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8.2 justification for exclusions

Due to lack of knowledge of the effects of axitinib on the fetus or on infants, as well as the possibility of teratogenic effects, pregnant and nursing women will be excluded from this trial. Patients with HIV on protease inhibitors are excluded because information on drug interactions of anti-HIV agents with axitinib are lacking. Patients with unstable or serious medical conditions (ongoing or active infection, symptomatic congestive heart failure (AHA Class II or worse),
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements) are excluded due to the possibility that axitinib may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events with respect to axitinib. Patients under the age of 18 will be excluded from study. The effect of axitinib in children may be investigated in studies that exclusively enroll children.
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8.3 study design/endpoints

The primary objective of this study is to conduct a Phase II trial to determine if axitinib is able to be associated with sufficient clinical responses to merit further consideration for use in patients with metastatic pheochromocytoma/paraganglioma. Secondary objectives are to determine the progression-free survival and to explore the relationship of potential biological markers of axitinib activity with clinical outcomes.  
Specifically, to examine the extent of activation of the VEGFR pathway in pheochromocytoma/paraganglioma in a qualitative manner by immunoblot and in a semiquantitative manner by immunohistochemistry staining; and also to assess the effect of axitinib on the VEGFR pathway for patients who have repeat biopsies taken while on treatment.  
The study will be conducted using a phase II optimal design 62**. The objective of the trial will be**
to determine if axitinib is able to be associated with a response rate (PR + CR), which can rule out 5% (that is, p 0 = 0.05) in favor of a more desirable 20% response rate (p1 = 0.20). Using alpha = 0.10 (probability of accepting a poor drug) and beta = 0.10 (probability of rejecting a good drug), initially 12 patients will be enrolled onto the trial. If zero of the 12 patients respond, then accrual will end, and we will conclude that the agent is unable to demonstrate a response rate that is worthy of further consideration in this population. If 1 or more of 12 patients have a CR or PR, then accrual will continue until a total of 37 patients with measurable disease have been enrolled. If 1-3 of these 37 have a CR or PR, this will be considered inadequate for further investigation, while if 4 or more of 37 have a response, this will warrant further investigation in a subsequent trial. Under the null hypothesis (5% response rate), the probability of early termination is 54%. Primary clinical responses (PR + CR) will be assessed at 12 weeks (+/- 1 week). If zero of 11 patients responded, accrual will stop up to 4 months waiting to evaluate the last patient's response before continuing accrual.
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8.4 sample size/accrual rate

The accrual ceiling to the trial will be set at 37 patients. It is expected that 1 - 3 patients per month will enroll onto this protocol. Thus, accrual is expected to complete within 2-3 years. We receive approximately 2 referrals from Dr. Karel Pacak in NICHD each month. Many of these will be eligible for this study. If we are unable to enroll 8 patients in the first year, accrual will be stopped.
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8.5 analysis of secondary endpoints

Exploratory non-parametric analyses using trend tests will be performed to describe the relationship between the translational endpoints and the clinical outcome, primarily. Since all of these analyses will be performed with exploratory intent, the analysis results will be presented without any adjustment for multiple comparisons, but with careful discussion of the hypothesisgenerating nature of the analyses undertaken. Analysis for statistically significant correlations will be planned for the following parameters defined as being of particular interest but are not limited to the following: VEGFR-1, -2 and -3, AKT, p-AKT, ERK1/2, p-ERK1/2, MEK, pMEK, IGF1R, pIGF1R. and Microvessel Density (CD31 staining)
In general, it is anticipated that non-parametric analyses will generally be used for these evaluations because of the limited number of subjects. In view of the exploratory nature of these analyses, any p-values reported will not be adjusted for multiple comparisons, and results of any such analyses will be stated carefully as being hypothesis generating, requiring additional confirmation.  
For all evaluable patients (subjects who received at least 2 cycles), Kaplan-Meier analyses of progression free survival will also be performed. Appropriate confidence intervals at selected time points will also be provided. Since these will be considered secondary endpoints. The results will be reported as part of the descriptive report of the study. Adverse events will be tabulated by type and grade, for all types of adverse events identified as being at least possibly attributable to the agent.
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9 collaborative agreements 9.1 agreement

Axitinib is an investigational agent supplied to investigators by the Pfizer Pharmaceuticals, Inc.  
Axitinib is provided to NCI under a Clinical Trial Agreement (CTA).
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10 human subjects protections 10.1

This study will be open to all individuals with pheochromocytoma/paraganglioma regardless of gender, ethnicity, or race provided that the aforementioned inclusion and exclusion criteria are met. This study will be recruited through internal referral, our local physician referral base, and through various cancer information hotlines (i.e., Clinical Studies Support Center, 1-8004Cancer). It should be noted that for the past several years we have seen on average over 80 new referrals per year. Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the eligibility criteria outlined in section 2. To date, there is no information that suggests that differences in drug metabolism or disease response would be expected in one ethnic group compared to another. Efforts will be made to extend accrual to each representative population, but in this preliminary study, a balance must be struck between patient safety considerations and limitations on the number of individuals exposed to potentially toxic and/or ineffective treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on the other hand. If differences in outcome that correlate to ethnic identity are noted, accrual may be expanded or a follow-up study may be written to investigate those differences more fully.
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10.2 participation of children

Patients under the age of 18 will be excluded from study. The effect of axitinib in children may be investigated in studies that exclusively enroll children.
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10.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section 10.4 **), all subjects will be offered the opportunity to fill in their** wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH
Ability to Consent Assessment Team for evaluation. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH MEC Policy 87-4 for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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10.4 evaluation of benefits and

The potential benefit to a patient who enters study is a reduction in the bulk of his/her tumor, which may or may not have a favorable impact on symptoms and/or survival. Potential risks include the possible occurrence of any of a range of side effects that are listed in the pharmaceutical section and the consent document. The procedure for protecting against or minimizing risks will be to medically evaluate patients on a regular basis as described earlier.
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10.5 risks/benefits analysis

All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent. If patients suffer any physical injury as a result of the biopsies, immediate medical treatment is available at NIH's Clinical Center in Bethesda, Maryland.  
Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations.
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10.6 consent process and documentation

An associate or principal investigator on the trial will inform patients of the purpose, alternatives, treatment plan, research objectives and follow-up of this trial. The patient will be provided an IRB-approved consent for review and signature and his/her questions will be answered. After a decision is made to enroll into the study, a signature will be obtained from the patient. The original of the signed informed consent will be placed in the patient's medical record and a copy in the research record. All patients must have a signed informed consent form and an on-study
(confirmation of eligibility) form filled out and signed by a participating investigator before entering on study.  
10.6.1 Reconsent via the telephone The informed consent document will be sent to the subject. An explanation of the study will be provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject's signature will sign and date the consent.  
The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. A fully executed copy will be returned via mail for the subject's records.  
The informed consent process will be documented on a progress note by the consenting investigator.  
10.6.2 Informed consent of non-English speaking subjects If there is an unexpected enrollment of a research participant for whom there is no translated extant IRB approved consent document, the principal investigator and/or those authorized to obtain informed consent will use the Short Form Oral Consent Process as described in MAS
Policy M77-2, OHSRP SOP 12, 45 CFR 46.117 (b) (2), and 21 CFR 50.27 (b) (2). The summary that will be used is the English version of the extant IRB approved consent document. Signed copies of both the English version of the consent and the translated short form will be given to the subject or their legally authorized representative and the signed original will be filed in the medical record.  
Unless the PI is fluent in the prospective subject's language, an interpreter will be present to facilitate the conversation (using either the long translated form or the short form). Preferably someone who is independent of the subject (i.e., not a family member) will assist in presenting information and obtaining consent. Whenever possible, interpreters will be provided copies of the relevant consent documents well before the consent conversation with the subject (24 to 48 hours if possible).  
Version Date: **3/26/2018**
We request prospective IRB approval of the use of the short form process for non-English speaking subjects and will notify the IRB at the time of continuing review of the frequency of the use of the Short Form.
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11 pharmaceutical and investigational device

Axitinib is an investigational agent supplied to investigators by the Pfizer Pharmaceuticals, Inc.  
Axitinib is provided to the NCI under a CTA (see section 9.1).
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11.1.2 toxicity

The most commonly reported treatment-related adverse events of severity Grade 3 or higher were hypertension (39 subjects, 14%), fatigue (27 subjects, 10%), diarrhea (12 subjects, 4%), palmar plantar erythrodysaesthesia syndrome (8 subjects, 3%), hypertension aggravated (5 subjects, 2%), and stomatitis (5 subjects, 2%), elevated triglycerides (1 subject, < 1%).  
Table 10: **Treatment-Emergent, All-Causality Adverse Events in at Least 10% of Subjects with**
Solid Tumors Receiving Single Agent Axitinib
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version date 3/26/2018

| Solid Tumor Single-                                                                     | AML/MDS     |           |            |           |            |           |
|-----------------------------------------------------------------------------------------|-------------|-----------|------------|-----------|------------|-----------|
| Single-Agent                                                                            | Total       |           |            |           |            |           |
| Agent                                                                                   |             |           |            |           |            |           |
| (N = 268)*                                                                              | (N = 12)    | (N = 280) |            |           |            |           |
| MedDRA Preferred Term                                                                   | All Grades  | Grade 3+  | All Grades | Grade 3+  | All Grades | Grade 3+  |
| n (%)                                                                                   | n (%)       | n (%)     | n (%)      | n (%)     | n (%)      |           |
| 36 (12.9)                                                                               |             |           |            |           |            |           |
| Fatigue                                                                                 | 167 (62.3)  | 36 (13.4) | 7 (58.3)   | 0         | 174 (62.1) |           |
| 12 (41.8)                                                                               | 10 (83.3)   | 1 (8.3)   | 122 (43.6) | 16 (5.7)  |            |           |
| Diarrhea                                                                                | 15 (5.6)    |           |            |           |            |           |
| Hypertension                                                                            | 13 (42.2)   | 35 (13.1) | 5 (41.7)   | 4 (33.3)  | 18 (42.1)  | 39 (13.9) |
| Nausea                                                                                  | 106 (39.55) | 4 (1.5)   | 6 (50.0)   | 0         | 12(40)     | 4 (1.4)   |
| Anorexia                                                                                | 98 (35.6)   | 6 (2.2)   | 2(16.7)    | 0         | 100 (35.7) | 6 (2.1)   |
| Dysphonia                                                                               | 69 (25.8)   | 0         | 9 (75.0)   | 0         | 78 (27.9)  | 0         |
| 73 (25.7)                                                                               | 17 (6.3)    | 4 (33.3)  | 7 (27.5)   | 18 (6.4)  |            |           |
| Dyspnea                                                                                 | 1 (8.3)     |           |            |           |            |           |
| Weight decreased                                                                        | 71 (26.5)   | 5 (1.9)   | 2(16.7)    | 73 (26.1) | 5 (1.8)    |           |
| 0                                                                                       |             |           |            |           |            |           |
| Arthralgia                                                                              | 69 (25.8)   | 9 (3.4)   | 0          | 0         | 69 (24.6)  | 9 (3.2)   |
| 65 (24.2)                                                                               | 2 (16.7)    | 67 (23.9) | 1 (0.4)    |           |            |           |
| Constipation                                                                            | 1 (0.4)     | 0         |            |           |            |           |
| Headache                                                                                | 62 (23.1)   | 9 (3.4)   | 3 (25.0)   | 0         | 65 (23.2)  | 9 (3.2)   |
| Vomiting                                                                                | 60 (22.4)   | 4 (1.5)   | 3 (25.0)   | 0         | 63 (22.5)  | 4 (1.4)   |
| 55 (20.5)                                                                               | 5 (1.9)     | 5 (41.7). | 0          | 60 (21.4) | 5 (1.8)    |           |
| Cough                                                                                   |             |           |            |           |            |           |
| Pain in extremity                                                                       | 54 (20.2)   | 5 (1.9)   | 0          | 0         | 54 (19.3)  | 5 (1.8)   |
| 0                                                                                       | 0           | 51 (18.2) | l (0.4)    |           |            |           |
| D spepsia                                                                               | 51 (19)     | 1 (0.4)   |            |           |            |           |
| Mucosal inflammation                                                                    | 37 (13.9)   | 1 (0.4)   | 4 (33.3)   | l (8.3)   | 41 (14.6)  | 2 (0.7)   |
| Stomatitis                                                                              | 37 (13.8)   | 7 (2.6)   | 4 (33.3)   | 0         | 41 (14.6)  | 7 (2.5)   |
| 2 (16.7)                                                                                | l (8.3)     | 37 (13.2) | 9 (3.2)    |           |            |           |
| Abdominal pain                                                                          | 35 (13.1)   | 8 (3.0)   |            |           |            |           |
| Back pain                                                                               | 3 (12.3)    | 4 (1.5)   | 3 (25.0)   | 0         | 36 (12.9)  | 4 (1.4)   |
| 3 (25.0)                                                                                | 38 (13.6)   |           |            |           |            |           |
| Insomnia                                                                                | 35 (13)     | l (0.4)   | 0          | 1 (0.4)   |            |           |
| Peripheral edema                                                                        | 32 (12)     | 0         | l (8.3)    | 0         | 3 (11.8)   | 0         |
| Rash                                                                                    | 29 (10.8)   | 1 (0.4)   | 4 (33.3)   | 0         | 3 (11.8)   | l (0.4)   |
| 2(16.7)                                                                                 | 3 (11.8)    | 1 (0.4)   |            |           |            |           |
| Dizziness                                                                               | 31 (11.2)   | l (0.4)   | 0          |           |            |           |
| Dry Skin                                                                                | 31 (11.6)   | 0         | l (8.3)    | 0         | 32 (11.4)  | 0         |
| Mvalgia                                                                                 | 29 (10.9)   | 3 (1.1)   | 0          | 0         | 29 (10.4)  | 3 (1.1)   |
| 28 (10)                                                                                 | 8 (2.9)     |           |            |           |            |           |
| Palmar plantar                                                                          | 28 (10.5)   | 8 (3.0)   | 0          | 0         |            |           |
| erythrodysaesthesia syndrome                                                            |             |           |            |           |            |           |
| *Includes Protocols A40600, A4061008, A4061011, A4061012, A4061013, A4061014, A4061015, |             |           |            |           |            |           |  
A4061023. Studies A4061022 and A4061027 are not included. See Table 38 for actual cutoff dates for various studies treating subjects with single agent AG-013736.  
AML/MDS = acute myeloid leukemia/mylodysplastic syndrome a Includes 8 patients enrolled in continued access Protocol A4061008.  
' Includes adverse events reported as hoarseness.  
Version Date: 3/26/2018 Table 11: Laboratory Test Results Reported for Subjects with Solid Tumors Receiving Single-  
| Agent Axitinib.                                                                                | n (%)* at Maximum Grade   |           |           |           |           |           |           |         |
|------------------------------------------------------------------------------------------------|---------------------------|-----------|-----------|-----------|-----------|-----------|-----------|---------|
| Group/Parameter b                                                                              | Std Units                 | N         | Grade 1   | Grade 2   | Grade 3   | Grade 4   | Total     |         |
| Chemistry                                                                                      |                           |           |           |           |           |           |           |         |
| Alkaline Phosphatase                                                                           | UL                        | 201       | 62 (30.8) | 13 (6.5)  | 3 (1.5)   | 78 (38.8) |           |         |
| 0                                                                                              |                           |           |           |           |           |           |           |         |
| Bicarbonate                                                                                    | mEq/L                     | 71        | 18 (25.4) | l (1.4)   | 19 (26.8) |           |           |         |
| 0                                                                                              | 0                         |           |           |           |           |           |           |         |
| Creatinine                                                                                     | mg/dL                     | 196       | 4 (22.4)  | 8 (4.1)   | l (0.5)   | 8 (4.1)   | 61 (31.1) |         |
| Hypoalbuminemia                                                                                | g/dL                      | 201       | 49 (24.4) | 17 (8.5)  | l (0.5)   | 67 (33.3) |           |         |
| Hypercalcemia                                                                                  | mg/dL                     | 86        | 13 (15.1) | l (1.2)   | l (1.2)   | 15 (17.4) |           |         |
| o                                                                                              |                           |           |           |           |           |           |           |         |
| Hypocalcemia                                                                                   | mg/dL                     | 86        | 8 (9.3)   | 0         | 2 (2.3)   | 10 (11.6) |           |         |
| 0                                                                                              |                           |           |           |           |           |           |           |         |
| Hyperglycemia                                                                                  | mg/dL                     | 199       | 86 (43.2) | 17 (8.5)  | 1 (5.5)   | 14 (57.3) |           |         |
| 0                                                                                              |                           |           |           |           |           |           |           |         |
| Hypoglycemia                                                                                   | mg/dL                     | 199       | 28(14.1)  | 3 (1.5)   | 2 (1.0)   | 3 (16.6)  |           |         |
| 0                                                                                              |                           |           |           |           |           |           |           |         |
| Hyperkalemia                                                                                   | mEq/L                     | 201       | 42 (20.9) | 10 (5.0)  | 2(1.0)    | 54 (26.9) |           |         |
| 0                                                                                              |                           |           |           |           |           |           |           |         |
| Hypokalemia                                                                                    | mEq/L                     | 201       | 27 (13.4) | 0         | 1 (0.5)   | 0         | 28 (13.9) |         |
| Hypermagnesemia                                                                                | mg/dL                     | 38        | 8(21.1)   | 0         | l (2.6)   | 0         | 9(23.7)   |         |
| Hypomagnesemia                                                                                 | mg/dL                     | 38        | 12 (31.6) | 0         | o         | 0         | 12 (31.6) |         |
| Hypernatremia                                                                                  | mEq/L                     | 201       | 8 (4.0)   | .)        | 0         | 0         | 0         | 8 (4.0) |
| Hyponatremia                                                                                   | mEq/L                     | 41 (20.4) |           |           |           |           |           |         |
| 201                                                                                            | 0                         | 7 (3.5)   | 2 (1.0)   | 50 (24.9) |           |           |           |         |
| SOT (AST)                                                                                      | UL                        | 201       | 50 (24.9) | 7 (3.5)   | 8 (4.0)   | 0         | 65 (32,3) |         |
| SGPT (ALT)                                                                                     | UL                        | 201       | 45 (22.4) | 9 (4.5)   | 7 (3.5)   | 0         | 61 (30.3) |         |
| Total Bilirubin                                                                                | mg/dL                     | 201       | 16 (8.0)  | 10 (5.0)  | 3 (1.5).  | 0         | 29 (14.4) |         |
| Hematology                                                                                     |                           |           |           |           |           |           |           |         |
| Hemoglobin                                                                                     | g/dL                      | 197       | 61 (31.0) | 12 (6.1)  | 0         | 3 (1.5)   | 76 (38.6) |         |
| Platelets                                                                                      | 10 3 /mm 3                | 197       | 25 (12.7) | l (0.5)   | 2 (1.0)   | o         | 28 (14.2) |         |
| White Blood Cells                                                                              | 10 3 /mm 3                | 197       | 13 (6.6)  | 3 (1,5)   | 0         | l (0.5)   | 17 (8.6)  |         |
| Ncutrophils (Abs)                                                                              | 10 3 /mm 3                | 12 (9.9)  | 3 (2.3)   |           |           |           |           |         |
| 131                                                                                            | 0                         | l (0.8)   | 15 (11.5) |           |           |           |           |         |
| Lymphocytes (Abs)                                                                              | 10 3 /mm 3                | 163       | 28 (17.2) | 17 (10.4) | 16 (9.8)  | 15 (9.2)  | 76 (46.6) |         |
| Urinalysis                                                                                     |                           |           |           |           |           |           |           |         |
| Urine Protein                                                                                  | QUAL                      | 239       | 32 (13.4) | 34 (14.2) | 2 (0.8)   | 0         | 68 (28.5) |         |
| Thirty-five (35) of 280 subjects (13%) treated with single agent axitinib discontinued therapy |                           |           |           |           |           |           |           |         |  
because of treatment-related adverse events (see Table 10).  
| Subjects Receiving Single Agent Axitinib at 5 mg twice daily                                |           |
|---------------------------------------------------------------------------------------------|-----------|
| No. of Subjects, n (%)                                                                      |           |
| Event                                                                                       | (N = 27). |
| 27(100)                                                                                     |           |
| Any treatment-related event leading to withdrawal                                           | 5 (19)    |
| Hypertension                                                                                | 4(15)     |
| Fatigue                                                                                     |           |
| Intestinal perforation                                                                      | 2 (7)     |
| Stomatitis                                                                                  | 2 (7)     |
| 2 (7)                                                                                       |           |
| Cerebral hemorrhage                                                                         | l (4)     |
| Abdominal pain (lower)                                                                      | l (4)     |
| Anorexia                                                                                    |           |
| Aphasia                                                                                     | 1 (4)     |
| Bone pain                                                                                   | l (4)     |
| Bradycardia                                                                                 | 1 (4)     |
| 1 (4)                                                                                       |           |
| Cardiomyopathy                                                                              |           |
| Cerebrovascular accident                                                                    | 1 (4)     |
| Diarrhea NOS                                                                                | 1 (4)     |
| Dyspnea                                                                                     | 1 (4)     |
| Gout                                                                                        | 1 (4)     |
| Headache                                                                                    | 1 (4)     |
| Hemoptysis                                                                                  | 1 (4)     |
| Hypotension                                                                                 | 1 (4)     |
| 1 (4)                                                                                       |           |
| Hypothermia                                                                                 |           |
| Medical device discomfort                                                                   | 1 (4)     |
| Myocardial infarction                                                                       | 1 (4)     |
| Myocardial ischemia                                                                         | 1 (4)     |
| Nausea                                                                                      | 1 (4)     |
| Proteinuria                                                                                 | 1 (4)     |
| Thrombosis                                                                                  | 1 (4)     |
| Wound complication                                                                          | 1 (4)     |
| Note : Axitinib in combination with other agents could cause an exacerbation of any adverse |           |  
Table 12: Treatment-Related Averse Events Resulting in Treatment Discontinuation for event currently known to be caused by the other agent, or the combination may result in events never previously associated with either agent.
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11.1.3 formulation and preparation

Axitinib is supplied as an immediate-release film-coated tablets containing either 5 mg or 1 mg of the free base, axitinib, and common compendial excipients.  The 5 mg tablets are red and triangular; the 1 mg tablet is red and oval. The film coating has no effect on the rate of release of the active axitinib.  
11.1.4  Stability and Storage Store at controlled room temperature storage within the temperature range 20° - 25°C (68° –
7°F) with excursions permitted to 15° - 30° C (59° - 86°F). Storage conditions should not exceed 25°C. The current shelf life is 24 months when stored at controlled room temperature.  
11.1.5 Administration procedures Oral, axitinib should be taken with at least 250 mL of water and will be given with or without food.  
11.1.6 Incompatibilities 11.1.6.1 Product Description Axitinib is white to light yellow crystalline powder. Chemical Name: N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl-)-1H-indazol-6-ylsulfanyl]-benzamide Other Names: AG-013736 Classification: Kinase inhibitor (VEGF-R, and PDGF-R) Mechanism of Action: Axitinib (AG-013736) is an oral, potent and selective inhibitor of VEGF
receptors 1, 2, 3 (vascular endothelial growth factor receptors 1, 2, 3). Preclinical data suggest that axitinib has anti-tumour activity that appears to result from its anti-angiogenic activity, which is reversible when treatment is discontinued Molecular Formula: C22H18N4OS Molecular Weight: 386.47 Daltons Structural formula:
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11.1.6.2 drug interactions

Incubation with recombinant CYP enzymes and human liver microsomes in the absence and presence of specific chemical inhibitors of human CYP suggest axitinib metabolism is primarily mediated by CYP3A4/5, and to a lesser extent by CYP1A2, CYP2C19 and UGT1A1. A mean 2-fold increase **in exposure of axitinib was observed when axitinib was co-administered with** ketoconazole, a potent inhibitor of CYP3A4/5. A mean 3.5-fold decrease **in axitinib plasma** exposure was observed when axitinib was co-administered with rifampin, a potent inducer of CYP3A4/5. Therefore, co-administration with potent inhibitors (ketoconazole, itraconazole, clarithromycin, erythromycin, diltiazem, verapamil, delavirdine, indinavir, saquinavir, ritonavir, atazanavir, nelfinavir) and inducers (rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, St. John's wort, efavirenz, tipranavir) of CYP3A4/5 may result in significant increases and decreases in exposure of axitinib, respectively, and may alter the safety/efficacy of the drug. All potent CYP3A4/5 inhibitors and inducers are not permitted within 7 and 12 days, respectively, before commencing axitinib administration. During the study, potent CYP3A4/5 inhibitors and inducers are not recommended in concurrent use with axitinib. Alternative therapies should be used when available. If usage of a potent CYP3A4/5 inhibitor or inducer is necessary, this must be in agreement with the Sponsor. The use of coumarin derivative  
Version Date: **3/26/2018**
anticoagulants such as warfarin (Coumadin **) is not recommended, though warfarin doses up to**
2 mg daily are permitted for prophylaxis of thrombosis.
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12 references

1. Stein PP, Black HR. A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience. Medicine. **1991;70(1):46-66.**
2. Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. **Annals of internal**
medicine. **2001;134(4):315-329.**
3. Bravo EL. Pheochromocytoma: new concepts and future trends. **Kidney international.**
1991;40(3):544-556.  
4. Motta-Ramirez GA, Remer EM, Herts BR, Gill IS, Hamrahian AH. Comparison of CT
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13 appendices 13.1 appendix a

Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH **ed. Hudson,**
OH; LexiComp Inc. 2007: 1899-1912. Only major substrates and effective inducers are listed.  
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/  
| CYP3A4 Substrates Albuterol Alfentanil Alprazolam Amiodarone Amlodipine Amprenavir Aprepitant Aripiprazole Atazanavir Atorvastatin Benzphetamine Bisoprolol Bortezomib Bosentan Bromazepam Bromocriptine Budesonide Buprenorphine Buspirone Busulfan Carbamazepine Cerivastatin Chlordiazepoxide Chloroquine Chlorpheniramine Cilostazol Cisapride Citalopram Clarithromycin Clobazam Clonazepam Clorazepate Cocaine Colchicine Conivaptan Dihydroergotamine  Diltiazem  Disopyramide  Docetaxel Doxepin Doxorubicin Doxycycline Efavirenz Eletriptan Enalapril Eplerenone Ergoloid mesylate Ergonovine Ergotamine Erythromycin Escitalopram Estradiol Estrogens, conj., synthetic Estrogens, conj., equine Estrogens, conj., esterified Estrone Estropipate Ethinyl estradiol Ethosuximide Etoposide Exemestane Felbamate Felodipine Fentanyl Flurazepam Flutamide Fluticasone Fosamprenavir Gefitinib Haloperidol   | Isradipine  Itraconazole Ketamine  Ketoconazole Lansoprazole Letrozole Levonorgestrel Lidocaine Losartan Lovastatin Medroxyprogesterone  Mefloquine Mestranol Methadone Methylergonovine Methysergide Miconazole Midazolam Miglustat Mirtazapine Modafinil Montelukast Moricizine Nateglinide Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nimodipine Nisoldipine Norethindrone Norgestrel Ondansetron Paclitaxel   | Quinidine Rabeprazole  Ranolazine Repaglinide Rifabutin Ritonavir Salmeterol Saquinavir Sibutramine Sildenafil Simvastatin Sirolimus Spiramycin Sufentanil Sunitinib Tacrolimus Tamoxifen Tamsulosin Telithromycin Teniposide Tetracycline Theophylline Tiagabine Ticlopidine Tipranavir Tolterodine Toremifene Trazodone Triazolam Trimethoprim Trimipramine Troleandomycin Vardenafil Venlafaxine Verapamil   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Version Date: **3/26/2018**  
| Cyclophosphamide Cyclosporine Dantrolene Dapsone Dasatinib (1) Delavirdine Diazepam                                                                  | Ifosfamide Imatinib Indinavir Irinotecan Isosorbide Isosorbide dinitrate Isosorbide mononitrate   | Pergolide Phencyclidine Pimozide Pipotiazine Primaquine Progesterone Quetiapine   | Vinblastine Vincristine Vinorelbine Zolpidem Zonisamide Zopiclone   |
|------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------|---------------------------------------------------------------------|
| Note: When drugs classified as 'substrates' are co-administered with Axitinib, there is the  potential for higher concentrations of the 'substrate'. |                                                                                                   |                                                                                   |                                                                     |  
| CYP3A4 Inhibitors Acetaminophen Acetazolamide Amiodarone Amlodipine Amprenavir Anastrozole Aprepitant Atazanavir Atorvastatin Azelastine Azithromycin Betamethasone Bortezomib Bromocriptine Caffeine Cerivastatin Chloramphenicol Chlorzoxazone Cimetidine Ciprofloxacin Cisapride Clarithromycin Clemastine Clofazimine Clotrimazole Clozapine Cocaine Conivaptan Cyclophosphamide Cyclosporine Danazol Dasatinib (1) Delavirdine Desipramine   | Diclofenac  Dihydroergotamine  Diltiazem Disulfram Docetaxel Doxorubicin Doxycycline Drospirenone Efavirenz Enoxacin Entacapone Ergotamine Erythromycin Ethinyl estradiol Etoposide Felodipine Fentanyl Fluconazole Fluoxetine Fluvastatin Fluvoxamine Fosamprenavir Glyburide Grapefruit juice (2) Haloperidol Hydralazine Ifosfamide Imatinib Indinavir Irbesartan Isoniazid Isradipine Itraconazole Ketoconazole   | Lomustine Losartan  Lovastatin Mefloquine Mestranol Methadone Methimazole Methoxsalen Methylprednisolone Metronidazole Miconazole Midazolam Mifepristone Mirtazapine Mitoxantrone Modafinil Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nisoldipine Nizatidine Norfloxacin Olanzapine Omeprazole Orphenadrine Oxybutynin Paroxetine Pentamidine Pergolide Phencyclidine Pilocarpine Pimozide   | Primaquine Progesterone Propofol  Propoxyphene Quinidine Quinine Quinupristin Rabeprazole Ranolazine Risperidone Ritonavir Saquinavir Selegiline Sertraline Sildenafil Sirolimus Sulconazole Tacrolimus Tamoxifen Telithromycin Teniposide Testosterone Tetracycline Ticlopidine Tranylcypromine Trazodone Troleandomycin Valproic acid Venlafaxine Verapamil Vinblastine Vincristine Vinorelbine Voriconazole   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Version Date: **3/26/2018**  
| Dexmedetomidine                                                                             | Lansoprazole   | Pravastatin   | Zafirlukast   |
|---------------------------------------------------------------------------------------------|----------------|---------------|---------------|
| Diazepam                                                                                    | Lidocaine      | Prednisolone  | Ziprasidone   |
| Note: When Axitinib is co-administered with compounds classified as 'inhibitors', increased |                |               |               |  
| CYP3A4 Inducers Aminoglutethimide Carbamazepine Fosphenytoin Nafcillin                            | Nevirapine Oxcarbazepine Pentobarbital Phenobarbital   | Phenytoin Primidone Rifabutin Rifampin   | Rifapentine St. John's wort (3)   |
|---------------------------------------------------------------------------------------------------|--------------------------------------------------------|------------------------------------------|-----------------------------------|
| Note: The co-administration of 'inducers' would potentially lower plasma Axitinib concentrations. |                                                        |                                          |                                   |  
Investigator's Brochure: Dasatinib (BMS 354825). Bristol-Myers Squibb. October 2006 Malhotra et al**. (2001). Clin Pharmacol Ther. 69:14-23.** Mathijssen et al**. (2002). J Natl Cancer Inst. 94:1247-1249** Frye et al**. (2004). Clin Pharmacol Ther. 76:323-329.** Updated on May 1, 2007 64  
| 13.2             | APPENDIX B: STUDY DIARY                                                                                                                                                                                       |                                                                                                      |
|------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------|
| Day / Date       | Axitinib taken                                                                                                                                                                                                | Blood Pressure: record your BP prior to taking axitinib. If                                          |
| yes/no           | >150/>100, repeat in 5 minutes. If still >150/>100, do not  take axitinib and repeat in one hour. If <150/<100 take the  axitinib; If still >150/>100 after one hour do not take the  axitinib for that dose. | Symptoms, other  medicines taken                                                                     |
| Sunday           | AM Y/N                                                                                                                                                                                                        |                                                                                                      |
| Date:            | time ___                                                                                                                                                                                                      | AM BP ________, time______ AM BP ________, time______ if needed AM BP ________, time______ if needed |
| PM Y/N  time ___ | PM BP ________, time______ PM BP ________, time______ if needed PM BP ________, time______ if needed                                                                                                          |                                                                                                      |
| Monday           | AM Y/N                                                                                                                                                                                                        |                                                                                                      |
| Date:            | time ___                                                                                                                                                                                                      | AM BP ________, time______ AM BP ________, time______ if needed AM BP ________, time______ if needed |
| PM Y/N  time ___ | PM BP ________, time______ PM BP ________, time______ if needed PM BP ________, time______ if needed                                                                                                          |                                                                                                      |
| Tuesday          | AM Y/N                                                                                                                                                                                                        |                                                                                                      |
| Date:            | time ___                                                                                                                                                                                                      | AM BP ________, time______ AM BP ________, time______ if needed AM BP ________, time______ if needed |
| PM Y/N  time ___ | PM BP ________, time______ PM BP ________, time______ if needed PM BP ________, time______ if needed                                                                                                          |                                                                                                      |
| Wednesday        | AM Y/N                                                                                                                                                                                                        |                                                                                                      |
| Date:            | time ___                                                                                                                                                                                                      | AM BP ________, time______ AM BP ________, time______ if needed AM BP ________, time______ if needed |
| PM Y/N  time ___ | PM BP ________, time______ PM BP ________, time______ if needed PM BP ________, time______ if needed                                                                                                          |                                                                                                      |
| Thursday         | AM Y/N                                                                                                                                                                                                        |                                                                                                      |
| Date:            | time ___                                                                                                                                                                                                      | AM BP ________, time______ AM BP ________, time______ if needed AM BP ________, time______ if needed |
| PM Y/N  time ___ | PM BP ________, time______ PM BP ________, time______ if needed PM BP ________, time______ if needed                                                                                                          |                                                                                                      |
| Friday           | AM Y/N                                                                                                                                                                                                        |                                                                                                      |
| Date:            | time ___                                                                                                                                                                                                      | AM BP ________, time______ AM BP ________, time______ if needed AM BP ________, time______ if needed |
| PM Y/N  time ___ | PM BP ________, time______ PM BP ________, time______ if needed PM BP ________, time______ if needed                                                                                                          |                                                                                                      |
| Saturday         | AM Y/N                                                                                                                                                                                                        |                                                                                                      |
| Date             | time ___                                                                                                                                                                                                      | AM BP ________, time______ AM BP ________, time______ if needed AM BP ________, time______ if needed |
| PM Y/N  time ___ | PM BP ________, time______ PM BP ________, time______ if needed PM BP ________, time______ if needed                                                                                                          |                                                                                                      |  
Version Date: **3/26/2018**
13.3 APPENDIX C: PFIZER FAX COVER F**ORM**
On following page
untitled h1
phzer

Investigator-Initiated Research Reportable Event Fax Cover Sheet Use this fax cover sheet to fax a Reportable Event for Investigator-Initiated Research studies.  
Include with this form the completed Pfizer Investigator-Initiated Research Serious Adverse Event (IIR SAE) form, MedWatch Form FDA 0500A-Mandatory Reporting, which can be obtained from the FDA website ww.fda.gov/medwatch/getforms.htm , or other Pfizer agreed-upon form for SAE reporting.  
If you are using the MedWatch Form to report, the following information should be included in block 5 of the Adverse Events section:
.  
.  
.  
The complete clinical course of the patient receiving Pfizer drug The causality assessment for each Reportable Event The action taken for each study drug and for each Reportable Event The outcome for each Reportable Event
.  
This cover sheet MUST be provided with each completed SAE form. Do not substitute forms/reports or submit additional documentation other than what is required.  
Do not fax these forms to any additional fax numbers other than the one listed below.  
| TO:                                                                           | Pfizer U.S. Clinical Trial Department                                    |
|-------------------------------------------------------------------------------|--------------------------------------------------------------------------|
| FAX:                                                                          | 1-866-997-8322                                                           |
| FROM: Maureen Edgerly, RN                                                     | DATE:                                                                    |
| TELEPHONE: 301-435-5604                                                       | FAX: 301-402-1608                                                        |
| NUMBER OF PAGES                                                               |                                                                          |
| (INCLUDING COVER SHEET);                                                      |                                                                          |
| PRODUCT                                                                       | Axitinib                                                                 |
| PFIZER                                                                        | EXTERNAL REFERENCE                                                       |
| REFERENCE                                                                     |                                                                          |
| NUMBER                                                                        | NUMBER                                                                   |
| PHASE II STUDY OF AXITINIB (AG-013736) WITH EVALUATION OF THE VEGF-PATHWAY IN |                                                                          |
| STUDY TITLE                                                                   | METASTATIC, RECURRENT OR PRIMARY UNRESECTABLE PHEOCHROMOCYTOMA CARCINOMA |
| PATIENT                                                                       |                                                                          |
| NUMBER                                                                        |                                                                          |
| INVESTIGATOR                                                                  | Antonio Tito Fojo, MD, PhD                                               |  
Confidentiality Notice:  The documents accompanying this telecopy transmission contain information belonging to Pfizer, which is intended only for the use of the addressee. If you are not the intended reoplent, you are hereby notified that any disclosure, copying, distribution or the taking of any action in reliance on the contents of this telecopied information is strictly prohibited. If you have received this telecopy in error, please immediately notify us by telephone to arrange for the return of the criginal documente to uc. Thank you