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134. Farace F, Gross-Goupil M, Tournay E, et al. Levels of circulating CD45(dim)CD34(+)VEGFR2(+) progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors. *Br J Cancer.*
2011;104(7):1144-1150.  
135. Vroling L VdVA, De Haas RR, Schuurhuis GJ, Van Cruijsen H CD34bright/CD133neg candidate circulating endothelial progenitor cells (ccEPCs) are a potential biomarker during treatment with sunitinib or bevacizumab. Proceedings of the 99th AACR Annual Meeting, San Diego (CA) 2008, Abstract 4956.  
136. Rafii S. Circulating endothelial precursors: mystery, reality, and promise. *Journal of* Clinical Investigation. 2000;105(1):17-19.  
137. Khan SS, Solomon MA, McCoy JP, Jr. Detection of circulating endothelial cells and endothelial progenitor cells by flow cytometry. *Cytometry B Clin Cytom.* 2005;64(1):1-8.  
138. Furstenberger G, von Moos R, Lucas R, et al. Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer. Br J Cancer. 2006;94(4):524-531.  
139. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. *N Engl J Med.* 2003;348(7):593-600.  
140. Xin H, Zhang C, Herrmann A, Du Y, Figlin R, Yu H. Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. Cancer Res. 2009;69(6):2506-2513.  
141. Ozao-Choy J, Ma G, Kao J, et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immunebased cancer therapies. *Cancer Res.* 2009;69(6):2514-2522.  
142. Deeken J, Rudek M, Moore P. A Phase I/PK study of Sunitinib With Highly Active Antiretroviral Therapy (HAART) HIV+ Patients with Solid Tumors: AIDS Malignancy Consortium Study 061. *13th International Conference on Malignancies in AIDS and* Other Acquired Immunodeficiencies, Bethesda, MD. 2011.  
143. Rieker RJ, Hoegel J, Morresi-Hauf A, et al. Histologic classification of thymic epithelial tumors: comparison of established classification schemes. *Int J Cancer.* 2002;98(6):900906.  
144. Kuo TT. Tumours of the thymus. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al., editors. World Health Organization Classification of Tumors: Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; pp. 146– 248, 2004.  
145. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). *Eur J Cancer.* 2009;45(2):228-247.  
| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                   |                                                                           |                                                                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|---------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                                                      | Descriptions                                                  | Percent                                                                   | Description                                                            |
| 100                                                                                                                                                                                        | Normal, no complaints, no evidence  of disease.               |                                                                           |                                                                        |
| Normal activity. Fully active, able                                                                                                                                                        |                                                               |                                                                           |                                                                        |
| 0                                                                                                                                                                                          | to carry on all pre-disease  performance without restriction. | 90                                                                        | Able to carry on normal activity;  minor signs or symptoms of disease. |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). | 80                                                            | Normal activity with effort; some  signs or symptoms of disease.          |                                                                        |
| 1                                                                                                                                                                                          | 70                                                            | Cares for self, unable to carry on  normal activity or to do active work. |                                                                        |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                             | Requires occasional assistance, but                           |                                                                           |                                                                        |
| 60                                                                                                                                                                                         | is able to care for most of his/her  needs.                   |                                                                           |                                                                        |
| 2                                                                                                                                                                                          | 50                                                            | Requires considerable assistance and  frequent medical care.              |                                                                        |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                     | 40                                                            | Disabled, requires special care and  assistance.                          |                                                                        |
| 3                                                                                                                                                                                          | 30                                                            | Severely disabled, hospitalization  indicated. Death not imminent.        |                                                                        |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                            | Very sick, hospitalization indicated.  Death not imminent.                |                                                                        |
| 4                                                                                                                                                                                          | 10                                                            | Moribund, fatal processes  progressing rapidly.                           |                                                                        |
| 5                                                                                                                                                                                          | Dead.                                                         | 0                                                                         | Dead.                                                                  |
untitled h1
21 appendix b new york

| Class   | Functional Capacity                                                                                                                                                                                                                                           | Objective Assessment                                              |
|---------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|
| I       | Patients with cardiac disease but without resulting limitations of  physical activity. Ordinary physical activity does not cause undue  fatigue, palpitation, dyspnea, or anginal pain.                                                                       | No objective evidence of  cardiovascular disease.                 |
| II      | Patients with cardiac disease resulting in slight limitation of  physical activity. They are comfortable at rest. Ordinary physical  activity results in fatigue, palpitation, dyspnea, or anginal pain.                                                      | Objective evidence of  minimal cardiovascular  disease.           |
| III     | Patients with cardiac disease resulting in marked limitation of  physical activity. They are comfortable at rest. Less than  ordinary activity causes fatigue, palpitation, dyspnea, or anginal  pain.                                                        | Objective evidence of  moderately severe  cardiovascular disease. |
| IV      | Patients with cardiac disease resulting in inability to carry on any  physical activity without discomfort. Symptoms of heart failure  or the anginal syndrome may be present even at rest. If any  physical activity is undertaken, discomfort is increased. | Objective evidence of  severe cardiovascular  disease.            |
cytochrome p450 (cyp) enzyme
cyp3a4 substrates inhibitors and inducers

| 3A4 Substrates Albuterol Alfentanil Alprazolam Amlodipine Amprenavir Aprepitant Aripiprazole Atazanavir Atorvastatin Benzphetamine Bisoprolol Bortezomib Bosentan Bromazepam Bromocriptine Buprenorphine Buspirone Busulfan Carbamazapine Cerivastatin Chlordiazepoxide Chloroquine Chlorpheniramine Cisapride Citalopram Clarithromycin Clobazam Clonazepam Clorazepate Cocaine Colchicine Cyclophosphamide Cyclosporine Dantrolene Dapsone Delavirdine Diazepam Digitoxin Dihydroergotamine Diltiazem Disopyramide   | Docetaxel Doxepin Doxorubicin Doxycycline Efavirenz Eletriptan Enalapril Eplerenone Ergoloid mesylates Ergonovine Ergotamine Erythromycin Escitalopram Estradiol Estrogens, conj., synthetic Estrogens, conj., equine Estrogens, conj., esterified Estrone Estropipate Ethinyl estradiol Ethosuximide Etoposide Felbamate Felodipine Fentanyl Flurazepam Flutamide Fosamprenavir Fulvestrant Gefitinib Halofantrine Haloperidol Ifosfamide Imatinib Indinavir Irinotecan Isosorbide dinitrate Isosorbide mononitrate Isradipine Itraconazole Ketamine   | Ketoconazole Lansoprazole Letrozole Levomethadyl acetate hydrochloride 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 Nitrendipine Norethindrone Norgestrel Ondansetron Paclitaxel Pergolide Phencyclidine Pimozide Pioglitazone Primaquine Progesterone   | Quetiapine Quinidine Rabeprazole Repaglinide Rifabutin Rifampin Ritonavir Saquinavir Sertraline Sibutramine Sildenafil Simvastatin Sirolimus Sufentanil Tacrolimus Tamoxifen Tamsulosin Telithromycin Teniposide Terbinafine Tetracycline Theophylline Tiagabine Ticlopidine Tolterodine Toremifene Trazodone Triazolam Trimethoprim Trimipramine Troleandomycin Vardenafil Venlafaxine Verapamil Vinblastine Vincristine Vinorelbine Zolpidem Zonisamide Zopiclone   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| 3A4 Inhibitors Acetominophen Acetazolamide Amioderone Amlodipine Amprenavir Anastrozole Aprepitant Atazanavir Atorvastatin Azelastine Azithromycin Betamethasone Bortezomib Bromocriptine Caffiene Cerivastatin Chloramphenicol Chlorzoxazone Cimetadine Ciprofloxacin Cisapride Clarithromycin Clemastine Clofazimine Clotrimazole Clozapine Cocaine Cyclophosphamide Cyclosporine Danazol Delavirdine Desipramine Dexmedetomidine Diazepam Diclofenac Dihydroergotamine   | Diltiazem Disulfiram Docetaxel Doxorubicin Doxycycline Drospirenone Efavirenz Enoxacin Entacapone Ergotamine Erythromycin Ethinyl estradiol Etoposide Felodipine Fentanyl Fluconazole Fluoxetine Fluvastatin Fluvoxamine Fosamprenavir Glyburide Grapefruit juice Haloperidol Hydralazine Ifosfamide Imatinib Indinavir Irbesartan Isoniazid Isradapine Itraconazole Ketoconazole Lansoprazole Lidocaine Lomustine Losartan   | Lovastatin Mefloquine Mestranol Methadone Methimazole Methoxsalen Methylprednisolone Metronidazole Miconazole Midazolam Mifepristone Mirtazapine Mitoxantrone Modafinil Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nisoldipine Nitrendipine Nizatidine Norfloxacin Olanzapine Omeprazole Orphenadrine Oxybutynin Paroxetine Pentamidine Pergolide Phencyclidine Pilocarpine Pimozide Pravastatin Prednisolone Primaquine   | Progesterone Propofol Propoxyphene Quinidine Quinine Quinupristin Rabeprazole Risperidone Ritonavir Saquinavir Selegiline Sertraline Sildenafil Sirolimus Sulconazole Tacrolimus Tamoxifen Telithromycin Teniposide Testosterone Tetracycline Ticlopidine Tranylcypromine Trazodone Troleandomycin Valproic acid Venlafaxine Verapimil Vinblastine Vincristine Vinorelbine Zafirlukast Ziprasidone   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 3A4 Inducers Aminoglutethimide Carbamazapine Efavirenz  Etravirine Fosphenytoin St. John's wort                                                                                                                                                                                                                                                                                                                                                                             | Nevirapine Oxcarbazepine Pentobarbital Phenobarbital                                                                                                                                                                                                                                                                                                                                                                          | Phenytoin Primidone Rifabutin Rifampin                                                                                                                                                                                                                                                                                                                                                                                                  | Rifapentine                                                                                                                                                                                                                                                                                                                                                                                          |  
When *Study Agent* is co-administered with drugs classified as "substrates," the plasma concentration of the substrate is high.  
When *Study Agent* is co-administered with drugs classified as 'inhibitors,' plasma concentrations of the *Study Agent* will be high. When *Study Agent* is co-administered with drugs classified as "inducers," the plasma concentration of the *Study Agent* will be low.  
In general, drug interactions occur significantly between substrates and either inhibitors or inducers of the same enzymes usually classified as "strong" substrates, inhibitors, or inducers. These lists are not all-inclusive. Check additional references or sources.  
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds.  
Drug Information Handbook 12TH ed. Hudson, OH; LexiComp Inc. 2004: 1619-1631.)
(1) Malhorta *et al*. (2000). Clin Pharmacol Ther. 69:14-23  
(2) Mathijssen *et al*. (2002). J Natl Cancer Inst. 94:1247-1249 Frye *et al*. (2004). Clin Pharmacol Ther. 76:323-329
cytochrome p450 (cyp) enzyme
23 appendix d patient's medication

Patient's name: Patient's study ID: Patient's Medication Diary - Group 1
cytochrome p450 (cyp) enzyme
instructions to the patient

1. Complete one form for each 6 week-period while you take sunitinib. 2. You will take your dose of sunitinib by mouth each day in the morning. You will take ____12.5 mg capsules and/or ____ 25 mg capsules or ___50 mg capsule. You may take the capsules with or without food as you wish. 3. Record the date, the number of capsules of each size you took, and when you took them. 4. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If you vomit after taking the tablets, the dose is replaced only if the tablets can actually be seen and counted. If you miss a dose, you should resume with the next scheduled dose. 5. If you have any comments or notice any side effects, please record them in the Comments column. 6. Wash your hands with soap and water after touching the capsule(s). Do not share this medication with anyone. 7. Please return unused sunitinib capsules (or empty bottles) and this form to your physician when you go for your next appointment.  
Day Date Time of daily dose  
| physician when you go for your next appointment.   |          |                       |               |    |          |
|----------------------------------------------------|----------|-----------------------|---------------|----|----------|
| Day                                                | Date     | Time  of  daily  dose | # of capsules | BP | Comments |
| taken                                              | readings |                       |               |    |          |
| 12.5                                               | 25 mg    | 50 mg                 |               |    |          |
| mg                                                 |          |                       |               |    |          |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15                |          |                       |               |    |          |  
| 16 17 18 19 20 21 22 23 24 25 26 27 28 29-42                                                                                                                                                                                                                                                                                                                                                                                                | Drug holiday   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|
| Physician's Office will complete this section: 1. Date patient started protocol treatment  __________________________________________  2. Date patient was removed from study  ________________________________________  3. Patient's planned total daily dose  ____________________________________________  4. Total number of tablets taken this month  ___________________________________  5. Physician/Nurse/Data Manager's Signature |                |
cytochrome p450 (cyp) enzyme
today's date patient's name patient's

1. Complete one form for each 3 week-period while you take sunitinib. 2. You will take your dose of sunitinib by mouth each day in the morning. You will take ____12.5 mg capsules and/or ____ 25 mg capsules or ___50 mg capsule. You may take the capsules with or without food as you wish. 3. Record the date, the number of capsules of each size you took, and when you took them. 4. Record the daily dose onto the diary, including missed, skipped, or vomited doses. If you vomit after taking the tablets, the dose is replaced only if the tablets can actually be seen and counted. If you miss a dose, you should resume with the next scheduled dose. 5. If you have any comments or notice any side effects, please record them in the Comments column. 6. Wash your hands with soap and water after touching the capsule(s). Do not share this medication with anyone. 7. Please return unused sunitinib capsules (or empty bottles) and this form to your physician when you go for your next appointment.  
Day Date Time of daily dose  
| 7. Please return unused sunitinib capsules (or empty bottles) and this form to your  physician when you go for your next appointment.   |              |                       |               |    |          |
|-----------------------------------------------------------------------------------------------------------------------------------------|--------------|-----------------------|---------------|----|----------|
| Day                                                                                                                                     | Date         | Time  of  daily  dose | # of capsules | BP | Comments |
| taken                                                                                                                                   | readings     |                       |               |    |          |
| 12.5                                                                                                                                    | 25 mg        | 50 mg                 |               |    |          |
| mg                                                                                                                                      |              |                       |               |    |          |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15-21                                                                                                  | Drug holiday |                       |               |    |          |
| Physician's Office will complete this section: 1. Date patient started protocol treatment  __________________________________________   |              |                       |               |    |          |  
2. Date patient was removed from study
cytochrome p450 (cyp) enzyme
24 appendix e ctep multicenter

If an institution wishes to collaborate with other participating institutions in performing a CTEP sponsored research protocol, then the following guidelines must be followed.
cytochrome p450 (cyp) enzyme
responsibility of the protocol chair

- The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office (PIO). The Protocol Chair is responsible for the coordination, development, submission, and approval of the protocol as well as its subsequent amendments. The protocol must not be rewritten or modified by anyone other than the Protocol Chair. There will be only one version of the protocol, and each participating institution will use that document. The Protocol Chair is responsible for assuring that all participating institutions are using the correct version of the protocol.  
- The Protocol Chair is responsible for the overall conduct of the study at all participating institutions and for monitoring its progress. All reporting requirements to CTEP are the responsibility of the Protocol Chair.  
- The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure safety of the patients.  
- The Protocol Chair will be responsible for the review of and timely submission of data for study analysis.
cytochrome p450 (cyp) enzyme
responsibilities of the coordinating center

- Each participating institution will have an appropriate assurance on file with the Office for Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for assuring that each participating institution has an OHRP assurance and must maintain copies of IRB approvals from each participating site.  
- Prior to the activation of the protocol at each participating institution, an OHRP form 310 (documentation of IRB approval) must be submitted to the CTEP PIO.  
- The Coordinating Center is responsible for central patient registration. The Coordinating Center is responsible for assuring that IRB approval has been obtained at each participating site prior to the first patient registration from that site.  
- The Coordinating Center is responsible for the preparation of all submitted data for review by the Protocol Chair.  
- The Coordinating Center will maintain documentation of AE reports. There are two options for AE reporting: (1) participating institutions may report directly to CTEP with a copy to the Coordinating Center, or (2) participating institutions report to the Coordinating Center who in turn report to CTEP. The Coordinating Center will submit AE reports to the Protocol Chair for timely review.  
Audits may be accomplished in one of two ways: (1) source documents and research records for selected patients are brought from participating sites to the Coordinating Center for audit, or (2) selected patient records may be audited on-site at participating sites. If the NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is responsible for having all source documents, research records, all IRB approval documents, NCI Drug Accountability Record forms, patient registration lists, response assessments scans, x-rays, etc. available for the audit.
cytochrome p450 (cyp) enzyme
agent ordering

- Except in very unusual circumstances, each participating institution will order DCTDsupplied investigational agents directly from CTEP. Investigational agents may be ordered by a participating site only after the initial IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO.
cytochrome p450 (cyp) enzyme
25 appendix f collection/recording of

1.0 **General Guidelines**
1.1 Frequency of monitoring. Blood pressure (BP) should be monitored at baseline, and then weekly thereafter; i.e., at every clinic visit, and at home on weeks when there is no clinic visit.  
1.2 Data recording. All required data should be recorded in the appropriate CRF or on the patient's blood pressure monitoring diary, as appropriate. The following data are required at baseline and at each subsequent assessment:
- Assessment date and time
- Pulse
- Systolic and diastolic BP
1.3 Risk factors for hypertension (assess and record data in baseline history/physical CRF)
- Diabetes (type 1 or type 2)
- Renal disease (specify on CRF)
- Endocrine condition associated with HTN (specify on CRF) - Use of steroids or NSAIDs (specify all concomitant meds)
- Underlying cardiovascular condition - specify (i.e., ischemic heart disease)
cytochrome p450 (cyp) enzyme
2.0 baseline data collection (at

2.1 All patients
- Current BP - Proteinuria, if present 2.2 Patients with preexisting hypertension (*i.e.*, those for whom "hypertension" is entered as a concomitant condition at study entry, or those who are currently receiving therapy with antihypertensive medication) -
also record:
- Date of HTN diagnosis (original)
- Type HTN (essential or secondary)
- CTCAE grade of HTN (at time of study entry)
- Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of the following:
- Antihypertensive agents taken at study entry
- Antihypertensive agents taken in past (e.g., discontinued for toxicity, lack of efficacy)
cytochrome p450 (cyp) enzyme
3.0 follow up bp data

3.2 Patients with treatment-emergent hypertension [defined as BP increase of >20 mmHg (diastolic) OR
systolic BP >139 OR diastolic BP > 90 (if previously normal or grade 1 per CTCAE v5) - record at time of hypertension diagnosis and at all subsequent clinic visits:
- BP changes from baseline (or from previous assessment) (specify CTCAE grade changes) - Hypertension-related symptoms as reported by patient (e.g., headache) - Other relevant changes associated with development of hypertension (e.g., ECG
abnormalities)
- Trade name, drug class*, dose, dose frequency, start/stop dates/ongoing of currently prescribed antihypertensive agents 3.3 Patients with pre-existing hypertension at study entry - record at each clinic visit
- BP changes from previous clinic visit (specify CTCAE grade changes)
- Hypertension-related symptoms reported by patient (e.g., headache)
- Other relevant changes associated with development of hypertension (e.g., ECG
abnormalities)
- Changes in antihypertensive medications since last assessment (*e.g.*, dose change, add/discontinue drug)
*Classes of antihypertensive drugs include ACE inhibitors, calcium channel blockers, alpha blockers, beta blockers, diuretics, angiotension II receptor antagonists.  
| Recommended Hypertension Monitoring and Management (BP in mmHg)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                               |                                                                    |                                          |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|------------------------------------------|
| Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Antihypertensive                                                                                                                                                              | Blood Pressure                                                     | Sunitinib                                |
| (CTCAE v5)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Therapy                                                                                                                                                                       | Monitoring                                                         | Dose Modification                        |
| Persistent Grade 1 Pre-hypertension Systolic 120-139 Diastolic 80-90                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Standard                                                                                                                                                                      | No change                                                          |                                          |
| Persistent Grade 2- Moderate Systolic 140-159  Diastolic 90-99    Protocol-specific  guidance supersedes  any other management  guidelines, including  CTCAE v5                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Step 1) Initiate LA DHP  CCB treatment and if  needed, after 24-48 hr Rx,  increase dose in stepwise  fashion every 24-48 hours  until BP is controlled or at  max dose of Rx | BP should be  monitored as  recommended by the  treating physician | No change except as  described in step 4 |
| Step 2) If BP still not  controlled, add another  antihypertensive Rx, a  BB, ACE1, ARB, or  ABB; increase dose of this  drug as described in step 1  Step 3) If BP still not  controlled, add 3rd drug  from the list of  antihypertensives in step  2; increase dose of this  drug as described in step 1 Step 4) If BP still not  controlled, consider either  1 dose reduction of  sunitinib or stopping  sunitinib  NOTE: Stopping or  reducing the dose of  sunitinib is expected to  cause a decrease in BP  The treating physician  should monitor the patient  for hypotension and adjust  the number and dose of  antihypertensive  medication(s) accordingly. |                                                                                                                                                                               |                                                                    |                                          |
cytochrome p450 (cyp) enzyme
26 appendix g management of

| Persistent Grade 3  Severe  Systolic >160 Diastolic >100                                                                                                                                                                                                                                                                                                                                                                                                                   | HOLD sunitinib until  systolic BP <159 and  diastolic BP <99.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | BP should be  monitored as  recommended by the  treating physician  unless the patient is  symptomatic with  systolic BP >180 or  diastolic BP >110 in  which case,  monitoring should  be intensive.   | HOLD sunitinib until  systolic BP <159 and  diastolic BP  <99.                                                                                                     |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Protocol-specific  guidance supersedes  any other management  guidelines, including  CTCAE v5                                                                                                                                                                                                                                                                                                                                                                              | BP management is  identical to that for Grade  2 (see steps 1-4 above) with 2 major exceptions:  1) If systolic BP >180 or  diastolic BP >110 and  the patient is  symptomatic: optimal  management with  intensive IV support in  ICU; STOP sunitinib  and notify hospital staff  that stopping sunitinib  may result in a decrease  in BP and  2) If systolic BP >180 or  diastolic BP >110 and  the patient is  asymptomatic, 2 new anti-hypertensives  must be given together  in step 1 (and dose  escalated appropriately  as in step 1). | In most  circumstances, if  BP cannot be  controlled after an  optimal trial of antihypertensive  medications,  consider either 1  dose reduction of  sunitinib or stopping  sunitinib. HOWEVER, if the patient  requires  hospitalization for  management of  symptomatic systolic BP >180 or  diastolic BP >110,  permanently  discontinue sunitinib  or if BP is controlled,  re-start sunitinib at 1  lower dose level after  consultation with the  study Principal  Investigator                                                                                                                                                                                                         |                                                                                                                                                                    |
| NOTE: Stopping or  reducing the dose of  sunitinib is expected to  cause a decrease in BP  The treating physician  should monitor the patient  for hypotension and adjust  the number and dose of  antihypertensive  medication(s) accordingly                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                         |                                                                                                                                                                    |
| Grade 4 Life-threatening  consequences of  hypertension                                                                                                                                                                                                                                                                                                                                                                                                                    | Optimal management  with intensive IV  support in ICU; STOP  sunitinib and notify  hospital staff that  stopping sunitinib may  result in a decrease in  BP                                                                                                                                                                                                                                                                                                                                                                                     | Intensive                                                                                                                                                                                               | Permanently  discontinue sunitinib  or if BP is controlled,  re-start sunitinib at 1  lower dose level after  consultation with the  study Principal  Investigator |
| Abbreviations: dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), angiotensin  converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), alpha beta blocker (ABB) - *See table below for suggested antihypertensive medications by class - If patients require a delay of >2 weeks for management of hypertension, discontinue protocol therapy - If patients require >2 dose reductions, discontinue protocol therapy97 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                         |                                                                                                                                                                    |  
- Patients may have up to 2 drugs for management of hypertension prior to any dose reduction in sunitinib
- 24-48 hours should elapse between modifications of anti-hypertensive therapy
- Hypertension should be graded using CTCAE v5.
cytochrome p450 (cyp) enzyme
oral antihypertensive medications

Agents in bold characters are suggested as optimal choices to avoid or minimize potential druginteractions with sunitinib through CYP450.  
| Agent                                            | Initial       | Intermediate   | Maximum        | Hepatic                          |                    |
|--------------------------------------------------|---------------|----------------|----------------|----------------------------------|--------------------|
| class                                            | Agent         | dose           | dose           | dose                             | metabolism         |
| Dihydropyridine CalciumChannel  Blockers (DHP CCB)                                                  | nifedipine XL | 30 mg daily    | 60 mg daily    | 90 mg daily                      | CYP 3A4  substrate |
| amlodipine                                       | 2.5 mg daily  | 5 mg daily     | 10 mg daily    | CYP 3A4  substrate               |                    |
| felodipine                                       | 2.5 mg daily  | 5 mg daily     | 10 mg daily    | CYP 3A4 substrate  and inhibitor |                    |
| metoprolol                                       | 25 mg         | 50 mg          | 100 mg         | CYP 2D6 substrate                |                    |
| twice daily                                      | twice daily   | twice daily    |                |                                  |                    |
| atenolol                                         | 25 mg daily   | 50 mg daily    | 100 mg daily   | No                               |                    |
| Selective β Blockers (BB)                        | acebutolol    | 100 mg         | 200-300 mg     | 400 mg                           | Yes (CYP450        |
| twice daily                                      | twice daily   | twice daily    | unknown)       |                                  |                    |
| bisoprolol                                       | 2.5 mg daily  | 5-10 mg daily  | 20 mg daily    | Yes (CYP450  unknown)            |                    |
| captopril                                        | 12.5 mg 3x    | 25 mg 3x daily | 50 mg 3x daily | CYP 2D6 substrate                |                    |
| daily                                            |               |                |                |                                  |                    |
| enalapril                                        | 5 mg daily    | 10-20 mg daily | 40 mg daily    | CYP 3A4 substrate                |                    |
| ramipril                                         | 2.5 mg daily  | 5 mg daily     | 10 mg daily    | Yes (CYP450  unknown)            |                    |
| Angiotensin Converting Enzyme Inhibitors (ACEIs) | lisinopril    | 5 mg daily     | 10-20 mg daily | 40 mg daily                      | No                 |
| fosinopril                                       | 10 mg daily   | 20 mg daily    | 40 mg daily    | Yes (CYP450  unknown)            |                    |
| Rarely used: perindopril                         | 4 mg daily    | none           | 8 mg daily     | Yes, but not  CYP450             |                    |
| Rarely used:                                     | 10 mg daily   | 20 mg daily    | 40 mg daily    | No                               |                    |
| quinapril losartan                               | 25 mg daily   | 50 mg daily    | 100 mg daily   | CYP 3A4 substrate                |                    |
| Angiotensin II  Receptor Blockers (ARBs)         | candesartan   | 4 mg daily     | 8-16 mg daily  | 32 mg daily                      | CYP 2C9 substrate  |
| irbesartan                                       | 75 mg daily   | 150 mg daily   | 300 mg daily   | CYP 2C9 substrate                |                    |
| telmisartan                                      | 40 mg daily   | none           | 80 mg daily    | Yes, but not                     |                    |
| 98                                               |               |                |                |                                  |                    |  
| Agent     | Initial     | Intermediate   | Maximum      | Hepatic              |                   |
|-----------|-------------|----------------|--------------|----------------------|-------------------|
| class     | Agent       | dose           | dose         | dose                 | metabolism CYP450 |
| valsartan | 80 mg daily | none           | 160 mg daily | Yes, but not  CYP450 |                   |
| α and β   | labetolol   | 100 mg twice   | 200 mg twice | 400 mg twice         | CYP 2D6 substrate |
| Blocker   | daily       | daily          | daily        | and inhibitor        |                   |
cytochrome p450 (cyp) enzyme
27 appendix h

Instructions to site investigators: Photocopy the following two pages back-to-back and provide the sheet to your patients at the time of enrollment. The third page following contains a walletsized information card for the patient to carry at all times.
cytochrome p450 (cyp) enzyme
information on possible interactions with

The patient _________________ is enrolled on a clinical trial using the experimental agent sunitinib. This clinical trial is sponsored by the National Cancer Institute. This form is addressed to the patient, but includes important information for others who care for this patient. Sunitinib interacts with many drugs that are processed by your liver. Because of this, it is very important to tell your study doctors about all of your medicine before you start this study. It is also very important to tell them if you stop taking any regular medicine, or if you start taking a new medicine while you take part in this study. When you talk about your medicine with your study doctor, include medicine you buy without a prescription at the drug store (over-the counter remedy), or anything that you buy from the health food store or grocery store (herbal supplement). Many health care prescribers can write prescriptions. You must also tell your other prescribers (doctors, physicians' assistants or nurse practitioners) that you are taking part in a clinical trial.  
Bring this paper with you. These are the things that you and they need to know:  
- Sunitinib is metabolized (converted in the body) by a liver enzyme called CYP3A4.  
Sunitinib must be used very carefully with other medicines that need this liver enzyme to be effective or to be cleared from your system.  
- You and healthcare providers who prescribe drugs for you must be careful about adding or removing any drug in this category.  
- Before you start the study, your study doctor will work with your regular prescriber to switch any medicines that are considered "strong inducers/inhibitors or substrates of CYP3A4."
- Your regular prescribers should look at this web site http://medicine.iupui.edu/clinpharm/ddis/table.asp to see if any medicine they want to prescribe is on a list of drugs to avoid.  
- Please be very careful! Over-the-counter drugs have a brand name on the label—it's usually big and catches your eye. They also have a generic name—it's usually small and printed on the ingredient list. Find the generic name (your pharmacist can help) and look at the table on the back of this page. Be careful.  
- You should not take St. John's wort or grapefruit juice with sunitinib.
- You should not receive steroids unless they are absolutely necessary; tell your study doctor if you are taking, have a prescription for, or have been given steroids.  
- You should not take drugs that affect your heart rhythm. Tell your study doctor if you are taking, have a prescription for, or have been given such heart medications.
Other medicines can be a problem with your study drugs.  
- You should check with your doctor or pharmacist whenever you need to use an over-thecounter medicine or herbal supplement.  
- Your regular prescriber should check a medical reference or call your study doctor before prescribing any new medicine for you. Your study doctor's name is ________________________________ and he or she can be contacted at ________________________________.  
| INFORMATION ON POSSIBLE DRUG INTERACTIONS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| You are enrolled on a clinical trial using the experimental agent  sunitinib. This clinical trial is sponsored by the NCI. Sunitinib interacts with drugs that are processed by your liver. Because of this,  it is very important to:  Tell your doctors if you stop taking regular medicine or if you start  taking a new medicine.  Tell all of your prescribers (doctor, physicians' assistant, nurse  practitioner, pharmacist) that you are taking part in a clinical trial.  Check with your doctor or pharmacist whenever you need to use  an over-the-counter medicine or herbal supplement. | Sunitinib interacts with a specific liver enzyme called CYP3A4, and  must be used very carefully with other medicines that interact with  this enzyme.   Before you start the study, your study doctor will work with your  regular prescriber to switch any medicines that are considered  "strong inducers/inhibitors or substrates of CYP3A4."  Before prescribing new medicines, your regular prescribers should  go to http://medicine.iupui.edu/clinpharm/ddis/table.asp for a list  of drugs to avoid, or contact your study doctor.   Your study doctor's name is ______________ and can be  contacted at ______________. |
cytochrome p450 (cyp) enzyme
28 appendix i list of

Medroxyprogesterone Mefloquine Mefloquine Mestranol Methadone Methimazole Methoxsalen Methylergonovine Methylprednisolone Methysergide Metronidazole Miconazole Midazolam Mifepristone Miglustat Mirtazapine Mitoxantrone Modafinil Montelukast Moricizine Nateglinide Nefazodone Nelfinavir Nevirapine Nicardipine Nifedipine Nimodipine Nisoldipine Nitrendipine Nizatidine Norethindrone Norfloxacin Norgestrel Olanzapine Omeprazole Orphenadrine Oxcarbazepine Oxybutynin Ondansetron Paclitaxel Paroxetine Pentobarbital Pergolide Phencyclidine Phenobarbital Phenytoin Pilocarpine Pimozide Pioglitazone Pravastatin Prednisolone Primaquine Primidone Progesterone Propofol Propoxyphene Quetiapine Quinidine Quinine Quinupristin Rabeprazole Repaglinide Rifabutin Rifampin  
| Aripiprazole Atazanavir Atorvastatin Azelastine Azithromycin Benzphetamine Betamethasone Bisoprolol Bortezomib Bosentan Bromazepam Bromocriptine Buprenorphine Buspirone Busulfan Caffeine Carbamazapine Cerivastatin Chloramphenicol Chlordiazepoxide Chloroquine Chlorpheniramine Chlorzoxazone Cimetadine Ciprofloxacin Cisapride Citalopram Clarithromycin Clemastine Clobazam Clofazimine Clonazepam Clorazepate Clotrimazole Clozapine Cocaine Colchicine Cyclophosphamide Cyclosporine Danazol Dantrolene Dapsone Delavirdine Desipramine Dexmedetomidine Diazepam Diclofenac Digitoxin Dihydroergotamine Diltiazem Disopyramide Disulfiram Docetaxel   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Doxepin Doxorubicin Doxycycline Drospirenone Efavirenz Eletriptan Enalapril Enoxacin Entacapone Eplerenone Ergoloid mesylates Ergonovine Ergotamine Erythromycin Escitalopram Estradiol Estrogens, conj., synthetic Estrogens, conj., equine Estrogens, conj., esterified Estrone Estropipate Ethinyl estradiol Ethosuximide Etoposide Felbamate Felodipine Fentanyl Fluconazole Fluoxetine Flurazepam Flutamide Fluvastatin Fluvoxamine Fosamprenavir Fosphenytoin Fulvestrant Gefitinib Glyburide Grapefruit juice Halofantrine Haloperidol Hydralazine Ifosfamide Imatinib Indinavir Irbesartan Irinotecan Isoniazid Isosorbide dinitrate Isosorbide mononitrate Isradipine Itraconazole Ketamine Ketoconazole Lansoprazole Letrozole Levomethadyl acetate hydrochloride Levonorgestrel Lidocaine Lomustine Losartan Lovastatin   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Rifapentine Risperidone Ritonavir Saquinavir Selegiline Sertraline Sibutramine Sildenafil Simvastatin Sirolimus St. John's wort Sufentanil Sulconazole Tacrolimus Tamoxifen Tamsulosin Telithromycin Teniposide Terbinafine Testosterone Tetracycline Theophylline Tiagabine Ticlopidine Tolterodine Toremifene Tranylcypromine Trazodone Triazolam Trimethoprim Trimipramine Troleandomycin Valproic acid Vardenafil Venlafaxine Verapamil Vinblastine Vincristine Vinorelbine Zafirlukast Ziprasidone Zolpidem Zonisamide Zopiclone