untitled h1
11.2.4.2 acyclovir

Acyclovir will be obtained by the Clinical Center Pharmacy Department from commercial sources. It will be used to prevent the occurrence of herpes virus infections in patients who cannot take oral medications. It is supplied as powder for injection in 500 mg/vials. Reconstitute in 10 mL of sterile water for injection to a concentration of 50 mg/mL. Reconstituted solutions should be used within 12 hours. IV solutions should be diluted to a concentration of 7 mg/mL or less and infused over 1 hour to avoid renal damage. Reversible renal insufficiency has been reported with IV but not oral acyclovir. Neurologic toxicity including delirium, tremors, coma, acute psychiatric disturbances, and abnormal EEGs have been reported with higher doses of acyclovir. Should this occur, a dosage adjustment will be made or the drug will be discontinued. Stomach upset, headache or nausea, rash or hives; peripheral edema; pain, elevated liver function tests; and leukopenia, diarrhea, lymphadenopathy, myalgias, visual abnormalities and elevated creatinine have been reported. Hair loss from prolonged use has been reported. Acyclovir will not be used concomitantly with other nucleoside analogs which interfere with DNA synthesis, e.g. ganciclovir. In renal disease, the dose is adjusted as per product labeling.
untitled h1
11.2.5 fluconazole

Fluconazole will be obtained by the Clinical Center Pharmacy Department from commercial sources. It will be used to prophylax against fungal infections. It is available in 200 mg tablets. It can cause headache, nausea, vomiting, diarrhea or abdominal pain, and liver damage which may be irreversible. It can cause rashes and itching, which in rare cases has caused Stevens Johnson Syndrome. It has several significant drug interactions. The package insert should be consulted prior to prescribing. For IV administration in patients who cannot tolerate the oral preparation, Fluconazole comes in 2 mg/mL solution for injection, and prepared according to Clinical Center Pharmacy standard procedures. It should be administered at a maximum IV rate of 200 mg/hour.  
11.2.6 Ondansetron Hydrochloride Ondansetron hydrochloride will be obtained by the Clinical Center Pharmacy Department from commercial sources. It will be used to control nausea and vomiting during the chemotherapy preparative regimen. It can cause headache, dizziness, myalgias, drowsiness, malaise, and weakness. Less common side effects include chest pain, hypotension, pruritis, constipation and urinary retention. Consult the package insert for specific dosing instructions.
untitled h1
11.2.7 furosemide

Furosemide will be obtained by the Clinical Center Pharmacy Department from commercial sources. It will be used to enhance urine output during the chemotherapy preparative regimen with cyclophosphamide. Adverse effects include dizziness, vertigo, paresthesias, weakness, orthostatic hypotension, photosensitivity, rash and pruritis. Consult the package insert for a complete list of all side effects.
untitled h1
12 references

1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57(1):43-66. 2. CBTRUS 2008 statistical report: primary brain tumors in the United States -CBTRUS, 2000-2004. 2008. 3. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-96. 4. Frankel SA, German WJ. Glioblastoma multiforme; review of 219 cases with regard to natural history, pathology, diagnostic methods, and treatment. J Neurosurg. 1958;15(5):489-503. 5. Bloom HJ. Combined modality therapy for intracranial tumors. Cancer. 1975;35(1):11120. 6. Salazar OM, Rubin P, Feldstein ML, Pizzutiello R. High dose radiation therapy in the treatment of malignant gliomas: final report. Int J Radiat Oncol Biol Phys. 1979;5(10):1733-40. 7. Scanlon PW, Taylor WF. Radiotherapy of intracranial astrocytomas: analysis of 417 cases treated from 1960 through 1969. Neurosurgery. 1979;5(3):301-8. 8. Walker MD, Green SB, Byar DP, Alexander E, Jr., Batzdorf U, Brooks WH, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med. 1980;303(23):1323-9. 9. Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys. 1979;5(10):1725-31. 10. Black PM, Schoene WC, Lampson LA. Astrocytomas : diagnosis, treatment, and biology. Boston: Blackwell Scientific Publications; 1993. xiv, 306 p., [4] p. of plates p. 11. DeVita VT, Hellman S, Rosenberg SA. Biologic therapy of cancer. Philadelphia: Lippincott; 1991. xiv, 800 p. p. 12. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature. 1985;313(5998):144-7. 13. Yamazaki H, Fukui Y, Ueyama Y, Tamaoki N, Kawamoto T, Taniguchi S, et al. Amplification of the structurally and functionally altered epidermal growth factor receptor gene (c-erbB) in human brain tumors. Mol Cell Biol. 1988;8(4):1816-20. 14. Chu CT, Everiss KD, Wikstrand CJ, Batra SK, Kung HJ, Bigner DD. Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). Biochem J. 1997;324 ( Pt 3):855-61. 15. Batra SK, Castelino-Prabhu S, Wikstrand CJ, Zhu X, Humphrey PA, Friedman HS, et al. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ. 1995;6(10):1251-9. 16. Lal A, Glazer CA, Martinson HM, Friedman HS, Archer GE, Sampson JH, et al. Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion. Cancer Res. 2002;62(12):3335-9.  
17. Boockvar JA, Kapitonov D, Kapoor G, Schouten J, Counelis GJ, Bogler O, et al.  
Constitutive EGFR signaling confers a motile phenotype to neural stem cells. Mol Cell Neurosci. 2003;24(4):1116-30. 18. Lammering G, Valerie K, Lin PS, Hewit TH, Schmidt-Ullrich RK. Radiation-induced activation of a common variant of EGFR confers enhanced radioresistance. Radiother Oncol. 2004;72(3):267-73. 19. Montgomery RB, Guzman J, O'Rourke DM, Stahl WL. Expression of oncogenic epidermal growth factor receptor family kinases induces paclitaxel resistance and alters betatubulin isotype expression. J Biol Chem. 2000;275(23):17358-63.  
20. Nagane M, Coufal F, Lin H, Bogler O, Cavenee WK, Huang HJ. A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Res. 1996;56(21):5079-86.  
21. Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, et al. Antisynthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A. 1990;87(11):4207-11. 22. Wong AJ, Ruppert JM, Bigner SH, Grzeschik CH, Humphrey PA, Bigner DS, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci U S A. 1992;89(7):2965-9. 23. Moscatello DK, Ramirez G, Wong AJ. A naturally occurring mutant human epidermal growth factor receptor as a target for peptide vaccine immunotherapy of tumors. Cancer Res. 1997;57(8):1419-24. 24. Heimberger AB, Crotty LE, Archer GE, Hess KR, Wikstrand CJ, Friedman AH, et al. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin Cancer Res. 2003;9(11):4247-54. 25. Ciesielski MJ, Kazim AL, Barth RF, Fenstermaker RA. Cellular antitumor immune response to a branched lysine multiple antigenic peptide containing epitopes of a common tumor-specific antigen in a rat glioma model. Cancer Immunol Immunother. 2005;54(2):107-19. 26. Heimberger AB, Archer GE, Crotty LE, McLendon RE, Friedman AH, Friedman HS, et al. Dendritic cells pulsed with a tumor-specific peptide induce long-lasting immunity and are effective against murine intracerebral melanoma. Neurosurgery. 2002;50(1):158-64; discussion 64-6. 27. Wu AH, Xiao J, Anker L, Hall WA, Gregerson DS, Cavenee WK, et al. Identification of EGFRvIII-derived CTL epitopes restricted by HLA A0201 for dendritic cell based immunotherapy of gliomas. J Neurooncol. 2006;76(1):23-30. 28. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Bigner DD. Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma. Semin Immunol. 2008;20(5):267-75. 29. Heimberger AB, Hussain SF, Aldape K, Sawaya R, Archer GA, Friedman H, et al. Tumor-specific peptide vaccination in newly-diagnosed patients with GBM. Journal of Clinical Oncology. 2006;24(18):107s-s.  
30. Bullain SS, Sahin A, Szentirmai O, Sanchez C, Lin N, Baratta E, et al. Genetically engineered T cells to target EGFRvIII expressing glioblastoma. J Neurooncol. 2009;94(3):37382. 31. Ohno M, Natsume A, Ichiro Iwami K, Iwamizu H, Noritake K, Ito D, et al. Retrovirally engineered T-cell-based immunotherapy targeting type III variant epidermal growth factor receptor, a glioma-associated antigen. Cancer Sci. 2010;101(12):2518-24. 32. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. Adoptive cell therapy for patients with metastatic melanoma: Evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26:5233-9. 33. Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, et al. Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci USA. 1994;91:3515-9. 34. Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Sakaguchi K, Appella E, et al. Identification of a human melanoma antigen recognized by tumor infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci USA. 1994;91:6458-62. 35. Kawakami Y, Eliyahu S, Sakaguchi K, Robbins PF, Rivoltini L, Yannelli JR, et al. Identification of the immunodominant peptides of the MART-1 human melanoma antigen recognized by the majority of HLA-A2-restricted tumor infiltrating lymphocytes. J Exp Med. 1994;180(1):347-52. 36. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314(5796):126-9. 37. Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009;114:535-46. 38. Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116:4099-102. 39. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843-51. 40. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008;14(11):1264-70. 41. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al.  
Updated response assessment criteria for high-grade gliomas: response assessment in neurooncology working group. J Clin Oncol. 2010;28(11):1963-72.  
42. Weitzner MA, Meyers CA, Gelke CK, Byrne KS, Cella DF, Levin VA. The Functional Assessment of Cancer Therapy (FACT) scale. Development of a brain subscale and revalidation of the general version (FACT-G) in patients with primary brain tumors. Cancer.  
1995;75(5):1151-61.  
43. Ballman KV, Buckner JC, Brown PD, Giannini C, Flynn PJ, LaPlant BR, et al. The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme. Neuro-oncology. 2007;9(1):29-38.
untitled h1
13 appendices 13.1 appendix a

Unless otherwise specified in this protocol, actual body weight is used for dose calculations of treatment agents. In patients who are determined to be obese (BMI > 35), the **practical weight**
(see 3 below) will be used.  
1. BMI Determination:
BMI = weight (kg) / [height (m)]2 2. Calculation of ideal body weight:
Male = 50 kg + 2.3 (number of inches over 60 inches)
Example: Ideal body weight of 5'10" male 50 + 2.3 (10) = 73 kg Female = 45.5 kg + 2.3 (number of inches over 60 inches)
Example: Ideal body weight of 5'3" female 45.5 + 2.3 (3) = 57 kg 3. Calculation of "practical weight":
Calculate the average of the actual and the ideal body weights. This is the practical weight to be used in calculating the doses of chemotherapy and associated agents designated in the protocol.  
*Practical weight will NOT be used in the calculation of dose for aldesleukin. 13.2 APPENDIX B: ADVERSE EVENTS OCCURRING IN ≥10% OF PATIENTS TREATED WITH
untitled h1
aldesleukin (n=525)1

| Body System                     | % Patients                          | Body System               | % Patients   |
|---------------------------------|-------------------------------------|---------------------------|--------------|
| Body as a Whole                 | Metabolic and Nutritional Disorders |                           |              |
| Chills                          | 52                                  | Bilirubinemia             | 40           |
| Fever                           | 29                                  | Creatinine increase       | 33           |
| Malaise                         | 27                                  | Peripheral edema          | 28           |
| Asthenia                        | 23                                  | SGOT increase             | 23           |
| Infection                       | 13                                  | Weight gain               | 16           |
| Pain                            | 12                                  | Edema                     | 15           |
| Abdominal pain                  | 11                                  | Acidosis                  | 12           |
| Abdomen enlarged                | 10                                  | Hypomagnesemia            | 12           |
| Cardiovascular                  | Hypocalcemia                        | 11                        |              |
| Hypotension                     | 71                                  | Alkaline phosphatase incr | 10           |
| Tachycardia                     | 23                                  | Nervous                   |              |
| Vasodilation                    | 13                                  | Confusion                 | 34           |
| Supraventricular tachycardia 12 | Somnolence                          | 22                        |              |
| Cardiovascular disordera        | 11                                  | Anxiety                   | 12           |
| Arrhythmia                      | 10                                  | Dizziness                 | 11           |
| Digestive                       | Respiratory                         |                           |              |
| Diarrhea                        | 67                                  | Dyspnea                   | 43           |
| Vomiting                        | 50                                  | Lung disorderb            | 24           |
| Nausea                          | 35                                  | Respiratory disorderc     | 11           |
| Stomatitis                      | 22                                  | Cough increase            | 11           |
| Anorexia                        | 20                                  | Rhinitis                  | 10           |
| Nausea and vomiting             | 19                                  | Skin and Appendages       |              |
| Hemic and Lymphatic             | Rash                                | 42                        |              |
| Thrombocytopenia                | 37                                  | Pruritus                  | 24           |
| Anemia                          | 29                                  | Exfoliative dermatitis    | 18           |
| Leukopenia                      | 16                                  | Urogenital Oliguria       | 63           |
untitled h1
legend

a. Cardiovascular disorder: fluctuations in blood pressure, asymptomatic ECG changes, CHF.  
b. Lung disorder: physical findings associated with pulmonary congestion, rales, rhonchi. c. Respiratory disorder: ARDS, CXR infiltrates, unspecified pulmonary changes.
1Source: Proleukin® Prescribing Information - June 2007  
| 13.3                                                                                                                                                                 | APPENDIX C: EXPECTED IL-2 TOXICITIES AND THEIR MANAGEMENT          |                                      |                  |                |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|--------------------------------------|------------------|----------------|
| Expected Toxicity                                                                                                                                                    | Expected                                                           | Supportive  Measures                 | Stop Cycle*      | Stop Treatment |
| Grade                                                                                                                                                                | **                                                                 |                                      |                  |                |
| Chills                                                                                                                                                               | 3                                                                  | IV Meperidine 25- 50 mg, IV q1h, prn | No               | No             |
| Acetaminophen 650  mg, po, q4h;  Indomethicin 50-75  mg, po, q8h                                                                                                     |                                                                    |                                      |                  |                |
| Fever                                                                                                                                                                | 3                                                                  | No                                   | No               |                |
| Hydroxyzine HCL  10-20 mg po q6h,  prn;  Diphenhydramine  HCL25-50 mg, po,  q4h, prn                                                                                 |                                                                    |                                      |                  |                |
| Pruritis                                                                                                                                                             | 3                                                                  | No                                   | No               |                |
| Ondansetron 10 mg,  IV, q8h, prn;  Granisetron 0.01  mg/kg IV daily prn;  Droperidol 1 mg, IV  q4-6h, prn;  Prochlorperazine 25  mg q4h PO, prn or  10 mg IV q6h prn |                                                                    |                                      |                  |                |
| Nausea/Vomiting/  Anorexia                                                                                                                                           | 3                                                                  | No                                   | No               |                |
| Loperamide 2mg,  po, q3h, prn;  Diphenoxylate HCl  2.5 mg and atropine  sulfate 25 mcg, po,  q3h, prn; codeine  sulfate 30-60 mg,  po, q4h, prn                      | If uncontrolled  after 24 hours  despite all  supportive  measures |                                      |                  |                |
| Diarrhea                                                                                                                                                             | 3                                                                  | No                                   |                  |                |
| If other  toxicities occur                                                                                                                                           | No                                                                 |                                      |                  |                |
| simultaneously                                                                                                                                                       |                                                                    |                                      |                  |                |
| Malaise                                                                                                                                                              | 3 or 4                                                             | Bedrest interspersed  with activity  | If other         |                |
| Hyperbilirubinemia                                                                                                                                                   | 3 or 4                                                             | Observation                          | toxicities occur | No             |
| simultaneously                                                                                                                                                       |                                                                    |                                      |                  |                |  
| Version Date: June 28, 2018                                            | If uncontrolled  despite all  supportive  measures   |                                   |                                                    |     |
|------------------------------------------------------------------------|------------------------------------------------------|-----------------------------------|----------------------------------------------------|-----|
| Anemia                                                                 | 3 or 4                                               | Transfusion with  PRBCs           | No                                                 |     |
| If uncontrolled  despite all  supportive  measures                     |                                                      |                                   |                                                    |     |
| Thrombocytopenia                                                       | 3 or 4                                               | Transfusion with  platelets       | No                                                 |     |
| Edema/Weight gain                                                      | 3                                                    | Diuretics prn                     | No                                                 | No  |
| If uncontrolled  despite all  supportive  measures                     |                                                      |                                   |                                                    |     |
| Fluid resuscitation                                                    |                                                      |                                   |                                                    |     |
| Hypotension                                                            | 3                                                    | No                                |                                                    |     |
| Vasopressor support                                                    | If requires  ventilatory                             | No                                |                                                    |     |
| support                                                                |                                                      |                                   |                                                    |     |
| Dyspnea                                                                | 3 or 4                                               | Oxygen or  ventilatory support    | If uncontrolled  despite all  supportive  measures |     |
| Fluid boluses or                                                       |                                                      |                                   |                                                    |     |
| Oliguria                                                               | 3 or 4                                               | dopamine at renal  doses          | No                                                 |     |
| Increased creatinine                                                   | 3 or 4                                               | Observation                       | Yes (grade 4)                                      | No  |
| Renal failure                                                          | 3 or 4                                               | Dialysis                          | Yes                                                | Yes |
| If uncontrolled  despite all  supportive  measures                     |                                                      |                                   |                                                    |     |
| Pleural effusion                                                       | 3                                                    | Thoracentesis                     | No                                                 |     |
| Bowel perforation                                                      | 3                                                    | Surgical intervention             | Yes                                                | Yes |
| Confusion                                                              | 3                                                    | Observation                       | Yes                                                | No  |
| Somnolence                                                             | 3 or 4                                               | Intubation for  airway protection | Yes                                                | Yes |
| If uncontrolled  despite all  supportive  measures                     |                                                      |                                   |                                                    |     |
| Correction of fluid  and electrolyte  imbalances;  chemical conversion |                                                      |                                   |                                                    |     |
| Arrhythmia                                                             | 3                                                    | No                                |                                                    |     |  
| or electrical  conversion therapy                        | If changes in LV  function have not  improved to  baseline by next  dose   |                 |                                                                              |     |
|----------------------------------------------------------|----------------------------------------------------------------------------|-----------------|------------------------------------------------------------------------------|-----|
| Elevated troponin  levels                                | 3 or 4                                                                     | Observation     | Yes                                                                          |     |
| Myocardial  infarction                                   | 4                                                                          | Supportive care | Yes                                                                          | Yes |
| If changes have  not improved to  baseline by next  dose |                                                                            |                 |                                                                              |     |
| For grade 4  without liver  metastases                   |                                                                            |                 |                                                                              |     |
| Elevated                                                 |                                                                            |                 |                                                                              |     |
| transaminases                                            | 3 or 4                                                                     | Observation     | If changes have  not improved to  baseline by next  dose                     |     |
| For grade 4                                              |                                                                            |                 |                                                                              |     |
| Hyperbilirubinemia                                       | 3 or 4                                                                     | Observation     | without liver  metastases If uncontrolled  despite all  supportive  measures |     |
| imbalances                                               | 3 or 4                                                                     | Electrolyte     |                                                                              |     |
| Electrolyte                                              | replacement                                                                | No              |                                                                              |     |
| Neutropenia                                              | 4                                                                          | Observation     | No                                                                           | No  |
| *Unless the toxicity is not reversed within 12 hours.    |                                                                            |                 |                                                                              |     |  
*Unless the toxicity is not reversed within 12 hours. ** Unless the toxicity is not reversed to grade 2 or less by next treatment.
untitled h1
13.4 a ppendix d i

| Table 8. Toxicity of Treatment with Interleukin-2   |       |     |       |      |     |     |     |       |
|-----------------------------------------------------|-------|-----|-------|------|-----|-----|-----|-------|
| Interleukin-2 Plus                                  | Alone | TNF | a IFN | MoAB | CYT | LAK | TIL | Total |
| 652®                                                |       |     |       |      |     |     |     |       |
| Number of Patients                                  | 155   | 38  | 128   | 32   | 19  | 214 | 66  |       |
| Number of Courses                                   | 236   | 85  | 210   | 35   | 30  | 348 | .95 | 1039  |
| Chills                                              | 75    | 16  | 68    | 8    | 8   | 191 | 33  | 39    |
| 53                                                  | 9     | 26  | 2     | 2    | 82  | 6   | 180 |       |
| Pruritus                                            |       |     |       |      |     |     |     |       |
| Necrosis                                            | 3     |     | 2     | 1    | l   | l   | .5  |       |
| Anaphylaxis                                         |       | l   |       | l    |     | l   |     |       |
| Mucositis (requiring liquid diet)                   | 6     | 1   | 7     | 2    | 12  | 2   | 30  |       |
|                                                     |       |     |       |      |     |     |     |       |
| Alimentation not possible                           | .     |     | 2     | 4    |     |     |     |       |
| i                                                   |       |     |       |      |     |     |     |       |
| 162                                                 | 42    | 17  | 14    | 20   | 263 | 48  |     |       |
| Nausea and vomiting                                 | 66    |     |       |      |     |     |     |       |
| Diarrhea                                            | 144   | 38  | 98    | 15   | 13  | 250 | 38  | 596   |
| Hyperbilirubinemia (maximum/mg %)                   |       |     |       |      |     |     |     |       |
| 21–6.0                                              | 126   | 49  | 97    | 21   | 18  | 190 | 46  | 547   |
| 6.1-10.0                                            | 49    | 12  | 179   |      |     |     |     |       |
| 3                                                   | 8     | 9   | 7272  | 26   |     |     |     |       |
| 10.1+                                               | 26    | l   | 4     | 3    | l   | 40  | 8   | 83    |
| Oliguria                                            |       |     |       |      |     |     |     |       |
| <80 ml/8 hours                                      | 37    | 67  | 9     | 14   | 25  | 347 |     |       |
| 81                                                  | 14    |     |       |      |     |     |     |       |
| <240 ml/24 hours                                    | 19    | 2   | 3     | 1    | 12  | s   | 42  |       |
| Weight gain (% body weight)                         |       |     |       |      |     |     |     |       |
| 0.0-5.0                                             | 106   | 23  | 65    | 8    | g   | 17  | 49  | 377   |
| 5.1-10.0                                            | 78    | 41  | 11    | 22   | 10  | 148 | 26  | 436   |
| 10.1-15.0                                           | 43    | 17  | 26    | I    | 9   | 62  | 15  | 175   |
| 15.1-20.0                                           | 7     | 3   | 00    | 1    | IS  | 3   | 38  |       |
| 2                                                   | 2     |     |       |      |     |     |     |       |
| 20.1 +                                              | .     | l   | 1     | 6    | 13  |     |     |       |
| Elevated creatinine (maximum/mg %)                  |       |     |       |      |     |     |     |       |
| 2.1-6.0                                             | 148   | 43  | 121   | 20   | 14  | 237 | 54  | 637   |
| 6.1-10.0                                            | 21    | 14  | 3     | 34   | 12  | 85  |     |       |
| I                                                   | (     |     |       |      |     |     |     |       |
| 10.1+                                               | S     | i   | i     | l    | 2   | i   | 10  |       |
| Hematuria (gross)                                   | 2     | 2   |       |      |     |     |     |       |
|                                                     | l     | l   | l     | l    |     |     |     |       |
| Edema (symptomatic nerve or vessel                  | 4     | 6   | 7     | n    |     |     |     |       |
| compression)                                        |       | l   |       |      |     |     |     |       |
| Tissue ischemia                                     | i     | l   | i     | l    |     | 2   |     |       |
| Resp. distress:                                     |       |     |       |      |     |     |     |       |
| not intubated                                       | 17    | i   | 9     | 4    | i   | 28  | 7   | 67    |
| intubated                                           | 15    | 6   | 3     | 12   | s   | 41  |     |       |
| Bronchospasm                                        | 2     | i   | 2     | i    | 4   |     | 9   |       |
| Pleural effusion (requiring                         |       |     |       |      |     |     |     |       |
| thoracentesis)                                      | 4,    | i   | i     | 2    | 8   | i   | 17  |       |
| Somnolence                                          | 29    | 13  | 22    | 6    | 2   | 45  | 8   | 14    |
| Coma                                                | 9     | --- | 8     | 8    | s   | 33  |     |       |
| Disorientation                                      | 52    | 50  | 7     | 4    | 89  | 10  | 215 |       |
| Hypotension (requiring pressors)                    | .119  | 16  | 40    | 17   | 12  | 259 | 45  | 508   |
| Angina                                              | s     | i   | 8     | 8    | 22  |     |     |       |
| l                                                   |       |     |       |      |     |     |     |       |
| Myocardial infarction                               | 4     | I   |       | l    | l   | l   | 6   |       |
| Arrythmias                                          | 15    | 2   | 13    | s    | l   | 39  | 6   | 78    |
| Anemia requiring transfusion (number)               |       |     |       |      |     |     |     |       |
| units transfused)                                   | 77    |     |       |      |     |     |     |       |
| 1-15                                                | 16    | 53  | 9     | 6    | 176 | 40  | 377 |       |
| 6-10                                                | 22    | l   | .51   | s    | 2   | 53  | 9   | .95   |
| 1-15                                                | 4     | l   | 15    | 4    | 24  |     |     |       |
| l                                                   |       |     |       |      |     |     |     |       |
| 16+                                                 | i     | l   | i     | l    | .11 | i   | 14  |       |
| l                                                   |       |     |       |      |     |     |     |       |
| Thrombocytopenia (minimum/mm 3 )                    |       |     |       |      |     |     |     |       |
| <20,000                                             | 28    | l   | 2     | 4    | 6   | 71  | 19  | 131   |
| 20,001-60,000                                       | 82    | 11  | 62    | 14   | 12  | 150 | 30  | 361   |
| 60,001-100,000                                      | 53    | 36  | 76    | 11   | 8   | 79  | 22  | 285   |
| Cntral line sepsis                                  | 13    | 7   | l     | 4    | 36  | 2   | .63 |       |
|                                                     |       |     |       |      |     |     |     |       |
| Death                                               | 4     | i   | 10    |      |     |     |     |       |
| 3                                                   |       |     |       |      |     |     |     |       |
| * Eleven patients are in two protocols.             |       |     |       |      |     |     |     |       |
untitled h1
13.5 appendix e certificate of

Date of preparation of final product: Patient:  
| Tests performed on final product:  Test Method                                                                           | Limits                              | Result                                | Tests  Performed by   | Initials /Date   |
|--------------------------------------------------------------------------------------------------------------------------|-------------------------------------|---------------------------------------|-----------------------|------------------|
| Cell viability1                                                                                                          | trypan blue exclusion               | >70%                                  |                       |                  |
| visual microscopic count                                                                                                 | >1 x107                             |                                       |                       |                  |
| Total viable cell  number1 Tumor reactivity2                                                                             | γ-IFN release vs. positive  control | >200 pg/mL, and > 2  times background |                       |                  |
| γ-IFN release vs. negative  control including wtEGFRvIII                                                                                                                          | <400 pg/mL                          |                                       |                       |                  |
| CAR expression2                                                                                                          | FACS analysis of the                | PBL, >10%                             |                       |                  |
| transduced cells                                                                                                         |                                     |                                       |                       |                  |
| Microbiological                                                                                                          | gram stain1,3,                      | no micro-organisms                    |                       |                  |
| studies                                                                                                                  | seen                                |                                       |                       |                  |
| aerobic culture3,4                                                                                                       | no growth                           |                                       |                       |                  |
| fungal culture3,4                                                                                                        | no growth                           |                                       |                       |                  |
| anaerobic culture3,4                                                                                                     | no growth                           |                                       |                       |                  |
| mycoplasma test5                                                                                                         | negative                            |                                       |                       |                  |
| Endotoxin                                                                                                                | limulus assay1                      | ≤ 5 E.U./kg                           |                       |                  |
| RCR                                                                                                                      | S+L- Assay4  RCR-PCR6               | negative                              |                       |                  |
| 1 Performed on sample of the final product immediately prior to infusion. Results are available at the time of infusion. |                                     |                                       |                       |                  |  
1 Performed on sample of the final product immediately prior to infusion. Results are available at the time of infusion.  
2 Performed 2-10 post transduction. Results are available at the time of infusion. 3 Performed 2-4 days prior to infusion. Results are available at the time of infusion but may not be definitive.  
4 Sample collected from the final product prior to infusion. Results will not be available before cells are infused into the patient.  
5 Performed 2-10 days prior to infusion. Results are available at the time of infusion.  
6 Performed on sample approximately 1-4 days prior to infusion. Results are available at the time of infusion. Prepared by: _______________________________________Date: ____________________ QC sign-off: _______________________________________Date: ____________________
Qualified Laboratory or Clinical Supervisor
untitled h1
13.6 appendix f karnofsky performance

| KPS   | Description                                                                       |
|-------|-----------------------------------------------------------------------------------|
| 100   | Normal, no complaints, no signs of disease                                        |
| 90    | Capable of normal activity, few symptoms or signs of disease                      |
| 80    | Normal activity with some difficulty, some symptoms or signs                      |
| 70    | Caring for self, not capable of normal activity or work                           |
| 60    | Requiring some help, can take care of most personal requirements                  |
| 50    | Requires help often, requires frequent medical care                               |
| 40    | Disabled, requires special care and help                                          |
| 30    | Severely disabled, hospital admission indicated but no risk of death              |
| 20    | Very ill, urgently requiring admission, requires supportive measures or treatment |
| 10    | Moribund, rapidly progressive fatal disease processes                             |
| 0     | Death                                                                             |
untitled h1
13.7 appendix g anti-epileptic medications

| Non-EIAEDs             | EIAEDs         |
|------------------------|----------------|
| Valproic acid          | Carbamazapine  |
| Gabapentin             | Oxcarbazepine* |
| Lamotrigine            | Phenytoin      |
| Topriamate             | Fosphenytoin   |
| Levetiracetam          | Phenobarbital  |
| Tiagabine              | Primidone      |
| Zonisamide  Clonazepam |                |  
* enzyme induction limited and less potent than carbamazapine