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14.4 cell preparation (e7 tcr

The procedure for the expanding the human PBL and the Certificate of Analysis (CoA) are similar to those approved by the Food and Drug Administration and used at the NCI in ongoing protocols. The PBL will be transduced with retroviral supernatant containing the E7 TCR. The risks of retroviral transduction of human PBL are discussed in section **1.2.4**.  
14.4.1 Retroviral Vector Containing the E7 TCR gene The retroviral vector supernatant (PG13-MSGV1-E7-TCR) encoding a T cell receptor directed against HPV16 E711-19) was prepared and preserved following cGMP conditions in the Surgery Branch Vector Production Facility (SBVPF). The E7 TCR vector was produced by the Surgery Branch Vector Production Facility. The backbone is the MSGV1 retrovirus that has been used in prior gene therapy clinical trials. It was produced using a PG13-based packaging line. The retroviral vector E7 TCR consists of 7,310 bps including the 5'LTR from the murine stem cell virus (promoter), packaging signal including the splicing donor (SD) and splicing acceptor sites, alpha and beta chain genes of the E7 TCR. The alpha and beta chains are linked by a P2A peptide. The vector was codon optimized for expression by human cells with constant region exchanged for murine counterparts with an added disulfide bond and hydrophobic substitutions in the alpha chain constant region transmembrane domain. The physical titer will be determined by transduction of PBL with serial dilutions of the vector. TCR expression on the cell surface will be measured using FACS following staining with an anti-mouse constant region antibody. The titer will be measured as transducing units per milliliter. Portions of the supernatant will be stored at -80°C at Surgery Branch, NCI, American Type Culture Collection (ATCC), Rockville, MD, and the NIH Clinical Center Department of Transfusion Medicine. These storage facilities are equipped with around-the-clock temperature monitoring. Upon request, supernatant will be delivered on dry ice to be used in *ex vivo* transduction of participant PBL. There will be no re-use of the same unit of supernatant for different participants. Retroviral titer has been shown to be stable after immediate thawing and immediate administration (coating the tissue culture wells previously coated with Retronectin). Handling of the vector should follow the guidelines of Biosafety Level-2 (BSL-2). The specific guidelines for Biosafety Level-2 (BSL-2) can be viewed at http://www.cdc.gov/biosafety/publications/bmbl5/BMBL5_sect_IV.pdf.
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14.5 hpv16 genotyping assay (nsr

In order to be eligible for the study, participants are required to have HPV16-associated, highgrade cervical intraepithelial neoplasia. HPV16 Genotyping assay testing is not FDA approved for this purpose; however, it is being used in this study as a diagnostic device. Validation assays to support the use of the assay have been submitted to the IND. All documentation is in the IND files. According to 21 CFR 812.3(m), a significant risk device presents a potential for serious risk to the health, safety and welfare of a subject and meets the significant risk criteria listed in the table below along with the sponsor's conclusions with regard to the applicability of these criteria to  
the current study. The device has been assessed by the sponsor as non-significant risk per the below.  
| below.                                                                                                                                        | Applicable to            | Justification                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
|-----------------------------------------------------------------------------------------------------------------------------------------------|--------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| current study                                                                                                                                 |                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Is an implant                                                                                                                                 | No                       | The HPV16 genotyping assay test is not  introduced into the subject                                                                                                                                                                                                                                                                                                                                                                                                                                                |
| No                                                                                                                                            | The device is diagnostic |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Is used in supporting or  sustaining human life                                                                                               | No                       | While the device is diagnostic, we do not  believe it presents a potential for serious risk  to the health and welfare of the subject. The  assessment of HPV16 positivity is only used  to determine eligibility for the study and is  assessed to help to increase the possibility that  all persons enrolling on the study might  derive benefit from therapy. Persons that are  deemed ineligible to enroll on the basis of this  test are eligible for studies within GMB that  are not reliant on this test. |
| Is of substantial importance  in diagnosing, mitigating or  treating disease or preventing  impairment of human health Otherwise poses a risk | No                       | Testing will be performed on archival  samples or on fresh tissue that is collected at  screening for confirmation of diagnosis.                                                                                                                                                                                                                                                                                                                                                                                   |
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27. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J,
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16 appendices

16.1 APPENDIX 1: PERFORMANCE STATUS CRITERIA  
| ECOG Performance Status Scale Grade Descriptions  Normal activity. Fully active, able  0  to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work).  1  In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.  2  In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.  3  100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair. 4  5 Dead.   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
16.3 APPENDIX 2: ADVERSE EVENTS OCCURRING IN ≥ 10% OF PARTICIPANTS TREATED WITH
ALDESLEUKIN (N=525)  
| Body System                          | % Participants                      | Body System               | %   |
|--------------------------------------|-------------------------------------|---------------------------|-----|
| Participants  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                     | 12                                  | Somnolence                | 22  |
| tachycardia 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                |     |  
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 16.4 APPENDIX 3: EXPECTED IL-2 **TOXICITIES AND THEIR MANAGEMENT**  
| Toxicity           | Grade                                                                                                                      | Supportive Medications                                                                                                           | Stop Cycle*                                                  | Stop  Treatment**   |
|--------------------|----------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------|---------------------|
| Chills             | 3                                                                                                                          | IV Meperidine 25-50mg IV                                                                                                         | No                                                           | No                  |
| q1hr, prn          |                                                                                                                            |                                                                                                                                  |                                                              |                     |
| Fever              | 3                                                                                                                          | Acetaminophen 650mg po  q4hr; Indomethacin 50-75mg  po q8h                                                                       | No                                                           | No                  |
| Pruritus           | 3                                                                                                                          | Hydroxyzine HCl 10-20mg po  q6h, prn; Diphenhydramine  HCl 25-50mg po q4h prn                                                    | No                                                           | No                  |
| Nausea/Vomiting/A  | 3                                                                                                                          | Ondansetron 10mg IV q8hr                                                                                                         |                                                              |                     |
| norexia            | prn, Granisetron 0.01 mg/kg  IV qday prn, Droperidol 1mg  IV a4-6h prn; Prochlorperazine  25mg PR prn or 10mg IV q6hr  prn | No                                                                                                                               | No                                                           |                     |
| Diarrhea           | 3                                                                                                                          | Loperamide 2mg po q3h prn;  Diphenoxylate HCl 2.5mg and  Atropine sulfate 25mcg po q3h  prn; Codeine sulfate 30-60mg  po q4h prn | If uncontrolled  after 24h despite  all supportive  measures | No                  |
| Malaise            | 3 or 4                                                                                                                     | Bedrest                                                                                                                          | If other toxicities  occur  simultaneously                   | No                  |
| Hyperbilirubinemia | 3 or 4                                                                                                                     | Observation                                                                                                                      | If other toxicities  occur  simultaneously                   | No                  |
| Anemia             | 3 or 4                                                                                                                     | Transfusion with PRBCs                                                                                                           | If uncontrolled  despite all  supportive  measures           | No                  |
| Thrombocytopenia   | 3 or 4                                                                                                                     | Transfusion with platelets                                                                                                       | If uncontrolled  despite all  supportive  measures           | No                  |  
75  
| Toxicity             | Grade                                                      | Supportive Medications                                                                                  | Stop Cycle*                                        | Stop  Treatment**   |
|----------------------|------------------------------------------------------------|---------------------------------------------------------------------------------------------------------|----------------------------------------------------|---------------------|
| Edema/Weight gain    | 3                                                          | Diuretics prn                                                                                           | No                                                 | No                  |
| Hypotension          | 3                                                          | Fluid resuscitation,                                                                                    | If uncontrolled                                    |                     |
| Vasopressor support  | despite all  supportive  measures                          | No                                                                                                      |                                                    |                     |
| Dyspnea              | 3 or 4                                                     | Oxygen or ventilator support                                                                            | If requires  ventilator  support                   | No                  |
| Oliguria             | 3 or 4                                                     | Fluid boluses or dopamine at                                                                            | If uncontrolled                                    |                     |
| renal doses          | despite all  supportive  measures                          | No                                                                                                      |                                                    |                     |
| Increased Creatinine | 3 or 4                                                     | Observation                                                                                             | Yes (Grade 4)                                      | No                  |
| Renal Failure        | 3 or 4                                                     | Dialysis/CVVH                                                                                           | Yes                                                | Yes                 |
| Pleural Effusion     | 3                                                          | Thoracentesis                                                                                           | If uncontrolled  despite all  supportive  measures | No                  |
| Bowel Perforation    | 3                                                          | Surgical intervention                                                                                   | Yes                                                | Yes                 |
| Confusion            | 3                                                          | Observation                                                                                             | Yes                                                | No                  |
| Somnolence           | 3 or 4                                                     | Intubation for airway                                                                                   | Yes                                                | Yes                 |
| protection           |                                                            |                                                                                                         |                                                    |                     |
| Arrhythmia           | 3                                                          | Correction of fluid and  electrolyte imbalances;  chemical conversion or  electrical conversion therapy | If uncontrolled  despite all  supportive  measures | No                  |
| Elevated Troponin    | 3 or 4                                                     | Observation                                                                                             | Yes                                                | If changes in       |
| Levels               | LV function  have not  improved to  baseline by  next dose |                                                                                                         |                                                    |                     |  
76  
| Toxicity                                                                                                                           | Grade                             | Supportive Medications                                    | Stop Cycle*                            | Stop  Treatment**                                         |
|------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------|-----------------------------------------------------------|----------------------------------------|-----------------------------------------------------------|
| Myocardial                                                                                                                         | 4                                 | Supportive care                                           | Yes                                    | Yes                                                       |
| Infarction Elevated                                                                                                                | 3 or 4                            | Observation                                               | For Grade 4                            |                                                           |
| Transaminases                                                                                                                      | without liver  metastases         | If changes  have not  improved to  baseline by  next dose |                                        |                                                           |
| Hyperbilirubinemia                                                                                                                 | 3 or 4                            | Observation                                               | For Grade 4  without liver  metastases | If changes  have not  improved to  baseline by  next dose |
| Electrolyte                                                                                                                        | 3 or 4                            | Electrolyte replacement                                   | If uncontrolled                        |                                                           |
| Imbalances                                                                                                                         | despite all  supportive  measures | No                                                        |                                        |                                                           |
| Neutropenia                                                                                                                        | 4                                 | Observation                                               | No                                     | No                                                        |
| *Unless the toxicity is not reversed within 12 hours.  **Unless the toxicity is not reversed to Grade 2 or less by next treatment. |                                   |                                                           |                                        |                                                           |  
| Table 8. Toxicity of Treatment with Interleukin-2   |       |     |       |      |     |     |       |       |
|-----------------------------------------------------|-------|-----|-------|------|-----|-----|-------|-------|
| Interleukin-2 Plus                                  | Alone | TNF | a-IFN | MoAB | CYT | LAK | TIL   | Total |
| Number of Patients                                  | 155   | 19  | 214   | 652® |     |     |       |       |
| 38                                                  | 128   | 32  | 66    |      |     |     |       |       |
| Number of Courses                                   | 236   | 85  | 210   | 35   | 30  | 348 | 95    | 1039  |
| Chills                                              | 75    | 16  | 68    | 8    | 8   | 191 | 3     | 39    |
| 53                                                  | 9     | 26  | 2     | 2    | 82  | -6  | 180   |       |
| Pruritus                                            | 3     |     |       |      |     |     |       |       |
| Necrosis                                            |       | 2   |       |      |     | .5  |       |       |
| Anaphylaxis                                         |       |     |       | r    |     |     |       | 1     |
| Mucositis (requiring liquid diet)                   | 6     | l   | 7     |      | 2   | 12  | 2     | 30    |
| Alimentation not possible                           | 1     |     |       | 2    | 4   |     |       |       |
| Nausea and vomiting                                 | 162   | 42  | 17    | 14   | 20  | 263 | 48    | 666   |
| Diarrhea                                            | 144   | 38  | 98    | 15   | 13  | 250 | 38    | 596   |
| Hyperbilirubinemia (maximum/mg %)                   |       |     |       |      |     |     |       |       |
| 2.1–6.0                                             | 126   | 49  | 97    | 21   | 18  | 190 | 46    | 547   |
| 6.1-10.0                                            | 49    | 3   | 12    | 00   | 19  | 72  | 26    | 179   |
| 40                                                  |       |     |       |      |     |     |       |       |
| 10.1+                                               | 26    | 1   | .4    | 3    | i   | 8   | 83    |       |
| Oliguria                                            |       |     |       |      |     |     |       |       |
| <80 ml/8 hours                                      | 81    | 37  | 67    | 14   | g   | 14  | 25    | 347   |
| <240 ml/24 hours                                    | 19    | 2   | 3     | 1    | 12  | S   | 42    |       |
| Weight gain (% body weight)                         |       |     |       |      |     |     |       |       |
| 0.0–5.0                                             | 106   | 23  | 65    | 8    | 9   | 17  | 49    | 377   |
| 5.1-10.0                                            | 4 l   | 111 | 22    | 10   | 148 | 436 |       |       |
| 78                                                  | 26    |     |       |      |     |     |       |       |
| 10.1-15.0                                           | 43    | 17  | 26    | 3    | 9   | 62  | 15    | 175   |
| 15.1-20.0                                           | 7     | 3   | 8     | I    | l   | 15  | 3     | 38    |
| 20.1+                                               | 2     |     | I     | 1    | 6   | 2   | 13    |       |
| Elevated creatinine (maximum/mg %)                  |       |     |       |      |     |     |       |       |
| 2.1-6.0                                             | 148   | 43  | 121   | 20   | 14  | 237 | 54    | 637   |
| 6.1-10.0                                            | 21    | I   | 14    | 3    | 34  | 12  | 85    |       |
|                                                     |       |     |       |      |     |     |       |       |
| 10.1+                                               | S     | l   | i     | 2    | 10  |     |       |       |
| l                                                   | l     |     |       |      |     |     |       |       |
| Hematuria (gross)                                   | l     | 2   | 12    |      |     |     |       |       |
|                                                     | l     | l   |       | l    |     |     |       |       |
| Edema (symptomatic nerve or vessel                  | 4     | 6   | 7     | 17   |     |     |       |       |
| compression)                                        | l     |     |       |      |     |     |       |       |
| Tissue ischemia                                     | l     | l   | i     | i    |     | 12  |       |       |
| Resp. distress:                                     |       |     |       |      |     |     |       |       |
| not intubated                                       | 17    |     | 9     | 4    | i   | 28  | 7     | 67    |
| intubated                                           | 15    | 6   | 3     | 12   | s   | 41  |       |       |
| 1                                                   |       |     |       |      |     |     |       |       |
| Bronchospasm                                        | 2     | 2   | i     | 4    | 9   |     |       |       |
|                                                     |       |     |       |      |     |     |       |       |
| Pleural effusion (requiring                         |       |     |       |      |     |     |       |       |
| thoracentesis)                                      | 4     | i   | l     | 2    | 8   | i   | 17    |       |
| Somnolence                                          | 29    | 12  | 22    | 6    | 2 2 | 45  | 8     | 114   |
| Coma                                                | 9     | i   | 18    |      | 8   | S   | 33    |       |
| Disorientation                                      | 52    | 3   | 50    | 7    | 4   | 89  | 10.10 | 215   |
| Hypotension (requiring pressors)                    | 19    | 16  | 40    | 17   | 12  | 259 | 45    | 508   |
| Angina                                              | s     | i   | 8     | I    | 8   | 2,  |       |       |
|                                                     |       |     |       |      |     |     |       |       |
| Myocardial infarction                               | 4     | i   | 1     |      |     |     |       |       |
| l                                                   | l     | l   | 6     |      |     |     |       |       |
| Arrythmias                                          | 15    | 2   | 13    | s    | 39  | 78  |       |       |
| l                                                   | 6     |     |       |      |     |     |       |       |
| Anemia requiring transfusion (number)               |       |     |       |      |     |     |       |       |
| units transfused)                                   | 77    | 16  | 553   | g    | 176 | 40  | 377   |       |
| 1-15                                                | 6     |     |       |      |     |     |       |       |
| 2                                                   |       |     |       |      |     |     |       |       |
| 6-10                                                | l     | S   | 3     | 2    | 53  | 9   | 95    |       |
| 1-15                                                | 4     | I   | 1     | l    | l   | 15. | 4     | 24    |
| 16+                                                 | l     | l   | i     | l    | l   | .11 | i     | 14    |
| Thrombocytopenia (minimum/mm 3 )                    |       |     |       |      |     |     |       |       |
| <20,000                                             | 28    | I   | 2     | 4    | 6   | 71  | 19    | 131   |
| 20,001-60,000                                       | 82    | 1   | 62    | 14   | 12  | 150 | 30    | 361   |
| 60,001-100,000                                      | 53    | 36  | 76    | 1    | 8   | 79  | 22    | 285   |
| Central line sepsis                                 | 13    |     | 7     | l    | 54  | 36  | 2     | .63   |
| Death                                               | 4     |     | 3     | 2    | 10  |     |       |       |
|                                                     |       |     |       |      |     |     |       |       |
| * Eleven patients are in two protocols.             |       |     |       |      |     |     |       |       |