BEXXAR^® Indication

The BEXXAR therapeutic regimen is indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with Rituximab-refractory non-Hodgkin’s lymphoma

Determination of the effectiveness of the BEXXAR therapeutic regimen is based on overall response rates in patients whose disease is refractory to chemotherapy alone or to chemotherapy and Rituximab The effects of BEXXAR therapeutic regimen on survival are not known

The BEXXAR therapeutic regimen is not indicated for the initial treatment of patients with CD20 positive non-Hodgkin’s lymphoma

The BEXXAR therapeutic regimen is intended as a single course of treatment. The safety of multiple courses of the BEXXAR therapeutic regimen, or combination of this regimen with other forms of irradiation or chemotherapy, has not been evaluated

BEXXAR^® Therapeutic Regimen

Unified Therapy Consisting of:

• Tositumomab
  • Anti-CD20 antibody (unlabeled, "cold" antibody)
• Iodine I 131 Tositumomab
  • I¹³¹ radioisotope covalently linked to anti-CD20 antibody (radiolabeled, "hot" antibody)

The BEXXAR^® Therapeutic Regimen
Treatment Schedule

Concomitant Medications

• Oral thyroid blocking agents
  • To decrease the risk of hypothyroidism
  • Starting at least 24 hours prior to the dosimetric dose and continuing for 14 days after receiving the therapeutic dose
    • SSKI 4 drops orally 3 times/day
    • Lugol’s solution 20 drops orally 3 times/day
    • Potassium iodide tablets 130 mg orally once/day
• Oral Acetaminophen 650 mg and diphenhydramine 50 mg
  • To reduce infusion-related events
  • 30 min prior to administration of each of the Tositumomab doses
    • The benefit of premedication in preventing and/or reducing infusion-related toxicity has not been evaluated

BEXXAR^® Therapeutic Regimen Characteristics of Components

• Tositumomab
  • Murine IgG_2a anti-CD20 MAb
  • Binds to normal and malignant B lymphocytes
• Iodine-131 radioisotope
  • Beta and gamma emissions
  • Physical half-life of 8 days
  • Principal beta emission mean energy = 191.6 keV
  • Principal gamma emission energy = 364.5 keV
  • Gamma emission allows dosimetry

BEXXAR^® Therapeutic Regimen Possible Mechanisms of Action

• Induction of apoptosis
• Complement-dependent cytotoxicity (CDC)
• Antibody-dependent cellular cytotoxicity (ADCC)
• Cytotoxicity from beta emissions

Rationale for Use of Iodine-131 Isotope

• Iodine-131 has long history of use
  (>60 years)
• Gamma radiation allows dosimetry for patient-specific dosing

Pharmacokinetics/ Pharmacodynamics

• Elimination of Iodine 131 occurs by decay and excretion in the urine
• Patients with high tumor burden, splenomegaly, or BM involvement had faster clearance, shorter terminal half-life and larger volume of distribution
• Total body clearance was dependent on the same factors noted for blood clearance
• Administration of the BEXXAR^® therapeutic regimen results in sustained depletion of circulating CD20 positive cells

Purpose of Administering Unlabeled Tositumomab Prior to
Iodine I 131 Tositumomab

• To decrease splenic targeting
• To increase the terminal half-life of the
  radiolabeled antibody

Effect of Unlabeled Tositumomab Pre-Dose on Distribution of Iodine I 131 Tositumomab

Courtesy of Richard Wahl, MD