untitled h1
12.1.8 toxicity

Adverse events (>0.1%) by system organ class and preferred term in vandetanib emerging safety profile  
63  
12.1.3 SOURCE  
| Percentage of patients from patients  receiving vandetanib 300 mg  monotherapy (N=1839)   |          |
|-------------------------------------------------------------------------------------------|----------|
| Event by system organ class Cardiovascular                                                | N (%)    |
| ECG QT prolongation                                                                       | 127(6.9) |
| Myocardial infarction                                                                     | 11 (0.6) |  
| Version Date: 06/27/2017                     | Percentage of patients from patients  receiving vandetanib 300 mg  monotherapy (N=1839)   |
|----------------------------------------------|-------------------------------------------------------------------------------------------|
| Event by system organ class Angina pectoris  | 10 (0.5)                                                                                  |
| Nervous System Headache                      | 228 (12.4)                                                                                |
| Dysgeusia                                    | 61 (3.3)                                                                                  |
| Cerebrovascular accident                     | 5 (0.3)                                                                                   |
| Gastrointestinal Diarrhea                    | 931 (50.6)                                                                                |
| Nausea                                       | 480 (26.1)                                                                                |
| Vomiting                                     | 256 (13.9)                                                                                |
| Constipation                                 | 230 (12.5)                                                                                |
| Abdominal pain                               | 119 (6.5)                                                                                 |
| Stomatitis                                   | 92 (5.0)                                                                                  |
| Dry mouth                                    | 85 (4.6)                                                                                  |
| Pancreatitis                                 | 3 (0.2)                                                                                   |
| Endocrine disorders Hypothyroidism           | 23 (1.3)                                                                                  |
| Blood and lymphatic system  Thrombocytopenia | 15 (0.8)                                                                                  |
| Investigations Weight loss                   | 141 (7.7)                                                                                 |
| Elevated liver function tests                | 34-42 (1.8 - 2.3)                                                                         |
| Metabolic and nutritional disorders          |                                                                                           |  
| Version Date: 06/27/2017                         | Percentage of patients from patients  receiving vandetanib 300 mg  monotherapy (N=1839)   |
|--------------------------------------------------|-------------------------------------------------------------------------------------------|
| Event by system organ class Decreased appetite   | 253 (13.8)                                                                                |
| Anorexia                                         | 182 (9.9)                                                                                 |
| Hypokalemia                                      | 81 (4.4)                                                                                  |
| Hypocalcemia                                     | 67 (3.6)                                                                                  |
| Dehydration                                      | 49 (2.7)                                                                                  |
| Hypomagnesemia                                   | 23 (1.3)                                                                                  |
| Hypophosphatemia                                 | 4 (0.2)                                                                                   |
| Skin/appendages Rash (variety of terms)#         | 46%                                                                                       |
| Renal Hematuria                                  | 5%                                                                                        |
| Proteinuria                                      | 1%                                                                                        |
| Respiratory Interstitial lung disease (including | 5%                                                                                        |
| pneumonitis)§ Pulmonary embolism                 | 2%                                                                                        |
| Vascular Arterial ischemic events¶               | 2%                                                                                        |
| Venous thromboembolism                           | 1%                                                                                        |
| General Asthenia                                 | 8%                                                                                        |
| Fatigue                                          | 40%                                                                                       |
| Psychiatric disorders£                           |                                                                                           |  
| Percentage of patients from patients  receiving vandetanib 300 mg  monotherapy (N=1839)   |     |
|-------------------------------------------------------------------------------------------|-----|
| Event by system organ class Anxiety                                                       | 12% |
| Depression                                                                                | 11% |
| Insomnia                                                                                  | 11% |  
* The values reflect the frequency of events as a reported adverse event and do not include out-of-range laboratory values or abnormal vital signs. The events of hypophosphatemia and ecchymosis occurred in phase I studies, but did not occur in study 6474IL/0003; the frequency has therefore been set as <1%. The events of interstitial lung disease/pneumonitis, pulmonary embolism and venous thromboembolism occurred in study 6474IL/0003, but these events are heavily confounded by advanced cancer, previous radiation and chemotherapy, and disease progression.  
† CIOMS Council for International Organization for Medical Sciences (subset of World Health Organization).  
\# Acneiform rash, pruritus, macular or macupapular rash (generalized or localized),
localized and generalized erythema, photosensitivity reaction, sweating. On occasion (especially when given with chemotherapy) these have progressed to more serious conditions to include exfoliative dermatitis, skin desquamation, erythroderma, toxicoderma, toxic epidermal necrolysis, erythema multiforme
§ Preliminary data from the Phase III program suggest that the incidence of interstitial lung disease may be higher in Japan (≈ 10%) than in rest of world (≈ 1%).  
¶ Includes myocardial infarction/stroke/peripheral arterial ischemia £ It is possible that these events are not direct effects of vandetanib, but rather are secondary to symptoms of cancer or to other effects of vandetanib (rash, etc). In addition to the above toxicity profile, we have also observed cramping abdominal pain associated with drug-related diarrhea and hypothyroidism manifested as an increase in TSH requiring an increase in the dose of thyroid hormone replacement.
untitled h1
12.2 enalapril

12.2.1 CHEMICAL INFORMATION Chemical name (IUPAC): 1-[2-(1-ethoxycarbonyl-3-phenyl-propyl) aminopropanoyl] pyrrolidine-2-carboxylic acid Other Names: Enalapril maleate Molecular Formula: C20H28N2O5 Molecular Weight: 376.45 Enalapril is an anti-hypertensive agent that inhibits angiotensin converting enzyme (ACE). 12.2.3 SOURCE Enalapril maleate tablets are available as a generic from commercial sources. Enalapril is on the NIH Pharmacy formulary. 12.2.4 FORMULATION AND PREPARATION Enalapril maleate is available in 2.5, 5, and 20 mg tablets. Enalaprilat (Vasotec) is also available as an IV formulation 12.2.5 STABILITY AND STORAGE Refer to the product label. 12.2.6 ADMINISTRATION PROCEDURES Enalapril tablets will be administered once daily in the morning at a dose of 2.5 mg in children weighing <50 kg and a dose of 5 mg for children who weigh ≥50 kg. 12.2.7 TOXICITY
67 12.2.2 MECHANISM OF ACTION In a study of 110 children between the ages of 6 and 16 years treat with enalapril at one of 3 dose levels (low dose = 0.625 mg if <50 kg or 1.25 mg if ≥50 kg; middle dose = 2.5 mg if <50 kg or 5 mg if ≥50 kg; or high dose = 20 mg if <50 kg or 40 mg if ≥50 kg), 14 adverse events that were believed to be possibly, probably, or definitely drug related were reported in 12 patients. Dizziness was the most common adverse event, occurring in 4 patients (3 in the high-dose group and 1 in the middle-dose group). Two patients complained of headaches. The following adverse experiences were recorded in 1 patient each: chest pain, increased blood pressure, hypotension, diarrhea, cough, dyspnea, pruritis, rash, and blurred vision. In the low-, middle-, and high-dose groups, 2, 4, and 6 patients reported adverse events. A total of 3 patients reported cough, but none were discontinued from the study and only one episode was considered drug related. None of the patients experienced renal failure, angioedema, or hyperkalemia. No serious laboratory abnormalities were observed. Five adverse events that were believed to be possibly, probably, or definitely related to the study drug were reported in 3 patients. The adverse events were slight increases in BUN, creatinine, and serum uric acid and decreased hemoglobin and hematocrit. In the aggregate, there were no differences in mean pre- and post-dose hemoglobin, serum sodium, potassium, creatinine, AST, or ALT. 1. Kouvaraki MA, Shapiro SE, Perrier ND, et al. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid 2005;15:531-44. 2. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658-71.  
3. Eng C, Clayton D, Schuffenecker I, et al. The relationship between specific RET protooncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996;276:1575-9. 4. Gorlin RJ, Sedano HO, Vickers RA, Cervenka J. Multiple mucosal neuromas, pheochromocytoma and medullary carcinoma of the thyroid--a syndrome. Cancer 1968;22:293-9 passim.  
5. Eng C. RET proto-oncogene in the development of human cancer. J Clin Oncol 1999;17:380-93. 6. Farndon JR, Leight GS, Dilley WG, et al. Familial medullary thyroid carcinoma without associated endocrinopathies: a distinct clinical entity. Br J Surg 1986;73:278-81. 7. Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000;88:1139-48. 8. Modigliani E, Cohen R, Campos JM, et al. Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'etude des tumeurs a calcitonine. Clin Endocrinol (Oxf) 1998;48:265-73. 9. Marsh DJ, Learoyd DL, Robinson BG. Medullary thyroid carcinoma: recent advances and management update. Thyroid 1995;5:407-24. 10. Di Bartolomeo M, Bajetta E, Bochicchio AM, et al. A phase II trial of dacarbazine, fluorouracil and epirubicin in patients with neuroendocrine tumours. A study by the Italian Trials in Medical Oncology (I.T.M.O.) Group. Ann Oncol 1995;6:77-9.  
68
untitled h1
13 references

11. Nocera M, Baudin E, Pellegriti G, Cailleux AF, Mechelany-Corone C, Schlumberger M. Treatment of advanced medullary thyroid cancer with an alternating combination of doxorubicin-streptozocin and 5 FU-dacarbazine. Groupe d'Etude des Tumeurs a Calcitonine (GETC). Br J Cancer 2000;83:715-8. 12. Wu LT, Averbuch SD, Ball DW, de Bustros A, Baylin SB, McGuire WP, 3rd. Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine. Cancer 1994;73:432-6. 13. Quayle FJ, Moley JF. Medullary thyroid carcinoma: including MEN 2A and MEN 2B syndromes. J Surg Oncol 2005;89:122-9. 14. Peczkowska M, Januszewicz A. Multiple endocrine neoplasia type 2. Fam Cancer 2005;4:25-36. 16. Skinner MA, DeBenedetti MK, Moley JF, Norton JA, Wells SA, Jr. Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 1996;31:177-81; discussion 81-2. 17. Skinner MA. Management of hereditary thyroid cancer in children. Surg Oncol 2003;12:101-4. 18. Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK, Wells SA, Jr. Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 2005;353:1105-13.  
19. Danko ME, Skinner MA. Surgical intervention in children with multiple endocrine neoplasia type 2. Curr Opin Pediatr 2006;18:312-5. 20. Gagel RF, Tashjian AH, Jr., Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 1988;318:478-84. 21. Pacini F, Fontanelli M, Fugazzola L, et al. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 1994;78:826-9. 22. Cohen R, Campos JM, Salaun C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d'Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab 2000;85:919-22. 23. Hirsch PF, Baruch H. Is calcitonin an important physiological substance? Endocrine 2003;21:201-8. 24. Findlay DM, Sexton PM. Calcitonin. Growth Factors 2004;22:217-24. 25. Reasbeck PG, Burns SM, Shulkes A. Calcitonin gene-related peptide: enteric and cardiovascular effects in the dog. Gastroenterology 1988;95:966-71. 26. Lakhani VT, You YN, Wells SA. The Multiple Endocrine Neoplasia Syndromes. Annu Rev Med 2006. 27. Chiefari E, Russo D, Giuffrida D, et al. Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma. J Endocrinol Invest 1998;21:358-64.  
28. Gujral TS, Singh VK, Jia Z, Mulligan LM. Molecular mechanisms of RET receptormediated oncogenesis in multiple endocrine neoplasia 2B. Cancer Res 2006;66:10741-9.  
29. Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 2002;62:7284-90.  
69 15. Wells SA, Jr., Skinner MA. Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. Exp Clin Endocrinol Diabetes 1998;106:29-34. 30. Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 2002;62:4645-55.  
70 31. Vidal M, Wells S, Ryan A, Cagan R. ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Cancer Res 2005;65:3538-41. 32. Herbst RS, Heymach JV, O'Reilly MS, Onn A, Ryan AJ. Vandetanib (ZD6474): an orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opin Investig Drugs 2007;16:239-49. 33. Ryan AJ, Wedge SR. ZD6474--a novel inhibitor of VEGFR and EGFR tyrosine kinase activity. Br J Cancer 2005;92 Suppl 1:S6-13.  
34. Checkley D, Tessier JJ, Kendrew J, Waterton JC, Wedge SR. Use of dynamic contrastenhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 prostate tumours. Br J Cancer 2003;89:1889-95.  
35. Holden SN, Eckhardt SG, Basser R, et al. Clinical evaluation of ZD6474, an orally active inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann Oncol 2005;16:1391-7. 36. Tamura T, Minami H, Yamada Y, et al. A phase I dose-escalation study of ZD6474 in Japanese patients with solid, malignant tumors. J Thoracic Oncol 2006;1:1002-9. 37. Natale RB, Bodkin D, Govindan R, et al. ZD6474 versus gefitinib in patients with advanced NSCLC: Final results from a two-part, double-blind, randomized phase II trial. Proc Am Soc Clin Oncol 2006;24:7000 (Abstr). 38. Lee DP, Skolnik JM, Adamson PC. Pediatric phase I trials in oncology: an analysis of study conduct efficiency. J Clin Oncol 2005;23:8431-41.  
39. Smith RP, Kennedy S, Robertson J, Sandall D, Oliver R. The effect of food on the intrasubject variability of the pharmacokinetics of ZD6474, a novel antiangiogenic agent, in healthy subjects. Proc Am Soc Clin Oncol 2005;23:3167. 40. Wells T, Frame V, Soffer B, et al. A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of enalapril for children with hypertension. J Clin Pharmacol 2002;42:870-80.  
41. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006;24:4764-74. 42. Mauro MJ. Defining and managing imatinib resistance. Hematology Am Soc Hematol Educ Program 2006:219-25.  
43. Bain G, Bearcroft PW, Berman LH, Grant JW. The use of ultrasound-guided cuttingneedle biopsy in paediatric neck masses. Eur Radiol 2000;10:512-5.  
| 14                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Appendix 1: Performance Status Scales/Scores   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------|
| PERFORMANCE STATUS CRITERIA Karnofsky and Lansky performance scores are intended to be multiples of 10 Karnofsky Lansky  Score Description Score Description 100 Normal, no complaints, no evidence of  100 Fully active, normal. disease 90 Able to carry on normal activity, minor  90 Minor restrictions in physically  signs or symptoms of disease. strenuous activity. 80 Normal activity with effort; some signs  80 Active, but tires more quickly or symptoms of disease. 70 Cares for self, unable to carry on normal  70 Both greater restriction of and less time  activity or do active work. spent in play activity. 60 Required occasional assistance, but is  60 Up and around, but minimal active play;  able to care for most of his/her needs.  keeps busy with quieter activities. 50 Requires considerable assistance and  50 Gets dressed, but lies around much of  frequent medical care. the day; no active play, able to  participate in all quiet play and  activities. 40 Disabled, requires special care and  40 Mostly in bed; participates in quiet  assistance. activities. 30 Severely disabled, hospitalization  30 In bed; needs assistance even for quiet  indicated. Death not imminent. play. 20 Very sick, hospitalization indicated.  20 Often sleeping; play entirely limited to  Death not imminent. very passive activities. 10 Moribund, fatal processes progressing  10 No play; does not get out of bed.  rapidly. Patients >10 years old : use Karnofsky performance criteria |                                                |  
Patients ≤ 10 years old: use Lansky performance criteria  
| Diastolic blood pressure levels for BOYS aged 1-18 years  1 2 3   | 4                           |                         |        |     |
|-------------------------------------------------------------------|-----------------------------|-------------------------|--------|-----|
| DBP ≤10  mmHg above  ULN                                          | 10<DBP ≤25  mmHg above  ULN | DBP>25  mmHg  above ULN |        |     |
| Age                                                               | ULN* DBP                    |                         |        |     |
| (years)                                                           | mmHg                        |                         |        |     |
| 1                                                                 | 58                          | 59-68                   | 69-83  | 84  |
| 2                                                                 | 62                          | 63-72                   | 73-87  | 88  |
| 3                                                                 | 66                          | 67-76                   | 77-91  | 92  |
| 4                                                                 | 69                          | 70-79                   | 80-94  | 95  |
| 5                                                                 | 71                          | 72-81                   | 82-96  | 97  |
| 6                                                                 | 73                          | 74-83                   | 84-98  | 99  |
| 7                                                                 | 74                          | 75-84                   | 85-99  | 100 |
| 8                                                                 | 75                          | 76-85                   | 86-100 | 101 |
| 9                                                                 | 77                          | 78-87                   | 88-102 | 103 |
| 10                                                                | 78                          | 79-88                   | 89-103 | 104 |
| 11                                                                | 79                          | 80-89                   | 90-104 | 105 |
| 12                                                                | 80                          | 81-90                   | 91-105 | 106 |
| 13                                                                | 82                          | 83-92                   | 93-107 | 108 |
| 14                                                                | 83                          | 84-93                   | 94-108 | 109 |
| 15                                                                | 83                          | 84-93                   | 94108  | 109 |
| 16                                                                | 84                          | 85-94                   | 95-109 | 110 |
| 17                                                                | 84                          | 85-94                   | 95-109 | 110 |
| 18                                                                | 84                          | 85-94                   | 95-109 | 110 |
| * ≤95th percentile for age and 50% height percentile              |                             |                         |        |     |  
Diastolic blood pressure levels for GIRLS aged 1-18 years  
Age  
(years)  
ULN* DBP  
mmHg  
DBP ≤10  
mmHg above  
ULN  
1 2 3 4  
1 57 58-67 68-82 83 2 61 62-71 72-86 87  
| 10<DBP ≤25  mmHg above  ULN   |
|-------------------------------|  
3 65 66-75 76-90 91 4 68 69-78 79-93 94 5 71 72-81 82-96 97 6 74 75-84 85-99 100 7 76 77-86 87-101 102 8 77 78-87 88-102 103 9 79 80-89 90-104 105 10 80 81-90 91-105 106 11 80 81-90 91-105 106 12 81 82-91 92-106 107 13 82 83-92 93-107 108  
14 82 83-92 93-107 108  
15 83 84-93 94-108 109 16 85 86-95 96-110 111 17 87 88-97 98-112 113 18 87 88-97 98-112 113  
* ≤95th percentile for age and 50% height percentile These Charts list DBP levels within the ULN (1), within 10 mmHg above the ULN (2), within 11-25 mmHg above the ULN (3), and >25 mmHg above the ULN (4).  
| DBP>25  mmHg  above ULN   |
|---------------------------|  
Instructions for using this BP Chart:
1. Measure the patient's blood pressure using an appropriate size cuff.  
2. Select appropriate chart for a female or male patient. 3. Using the "age" row determine if the DBP is within the ULN (1) or elevated (2, 3, 4). 4. See Section **3.1.4** for definition of dose limiting hypertension. 5. See Section 6.1 for management of vandetanib related hypertension.  
74 Patient Study ID \#:
Height (cm):  
  
  
Weight  
   
BSA (m2): Dose level (mg/m2): Actual Dose  
  
  
Date: Time dose taken: Cycle/Day:  
| Sample  #   | Cycl   | Day    | Hour        | Target Date &   |
|-------------|--------|--------|-------------|-----------------|
| e           | Time   | Actual | Time        |                 |
| Obtained    |        |        |             |                 |
| Pre         | 1      | 0      | Pre dose #1 |                 |
| 1           | 1      | 2      | 24*         |                 |
| 2           | 2      | 1      | 24*         |                 |
| 3           | 2      | 28     | Pre dose    |                 |
| 4           | 2      | 28     | 1           |                 |
| 5           | 2      | 28     | 2           |                 |
| 6           | 2      | 28     | 4           |                 |
| 7           | 2      | 28     | 6           |                 |
| 8           | 2      | 28     | 8           |                 |
| 9           | 2      | 28     | 10 to 12    |                 |
| 10          | 3      | 1      | 24*         |                 |  
  
Blood samples of approximately 2 ml will be collected by venipuncture or from an indwelling venous central or peripheral line (after discarding appropriate waste) into a lithium heparin Vacutainer tube (green top). Following blood collection, the tubes should be inverted several times to ensure mixing with the anticoagulant. The tubes should be placed on crushed ice, and samples centrifuged for 10 minutes at approximately 1000 x g at room temperature within 30 minutes after collection. The plasma samples will be transferred using plastic pipettes into screw-capped polypropylene tubes labeled with vandetanib study number, the patient ID number, date, study day, collection time, and sample \#. The plasma samples will be frozen within 1 hours after collection and will remain frozen at < -20°C until shipped.  
Plasma samples can be stored frozen at -20qC or -70qC for a period of up to 6 months after which time they should be shipped to BASi (see details below). They should be packed securely to avoid breakage during transit and with enough dry ice to prevent thawing for at least 72 hours. A sample itinerary detailing sample numbers and identification should be sent with each shipment and BASi should be contacted by fax or email prior to each sample shipment. Samples should be shipped to avoid arrival at the laboratory during weekends and public holidays and should be sent to the following address.  
Jason Plassard Bioanalytical Systems Inc. (BASi) 2701 Kent Avenue West Lafayette IN 47906-1350 Phone: 765.497.5853 Fax: 765.497.5863 Email: japlassard@bioanalytical.com It has been recognized for a number of years that certain medications can prolong the QT/QTc interval and cause a form of acquired Long QT syndrome, known as drug induced LQTS. The drugs that prolong the QT interval or have a risk of inducing Torsade de Pointes (TdP) are listed below, divided into two groups based on their known or perceived risk of causing TdP. Group 1. Drugs that are generally accepted as having a risk of causing Torsades de Pointes Concomitant use of these drugs is not allowed during the study or within 2 weeks of enrollment (at least four weeks for levomethadyl). These drugs should also be avoided for up to 4 weeks following discontinuation of vandetanib:  
| Drug (Generic Names)    | Drug Class (Clinical Usage)           | Comments                          |
|-------------------------|---------------------------------------|-----------------------------------|
| Amiodarone              | Anti-arrhythmic (heart rhythm)        | F>M, TdP Cases in  Literature     |
| Arsenic trioxide        | Anti-cancer (leukemia)                | TdP Cases in Literature           |
| Astemizole              | Antihistamine (Allergic rhinitis)     | No longer available in U.S.       |
| Bepridil                | Anti-anginal (heart pain)             | F>M                               |
| Chlorpromazine          | Anti-psychotic/antiemetic             | TdP Cases in Literature           |
| (schizophrenia/nausea)  |                                       |                                   |
| Chloroquine             | Anti-malaria (malaria infection)      |                                   |
| Cisapride               | GI stimulant (stimulates GI motility) | Open Prescription Restricted  F>M |
| Clarithromycin          | Antibiotic (bacterial infection)      |                                   |
| Disopyramide            | Anti-arrhythmic (heart rhythm)        | F>M                               |
| Dofetilide              | Anti-arrhythmic (heart rhythm)        |                                   |
| Domperidone             | Anti-nausea (nausea)                  |                                   |
| Droperidol              | Sedative/hypnotic (anesthesia         | TdP Cases in Literature           |
| adjunct)                |                                       |                                   |
| Erythromycin            | Antibiotic/GI stimulant               | F>M                               |
| (infection/GI motility) |                                       |                                   |
| Halofantrine            | Anti-malarial (malaria infection)     | F>M                               |  
| Version Date: 06/27/2017  Haloperidol   | Anti-psychotic (schizophrenia,  agitation)                                 |                               |
|-----------------------------------------|----------------------------------------------------------------------------|-------------------------------|
| Ibutilide                               | Anti-arrhythmic (heart rhythm)                                             | F>M                           |
| Levomethadyl                            | Opiate agonist (narcotic  dependence)                                      |                               |
| Mesoridazine                            | Anti-psychotic (schizophrenia)                                             |                               |
| Methadone                               | Opiate agonist (pain control/narcotic                                      | F>M                           |
| dependence)                             |                                                                            |                               |
| Moxifloxacin                            | Antibiotic (bacterial infection)                                           |                               |
| Pentamidine                             | Anti-infective (pneumocystis                                               | F>M                           |
| pneumonia)                              |                                                                            |                               |
| Pimozide                                | Anti-psychotic (Tourette's tics)                                           | F>M, TdP Cases in  Literature |
| Probucol                                | Antilipemic (hypercholesterolemia)                                         | No longer available in U.S.   |
| Procainamide                            | Anti-arrhythmic (heart rhythm)                                             |                               |
| Quinidine                               | Anti-arrhythmic (abnormal heart                                            | F>M                           |
| rhythm)                                 |                                                                            |                               |
| Sotalol                                 | Anti-arrhythmic (heart rhythm)                                             | F>M                           |
| Sparfloxacin                            | Antibiotic (bacterial infection)                                           |                               |
| Terfenadine                             | Antihistamine (allergic rhinitis)                                          | No longer available in U.S.   |
| Thioridazine                            | Anti-psychotic (schizophrenia)                                             |                               |
| Vandetanib (*Does not                   | Anti-cancer (thyroid cancer)                                               | "Zactima®" is the proposed    |
| apply in this study)                    | brand name                                                                 |                               |
| Group 2.                                | Drugs that may be associated with Torsades de Pointes but lack substantial |                               |  
Group 2. Drugs that may be associated with Torsades de Pointes but lack substantial evidence of causing Torsades de Pointes.  
These drugs will be allowed during the study, at the discretion of the Investigator, if considered absolutely necessary (no alternative is available). In such cases, the patient must be closely monitored, including regular checks of QTc and electrolytes.  
| Version Date: 06/27/2017  Drug (Brand Names)   | Drug Class (Clinical Usage)                            | Comments                    |
|------------------------------------------------|--------------------------------------------------------|-----------------------------|
| Alfuzocin                                      | Alpha 1-blocker (Benign prostatic  hyperplasia)        |                             |
| Amantadine                                     | Dopaminergic/Antiviral/Antiinfective (Parkinson's  disease)                                                        |                             |
| Atazanavir                                     | Protease inhibitor (HIV)                               |                             |
| Azithromycin                                   | Antibiotic (bacterial infection)                       |                             |
| Chloral hydrate                                | Sedative (sedation/insomnia)                           |                             |
| Clozapine                                      | Anti-psychotic (schizophrenia)                         |                             |
| Dolasetron                                     | Anti-nausea (nausea and vomiting)                      |                             |
| Dronedarone                                    | Anti-arrhythmic (atrial fibrillation)                  |                             |
| Escitalopram                                   | Anti-depressant (major depression,  Anxiety disorders) |                             |
| Famotidine                                     | H2-receptor antagonist (peptic ulcer,  GERD)           |                             |
| Felbamate                                      | Anti-convulsant (seizures)                             |                             |
| Flecainide                                     | Anti-arrhythmic (heart rhythm)                         | Association not clear       |
| Foscarnet                                      | Antiviral (HIV infection)                              |                             |
| Fosphenytoin                                   | Anticonvulsant (seizures)                              |                             |
| Gatifloxacin                                   | Antibiotic (bacterial infection)                       |                             |
| Gemifloxacin                                   | Antibiotic (bacterial infection)                       |                             |
| Granisetron                                    | Anti-nausea (nausea and vomiting)                      |                             |
| Indapamide                                     | Diuretic (stimulates urine & salt                      | TdP Cases in Literature, QT |
| loss)                                          | in animals                                             |                             |
| Isradipine                                     | Anti-hypertensive (high blood  pressure)               |                             |  
| Version Date: 06/27/2017  Drug (Brand Names)   | Drug Class (Clinical Usage)                       | Comments                |
|------------------------------------------------|---------------------------------------------------|-------------------------|
| Lapatinib                                      | Anti-cancer (breast cancer,  metastatic)          |                         |
| Levofloxacin                                   | Antibiotic (bacterial infection)                  | Association not clear   |
| Lithium                                        | Anti-mania (bipolar disorder)                     |                         |
| Moexipril/HCTZ                                 | Anti-hypertensive (high blood  pressure)          |                         |
| Nicardipine                                    | Anti-hypertensive (high blood  pressure)          |                         |
| Nilotinib                                      | Anti-cancer (leukemia)                            |                         |
| Octreotide                                     | Endocrine (acromegaly/carcinoid  diarrhea)        |                         |
| Ofloxacin                                      | Antibiotic (bacterial infection)                  |                         |
| Ondansetron                                    | Anti-emetic (nausea &vomiting)                    |                         |
| Oxytocin                                       | Oxytocic (labor stimulation)                      |                         |
| Paliperidone                                   | Antipsychotic, atypical  (Schizophrenia)          |                         |
| Perflutren lipid                               | Imaging contrast agent                            |                         |
| microspheres                                   | (echocardiography)                                |                         |
| Quetiapine                                     | Anti-psychotic (schizophrenia)                    |                         |
| Ranolazine                                     | Anti-anginal (chronic angina)                     |                         |
| Risperidone                                    | Anti-psychotic (schizophrenia)                    |                         |
| Roxithromycin                                  | Antibiotic (bacterial infection)                  |                         |
| Sertindole                                     | Antipsychotic, atypical (anxiety,  schizophrenia) |                         |
| Sunitinib                                      | Anti-cancer (RCC, GIST)                           |                         |
| Tacrolimus                                     | Immune suppressant                                | TdP Cases in Literature |  
81  
Drug (Brand Names) Drug Class (Clinical Usage) Comments  
| Drug (Brand Names)     | Drug Class (Clinical Usage)                | Comments   |
|------------------------|--------------------------------------------|------------|
| Tamoxifen              | Anti-cancer (breast cancer)                |            |
| Telithromycin          | Antibiotic (bacterial infection)           |            |
| Tizanidine             | Muscle relaxant                            |            |
| Vardenafil             | Phosphodiesterase inhibitor  (vasodilator) |            |
| Venlafaxine            | Antidepressant (depression)                |            |
| Voriconazole           | Anti-fungal (fungal infection)             |            |
| Ziprasidone            | Anti-psychotic (schizophrenia)             |            |
| Updated 19 August 2011 |                                            |            |  
Introduction: *As of Amendment J,* the requirements for the care, monitoring and management of all patients remaining on the trial on long term treatment with vandetanib will be consistent with the package insert Medication Guide recommendations. Evaluations may be performed by local medical doctor (LMD) or health care institution that will provide status updates to the NCI. At least annually, safety and response evaluations will be performed at NCI. LMDs will be requested to complete evaluations (as per attached letter) and notify the NCI study team of patient status. Source documents will be sent to the NIH and once the status is verified by the NCI study team, vandetanib will be ordered from the NIH CC Pharmacy (See Drug Ordering Below). DRUG ADMINISTRATION: Vandetanib is administered orally, once daily on a continuous dosing schedule. A cycle of vandetanib is defined as 28 consecutive days starting with the first day of treatment (day 1). The dose of vandetanib is determined from the patient's body surface area using the dosing nomogram below. The BSA should be recalculated at least annually (at least every 12 cycles, or with a major change in height or weight). Vandetanib is supplied as either a 10 mg/ml suspension or 50 and 100 mg tablets. Vandetanib should be stored at room temperature in the original pack until use. Vandetanib should be taken once daily at the same time of day, irrespective of meals. If liquid suspension or 50 mg tablets are not available, an every other day dosing schedule can be used to achieve the correct dose, but is not preferred. See package insert for directions regarding missed doses. Supportive care and concomitant medications may be administered as clinically indicated and as according to the Vandetanib package insert (**Appendix 6**: Vandetanib Package Insert). Dose Level [mg/m2] 100
: 06/27/20171882 Appendix 5: As of Amendment J: Care, Monitoring and Management of all Patients Remaining on Study on Long Term **Vandetanib Therapy**  
  
| >1.75                | 200        | >1.83      | 300        |     |
|----------------------|------------|------------|------------|-----|
| 150                  | 1.25- 1.75 | 150        | 1.51- 1.83 | 250 |
| 125                  | 1.17- 1.50 | 200        |            |     |
| 084-1.16             | 150        |            |            |     |
| 100                  | 0.75- 1.24 | 100        |            |     |
| 75                   | 0.50- 0.74 | 50         | 0.50- 0.83 | 100 |
| 50 Dose  [mg]        | BSA  [m2]  | Dose  [mg] |            |     |
| 100  (tablets  only) | BSA  [m2]  | Dose  [mg] |            |     |
| 150                  |            |            |            |     |  
| EVALUATIONS:   | Quarterly evaluations should be performed by LMD or health care institution that has agreed to supply the information to the NCI (see  attached letter)   | 1. Every 3 cycles (± 30 days)   | x Monitor laboratory values: serum potassium, calcium, magnesium, and thyroid function tests, other evaluations as clinically  indicated   | x Obtain 12-lead electrocardiogram and evaluate QTc   | x Evaluate for unanticipated problems (UPs); if clinical evaluations are performed by the LMD as clinically indicated, study staff  will contact the patient via phone to ascertain UPs since last contact.  2. Every 6 cycles (± 30 days)   | x Monitor laboratory values: serum potassium, calcium, magnesium, and thyroid function tests, Serum CTN and CEA, other  evaluations as clinically indicated   | x Obtain 12-lead electrocardiogram and evaluate QTc   | x Evaluate for UPs; clinical evaluations are performed by the LMD as clinically indicated, study staff will contact the patient via  phone to ascertain UPs since last contact.   | x Pregnancy test prior to imaging tests in women of child-bearing potential   | x Radiographic evaluation of disease  3. Every 12 cycles (must be performed at NIH) (± 30 days)   |
|----------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------|  
: 06/27/201783  
DOSE MODIFICATIONS: Study drug dose reductions will be allowed and are to be made based on discussions between the subject, the subject's LMD and the study investigator. Physicians (LMDs and investigators) should fully document the findings of these calls/visits in thesubject's medical records. Dose modifications and delays may be made according to the package insert (See **Appendix 6**: Vandetanib Package Insert) and good clinical practice. DATA COLLECTION AND DOCUMENTATION: As of approval of Amendment J for all subjects remaining on trial and receiving long term therapy, only SAEs and response data will be captured in C3D. All evaluations and physician visits should be documented in the patient's medical record.PHARMACY DISPENSING OF VANDETANIB: Patients returning to NIH for follow up visits will be dispensed vandetanib from the Clinical Center (CC) Pharmacy. At the time of the NIH visit, patients should return any unused drug supplies, which will be discarded in CC Pharmacy as medical waste. Patients who are evaluated by their LMD / health care institution will be contacted by phone by the study team and evaluated for UPs and drug accountability (doses left). Once the study team determines the patient is eligible to continue therapy (information received from LMD), a CRIS order will be submitted for a 6 cycle supply of study drug to be shipped to the patient via priority mail, when feasible. Subjects should be directed not to finish the study drug from the previous visit. Instead, when the new drug supply arrives, the patient should be directed to hold all unused drug and bottles and to bring them to the study site at the next scheduled visit. Noncompliance by the patient in returning study drug back to the site can result in the patient being terminated from the study.  
: 06/27/201784 x History and Physical Exam with height and weight (BSA), x Monitor laboratory values: serum potassium, calcium, magnesium, and thyroid function tests, Serum CTN and CEA, other evaluations as clinically indicated x Obtain 12-lead electrocardiogram and evaluate QTc x Evaluate for UPs x Pregnancy test prior to imaging tests in women of child-bearing potential x Radiographic evaluation of disease Public Health Service National Institutes of Health Memorandum
[Recipient Name] [Title] [Company Name] [Street Address] [**City, ST ZIP Code**] Dear Health Care Provider/ insert MD name, Your patient __<name>____ is enrolled on a research protocol at the National Institutes of Health Pediatric Oncology Branch ("A phase I/II Trial of Vandetanib (ZD6474, ZACTIMA) in Children and Adolescents with Hereditary Medullary Thyroid Carcinoma"). Your patient has been receiving vandetanib as part of this study for over two years. As part of our research, we ask for your participation in monitoring and evaluating _<name>____ every three cycles (each cycle is 28 days), and as clinically needed. Vandetanib is approved by the FDA for treatment of medullary thyroid carcinoma in adults, but has not been approved in children. We have an agreement with AstraZeneca, the drug manufacturer, to supply vandetanib on this study for your patient. As part of our agreement, the following evaluations must be performed and the results sent to the NIH: 1. Every 3 cycles, please perform the following tests: x Monitor laboratory values: serum potassium, calcium, magnesium, and thyroid function tests; correct electrolyte abnormalities as needed. Other evaluations performed as clinically indicated. x Obtain 12-lead electrocardiogram and evaluate QTc x Evaluate for serious adverse events (SAEs) x Fax or e-mail the test results and any follow up to: Claudia Derse-Anthony, R.N. 10 Center Drive, Room 1C244 Bethesda, MD 20982 Office Phone: (240) 760-6102
: 06/27/201785  
  
  
  
Email: derseanthonycp@mail.nih.gov 2. Every 6 cycles x Monitor laboratory values: serum potassium, calcium, magnesium, and thyroid function tests, Serum CTN and CEA; correct electrolyte abnormalities as needed. Other evaluations performed as clinically indicated. x Obtain 12-lead electrocardiogram and evaluate QTc x Evaluate for serious adverse events (SAEs) x Radiographic evaluation of disease (if indicated, perform pregnancy evaluation prior to scans) x Fax or e-mail the test results and any follow up to: Claudia Derse-Anthony, R.N. 10 Center Drive, Room 1C244 Bethesda, MD 20982 Office Phone: (240) 760-6102
: 06/27/201786 Email: derseanthonycp@mail.nih.govIf your patient experiences any toxicities related to the vandetanib that meet the criteria in the attached package insert for dose modification, please contact Dr. Brigitte Widemann at 240-760-6203 or widemanb@mail.nih.gov todiscuss any dose modifications to the vandetanib daily dose. We will have your patient return annually to the NIH for evaluation. After we receive your evaluation results, we will contact your patient and if the patient does not have unacceptable toxicity or progression of disease, we will have a 6- cycle supply of vandetanib shipped directly to your patient. We thank you for your participation. If you have any questions at all, please do not hesitate to contact Dr. Brigitte Widemann at 240-760-6203 or widemanb@mail.nih.gov. Best regards, Brigitte Widemann, M.D. Head, Pharmacology and Experimental Therapeutics Section, POB, CCR, NCI, NIH 10 Center Drive, MSC 1104 Bldg. 10 CRC, Rm. 1-3750 Bethesda, MD 20814-1104  
  
Abbreviated Title: Vandetanib in Hereditary MTC
Version Date : 06/27/2017  
http://ww.caprelsa.com/tcp/references.aspx[10/8/13 1:35:36 PM]  
  
| Photosensitivity reactions can occur during CAPRELSA treatment and up to 4 months after treatment discontinuation   | Interstitial lung disease (ILD) or pneumonitis, including fatalities, has occurred in patients treated with CAPRELSA.   | interrupt CAPRELSA for acute or worsening pulmonary symptoms and discontinue CAPRELSA if ILD is confirmed        |                                                                                         |
|---------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|
| Because of the risk of QT prolongation, obtain an ECG and serum potassium, calcium, magnesium, and thyroid-         | stimulating hormone (TSH) at baseline, 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and             | Ischemic cerebrovascular events, including fatalities, occurred in patients treated with CAPRELSA. The safety of |                                                                                         |
| Stop CAPRELSA in patients who develop a QTcF greater than 500 ms until QTcF returns to less than 450 ms.            | Severe skin reactions (including Stevens-Johnson syndrome), some leading to death, have occurred in patients            | Serious hemorrhagic events, including fatalities, occurred in patients treated with CAPRELSA. Do not administer  |                                                                                         |
| resumption of CAPRELSA therapy after resolution of an ischemic cerebrovascular event has not been studied.          |                                                                                                                         |                                                                                                                  |                                                                                         |
| every 3 months thereafter. Following any dose reduction or interruptions greater than 2 weeks, conduct QT           |                                                                                                                         |                                                                                                                  |                                                                                         |
| 450 ms or who have a history of Torsades de pointes, bradyarrhythmias, or uncompensated heart failure.              | CAPRELSA has not been studied in patients with ventricular arrhythmias or recent myocardial infarction                  | reated with CAPRELSA. Consider permanent discontinuation of CAPRELSA for severe skin reactions                   | Discontinue CAPRELSA in patients who experience a severe ischemic cerebrovascular event |
| Dosing of CAPRELSA can then be resumed at a reduced dose                                                            | assessments as described above.                                                                                         |                                                                                                                  |                                                                                         |  
| CAPRELSA to patients with a recent history of hemoptysis of   1/2 teaspoon of red blood. Discontinue CAPRELSA   | patients with severe hemorrhage   |
|-----------------------------------------------------------------------------------------------------------------|-----------------------------------|  
Heart failure, including fatalities, occurred in patients treated with CAPRELSA. Monitor for signs and symptoms of  
| heart failure. Consider discontinuation of CAPRELSA in patients with heart failure. Heart failure may not be reversible   | Increased dosing of thyroid replacement therapy was required in 49% of CAPRELSA-treated patients. Obtain TSH at     | signs or symptoms of hypothyroidism occur, examine thyroid hormone levels and adjust thyroid replacement therapy   | Hpertension, including hypertensive crisis, has occurred in patients treated with CAPRELSA. Monitor all patients for   | hypertension. Dose reduction or interruption for hypertension may be necessary. If hypertension cannot be controlled,   | CAPRELSA can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should   |
|---------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|
| paseline, at 2-4 weeks and 8-12 weeks after starting treatment with CAPRELSA, and every 3 months thereafter. If           | Consider this syndrome in any patient presenting with seizures, headache, visual disturbances, confusion or altered | CAPRELSA is not recommended for patients with moderate and severe hepatic impairment, as safety and efficacy       |                                                                                                                        |                                                                                                                         |                                                                                                               |
| mental function. In clinical studies, three of four patients who developed RPLS while taking CAPRELSA also had            | Vandetanib exposure is increased in patients with impaired renal function. Reduce the starting dose to 200 mg in    |                                                                                                                    |                                                                                                                        |                                                                                                                         |                                                                                                               |
| Avoid administration of CAPRELSA with anti-arrhythmic drugs and other drugs that may prolong the QT interval              |                                                                                                                     |                                                                                                                    |                                                                                                                        |                                                                                                                         |                                                                                                               |
| Darrhea of Grade 3 or greater severity occurred in patients receiving CAPRELSA. If diarrhea occurs, carefully             | Reversible posterior leukoencephalopathy syndrome (RPLS) has occurred in patients treated with CAPRELSA.            | patients with moderate to severe renal impairment and monitor the QT interval closely. There is no information     |                                                                                                                        |                                                                                                                         |                                                                                                               |
| monitor serum electrolytes and ECGs to enable early detection of QT prolongation resulting from dehydration.              | interrupt CAPRELSA for severe diarrhea and upon improvement resume CAPRELSA at a reduced dose                       | hypertension. Discontinue CAPRELSA treatment in patients with RPLS                                                 | available for patients with end-stage renal disease requiring dialysis                                                 |                                                                                                                         |                                                                                                               |
| d not resume CAPRELSA                                                                                                     |                                                                                                                     |                                                                                                                    |                                                                                                                        |                                                                                                                         |                                                                                                               |
| upon stopping CAPRELSA                                                                                                    | have not been established                                                                                           |                                                                                                                    |                                                                                                                        |                                                                                                                         |                                                                                                               |
| accordingly                                                                                                               |                                                                                                                     |                                                                                                                    |                                                                                                                        |                                                                                                                         |                                                                                                               |  
Abbreviated Title: Vandetanib in Hereditary MTC
Version Date : 06/27/2017  
  
http://ww.caprelsa.com/bcp/references.asps[10/8/13 1:35:36 PM]