Clinical Trials Utilizing Anticd20 In Therapy

Investigators have taken two broad approaches with the use of anti-CD20 radio-immunoconjugates. First approach limits the dose of radioisotopes by its myelo-suppressive effect. This nonmyeloablative therapy has been evaluated both with I-131 and Y-90 radioconjugates. Some of the earliest experience with this approach comes from the University of Michigan. Dr. Kaminsky et al. (10) utilized whole-body dosimetry to determine the maximal safe dose of I-131 tositumomab (anti-CD20) therapy. The initial phase I studies used trace-labeled (5-10 mCi) antibody to evaluate the whole-body biodistribution. The therapeutic dose was then delivered in a dose-escalation schema ranging from 25 to 85 cGy whole-body dose with dose escalation occurring in 10 cGy increments. The dose-limiting toxicity was hematologic and 75 cGy was established as the maximally tolerated dose for patients with normal platelet counts and 65 cGy for patients with platelet counts between 100 and 150,000/ml. Hemato-logic nadirs typically occurred six to eight weeks after treatment, though patients experienced a few other toxicities associated with this therapy in contrast to what one would expect with traditional chemotherapeutic approaches. Finally, though response was a secondary endpoint 22 of the 28 patients achieved objective responses. Since these initial studies, numerous phase II trials have been carried out both by the University of Michigan group as well as other sites evaluating the efficacy of nonablative I-131 tositumomab in a variety of clinical settings of patients with indolent B-cell lymphomas that has continued to demonstrate clinical activity and safety.

Another approach to nonablative anti-CD20 RIT utilizing Y-90 has also been investigated. Instead of a patient-specific cGy approach, most of these studies were carried out utilizing a mCi/kg dose escalation schema. Patients were first pretreated with the chimeric anti-CD20 antibody rituximab to optimize the biodistribution. Patients then received ibritumomab tiuxetan trace-labeled with 111In. Serial whole-body gamma camera images were then taken to ensure that aberrant biodistribution did not occur. Approximately one week later, patients were then treated with the therapeutic dose of rituximab followed by the therapeutic dose of Y-90-labeled ibritumomab tiuxietan. Patients were initially treated at 0.2 mCi/kg of Y-90 (11). The maximally tolerated doses was determined based on hematological toxicity and was found to be 0.4 mCi/kg in patients with platelet counts above 150,000 and normal white blood counts and 0.3 mCi/kg in patients with platelet counts of 100,000 to

149,000/mL. As with the I-131 tositumomab therapy, the nonhematologic toxicities were minimal with the exception of infusion-related toxicities primarily associated with the infusion of the chimeric anti-CD20 antibody rituximab. Responses were seen in 67% of the treated patients, the majority of which had indolent lymphoma. Selected trials evaluating nonmyeloablative RIT are summarized in Table 3.

Both the I-131 and Y-90 investigators have also shown that the addition of the radionuclide improves response rates over the radiolabeled antibody alone for patients with relapsed indolent lymphomas. These were demonstrated in two separate randomized phases III trials. In the first trial, I-131 tositumomab was compared with tositumomab alone. Patients receiving I-131 tositumomab had complete and overall response rates of 33% and 55%, respectively, as compared with patients receiving unlabeled tositumomab who had complete and overall response rates of 8% and 19%, respectively (P = 0.002). Similarly, a randomized trial was carried out comparing Y-90 ibritumomab tiuxetan-based RIT at the 0.4 mCi/kg dose with unlabeled rituximab at 375 mg/m2 four times a week. The overall response rate in the Y-90 group was 80% as compared with 56% for the rituximab group (P = 0.002). The duration of responses however was nonstatistically significantly different, though this study was not powered to show differences in response duration. Nevertheless, these studies do confirm the principle that the addition of a radioisotope can improve the response rates as compared with unlabeled CD-20 antibodies.

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