General Information

The BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) is an anti-neoplastic radioimmunotherapeutic monoclonal antibody-based treatment. It is composed of the monoclonal antibody, Tositumomab, and the radiolabeled monoclonal antibody, Iodine I 131 Tositumomab.

Treatment with BEXXAR (Tositumomab and Iodine I 131Tositumomab) is indicated for the treatment of patients with CD20 positive, follicular, non-Hodgkin's lymphoma, with and without transformation, whose disease is refractory to Rituximab and has relapsed following chemotherapy. BEXXAR is not indicated for the initial treatment of patients with CD20 positive non- Hodgkin’s lymphoma.

BEXXAR consists of four lengthy components administered in two discrete steps: the dosimetric step, followed 7-14 days later by a therapeutic step.

Clinical Results

FDA approval of BEXXAR was based on a multi-center, single-arm study in subjects with low grade or transformed low- grade or follicular large-cell lymphoma whose disease had not responded to or had progressed after Rituximab therapy. The study enrolled 40 subjects aged 35-78. Subjects were required to have received prior treatment with at least four doses of Rituximab without an objective response, or to have progressed following treatment. Overall, 35 of the 40 patients met the definition of “Rituximab refractory”, defined as no response or a response of less than 6 months duration. Clinical benefit was based on evidence of durable responses without any evidence of an effect on survival.

Results demonstrated a durable objective responses in four single arm studies enrolling 190 subjects evaluable for efficacy with Rituximab-naïve, follicular non-Hodgkin’s lymphoma with or without transformation, who had relapsed following or were refractory to chemotherapy. In these studies, the overall response rates ranged from 47% to 64% and the median duration of response ranged from 12 to 18 months.

The effect of BEXXAR on circulating CD20 positive cells was assessed in two clinical studies, one conducted in chemotherapy naïve patients and one in heavily pretreated patients. Results showed that administration with BEXXAR results in sustained depletion of circulating CD20 positive cells. At seven weeks, the median number of circulating CD20 positive cells was zero (range: 0 - 490 cells/ mm3). Lymphocyte recovery began at approximately 12 weeks following treatment.

Mechanism of Action

Tositumomab is a murine IgG2a lambda monoclonal antibody directed against the CD20 antigen, which is found on the surface of normal and malignant B lymphocytes. Tositumomab is produced in an antibiotic-free culture of mammalian cells and is composed of two murine gamma 2a heavy chains of 451 amino acids each and two lambda light chains of 220 amino acids each.

Iodine 131 Tositumomab is a radio-iodinated derivative of Tositumomab that has been covalently linked to Iodine-131. Unbound radio-iodine and other reactants have been removed by chromatographic purification steps. Iodine I 131 Tositumomab is supplied as a sterile, clear, preservative-free liquid for IV administration. Possible mechanisms of action of the BEXXAR therapeutic regimen include induction of apoptosis, complement- dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC) mediated by the antibody. Additionally, cell death is associated with ionizing radiation from the radioisotope.

Literature References

Anderson, KC, Bates MP, Slaughenhoupt BL, Pinkus GS, Schlossman SF, Nadler LM. Expression of human B cell-associated antigens on leukemias and lymphomas: a model of human B cell differentiation. Blood 1984; 63(6): 1424-1433.

Cardarelli PM, Quinn M, Buckman D, Fang Y, Colcher D, King DJ, Bebbington C, et al. Binding to CD20 by anti-B1 antibody or F(ab')(2) is sufficient for induction of apoptosis in B-cell lines. Cancer Immunol Immunother 2002 Mar;51(1):15-24

Press OW, Howell-Clark J, Anderson S, Bernstein I. Retention of B-cell-specific monoclonal antibodies by human lymphoma cells. Blood 1994;83:1390:7

Stashenko P, Nadler LM, Hardy R, Schlossman SF. Characterization of a human B lymphocyte-specific antigen. J Immunol 1980; 125:1678:85.

Weber DA, Eckman KF, Dillman LT, Ryman JC. In: MIRD: radionuclide data and decay schemes. New York: Society of Nuclear Medicine Inc. 1989:229.