BEXXAR (Tositumomab and Iodine I 131 Tositumomab) | BEXXAR

05:12 EDT 2nd September 2014 | BioPortfolio
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WARNINGS

Hypersensitivity Reactions, including Anaphylaxis: Serious hypersensitivity reactions, including some with fatal outcome, have been reported with the BEXXAR therapeutic regimen. Medications for the treatment of severe hypersensitivity reactions should be available for immediate use. Patients who develop severe hypersensitivity reactions should have infusions of the BEXXAR therapeutic regimen discontinued and receive medical attention (see WARNINGS).

Prolonged and Severe Cytopenias: The majority of patients who received the BEXXAR therapeutic regimen experienced severe thrombocytopenia and neutropenia. The BEXXAR therapeutic regimen should not be administered to patients with >25% lymphoma marrow involvement and/or impaired bone marrow reserve (see WARNINGS and ADVERSE REACTIONS).

Pregnancy Category X: The BEXXAR therapeutic regimen can cause fetal harm when administered to a pregnant woman.

Special requirements: The BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) contains a radioactive component and should be administered only by physicians and other health care professionals qualified by training in the safe use and handling of therapeutic radionuclides. The BEXXAR therapeutic regimen should be administered only by physicians who are in the process of being or have been certified by GlaxoSmithKline in dose calculation and administration of the BEXXAR therapeutic regimen.

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 is a murine IgGlambda 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 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.

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

BEXXAR Therapeutic Packaging

Iodine-131 decays with beta and gamma emissions with a physical half-life of 8.04 days. The principal beta emission has a mean energy of 191.6 keV and the principal gamma emission has an energy of 364.5 keV (Ref 1).

The specific gamma ray constant for Iodine-131 is 2.2 R/millicurie hour at 1 cm. The first half-value layer is 0.24 cm lead (Pb) shielding. A range of values is shown in Table 1 for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb. To facilitate control of the radiation exposure from this radionuclide, the use of a 2.55 cm thickness of Pb will attenuate the radiation emitted by a factor of about 1,000.

The fraction of Iodine-131 radioactivity that remains in the vial after the date of calibration is calculated as follows:

Fraction of remaining radioactivity of Iodine-131 after x days = 2.

Physical decay is presented in Table 2.

* (Calibration day)

Table 1: Radiation Attenuation by Lead Shielding
Shield Thickness (Pb) cm Attenuation Factor
0.24 0.5
0.89 10-1
1.60 10-2
2.55 10-3
3.7 10-4
Table 2: Physical Decay Chart: Iodine-131: Half-Life 8.04 Days
Days Fraction Remaining
0* 1.000
1 0.917
2 0.842
3 0.772
4 0.708
5 0.650
6 0.596
7 0.547
8 0.502
9 0.460
10 0.422
11 0.387
12 0.355
13 0.326
14 0.299

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).

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.

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 naïve 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/mm). 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 naïve 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.

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

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/mm, a platelet count ≥100,000/mm, 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.

CI = Confidence Interval

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

Complete 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-naïve 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.

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

The BEXXAR therapeutic regimen (Tositumomab and Iodine I 131 Tositumomab) 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 the 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. (See ADVERSE REACTIONS, Immunogenicity.)

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.

The BEXXAR therapeutic regimen is contraindicated in patients with known hypersensitivity to murine proteins or any other component of the BEXXAR therapeutic regimen.

Iodine I 131 Tositumomab (a component of the BEXXAR therapeutic regimen) is contraindicated for use in women who are pregnant. Iodine-131 may cause harm to the fetal thyroid gland when administered to pregnant women. Review of the literature has shown that transplacental passage of radioiodide may cause severe, and possibly irreversible, hypothyroidism in neonates. While there are no adequate and well-controlled studies of the BEXXAR therapeutic regimen in pregnant animals or humans, use of the BEXXAR therapeutic regimen in women of childbearing age should be deferred until the possibility of pregnancy has been ruled out. If the patient becomes pregnant while being treated with the BEXXAR therapeutic regimen, the patient should be apprised of the potential hazard to the fetus (see BOXED WARNING, Pregnancy Category X).

The most common adverse reactions associated with the BEXXAR therapeutic regimen were severe or life-threatening cytopenias (NCI CTC grade 3 or 4) with 71% of the 230 patients enrolled in clinical studies experiencing grade 3 or 4 cytopenias. These consisted primarily of grade 3 or 4 thrombocytopenia (53%) and grade 3 or 4 neutropenia (63%). The time to nadir was 4 to 7 weeks and the duration of cytopenias was approximately 30 days. Thrombocytopenia, neutropenia, and anemia persisted for more than 90 days following administration of the BEXXAR therapeutic regimen in 16 (7%), 15 (7%), and 12 (5%) patients respectively (this includes patients with transient recovery followed by recurrent cytopenia). Due to the variable nature in the onset of cytopenias, complete blood counts should be obtained weekly for 10-12 weeks. The sequelae of severe cytopenias were commonly observed in the clinical studies and included infections (45% of patients), hemorrhage (12%), a requirement for growth factors (12% G- or GM-CSF; 7% Epoetin alfa) and blood product support (15% platelet transfusions; 16% red blood cell transfusions). Prolonged cytopenias may also influence subsequent treatment decisions.

The safety of the BEXXAR therapeutic regimen has not been established in patients with >25% lymphoma marrow involvement, platelet count<100,000 cells/mmor neutrophil count <1,500 cells/mm.

Serious hypersensitivity reactions, including some with fatal outcome, were reported during and following administration of the BEXXAR therapeutic regimen. Emergency supplies including medications for the treatment of hypersensitivity reactions, e.g., epinephrine, antihistamines and corticosteroids, should be available for immediate use in the event of an allergic reaction during administration of the BEXXAR therapeutic regimen. Patients who have received murine proteins should be screened for human anti-mouse antibodies (HAMA). Patients who are positive for HAMA may be at increased risk of anaphylaxis and serious hypersensitivity reactions during administration of the BEXXAR therapeutic regimen.

Myelodysplastic syndrome (MDS) and/or acute leukemia were reported in 10% (24/230) of patients enrolled in the clinical studies and 3% (20/765) of patients included in expanded access programs, with median follow-up of 39 and 27 months, respectively. Among the 44 reported cases, the median time to development of MDS/leukemia was 31 months following treatment; however, the cumulative rate continues to increase.

Additional non-hematological malignancies were also reported in 54 of the 995 patients enrolled in clinical studies or included in the expanded access program. Approximately half of these were non-melanomatous skin cancers. The remainder, which occurred in 2 or more patients, included colorectal cancer (7), head and neck cancer (6), breast cancer (5), lung cancer (4), bladder cancer (4), melanoma (3), and gastric cancer (2). The relative risk of developing secondary malignancies in patients receiving the BEXXAR therapeutic regimen over the background rate in this population cannot be determined, due to the absence of controlled studies (see ADVERSE REACTIONS).

(see BOXED WARNINGS; CONTRAINDICATIONS).

Administration of the BEXXAR therapeutic regimen may result in hypothyroidism (see ADVERSE REACTIONS, Hypothyroidism). Thyroid-blocking medications should be initiated at least 24 hours before receiving the dosimetric dose and continued until 14 days after the therapeutic dose (see DOSAGE and ADMINISTRATION). All patients must receive thyroid-blocking agents; any patient who is unable to tolerate thyroid-blocking agents should not receive the BEXXAR therapeutic regimen. Patients should be evaluated for signs and symptoms of hypothyroidism and screened for biochemical evidence of hypothyroidism annually.

Iodine I 131 Tositumomab is radioactive. Care should be taken, consistent with the institutional radiation safety practices and applicable federal guidelines, to minimize exposure of medical personnel and other patients.

Iodine I 131 Tositumomab and Iodine-131 are excreted primarily by the kidneys. Impaired renal function may decrease the rate of excretion of the radiolabeled iodine and increase patient exposure to the radioactive component of the BEXXAR therapeutic regimen. There are no data regarding the safety of administration of the BEXXAR therapeutic regimen in patients with impaired renal function.

The safety of immunization with live viral vaccines following administration of the BEXXAR therapeutic regimen has not been studied. The ability of patients who have received the BEXXAR therapeutic regimen to generate a primary or anamnestic humoral response to any vaccine has not been studied.

Prior to administration of the BEXXAR therapeutic regimen, patients should be advised that they will have a radioactive material in their body for several days upon their release from the hospital or clinic. After discharge, patients should be provided with both oral and written instructions for minimizing exposure of family members, friends and the general public. Patients should be given a copy of the written instructions for use as a reference for the recommended precautionary actions.

The pregnancy status of women of childbearing potential should be assessed and these women should be advised of the potential risks to the fetus (see CONTRAINDICATIONS). Women who are breastfeeding should be instructed to discontinue breastfeeding and should be apprised of the resultant potential harmful effects to the infant if these instructions are not followed.

Patients should be advised of the potential risk of toxic effects on the male and female gonads following the BEXXAR therapeutic regimen, and be instructed to use effective contraceptive methods during treatment and for 12 months following the administration of the BEXXAR therapeutic regimen.

Patients should be informed of the risks of hypothyroidism and be advised of the importance of compliance with thyroid blocking agents and n

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GlaxoSmithKline LLC

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Clinical Trials [9 Associated Clinical Trials listed on BioPortfolio]

Study Looking at Effectiveness of 131-Tositumomab (Bexxar) Consolidation for Patients With CLL or SLL

This study is evaluating the use of radioimmunotherapy (Bexxar®) in patients who have achieved a first remission following chemotherapy (ex. Fludarabine and Rituximab, Fludarabine,Cycloph...

Study to Treat Relapsed Follicular Non-Hodgkin's Lymphoma With Radiation and Bexxar

The purpose of this study is to determine the feasibility of treating relapsed follicular lymphoma with a combination of Bexxar and EBRT. Patients will receive External Beam Radiation The...

Safety and Efficacy of Bexxar Therapy in the Treatment of Relapsed/Residual B-Cell Lymphoma After Autologous Transplant

Patients with B-cell lymphoma who relapse after autologous transplant tend to have a poor prognosis. Currently, there is no standard treatment for such patients. Bexxar is a radioactive ...

Comparison of Rituxan Versus Bexxar When Combined With Carmustine, Etoposide, Cytarabine and Melphalan (BEAM) With Autologous Hematopoietic Stem Cell Transplantation (ASCT)

This study is designed as a Phase III, multicenter trial, comparing progression-free survival (PFS) after autologous hematopoietic stem cell transplantation using a standard Rituxan plus B...

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This study is for patients with newly diagnosed or relapsed multiple myeloma. The main purpose of this study is to see how their disease responds to consolidation treatment (treatment aim...

PubMed Articles [0 Results]

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