Bexxar (Tositumomab / Iodine I 131 Tositumomab) - Description and Clinical Pharmacology

DESCRIPTION

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

Tositumomab

Tositumomab is a murine IgG_2a 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. The approximate molecular weight of Tositumomab is 150 kD.

Tositumomab is supplied as a sterile, pyrogen-free, clear to opalescent, colorless to slightly yellow, preservative-free liquid concentrate. It is supplied at a nominal concentration of 14 mg/mL Tositumomab in 35 mg and 225 mg single-use vials. The formulation contains 10% (w/v) maltose, 145 mM sodium chloride, 10 mM phosphate, and Water for Injection, USP. The pH is approximately 7.2.

Iodine I 131 Tositumomab

Iodine I 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. The dosimetric dosage form is supplied at nominal protein and activity concentrations of 0.1 mg/mL and 0.61 mCi/mL (at date of calibration), respectively. The therapeutic dosage form is supplied at nominal protein and activity concentrations of 1.1 mg/mL and 5.6 mCi/mL (at date of calibration), respectively. The formulation for the dosimetric and the therapeutic dosage forms contains 4.4%−6.6% (w/v) povidone, 1—2 mg/mL maltose (dosimetric dose) or 9—15 mg/mL maltose (therapeutic dose), 8.5—9.5 mg/mL sodium chloride, and 0.9—1.3 mg/mL ascorbic acid. The pH is approximately 7.0.

BEXXAR Therapeutic Regimen

The BEXXAR therapeutic regimen is administered in two discrete steps: the dosimetric and therapeutic steps. Each step consists of a sequential infusion of Tositumomab followed by Iodine I 131 Tositumomab. The therapeutic step is administered 7-14 days after the dosimetric step. The BEXXAR therapeutic regimen is supplied in two distinct package configurations as follows:

BEXXAR Dosimetric Packaging

• A carton containing two single-use 225 mg vials and one single-use 35 mg vial of Tositumomab supplied by McKesson BioServices and

• A package containing a single-use vial of Iodine I 131 Tositumomab (0.61 mCi/mL at calibration), supplied by MDS Nordion.

BEXXAR Therapeutic Packaging

• A carton containing two single-use 225 mg vials and one single-use 35 mg vial of Tositumomab, supplied by McKesson BioServices and

• A package containing one or two single-use vials of Iodine I 131 Tositumomab (5.6 mCi/mL at calibration), supplied by MDS Nordion.

CLINICAL PHARMACOLOGY

General Pharmacology

Tositumomab binds specifically to the CD20 (human B-lymphocyte−restricted differentiation antigen, Bp 35 or B1) antigen. This antigen is a transmembrane phosphoprotein expressed on pre-B lymphocytes and at higher density on mature B lymphocytes (Ref. 2). The antigen is also expressed on >90% of B-cell non-Hodgkin’s lymphomas (NHL) (Ref. 3). The recognition epitope for Tositumomab is found within the extracellular domain of the CD20 antigen. CD20 does not shed from the cell surface and does not internalize following antibody binding (Ref. 4).

Mechanism of Action

Possible mechanisms of action of the BEXXAR therapeutic regimen include induction of apoptosis (Ref. 5), complement-dependent cytotoxicity (CDC) (Ref. 6), and antibody-dependent cellular cytotoxicity (ADCC) (Ref. 5) mediated by the antibody. Additionally, cell death is associated with ionizing radiation from the radioisotope.

Pharmacokinetics/Pharmacodynamics

The phase 1 study of Iodine I 131 Tositumomab determined that a 475 mg predose of unlabeled antibody decreased splenic targeting and increased the terminal half-life of the radiolabeled antibody. The median blood clearance following administration of 485 mg of Tositumomab in 110 patients with NHL was 68.2 mg/hr (range: 30.2—260.8 mg/hr). Patients with high tumor burden, splenomegaly, or bone marrow involvement were noted to have a faster clearance, shorter terminal half-life, and larger volume of distribution. The total body clearance, as measured by total body gamma camera counts, was dependent on the same factors noted for blood clearance. Patient-specific dosing, based on total body clearance, provided a consistent radiation dose, despite variable pharmacokinetics, by allowing each patient’s administered activity to be adjusted for individual patient variables. The median total body effective half-life, as measured by total body gamma camera counts, in 980 patients with NHL was 67 hours (range: 28-115 hours).

Elimination of Iodine-131 occurs by decay (see Table 2) and excretion in the urine. Urine was collected for 49 dosimetric doses. After 5 days, the whole body clearance was 67% of the injected dose. Ninety-eight percent of the clearance was accounted for in the urine.

Administration of the BEXXAR therapeutic regimen results in sustained depletion of circulating CD20 positive cells. The impact of administration of the BEXXAR therapeutic regimen on circulating CD20 positive cells was assessed in two clinical studies, one conducted in chemotherapy na¯ve patients and one in heavily pretreated patients. The assessment of circulating lymphocytes did not distinguish normal from malignant cells. Consequently, assessment of recovery of normal B cell function was not directly assessed. 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. Among patients who had CD20 positive cell counts recorded at baseline and at 6 months, 8 of 58 (14%) chemotherapy na¯ve patients had CD20 positive cell counts below normal limits at six months and 6 of 19 (32%) heavily pretreated patients had CD20 positive cell counts below normal limits at six months. There was no consistent effect of the BEXXAR therapeutic regimen on post-treatment serum IgG, IgA, or IgM levels.

Radiation Dosimetry

Estimations of radiation-absorbed doses for Iodine I 131 Tositumomab were performed using sequential whole body images and the MIRDOSE 3 software program. Patients with apparent thyroid, stomach, or intestinal imaging were selected for organ dosimetry analyses. The estimated radiation-absorbed doses to organs and marrow from a course of the BEXXAR therapeutic regimen are presented in Table 3.

Table 3: Estimated Radiation-Absorbed Organ Doses

		BEXXAR	BEXXAR
		mGy/MBq	mGy/MBq
		Median	Range
From Organ ROIs
	Thyroid	2.71	1.4 - 6.2
	Kidneys	1.96	1.5 - 2.5
	ULI Wall	1.34	0.8 - 1.7
	LLI Wall	1.30	0.8 - 1.6
	Heart Wall	1.25	0.5 - 1.8
	Spleen	1.14	0.7 - 5.4
	Testes	0.83	0.3 - 1.3
	Liver	0.82	0.6 - 1.3
	Lungs	0.79	0.5 - 1.1
	Red Marrow	0.65	0.5 - 1.1
	Stomach Wall	0.40	0.2 - 0.8
From Whole Body ROIs
	Urine Bladder Wall	0.64	0.6 - 0.9
	Bone Surfaces	0.41	0.4 - 0.6
	Pancreas	0.31	0.2 - 0.4
	Gall Bladder Wall	0.29	0.2 - 0.3
	Adrenals	0.28	0.2 - 0.3
	Ovaries	0.25	0.2 - 0.3
	Small Intestine	0.23	0.2 - 0.3
	Thymus	0.22	0.1 - 0.3
	Uterus	0.20	0.2 - 0.2
	Muscle	0.18	0.1 - 0.2
	Breasts	0.16	0.1 - 0.2
	Skin	0.13	0.1 - 0.2
	Brain	0.13	0.1 - 0.2
	Total Body	0.24	0.2 - 0.3

CLINICAL STUDIES

The efficacy of the BEXXAR therapeutic regimen was evaluated in 2 studies conducted in patients with low-grade, transformed low-grade, or follicular large-cell lymphoma. Determination of clinical benefit of the BEXXAR therapeutic regimen was based on evidence of durable responses without evidence of an effect on survival. All patients had received prior treatment without an objective response or had progression of disease following treatment. Patients were required to have a granulocyte count >1500 cells/mm³, a platelet count ≥100,000/mm³, an average of ≤25% of the intratrabecular marrow space involved by lymphoma, and no evidence of progressive disease arising in a field irradiated with >3500 cGy within 1 year of completion of irradiation.

Study 1 was a multicenter, single-arm study of 40 patients whose disease had not responded to or had progressed after at least four doses of Rituximab therapy. The median age was 57 (range: 35—78); the median time from diagnosis to protocol entry was 50 months (range: 12—170); and the median number of prior chemotherapy regimens was 4 (range: 1—11). The efficacy outcome data from this study, as determined by an independent panel that reviewed patient records and radiologic studies, are summarized in Table 4.

Among the forty patients in the study, twenty-four patients had disease that did not respond to their last treatment with Rituximab, 11 patients had disease that responded to Rituximab for less than 6 months, and five patients had disease that responded to Rituximab, with a duration of response of 6 months or greater. 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. In this subset of patients the overall objective response was 63% (95% confidence interval 45%, 79%) with a median duration of 25 months (range of 4 - 38+ months). The complete response in this subset of patients was 29% (95% CI of 15%, 46%) with a median duration of response not yet reached (range of 4 - 38+ months).

Study 2 was a multicenter, single arm, open-label study of 60 chemotherapy refractory patients. The median age was 60 (range 38-82), the median time from diagnosis to protocol entry was 53 months (range: 9-334), and the median number of prior chemotherapy regimens was 4 (range 2-13). Fifty-three patients had not responded to prior therapy and 7 patients had responded with a duration of response of<6 months. The efficacy outcome data from this study, as determined by an independent panel that reviewed patient records and radiologic studies are also summarized in Table 4. Investigators continued to follow eight patients with complete response after the last independent review panel assessment. The updated duration of ongoing response as per investigators was reported to range from 42 to 85 months.

Table 4: Efficacy Outcomes in BEXXAR Clinical Studies

	Study 1 (n = 40)	Study 2 (n = 60)
Overall Response
Rate 95% CI a	68% (51%, 81%)	47% (34%, 60%)
Response Duration (mos)
Median 95% CI a Range	16 (10, NRb) 1+ to 38+	12 (7, 47) 2 to 47
Complete Response c
Rate 95% CI a	33% (19%, 49%)	20% (11%, 32%)
Complete response c duration (mos)
Median 95% CI a Range	NR b (15, NR) 4 to 38+	47 (47, NR) 9 to 47

^aCI = Confidence Interval

^bNR = Not reached, Median duration of follow up: Study 1 = 26 months; Study 2 = 30 months

^cComplete response rate = Pathologic and clinical complete responses

The results of these studies were supported by demonstration of durable objective responses in three single-arm studies. In these studies, 130 patients with Rituximab-na¯ve follicular non-Hodgkin’s lymphoma with or without transformation were evaluated for efficacy. All patients had relapsed following, or were refractory to, chemotherapy. The overall response rates ranged from 49% to 64% and the median durations of response ranged from 13 to 16 months. Due to small sample sizes in the supportive studies, as in studies 1 and 2, the 95% confidence intervals for the median durations of response are wide.