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15 appendices 15.1 appendix a

| ECOG Performance Status Scale   | Karnofsky Performance Scale                                                                                                                                                                 |                                                            |                                                                                                      |
|---------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|------------------------------------------------------------------------------------------------------|
| Grade                           | Descriptions                                                                                                                                                                                | Percent                                                    | Descriptions                                                                                         |
| 100                             | Normal, no complaints, no  evidence of disease.                                                                                                                                             |                                                            |                                                                                                      |
| 0                               | Normal activity. Fully active,  able to carry on all pre-disease  performance without  restriction.                                                                                         | 90                                                         | Able to carry on normal activity;  minor signs or symptoms of  disease. Normal activity with effort; |
| 80                              | some signs or symptoms of  disease.                                                                                                                                                         |                                                            |                                                                                                      |
| 1                               | 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). | Cares for self, unable to carry on                         |                                                                                                      |
| 70                              | normal activity or to do active  work.                                                                                                                                                      |                                                            |                                                                                                      |
| In bed <50% of the time.        | Requires occasional assistance,                                                                                                                                                             |                                                            |                                                                                                      |
| Ambulatory and capable of all   | 60                                                                                                                                                                                          | but is able to care for most of  his/her needs.            |                                                                                                      |
| 2                               | self-care, but unable to carry  out any work activities. Up                                                                                                                                 | Requires considerable assistance                           |                                                                                                      |
| and about more than 50% of      | 50                                                                                                                                                                                          | and frequent medical care.                                 |                                                                                                      |
| waking hours.                   | 40                                                                                                                                                                                          | Disabled, requires special care  and assistance.           |                                                                                                      |
| 3                               | In bed >50% of the time.  Capable of only limited selfcare, confined to bed or chair                                                                                                                                                                                             | Severely disabled,                                         |                                                                                                      |
| more than 50% of waking         | 30                                                                                                                                                                                          | hospitalization indicated. Death                           |                                                                                                      |
| hours.                          | not imminent.                                                                                                                                                                               |                                                            |                                                                                                      |
| 100% bedridden. Completely      | 20                                                                                                                                                                                          | Very sick, hospitalization  indicated. Death not imminent. |                                                                                                      |
| 4                               | disabled. Cannot carry on any  self-care. Totally confined to  bed or chair.                                                                                                                | 10                                                         | Moribund, fatal processes  progressing rapidly.                                                      |
| 5                               | Dead.                                                                                                                                                                                       | 0                                                          | Dead.                                                                                                |  
15.2 APPENDIX B: NEW YORK HEART ASSOCIATION C**LASSIFICATION**  
| Class                | Patient Symptoms                                                                                                                                                            |
|----------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Class I (Mild)       | No limitation of physical activity. Ordinary physical activity  does not cause undue fatigue, palpitation, or dyspnea  (shortness of breath).                               |
| Class II (Mild)      | Slight limitation of physical activity. Comfortable at rest, but  ordinary physical activity results in fatigue, palpitation, or  dyspnea.                                  |
| Class III (Moderate) | Marked limitation of physical activity. Comfortable at rest,  but less than ordinary activity causes fatigue, palpitation, or  dyspnea.                                     |
| Class IV (Severe)    | Unable to carry out any physical activity without  discomfort. Symptoms of cardiac insufficiency at rest. If any  physical activity is undertaken, discomfort is increased. |
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15.3 appendix c guidelines for

Rituximab will be supplied in 50-mL vials containing 500 mg of antibody (50 mL of solution) at a concentration of 10 mg/mL and 10-mL vials containing 100 mg of antibody (10 mL of solution) at a concentration of 10mg/ML. Rituximab vials are sterile, preservative-free, and intended for single use only.
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stability and storage

Rituximab is biologically and chemically stable at 2C to 8C (36F to 46F) and has a proposed shelf-life stability of 30 months. Once reconstituted into IV bags, rituximab is chemically stable for up to 24 hours at 2C to 8C (36F to 46F), followed by up to 24 hours at room temperature (23C). However, since rituximab solutions do not contain preservative, diluted solutions should be stored refrigerated (2°C to 8°C). No incompatibilities between rituximab and polyvinylchloride or polyethylene bags have been observed. Rituximab vials should be protected from direct sunlight. Rituximab vials are intended for single use only. Do not use beyond the expiration date stamped on the carton.
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dose calculation

1. Before the first infusion only, calculate the subject's body surface area (BSA).  
Actual body weight measured within 4 weeks prior to initial treatment with rituximab will be used for calculation of body surface area.  
2. Calculate the dose to be administered. The formula for the dose calculation is as follows:
(Subject BSA in m2) (375 mg/ m2) = 10 mg/mL
$\huge\begin{array}{l}-\quad\wedge\quad\vdash\quad\vdash\quad\vdash\\ \mathrm{tion})\end{array}$  
= ___ mL (volume of rituximab for
reconstitution)
3. The same volume of rituximab for reconstitution will be used for each subsequent infusion.
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preparation of rituximab for intravenous

1. Using aseptic technique, withdraw the necessary amount of rituximab and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. It is recommended that a dilution of 2 mg/mL be used for ease in calculating dose. Gently invert the bag to mix the solution. Discard any unused portion left in the vial. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.  
2. **DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.** Do not infuse rituximab concomitantly with another IV solution or other IV medications.  
3. The first infusion of rituximab should be administered IV at an initial rate of 50 mg/hr. If hypersensitivity or infusion-related reactions **do not** occur, the infusion rate can be escalated in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Such an infusion schedule is listed below for a 1000mg total dose:  
| Time                                                                        | Infusion Rate   | Dose in 30   |                      |
|-----------------------------------------------------------------------------|-----------------|--------------|----------------------|
| (Minutes)                                                                   | (mg/h)          | minutes (mg) | Cumulative Dose (mg) |
| 0-30                                                                        | 50              | 25           | 25                   |
| 31-60                                                                       | 100             | 50           | 75                   |
| 61-90                                                                       | 150             | 75           | 150                  |
| 91-120                                                                      | 200             | 100          | 250                  |
| 121-150                                                                     | 250             | 125          | 375                  |
| 151-180                                                                     | 300             | 150          | 525                  |
| 181-210                                                                     | 350             | 175          | 700                  |
| 212-240                                                                     | 400             | 200          | 900                  |
| 241-255*                                                                    | 400             | 200          | 1000                 |
| *Should complete at 255 minutes (4h 15min) to complete a 1000mg total dose. |                 |              |                      |  
4. Infusion and hypersensitivity reactions may occur. Premedication consisting of acetaminophen and diphenhydramine should be considered before each infusion of rituximab. Premedication may attenuate infusion reactions. Since transient hypotension may occur during rituximab infusion, consideration should be given to withholding antihypertensive medications 12 hours before rituximab infusion.  
5. If a hypersensitivity (non-IgE-mediated) or an infusion reaction develops, the infusion rate should be reduced to half that rate, i.e. from 100 mg/h to 50 mg/h. Subjects who experience a moderate to severe infusion related reaction (fever, chills, or hypotension) should have their infusion interrupted immediately and should receive aggressive symptomatic treatment. The infusion should not be restarted before all the symptoms have disappeared and then the infusion can continue at one-half the previous rate.
6. After the end of infusion, the intravenous line should remain in situ for at least 1 hour in order to be able to administer drugs intravenously if necessary. If there are no adverse events during this period of time, the intravenous line may be removed.
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preparation of rituximab for subsequent

1. Using aseptic technique, withdraw the necessary amount of rituximab and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. It is recommended that a dilution of 2 mg/mL be used for ease in calculating dose. Gently invert the bag to mix the solution. Discard any unused portion left in the vial. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
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2. do not administer as

infuse rituximab concomitantly with another IV solution or other IV medications. Rituximab infusions should be made through a dedicated line.  
3. If the subject tolerated the first infusion well, subsequent study drug infusions can be administered at an initial rate of 100 mg/hr and increased by 100 mg/hr increments at 30-minute intervals to a maximum of 400 mg/hr as tolerated. Such an infusion schedule is listed below. If the subject did not tolerate the first infusion well, the above guidelines for the first infusion should be followed for subsequent infusions.  
| Time                                                                       | Infusion Rate   | Dose in 30   |                      |
|----------------------------------------------------------------------------|-----------------|--------------|----------------------|
| (Minutes)                                                                  | (mg/h)          | minutes (mg) | Cumulative Dose (mg) |
| 0-30                                                                       | 100             | 50           | 50                   |
| 31-60                                                                      | 200             | 100          | 150                  |
| 61-90                                                                      | 300             | 150          | 300                  |
| 91-120                                                                     | 400             | 200          | 500                  |
| 121-150                                                                    | 400             | 200          | 700                  |
| 151-180                                                                    | 400             | 200          | 900                  |
| 181-195*                                                                   | 400             | 200          | 1000                 |
| Should complete at 195 minutes (3h 15 min) to complete a 1000mg total dose |                 |              |                      |  
4. Infusion and hypersensitivity reactions may occur. Premedication consisting of acetaminophen and diphenhydramine should be considered before each infusion of rituximab. Premedication may attenuate infusion reactions. Since transient hypotension may occur during rituximab infusion, consideration should be given to withholding antihypertensive medications 12 hours before rituximab infusion.  
5. If a hypersensitivity (non-IgE-mediated) or an infusion reaction develops, the infusion rate should be reduced to half that rate, i.e. from 100 mg/h to 50 mg/h. Subjects who experience a moderate to severe infusion related reaction (fever, chills, or hypotension) should have their infusion interrupted immediately and should receive aggressive symptomatic treatment. The infusion should not be restarted before all the symptoms have disappeared and then the infusion can continue at one-half the previous rate.  
6. After the end of infusion, the intravenous line should remain in situ for at least 1 hour in order to be able to administer drugs intravenously if necessary. If there are no adverse events during this period of time, the intravenous line may be removed.
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15.4 appendix d local physician

Note*: This list is no longer applicable, but it is being kept for historical purposes.*  
| Physician Name         | Facility Name                                              | Facility Address                                        | Facility Contact  Number   |
|------------------------|------------------------------------------------------------|---------------------------------------------------------|----------------------------|
| Elizabeth Bengtson, MD | Dartmouth                                                  | 1 Medical Center Dr.                                    | 603-650-5529               |
| College                | Lebanon, NH 03756                                          |                                                         |                            |
| Pamela Oster, MD       | FremontRideout Cancer  Center                                                            | 618 5th Street                                          | 530-749-4400               |
| Marysville, CA 95901   |                                                            |                                                         |                            |
| Michael Crump, MD      | Princess  Margaret  Cancer Centre                          | 610 University Ave,  Toronto, ON  Canada M5G 2M9        | 416-946-4501               |
| Philip Kuriakose, MD   | Henry Ford  West  Bloomfield  Hospital                     | 6777 West Maple Rd. West Bloomfield  Township, MI 48322 | 800-436-7936               |
| Paul Hendrie, MD       | University of  Washington/  Seattle Cancer  Care Alliance* | 825 Eastlake Ave. E PO Box 19023 Seattle, WA 98109      | 206-541-6426               |