Bexxar4

Radiation Therapy

Therapeutic Goal of Radiation Therapy
- To maximize the amount of radiation delivered to the tumor while minimizing the radiation dose to critical normal tissues
Method of Achieving the Above Goal
- Dosimetry is used routinely in radiation therapy planning

Determination of Maximum Tolerated Total Body Dose (TBD) of BEXXAR^®
75 cGy was established as Maximum Tolerated TBD

Dose Level (cGy)	*Patients with DLT/ Number Treated**
25	0/3
35	0/4
45	0/3
55	0/3
65	0/3
75**	1/6
85	2/3
* DLT (Dose-Limiting Toxicity) = Grade 3 hematologic toxicity ≥ 2 weeks’ duration, Grade 4 hematologic toxicity ≥ 1 week duration, or Grade 3/4 non-hematologic toxicity. ** 75 cGy = MTD Data on File: GlaxoSmithKline

Dosimetry for BEXXAR^®

Using dosimetry with Iodine 131-labeled antibodies enables physicians to directly measure the clearance rate in order to prospectively individualize the therapeutic dose
Dosimetry studies confirmed a 4-fold variation in the clearance rate (or effective half-life) of Iodine I 131 Tositumomab
Due to variations in the clearance rate, the administered amount of radioactivity (in mCi) is adjusted individually to ensure that all patients receive the prescribed TBD
of 75 cGy

Role of Dosimetry:
Achieve Equal Area Under Curve

Patient-specific dosing, based on total body clearance
- provided a consistent radiation dose
- despite variable pharmacokinetics
- allowed each patient’s dose to be adjusted for individual patient variables
Patients with high tumor burden, splenomegaly, or bone marrow involvement were noted to have faster clearance, shorter terminal half-life and larger volume of distribution

Adapted with permission from the Society of Nuclear Medicine from Seldin DW. Techniques for using BEXXAR for the treatment of non-Hodgkin's lymphoma. J Nucl Med Technol. 2002;30:109-114. Figure 3.

These images are for illustrative purposes only. They are intended to represent the concept of patient-specific dosing and are not derived from actual data.

* Patients were prescribed either 65cGy or 75 cGy depending on their platelet count. Data were standardized to 75 cGy.

Data on File: GlaxoSmithKline

Effect of Dose Reduction in Patients with Mild Thrombocytopenia*
The prescribed 75 cGy was adjusted to 65 cGy for patients with a platelet count between 100,000/mm³and 150,000/mm³

Grade/Counts (1000 cells/mm³	Reduced Dose (65 cGy; n=38)	Standard Dose (75 cGy; n=20
ANC Grade 3/4**	50%	70%
Platelets Grade 3/4***	58%	65%
* Patients with a baseline platelet count between 100,000 and 150,000/mm³ ANC<1.0 to 10³cells/mm³* platelet count<50X10³/mm³ Data on File: GlaxoSmithKline

Effect of Dose Dose Adjustment for Baseline Obesity
The dose for obese patients adjusted to 137% of their calculated lean body mass

Grade/Counts (1000 cells/mm³	Adjusted* (n=14)	Non Adjusted n=3**
ANC Grade 4***	21%	67%
Platelets Grade 4****	14%	67%
* Patients dosed at 75 cGy ^{Patients dosed based on 137% of their lean body mass}* ANC:Grade 4 <500 cells/mm³^Platelets:Grade 4 <25,000 /mm³ Data on File: GlaxoSmithKline

Calculation of the Therapeutic Dose

The therapeutic dose may be calculated either by using the BEXXAR Patient Management Templates or manually
Determine activity hours to deliver a 75 cGy TBD
- Table look-up by patient mass (look-up table provided)
- For obese patients,* use 137% of lean body weight
  *Those weighing >137% of lean body weight
Determine total body residence time (clearance rate)
- Semi-log graph of 3 imaging time points

Calculate amount of radioactivity required to deliver a total body dose of radiation of 75 cGy (65 cGy for patients with mild thrombocytopenia)

The Equation Used to Calculate the Therapeutic Dose

Therapeutic Dose (mCi) =

Activity Hours (mCi h) _X Desired TBD (cGy)
Residence Time (h) 75 cGy*

*65 cGy for platelet count > 100,000 and < 150,000mm³

Conclusions

Dosimetry with Iodine I 131 Tositumomab allows for patient-specific dosing, based on individual clearance rate, and prospective determination of the radioactivity (mCi) needed to deliver the prescribed total body dose (65 cGy or 75 cGy*)

*65 cGy for platelet count > 100,000 and < 150,000mm³