CLINICAL PHARMACOLOGY
GENERAL PHARMACOLOGY
Ibritumomab Tiuxetan binds specifically to the CD20 antigen (human B-lymphocyte-restricted differentiation antigen, Bp35) [2,3] . The apparent affinity (KD) of Ibritumomab Tiuxetan for the CD20 antigen ranges between approximately 14 to 18 nM. The CD20 antigen is expressed on pre-B and mature B lymphocytes and on > 90% of B-cell non-Hodgkin's lymphomas (NHL) [4,5] . The CD20 antigen is not shed from the cell surface and does not internalize upon antibody binding[6].
Mechanism of Action: The complementarity-determining regions of Ibritumomab bind to the CD20 antigen on B lymphocytes. Ibritumomab, like Rituximab, induces apoptosis in CD20+ B-cell lines in vitro [6]. The chelate tiuxetan, which tightly binds In-111 or Y-90, is covalently linked to the amino groups of exposed lysines and arginines contained within the antibody. The beta emission from Y-90 induces cellular damage by the formation of free radicals in the target and neighboring cells[7].
Normal Human Tissue Cross-Reactivity: Ibritumomab Tiuxetan binding was observed in vitro on lymphoid cells of the bone marrow, lymph node, thymus, red and white pulp of the spleen, and lymphoid follicles of the tonsil, as well as lymphoid nodules of other organs such as the large and small intestines. Binding was not observed on the nonlymphoid tissues or gonadal tissues (see CLINICAL PHARMACOLOGY, Radiation Dosimetry)
PHARMACOKINETICS / PHARMACODYNAMICS
Pharmacokinetic and biodistribution studies were performed using In-111 ZEVALIN (5 mCi [185 MBq] In-111, 1.6 mg Ibritumomab Tiuxetan). In an early study designed to assess the need for pre-administration of unlabeled antibody, only 18% of known sites of disease were imaged when In-111 ZEVALIN was administered without unlabeled Ibritumomab. When preceded by unlabeled Ibritumomab (1.0 mg/kg or 2.5 mg/kg), In-111 ZEVALIN detected 56% and 92% of known disease sites, respectively. These studies were conducted with a ZEVALIN therapeutic regimen that included unlabeled Ibritumomab.
In pharmacokinetic studies of patients receiving the ZEVALIN therapeutic regimen, the mean effective half-life for Y-90 activity in blood was 30 hours, and the mean area under the fraction of injected activity (FIA) vs. time curve in blood was 39 hours. Over 7 days, a median of 7.2% of the injected activity was excreted in urine.
In clinical studies, administration of the ZEVALIN therapeutic regimen resulted in sustained depletion of circulating B cells. At four weeks, the median number of circulating B cells was zero (range, 0-1084 cell/mm3). B-cell recovery began at approximately 12 weeks following treatment, and the median level of B cells was within the normal range (32 to 341 cells/mm3) by 9 months after treatment. Median serum levels of IgG and IgA remained within the normal range throughout the period of B-cell depletion. Median IgM serum levels dropped below normal (median 49 mg/dL, range 13-3990 mg/dL) after treatment and recovered to normal values by 6-month post therapy.
RADIATION DOSIMETRY
Estimations of radiation-absorbed doses for In-111 ZEVALIN and Y-90 ZEVALIN were performed using sequential whole body images and the MIRDOSE 3 software program[8,9] . The estimated radiation absorbed doses to organs and marrow from a course of the ZEVALIN therapeutic regimen are summarized in Table 5. Absorbed dose estimates for the lower large intestine, upper large intestine, and small intestine have been modified from the standard MIRDOSE 3 output to account for the assumption that activity is within the intestine wall rather than the intestine contents.
Table 5.
Estimated Radiation Absorbed Doses From Y-90 ZEVALIN and In-111 ZEVALIN
|
|
Y-90 ZEVALIN
mGy/MBq
|
In-111 ZEVALIN
mGy/MBq
|
| Organ |
Median |
Range |
Median |
Range |
|
Spleen 1 |
9.4
|
1.8-14.4
|
0.9
|
0.2-1.2
|
|
Testes 1 |
9.1
|
5.4-11.4
|
0.6
|
0.4-0.8
|
|
Liver 1 |
4.8
|
2.3-8.1
|
0.7
|
0.3-1.1
|
|
Lower Large Intestinal Wall 1 |
4.8
|
3.1-8.2
|
0.4
|
0.2-0.6
|
|
Upper Large Intestinal Wall 1 |
3.6
|
2.0-6.7
|
0.3
|
0.2-0.6
|
|
Heart Wall 1 |
2.8
|
1.5-3.2
|
0.4
|
0.2-0.5
|
|
Lungs 1 |
2.0
|
1.2-3.4
|
0.2
|
0.1-0.4
|
|
Small Intestine 1 |
1.4
|
0.8-2.1
|
0.2
|
0.1-0.3
|
|
Red Marrow 2 |
1.3
|
0.7-1.8
|
0.2
|
0.1-0.2
|
|
Urinary Bladder Wall 3 |
0.9
|
0.7-2.1
|
0.2
|
0.1-0.2
|
|
Bone Surfaces 2 |
0.9
|
0.5-1.2
|
0.2
|
0.1-0.2
|
|
Ovaries 3 |
0.4
|
0.3-0.5
|
0.2
|
0.2-0.2
|
|
Uterus 3 |
0.4
|
0.3-0.5
|
0.2
|
0.1-0.2
|
|
Adrenals 3 |
0.3
|
0.0-0.5
|
0.2
|
0.1-0.3
|
|
Brain 3 |
0.3
|
0.0-0.5
|
0.1
|
0.0-0.1
|
|
Breasts 3 |
0.3
|
0.0-0.5
|
0.1
|
0.0-0.1
|
|
Gallbladder Wall 3 |
0.3
|
0.0-0.5
|
0.3
|
0.1-0.4
|
|
Muscle 3 |
0.3
|
0.0-0.5
|
0.1
|
0.0-0.1
|
|
Pancreas 3 |
0.3
|
0.0-0.5
|
0.2
|
0.1-0.3
|
|
Skin 3 |
0.3
|
0.0-0.5
|
0.1
|
0.0-0.1
|
|
Stomach 3 |
0.3
|
0.0-0.5
|
0.1
|
0.1-0.2
|
|
Thymus 3 |
0.3
|
0.0-0.5
|
0.1
|
0.1-0.2
|
|
Thyroid 3 |
0.3
|
0.0-0.5
|
0.1
|
0.0-0.1
|
|
Kidneys 1 |
0.1
|
0.0-0.2
|
0.2
|
0.1-0.2
|
|
Total Body 3 |
0.5
|
0.2-0.7
|
0.1
|
0.1-0.2
|
| 1 Organ region of interest
|
| 2 Sacrum region of interest[10] |
| 3 Whole body region of interest
|
|
CLINICAL STUDIES
The safety and efficacy of the ZEVALIN therapeutic regimen were evaluated in two multi-center trials enrolling a total of 197 subjects. The ZEVALIN therapeutic regimen was administered in two steps (see DOSAGE AND ADMINISTRATION). The activity and toxicity of a variation of the ZEVALIN therapeutic regimen employing a reduced dose of Y-90 ZEVALIN was further defined in a third study enrolling a total of 30 patients who had mild thrombocytopenia (platelet count 100,000 to 149,000 cells/mm3).
Study 1 was a single arm study of 54 patients with relapsed follicular lymphoma refractory to Rituximab treatment. Patients were considered refractory if their last prior treatment with Rituximab did not result in a complete or partial response, or if time to disease progression (TTP) was < 6 months11. The primary efficacy endpoint of the study was the overall response rate (ORR) using the International Workshop Response Criteria (IWRC) [12] . Secondary efficacy endpoints included time to disease progression (TTP) and duration of response (DR). In a secondary analysis comparing objective response to the ZEVALIN therapeutic regimen with that observed with the most recent treatment with Rituximab, the median duration of response following the ZEVALIN therapeutic regimen was 6 vs. 4 months. Table 6 summarizes efficacy data from this study.
Study 2 was a randomized, controlled, multicenter study comparing the ZEVALIN therapeutic regimen to treatment with Rituximab. The trial was conducted in 143 patients with relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL), or transformed B-cell NHL. A total of 73 patients received the ZEVALIN therapeutic regimen, and 70 patients received Rituximab given as an IV infusion at 375 mg/m2 weekly times 4 doses. The primary efficacy endpoint of the study was to determine the ORR using the IWRC[12] (see Table 6). The ORR was significantly higher (80% vs. 56%, p = 0.002) [13] for patients treated with the ZEVALIN therapeutic regimen. The secondary endpoints, duration of response and time to progression, were not significantly different between the two treatment arms.
Table 6.
Summary of Efficacy Data 1
|
|
Study 1 |
Study 2 |
ZEVALIN
therapeutic regimen N = 54 |
ZEVALIN
therapeutic regimen N = 73 |
Rituximab N = 70 |
|
Overall Response Rate (%)
|
74
|
80
|
56
|
|
Complete Response Rate (%)
|
15
|
30
|
16
|
|
CRu Rate 2 (%)
|
0
|
4
|
4
|
|
Median DR 3, 4 |
|
(Months)
|
6.4
|
13.9
|
11.8
|
|
[Range 5 ]
|
[0.5-24.9 + ]
|
[1.0-30.1 + ]
|
[1.2-24.5] |
|
Median TTP 3, 6 |
|
(Months)
|
6.8
|
11.2
|
10.1
|
|
[Range 5 ]
|
[1.1-25.9 + ]
|
[0.8-31.5 + ]
|
[0.7-26.1] |
| 1 IWRC: International Workshop response criteria
|
| 2 CRu: Unconfirmed complete response
|
| 3 Estimated with observed range.
|
| 4 Duration of response: interval from the onset of response to disease progression.
|
| 5"+" indicates an ongoing response.
|
| 6 Time to Disease Progression: interval from the first infusion to disease progression.
|
|
Study 3 was a single arm study of 30 patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL who had mild thrombocytopenia (platelet count 100,000 to 149,000 cells/mm3). Excluded from the study were patients with >/= 25% lymphoma marrow involvement and/or impaired bone marrow reserve. Patients were considered to have impaired bone marrow reserve if they had any of the following: prior myeloablative therapy with stem cell support; prior external beam radiation to > 25% of active marrow; a platelet count <100,000 cells/mm3; or neutrophil count <1,500 cells/mm3. In this study, a modification of the ZEVALIN therapeutic regimen with a lower Y-90 ZEVALIN dose [Y-90 ZEVALIN at 0.3 mCi/kg (11.1 MBq/kg)] was used. Objective, durable clinical responses were observed [67% ORR (95% CI: 48-85%) [14] , 11.8 months median DR (range: 4-17 months)] and resulted in a greater incidence of hematologic toxicity (see ADVERSE REACTIONS) than in Studies 1 and 2.
|
