including transient 
ischemic attack, cerebrovascular accident, myocardial infarction, cerebral infarction, arterial 
embolism, lucunar infarction, and retinal artery occlusion) were reported in 16/699 subjects 
(2%). 
Axitinib should be used with caution in patients who are at risk for, or who have a history of, 
these events. Axitinib has not been studied in patients who had an arterial thromboembolic event 
within the previous 12 months. 


 
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Venous thromboembolic events 
In Phase 3 study A4061032 with axitinib for the treatment of patients with RCC, venous 
thromboembolic events were reported in 11/359 patients (3%) receiving axitinib. Grade 3/4 
venous thromboembolic events (including pulmonary embolism, deep vein thrombosis, and 
retinal-vein occlusion/thrombosis) were reported in 9/359 patients (3%). Fatal pulmonary 
embolism was reported in 1/359 patients (<1%). 
Axitinib should be used with caution in patients who are at risk for, or who have a history of, 
these events. Axitinib has not been studied in patients who had a venous thromboembolic event 
within the previous 6 months. 
Elevation of hemoglobin or hematocrit 
Increases in hemoglobin or hematocrit, reflective of increases in red blood cell mass, may occur 
during treatment with axitinib. An increase in red blood cell mass may increase the risk of 
thromboembolic events. 
In Phase 3 study A4061032 with axitinib for treatment of patients with RCC, elevated 
hemoglobin above the upper limit of normal (ULN) was observed in 31/320 patients (10%) 
receiving axitinib. 
Monitoring of hemoglobin/hematocrit will be performed before initiation of, and periodically 
throughout, treatment with axitinib. If hemoglobin or hematocrit becomes elevated above the 
normal level, patients should be treated according to standard medical practice to decrease 
hemoglobin or hematocrit to an acceptable level. 
Hemorrhage 
In Phase 3 study A4061032 with axitinib for the treatment of patients with RCC, hemorrhagic 
events were reported in 58/359 patients (16%) receiving axitinib. The most common 
hemorrhagic events in patients treated with axitinib were epistaxis (6%), hematuria (3%), 
hemoptysis (2%), and rectal hemorrhage (2%). Grade 3/4 hemorrhagic events (including 
cerebral hemorrhage, haematuria, hemoptysis, lower gastrointestinal hemorrhage, and melaena) 
were reported in 5/359 (1%) patients. Fatal hemorrhage (gastric hemorrhage) was reported in 
1/359 patients (<1%) receiving axitinib. 
Axitinib has not been studied in patients who have evidence of untreated brain metastasis or 
recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding 
requires medical intervention, temporarily interrupt the axitinib dose. 
Gastrointestinal perforation and fistula formation 
In Phase 3 study A4061032 with axitinib for the treatment of patients with RCC, gastrointestinal 
perforation was reported in 1/359 patients (<1%) receiving axitinib. In addition to cases of 
gastrointestinal perforation, fistulas were reported in 2/359 patients (1%). In monotherapy 
studies with axitinib (N=699), fatal gastrointestinal perforation was reported in 1/699 patient 
(<1%). 
Monitoring for symptoms of gastrointestinal perforation should be performed throughout 
treatment with axitinib. 


 
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Wound healing complications 
No formal studies of the effect of axitinib on wound healing have been conducted. In Phase 3 
study A4061032 with axitinib for the treatment of patients with RCC, all-causality adverse 
events suggestive of wound healing complications were reported in 4/359 patients (1%). 
Treatment with axitinib should be stopped at least 24 hours prior to scheduled surgery. The 
decision to resume axitinib therapy after surgery should be based on clinical judgment of 
adequate wound healing. 
Reversible posterior leukoencephalopathy syndrome/posterior reversible 
encephalopathy syndrome 
In Phase 3 study A4061032 with axitinib for the treatment of patients with RCC, reversible 
posterior leukoencephalopathy syndrome (RPLS)/posterior reversible encephalopathy 
syndrome (PRES) was reported in 1/359 patients (<1%). 
RPLS/PRES is a neurological disorder which can present with headache, seizure, lethargy, 
confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension 
may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of 
RPLS/PRES. In patients with signs/symptoms of RPLS/PRES, temporarily interrupt or 
permanently discontinue axitinib. The safety of reinitiating axitinib therapy in patients 
previously experiencing RPLS/PRES is not known. 
Proteinuria 
In Phase 3 study A4061032 with axitinib for the treatment of patients with RCC, proteinuria 
was reported in 39/359 patients (11%). Grade 3 or 4 proteinuria was reported in 11/359 patients 
(3%). 
Monitoring for proteinuria will be performed before initiation of, and periodically throughout, 
treatment with axitinib. 
Elevation of liver enzymes 
In the first-in-human dose-finding study A4060010, concurrent elevations of alanine 
aminotransferase [ALT] (12 times the ULN) and bilirubin (2.3 times the ULN), considered to 
be drug-related hepatotoxicity, were observed in 1 patient who received axitinib at a starting 
dose of 20 mg twice daily (4 times the recommended starting dose). In Phase 3 study A4061032 
with axitinib for the treatment of patients with RCC, no concurrent elevations of ALT (>3 times 
the ULN) and bilirubin (>2 times the ULN) were observed for axitinib (N=359). 
ALT, aspartate aminotransferase (AST) and bilirubin will be monitored before initiation of and 
periodically throughout treatment with axitinib. 
Cardiac failure events 
In clinical studies with axitinib for the treatment of patients with renal cell carcinoma, cardiac 
failure events (including cardiac failure, cardiac failure congestive, cardiopulmonary failure, 
left ventricular dysfunction, ejection fraction decreased, and right ventricular failure) were 
reported in 12/672 patients (1.8%) receiving axitinib. Grade 3/4 cardiac failure events were 
reported in 7/672 patients (1.0%) and fatal cardiac failure events were reported in 2/672 
patients (0.3%) receiving axitinib. 


 
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Monitoring for cardiac events will include a physical examination and measuring of vital 
signs at each study visit, in addition to a baseline ECG. Any additional cardiac assessments 
will be performed when clinically indicated.  
7.3.5 Concomitant therapy 
CYP3A4/5 inhibitors/inducers 
In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5. Ketoconazole, a 
strong inhibitor of CYP3A4/5, administered at a dose of 400 mg once daily for 7 days, increased 
the mean area under the curve (AUC) 2-fold and Cmax 1.5-fold of a single 5-mg oral dose of 
axitinib in healthy volunteers[Information from Investigator’s Brochure, September 2012]. Co-
administration of axitinib with strong CYP3A4/5 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, and 
telithromycin) may increase axitinib plasma concentrations. Grapefruit may also increase 
axitinib plasma concentrations. Rifampin, a strong inducer of CYP3A4/5, administered at a 
dose of 600 mg once daily for 9 days, reduced the mean AUC by 79% and Cmax by 71% of a 
single 5-mg dose of axitinib in healthy volunteers. Co-administration of axitinib with strong 
CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, 
rifapentin, phenobarbital, and Hypericum perforatum [also known as St. John’s wort]) may 
decrease axitinib plasma concentrations. Concomitant medication with strong CYP3A4/5 
inhibition potential is therefore not allowed on study.  
Anticoagulants 
Patients who require therapeutic anticoagulant therapy with oral vitamin K antagonists are 
ineligible for enrollment; 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. 
Steroids 
If clinically indicated, short (≤7 days) courses of steroids, such as dexamethasone, are allowed 
for patients with vestibular schwannomas and sudden-onset, transient hearing loss on protocol 
therapy. All such treatments must be documented in the clinical chart and study records. 
7.4 Visit Schedule and Assessments 
Visit schedule and required on-study evaluations are outlined below: 
 


 
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7.4.1 Visit schedule 
Table 3-4  Evaluation and visit schedule 
Examination 
Baseline 
Day† 
Week 
Cycle (each cycle is 28 days) 
 
 
1 
2 
3 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NFTI-QOL# 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI‡ 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Audiogram* 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Free T4/TSH 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
pregnancy 
test** 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC, diff., 
comprehensive 
metabolic 
panel, Mg, 
Phos 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
† Includes drug dispensing and repeat baseline evaluations if time between first screening and 
dispensing exceeds 4 weeks. Otherwise, Day 1 not performed. 
# Only in adult patients ≥18 years of age 
‡ Should be performed at the end of cycle 
*Should be performed at the end of cycle. Not required for patients with no measurable hearing 
**Required for women of childbearing potential within 7 days of starting axitinib 
Additional treatment cycles beyond 12, if applicable, will continue according to the same schedule. 
7.4.2 Efficacy assessments 
Primary efficacy endpoint is best radiographic tumor response (i.e. maximum tumor shrinkage) 
during the first 12 cycles of treatment; secondary efficacy endpoint is audiologic response, as 
defined by the following Response Criteria, which were chosen based on recently published 
recommendations for NF2 clinical trials:22 


 
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Primary: Radiographic response: for study purposes, a ≥20% reduction in tumor volume in 
any of the target tumors will constitute a partial response (PR). Complete disappearance of any 
of the target tumors will constitute a complete response (CR). 
Secondary: Audiologic response: improvement in speech discrimination score (SDS), defined 
as an improvement in the score above the 95% critical difference threshold, compared to 
baseline audiogram at initiation of treatment. Audiologic worsening: decrease in SDS score 
below the 95% critical difference threshold, compared to baseline audiogram at initiation of 
treatment. 
MRI of the brain and spine (in patients with spinal tumors with medically relevant or 
symptomatic lesions) with 3D tumor volumetrics will be performed every 3 months. Patients 
with vestibular schwannomas will receive baseline audiograms within 28 days before 
enrollment and subsequent audiograms at the time of each MRI. If an objective response, 
defined as a 20% reduction in tumor volume compared to baseline is observed in any target 
tumor or stable disease in all target tumors (i.e. less than 20% increase in size), Axitinib will be 
continued. Therapy will be discontinued if the primary target tumor enlarges by 20%. All 
additional target tumors will be monitored for growth or response, but any progression 
in those tumors will not trigger discontinuation of therapy. Audiologic responses will be 
determined, but will not be used as primary response criteria. 
7.4.3 Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to return 
all unused study medication. 
7.4.4 Safety assessments 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine values, regular 
measurement of vital signs and the performance of physical examinations. 
These assessments should be performed within ±2 days of the scheduled day of assessment 
except for adverse events that will be evaluated continuously through the study. Safety and 
tolerability will be assessed according to the NIH/NCI Common Toxicity Criteria 
(CTC)(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf).  
Patients who will discontinue study treatment for any reasons are to be followed until one of 
the following occurs:  
• Thirty days after the last dose of axitinib or until any significant drug-related toxicity resolves, 
whichever is longer; 
• Death; 
• Lost to follow-up after at least two reasonable attempts to contact the patient have been made; 


 
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• Withdrawal of consent for any further data collection or submission; 
• Initiation of any other disease-directed treatment for NF2-related tumors 
7.4.4.1 
Adverse events 
Information about all adverse events (AEs), whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after starting study drug. Abnormal laboratory values 
or test results constitute adverse events only if they induce clinical signs or symptoms, are 
considered clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. the severity grade (mild, moderate, severe) or (grade 1─4) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
5. whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include changes in study 
drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
7.4.4.2 
Serious adverse events 
A serious adverse event (SAE) is an undesirable sign, symptom or medical condition which: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 


 
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• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient begins taking study drug and until 4 weeks after the patient has stopped study treatment 
must be reported to Pfizer immediately upon learning of its occurrence. Any SAEs experienced 
after this 4-week period should only be reported to Pfizer if the investigator suspects a causal 
relationship to the study drug. Recurrent episodes, complications, or progression of the initial 
SAE must be reported as follow-up to the original episode within 24 hours of the investigator 
receiving the follow-up information. An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one should be reported separately as 
a new event. 
7.4.5 Instructions for rapid notification of serious adverse events 
The principal investigator has the obligation to report all serious adverse events to the FDA, 
IRB, and Pfizer. 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 3500A 
(MedWatch Form).  
From the time that the subject receives the first dose of axitinib and including 28 calendar 
days after the last administration, all events must be reported to Pfizer within 24 hours of 
learning of its occurrence. Furthermore, serious adverse events must be reported 
immediately upon awareness if the SAE is fatal or life-threatening —regardless of the 
extent of available information.  
Like an SAE, all other reportable events must be reported to Pfizer within 24 hours of 
awareness on an IIR SAE Form (or other agreed reporting method) and followed up to 
determine outcome, including the later occurrence of an associated SAE..  
Any serious adverse event occurring after the patient has provided informed consent and until 
4 weeks after the patient has stopped study participation must be reported to the Institutional 
Review Board. 
Serious adverse events occurring more than 4 weeks after study discontinuation need only be 
reported if a relationship to the Pfizer study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 


 
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7.4.5.1 
Pregnancies 
Any pregnancy that occurs during study participation should be reported. To ensure patient 
safety each pregnancy must also be reported to Pfizer within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
7.4.6 Laboratory evaluations 
Schedule and timing of all laboratory evaluations are listed in Table 3-4. 
Pregnancy Test 
A serum pregnancy test is required for all females of child-bearing potential within 7 days prior 
to the first dose of axitinib and during treatment. 
Hematology 
Hematology must include hemoglobin, hematocrit, platelets, total white blood cell count 
(WBC) and differential. PT (INR) evaluation will be mandatory at baseline only. 
Blood chemistry 
Blood chemistry must include a comprehensive metabolic panel (sodium, potassium, chloride, 
bicarbonate, calcium, glucose, creatinine, blood urea nitrogen, albumin, total protein, SGOT 
(AST), SGPT (ALT), total bilirubin, alkaline phosphatase), as well as magnesium and 
phosphorus. 
Urinalysis 
Standard urinalysis dipstick assessment (pH, protein, glucose, blood, ketones, and leukocytes) 
will be performed. This must be supplemented with laboratory quantification of any potentially 
relevant abnormalities. 
 
Sample Storage and Genetic Testing 
Samples will not be stored for future use and will not be used for genetic testing.  
7.4.6.1 
Vital signs 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight. Blood pressure, pulse and respiration rate should be measured on 
patients after at least 3 minutes in the sitting position 
7.4.6.2 
Physical examination 
Physical examination will be performed which must comprise a neurological examination. 
Significant findings made after the start of study drug which meet the definition of an Adverse 
Event must be recorded. 
7.4.6.3 
ECG 
A standard 12 lead ECG is to be performed during screening and significant findings must be 
recorded. 


 
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7.4.6.4 
Performance status 
Performance status (PS) will be assessed using the Karnofsky scale for patients >16 years and 
Lansky scale for patients ≤16 years of age. 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. 
7.4.6.5 
Drug levels and pharmacokinetic assessments 
None. 
7.4.6.6 
NFTI-QOL (Neurofibromatosis 2 Impact on Quality of Life) 
At Baseline, 6-months, and off-study, adult subjects (≥18 years of age) will be asked to 
complete the validated NFTI-QOL,24 to assess the impact of their disease on their ability to 
perform activities of daily life. The questionnaire has not been validated in pediatric NF2 
patients. 
7.4.6.7 
MRI and audiogram 
MRI (including volumetrics) and audiogram, i.e. efficacy assessments, will be obtained at 
baseline and after every 3rd cycle, as previously described21 and outlined in Section 7.4.1. 
 
8 Protocol Amendments, or Changes in Study Conduct 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by Pfizer and the investigator before implementation. 
Amendments significantly affecting the safety of subjects, the scope of the investigation or the 
scientific quality of the study require additional approval by the IRB.  A copy of the written 
approval of the IRB must be provided to Pfizer. Examples of amendments requiring such 
approval are: 
1. increases in drug dose or duration of exposure of subjects, 
2. significant changes in the study design (e.g. addition or deletion of a control group), 
3. increases in the number of invasive procedures, 
4. addition or deletion of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Pfizer in the interests of preserving the safety of all patients 
included in the trial.  If an immediate change to the protocol is felt to be necessary by the 
investigator and is implemented for safety reasons, Pfizer must be notified and the IRB at the 
center must be informed immediately.   Amendments affecting only administrative aspects of 
the study do not require formal protocol amendments or IRB approval but the IRB must be kept 
informed of such administrative changes.  
 


 
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Examples of administrative changes not requiring formal protocol amendments and IRB 
approval include: 
1. changes in the staff used to monitor trials 
2. minor changes in the packaging or labeling of study drug 
 
9 Description of the Informed Consent/Assent Process 
Patients will be recruited by physicians at NYULMC and approved study sub-sites. 
Consenting will take place under the direct supervision of the PI or one of the approved study 
co-investigators. Prospective subjects will receive detailed information about this study and its 
investigational nature. They will also be informed about risks and potential benefits of the 
study. All questions will be answered by the PI or one of the approved study co-investigators. 
All patients (or their legal guardian for pediatric patients, as applicable) will sign an IRB-
approved informed consent detailing the patient’s protection of human subjects involved in 
clinical trials. In addition, assent will be sought from pediatric patients ≥7 years of age. All 
subjects will receive a copy of their signed consent/assent form. The IRB-approved informed 
consent document will also be signed by one of the approved study investigators. This process 
as well as patient eligibility will be documented in the medical record. This study will be 
conducted in accordance with the Declaration of Helsinki and in compliance with all 
applicable laws and regulations of the locale where the study is conducted. 
It is the responsibility of the PI and study investigators that the patient is made aware and 
consent is given that personal information may be scrutinized during audits by competent 
authorities and properly authorized persons, but that personal information will be treated as 
strictly confidential and not be publicly available. The investigator is responsible for the 
retention of the patient log and patient records. 
 
10  Withdrawal from the Protocol 
Volunteers may discontinue participation in the study at any time without penalty or loss of 
benefits to which the volunteer is otherwise entitled.  
If a patient decides to withdraw his/her consent, we will ask that he/she contact Dr. Theodore 
Nicolaides and let her know that he/she is withdrawing from the study. Her mailing address is 
160 East 32nd Street, 2nd Floor, New York, NY 10016. If he/she wishes to withdraw his/her 
Authorization as well he/she must contact Dr. Theodore Nicolaides in writing.  
Remember that withdrawing Authorization only affects uses and sharing of information after 
the subject’s written request has been received, and he/she may not withdraw his/her 
Authorization for uses or disclosures that we have previously made or must continue to make 
to complete analyses or report data from the research 
 
 


 
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11  Data Management and Collection 
The investigators will record all information required by the protocol.  
11.1 Confidentiality 
Each subject enrolled will, from that point forward, be identified by a unique identifier 
(subject number). This subject number will also be used for research specimens collected and 
shipped to analysts outside of the study sites. All records generated will be stored in a locked 
office area, only accessible to study personnel. Clinical information will be accessed, 
according to HIPAA requirements, by study personnel to complete study documents, as 
needed. 
Only the PI and the study coordinator will have access to the log linking the subject number to 
the patient name, birth date and medical record number. The log will be kept in a locked 
drawer in the study coordinator’s office. A secure password-protected computer file will be 
generated as well.  
Medical records will be kept in accordance with state and federal laws concerning the privacy 
and confidentiality of medical information. Each participant in this research study may be 
asked to sign a separate informed consent document for specific procedures or treatment, and 
that informed consent form may be included in the medical record of that facility. The 
confidentiality of each volunteer’s medical record is also protected by federal privacy 
regulations, as described below. 
Study records include information that identifies the patient and that is kept in research files. 
All efforts will be made to keep this information confidential, but it cannot be guaranteed. If 
data from this study are to be published or presented, all information that identifies the patient 
will be first taken out. Volunteers will be informed of all protected health information used in 
this study. The consent form will seek written permission from the participant to use and 
disclose the following information for this research. The volunteer is required to sign this 
form. This Authorization will not expire unless the volunteer withdraws it in writing. The 
volunteer has the right to withdraw authorization at any time, except to the extent that 
NYULMC has already relied upon it or must continue to use the information to complete data 
analysis or to report data for this study. 
 
12  Data Monitoring 
12.1 
Monitoring Plan 
An internal Data and Safety Monitoring Committee (DSMC) of the NYUCI is the monitoring 
board for this study. The committee will review safety at scheduled intervals (not less than 
once/year) and at the time of planned interim analyses according to the NYUCI DSMC Charter. 
As described further in the “Statistical Methods” section of this protocol, an interim analysis 
will be done after stage 1 is completed (9 evaluable patients have been enrolled). 


 
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12.2 
Stopping Rules 
If safety concerns arise, the DSMC will identify these concerns and recommend modification 
or termination of the clinical trial. As described further in the “Statistical Methods” section of 
this protocol, if the number of responses is <1 after the first stage is completed, axitinib will be 
deemed ineffective and the trial terminated. Recruitment will be halted after the 9th evaluable 
patient is enrolled (stage 1) until at least one response is observed. 
13  Statistical Methods 
To evaluate efficacy, radiographic response is treated as a binary variable whereby patients who 
achieve either a CR or a PR in any of the target tumors at any point within 12 months from 
beginning of therapy are considered responders and all others nonresponders.. A 2-stage Simon 
design will be used 23. Axitinib will be considered not of sufficient interest for further evaluation 
if the true response rate is 5% (p0) or less and considered active if the true response rate is 25% 
or greater (p1). With beta (probability of rejecting axitinib with true response rate 5%) set at 0.2 
and alpha (probability of failing to reject a treatment with response probability of 25%) set at 
0.05, the required sample size is 9 patients for stage 1 and an additional 8 patients for stage 2.If 
there are no responses after the first stage is completed, axitinib will be deemed ineffective and 
the trial terminated. Recruitment will be halted after the 9th evaluable patient is enrolled (stage 
1) until at least one response is observed during the first 12 cycles. Axitinib will be considered 
effective and of interest for further study if after successful completion of both stages, the 
cumulative number of responses is ≥3. Using this 2-stage design, the probability of early 
termination is 0.63 if the true response rate to axitinib is 5%. 
 
 
 
 
 
 
 
 
 
Disease and patient characteristics at baseline will be summarized using descriptive statistics. 
For qualitative variables, frequency distributions and proportions will be provided; for 
quantitative variables, summary statistics (e.g., mean, median, quartiles, standard deviations, 
etc.) and graphical displays (e.g., boxplots).  Overall response rates will be estimated upon 
completion of the study along with exact 95% confidence intervals. 
Secondary endpoints: Audiologic responses will be summarized over time using descriptive 
statistics and graphical displays. Similarly, quality of life will be summarized over time in these 
patients.  
Stage 
Cumulative number of 
patients with radiographic 
responses 
Decision 
Stage 1: 
enter 9 patients 
0 
Terminate the trial: 
agent ineffective 
1 or more 
Inconclusive result: 
continue trial (proceed to Stage 2) 
Stage 2: 
enter 8 additional 
patients 
2 or less 
Terminate the trial: 
agent ineffective 
3 or more 
Terminate the trial: 
agent effective 


 
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14  References 
1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus 
sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. Dec 
3 2011;378(9807):1931-1939. 
2. Evans DG, Huson SM, Donnai D, et al. A clinical study of type 2 neurofibromatosis. Q J 
Med. Aug 1992;84(304):603-618. 
3. Blakeley JO, Evans DG, Adler J, et al. Consensus recommendations for current treatments 
and accelerating clinical trials for patients with neurofibromatosis type 2. Am J Med Genet 
A. Jan 2012;158A(1):24-41. 
4. Tos M, Stangerup SE, Caye-Thomasen P, Tos T, Thomsen J. What is the real incidence of 
vestibular schwannoma? Arch Otolaryngol Head Neck Surg. Feb 2004;130(2):216-220. 
5. Poller B, Iusuf D, Sparidans RW, Wagenaar E, Beijnen JH, Schinkel AH. Differential 
impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on 
axitinib brain accumulation and oral plasma pharmacokinetics. Drug metabolism and 
disposition: the biological fate of chemicals. May 2011;39(5):729-735. 
6. Uesaka T, Shono T, Suzuki SO, et al. Expression of VEGF and its receptor genes in 
intracranial schwannomas. J Neurooncol. Jul 2007;83(3):259-266. 
7. Caye-Thomasen P, Werther K, Nalla A, et al. VEGF and VEGF receptor-1 concentration in 
vestibular schwannoma homogenates correlates to tumor growth rate. Otol Neurotol. Jan 
2005;26(1):98-101. 
8. Plotkin SR, Stemmer-Rachamimov AO, Barker FG, 2nd, et al. Hearing improvement after 
bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. Jul 23 
2009;361(4):358-367. 
9. Wong HK, Lahdenranta J, Kamoun WS, et al. Anti-vascular endothelial growth factor 
therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors. 
Cancer research. May 1 2010;70(9):3483-3493. 
10. Mautner VF, Nguyen R, Knecht R, Bokemeyer C. Radiographic regression of vestibular 
schwannomas induced by bevacizumab treatment: sustain under continuous drug 
application and rebound after drug discontinuation. Ann Oncol. Nov 2010;21(11):2294-
2295. 
11. Mautner VF, Nguyen R, Kutta H, et al. Bevacizumab induces regression of vestibular 
schwannomas in patients with neurofibromatosis type 2. Neuro Oncol. Jan 2010;12(1):14-
18. 
12. Goutagny S, Raymond E, Sterkers O, Colombani JM, Kalamarides M. Radiographic 
regression of cranial meningioma in a NF2 patient treated by bevacizumab. Annals of 
oncology : official journal of the European Society for Medical Oncology / ESMO. Apr 
2011;22(4):990-991. 
13. Eccleston PA, Funa K, Heldin CH. Expression of platelet-derived growth factor (PDGF) 
and PDGF alpha- and beta-receptors in the peripheral nervous system: an analysis of sciatic 
nerve and dorsal root ganglia. Dev Biol. Feb 1993;155(2):459-470. 


 
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14. Meier C, Parmantier E, Brennan A, Mirsky R, Jessen KR. Developing Schwann cells 
acquire the ability to survive without axons by establishing an autocrine circuit involving 
insulin-like growth factor, neurotrophin-3, and platelet-derived growth factor-BB. The 
Journal of neuroscience : the official journal of the Society for Neuroscience. May 15 
1999;19(10):3847-3859. 
15. Peulve P, Laquerriere A, Paresy M, Hemet J, Tadie M. Establishment of adult rat Schwann 
cell cultures: effect of b-FGF, alpha-MSH, NGF, PDGF, and TGF-beta on cell cycle. 
Experimental cell research. Oct 1994;214(2):543-550. 
16. Monje PV, Rendon S, Athauda G, Bates M, Wood PM, Bunge MB. Non-antagonistic 
relationship between mitogenic factors and cAMP in adult Schwann cell re-differentiation. 
Glia. Jul 2009;57(9):947-961. 
17. Ammoun S, Flaiz C, Ristic N, Schuldt J, Hanemann CO. Dissecting and targeting the 
growth factor-dependent and growth factor-independent extracellular signal-regulated 
kinase pathway in human schwannoma. Cancer Res. Jul 1 2008;68(13):5236-5245. 
18. Fraenzer JT, Pan H, Minimo L, Jr., Smith GM, Knauer D, Hung G. Overexpression of the 
NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation. 
Int J Oncol. Dec 2003;23(6):1493-1500. 
19. Mukherjee J, Kamnasaran D, Balasubramaniam A, et al. Human schwannomas express 
activated platelet-derived growth factor receptors and c-kit and are growth inhibited by 
Gleevec (Imatinib Mesylate). Cancer research. Jun 15 2009;69(12):5099-5107. 
20. Ammoun S, Schmid MC, Triner J, Manley P, Hanemann CO. Nilotinib alone or in 
combination with selumetinib is a drug candidate for neurofibromatosis type 2. Neuro 
Oncol. Jul 2011;13(7):759-766. 
21. Karajannis MA, Legault G, Hagiwara M, et al. Phase II trial of lapatinib in adult and 
pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. 
Neuro Oncol. Sep 2012;14(9):1163-1170. 
22. Plotkin SR, Halpin C, Blakeley JO, et al. Suggested response criteria for phase II antitumor 
drug studies for neurofibromatosis type 2 related vestibular schwannoma. J Neurooncol. 
May 2009;93(1):61-77. 
23. Simon R. Optimal two-stage designs for phase II clinical trials. Controlled clinical trials. 
Mar 1989;10(1):1-10. 
24. Hornigold RE, Golding JF, Leschziner G, et al. The NFTI-QOL: A Disease-Specific Quality 
of Life Questionnaire for Neurofibromatosis 2. Journal of neurological surgery. Part B, 
Skull base. Apr 2012;73(2):104-111. 
 
 
 
 
 


 
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Appendix I 
 
 
List of Strong CYP3A4/5 inhibitors and inducers 
 
Inhibitors 
Inducers 
• Atazanavir  
• Clarithromycin  
• Conivaptan  
• Delavirdine  
• Grapefruit juice  
• Indinavir  
• Itraconazole  
• Ketoconazole  
• Nefazodone  
• Nelfinavir  
• Posaconazole  
• Ritonavir 
• Saquinavir   
• Voriconazole  
• Seville oranges  
• Star fruit products 
• Aprepitant  
• Armodafinil (unknown) 
• Carbamazepine  
• Dabrafenib (unknown)  
• Eslicarbazepine (unknown) 
• Felbamate (unknown) 
• Fosphenytoin  
• Modafinil (unknown) 
• Nevirapine (unknown)  
• Oxcarbazepine (unknown) 
• Pioglitazone (unknown) 
• Phenytoin  
• Phenobarbital  
• Primidone  
• Rifabutin  
• Rifampin  
• Topiramate (unknown) 
• Vemurafenib (unknown)  
• St. John’s Wort