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Antonio J. Grillo-López
IDEC Pharmaceuticals
Corporation
San Diego, CA
Development of the Anti-CD20 Antibody, Rituxan™, for the Treatment of Low-grade or Follicular Non-Hodgkin’s Lymphoma
Rituxan (rituxumab, IDEC-C2B8) was discovered in 1990 and developed through Phase III (PIII) clinical trials (1993-1996) by IDEC Pharmaceuticals. The Biologics License Application was submitted to the US FDA (and simultaneously in Europe) in February 1997. The Biological Response Modifiers Advisory Committee recommended approval in July 1997. Marketing approval was granted by the FDA in November 1997 for the indication of relapsed or refractory, CD20 positive, B-cell, low-grade or follicular non-Hodgkin’s lymphoma (LG/F NHL). Rituxan is the first monoclonal antibody approved for the treatment of cancer and the first single agent approved specifically for therapy of lymphoma.
The chimeric (IgG1 kappa) monoclonal antibody has mouse variable and human constant regions that recognize the CD20 antigen expressed on normal and malignant B lymphocytes. The antigen, important in cell cycle initiation and differentiation, is expressed strongly on more than 90% of B cell lymphomas. Rituxan shows specificity for CD20 and binds with an apparent affinity of 5.2 x 10-9M. In vitro mechanism of action studies have demonstrated that this antibody effects CDC and ADCC. Further studies have demonstrated that Rituxan induces tyrosine phosphorylation, inhibits proliferation, induces apoptosis, and sensitizes drug resistant human lymphoma cell lines to the cytotoxic effects of ricin, VP-16, and CDDP.
An overall (CR+PR) response rate (RR) of 50% (17/34) with a median TTP in responders of 10.2 months (mo) was reported in a PII trial in patients with relapsed LG/F NHL [Maloney, et al. Blood, 1997; JCO, 1997]. In a single-agent, multicenter, clinical trial (PIII) in a total of 166 pts with relapsed LG/F NHL (IWF classes A, B, C, D) treated with Rituxan at 375 mg/m2 weekly for 4 infusions, the overall response rate (ORR) was 48% (6% CR and 42% PR). Evaluable pts (151/166) had an ORR of 50% (6% CR and 44% PR). Responses (CT scans) were confirmed (blinded audit) by an independent panel of lymphoma experts (LEXCOR panel) using established response criteria. Median time to progression for responders has not been reached (12+ mo. median follow-up). The ORR in pts resistant to first, last, or all chemotherapy were 43%, 34%, and 32% respectively. In 23 pts relapsed after ABMT, the ORR was 78%. Five single-agent trials were analyzed for safety. The majority of adverse events (AEs) were infusion-related and occurred within the first few hours of the infusion, particularly during the first infusion. The most common events included chills, fever, nausea, fatigue, headache, pruritus, asthenia, and a sensation of tongue and throat swelling. Less frequent occurrences included vomiting, bronchospasm/asthma, mild hypotension, rhinitis, rash, urticaria, flushing, tumor-related pain, and exacerbation of pre-existing cardiac conditions (arrhythmia, angina). The median duration of infusion-related events in hours was 0.63 (angioedema), 1.5 (arrhythmia), 0.42 (bronchospasm), 0.5 (chills), 2.8 (fever), 1.5 (headache), 1.6 (hypotension), and 0.75 (nausea). During the treatment period, 23% of pts experienced Grade 3 or 4 AEs. The most frequent were infusion-related or hematologic. Grade 3 and 4 chills and leukopenia were reported in 2.1% (6 of 282) of pts, neutropenia and thrombocytopenia in 1.8% (5 of 282) of pts, and anemia and bronchospasm in 1.4% (4 of 282) of pts. The remaining Grade 3 and Grade 4 events occurred in £ 1.1% of pts. Analysis of integrated safety data was performed to evaluate risk related to B cell depletion. Of 282 pts from 5 single-agent trials, 217 received 375 mg/m2/IVqwkx4. Median circulating B-lymphocyte counts dropped to zero following the 1st dose of Rituxan; CD3, CD4, CD8, and NK cells remained unchanged. Median B cell recovery began at 9 mo and was complete by 12 mo. Mean IgG and IgA levels remained normal. Mean IgM dropped transiently. 12% of pts had >50% drop in either IgG, IgA or IgM. Pts with low immunoglobulins were no more likely to develop infection. Only 2% of pts required hospitalization for infections during treatment and 2% during the one-year follow up period. Rituxan is well tolerated and does not impair marrow reserves. Thus, subsequent chemotherapy is not precluded. Outpatient therapy is feasible and is completed within 22 days (days 1, 8, 15, and 22). AEs are mostly grades 1 and 2 and occur primarily with the first infusion. Rituxan is safe and effective in the treatment of pts with relapsed or refractory, CD20 positive, B cell, low grade or follicular NHL.