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At least 109 records · Page 6Linked to original sources
PubMed2000

Optimizing the use of rituximab for treatment of B-cell non-Hodgkin's lymphoma: a benefit-risk update.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA), the first monoclonal antibody approved in the United States for the treatment of cancer, is indicated for the treatment of patients with relapsed or refractory CD20+ low-grade non-Hodgkin's lymphoma. From November 1997 through May 1999, approximately 36,000 patients have been treated with rituximab. Serious cardiopulmonary infusion reactions culminating in death have been reported to occur in approximately 0.04% to 0.07% of patients. Post-approval tumor lysis syndrome has been reported within 12 to 24 hours after the first antibody infusion and is estimated to occur in 0.04% to 0.05% of patients. The risk of tumor lysis appears to be higher in patients with high numbers of circulating malignant cells. Serious infusion-related adverse drug reactions, most often consisting of cardiopulmonary reactions associated with the rapid lysis of large numbers of circulating malignant cells, have been fatal in approximately 0.5 per 1,000 treated patients. Major risk factors include high numbers of circulating malignant lymphoma cells, pulmonary infiltrates or lymphoma involvement, and prior cardiovascular disease. This report updates the safety experience of rituximab therapy with data from clinical trials and postmarketing safety experience, and examines how this information can be used to optimize therapy.

Antibodies, Monoclonal↗
PubMed2000

The use of ibritumomab tiuxetan radioimmunotherapy for patients with relapsed B-cell non-Hodgkin's lymphoma.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is a monoclonal antibody that targets the CD20 antigen present in most B-cell non-Hodgkin's lymphomas. Previous studies have shown overall response rates (ORR) of approximately 50% in relapsed patients. Ibritumomab is the murine parent anti-CD20 antibody that is linked through a MX-DTPA chelator to yttrium 90 (90Y) to form the radioimmunoconjugate 90Y-ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals, San Diego, CA). A phase I study of 90Y-ibritumomab tiuxetan determined that 0.4 mCi/kg was the maximum tolerated dose, and responses were reported in 67% of all patients and in 82% of patients with low-grade non-Hodgkin's lymphoma. A separate trial randomized eligible patients to either rituximab or 90Y-ibritumomab tiuxetan. An interim analysis of the first 90 patients showed an ORR of 80% with 90Y-ibritumomab tiuxetan versus 44% with rituximab (P < .05). A subsequent trial for patients with rituximab-refractory disease showed a 46% ORR. These studies show that 90Y-ibritumomab tiuxetan is an active agent in relapsed non-Hodgkin's lymphoma and appears to have a higher ORR compared with unconjugated rituximab.

Antibodies, Monoclonal↗
PubMed2000

The use of rituximab in the treatment of malignant and nonmalignant plasma cell disorders.

CD20 is a B-cell-restricted antigen that, for the most part, is expressed from the pre-B-cell to the mature B-cell stage of B-cell differentiation. Several transcription factors regulate CD20 expression during B-cell differentiation, the most important of which appear to be PU.1 and Pip (PU.1 interacting protein). As B cells differentiate to plasma cells, CD20 expression is down-regulated, which coincides with PU.1 downregulation in plasma cells. Analogous to their normal B-cell counterparts, CD20 is expressed on malignant lymphoplasmacytic cells from most patients with Waldenstrom's macroglobulinemia and on malignant plasma cells from a fraction (20%) of multiple myeloma patients. CD20 also is expressed on subpopulations of normal donor plasma cells, which may include autoantibody-secreting plasmacytes. In view of these findings, the anti-CD20 chimeric monoclonal antibody, rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA), has been evaluated in the treatment of Waldenstrom's macroglobulinemia and multiple myeloma, as well as in nonmalignant plasma cell disorders including IgM polyneuropathies, immune thrombocytopenias, and autoimmune hemolytic anemias, with reported activity in these entities. An update of these clinical efforts is presented in this report.

Antibodies, Monoclonal↗
PubMed2000

High-dose rituximab therapy in chronic lymphocytic leukemia.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is a chimeric monoclonal antibody that targets mature B cells in most lymphoid B-cell malignancies. Rituximab is approved by the US Food and Drug Administration for therapy for recurrent B-cell lymphoma. In initial clinical trials the activity in small lymphocytic lymphoma, the counterpart of chronic lymphocytic leukemia (CLL), was less than 20%. In an attempt to increase the level of rituximab activity in CLL, we conducted a phase I dose-escalation study to overcome both the lower CD20 antigen density on CLL cells compared with lymphoma cells and the shorter half-life of rituximab in small lymphocytic lymphoma. Cohorts of patients were treated with escalated doses on weeks 2, 3, and 4 after an initial rituximab dose of 375 mg/m2 on day 1. The maximum dose of rituximab evaluated was 2,250 mg/m2. There is clear evidence of a dose-response relationship. Severe toxicity (grades 3 and 4) noted following the first dose of therapy in variant forms of CLL, namely mantle cell lymphoma and prolymphocytic leukemia, was uncommon in typical CLL. No unusual toxicity was noted at higher doses. Further exploration of the dosing schedule of rituximab in CLL and development of combination therapies is necessary. This agent shows promise for interaction in combined chemoimmunotherapy strategies for front-line and relapsed patients with CLL.

Aged↗
PubMed2000

Overview of idiopathic thrombocytopenic purpura: new approach to refractory patients.

Idiopathic thrombocytopenic purpura is a disorder in which autoantibodies are made to platelets, resulting in accelerated platelet destruction. The diagnosis may be made in outpatients who are previously well or in patients with multiple medical conditions and medications. There are no unequivocal ways to distinguish immune thrombocytopenias from other thrombocytopenias, even with state-of-the-art tests including anti-platelet antibodies, thrombopoietin, glycocalicin, and platelet reticulocyte counts. Clinical evaluation includes ruling out a systemic process such as a viral infection or leukemia. Treatment of idiopathic thrombocytopenic purpura should be individualized. Substantial platelet increases are seen in more than 50% of patients who receive intravenous IgG, intravenous anti-D, steroids, or splenectomy. Two additional agents showing promising clinical trial experience are anti-CD40 ligand and rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA).

Antibodies, Monoclonal↗
PubMed2000

A pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia.

We conducted a prospective pilot phase I/II clinical trial to evaluate the toxicity and response rate of the chimeric anti-CD20 monoclonal antibody, rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceutical Corporation, San Diego, CA), in the treatment of patients with immune thrombocytopenic purpura. Patients with a clinical diagnosis of idiopathic thrombocytopenic purpura who had failed corticosteroid therapy and whose platelet count was less than 75,000/microL were eligible for the study. Rituximab was administered in a dose-escalation fashion using doses ranging from 50 to 375 mg/m2 weekly for 4 weeks. Thirteen patients have been enrolled on the trial to date and 12 have completed the full course of treatment. No unusual toxicity was noted in this patient population. None of the three patients at the lowest dose level achieved a clinical response. Three of nine patients (30%) who have received rituximab at doses close or equal to the full dose have shown an objective clinical response (two complete responses, one partial response). The study is currently ongoing, and conclusions regarding the overall response rate, clinical parameters that influence response, surrogate markers of response, and the underlying mechanism of response remain to be addressed. The current study should provide answers to a number of important questions regarding the role of rituximab in the treatment of this and other autoimmune disorders.

Adult↗
PubMed2000

Trastuzumab and chemotherapeutics: drug interactions and synergies.

Previous studies have shown a synergistic interaction between trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) and the cytotoxic drug cisplatin in human breast cancer cells. To define the nature of the interaction between trastuzumab and other classes of cytotoxic drugs, we applied multiple drug effect/combination index isobologram analysis to a variety of chemotherapeutic drug/trastuzumab combinations in vitro. Synergistic interactions at clinically relevant drug concentrations were observed for trastuzumab in combination with cisplatin, docetaxel, thiotepa, 4-OH cyclophosphamide, vinorelbine, and etoposide. Additive cytotoxic effects were observed with trastuzumab plus doxorubicin, paclitaxel, methotrexate, and vinblastine. One drug, 5-fluorouracil was found to be antagonistic with trastuzumab in vitro. In vivo drug/trastuzumab studies were conducted with HER-2/neu-transfected MCF7 human breast cancer xenografts in athymic mice. Combinations of trastuzumab plus cisplatin, docetaxel, cyclophosphamide, doxorubicin, paclitaxel, methotrexate, etoposide, and vinblastine in vivo resulted in a significant reduction in xenograft volume compared to chemotherapy-alone controls (P < .05). The synergistic interaction of trastuzumab with specific chemotherapeutic agents suggests rational combinations for testing in human clinical trials.

Antibodies, Monoclonal↗
PubMed2000

Ongoing and planned adjuvant trials with trastuzumab.

HER-2 (c-erbB-2, neu) is an important prognostic and predictive factor in breast cancer. Clinical trials utilizing a humanized version of the anti-HER-2 murine monoclonal antibody 4DS, trastuzumab (Herceptin; Genentech Inc, South San Francisco, CA), have shown antitumor activity in patients with HER-2-positive metastatic breast cancer. Improved response and survival rates have been shown when trastuzumab was added to first-line combination chemotherapy with anthracycline/cyclophosphamide or paclitaxel, compared to the same chemotherapy alone. The Breast Cancer Intergroup has recently completed several trials evaluating new chemotherapy treatment approaches for patients with node-positive breast cancer, which form the basis for several ongoing and planned clinical trials incorporating trastuzumab. These clinical trials and the evolving role of trastuzumab-containing adjuvant systemic therapy for breast cancer will be reviewed.

Antibodies, Monoclonal↗
PubMed2000

Ongoing and planned trials of hormonal therapy and trastuzumab.

Studies with human breast cancer cell lines have shown a causal association between overexpression of the HER-2/neu proto-oncogene receptor and the acquisition of resistance to tamoxifen. Some clinical studies also indicate that patients with tumors showing high HER-2 levels or high levels of the circulating ectodomain of HER-2 may have a lower response to tamoxifen compared with tumors with low HER-2 levels or low circulating ectodomain. Treatment with anti-HER-2 antibodies seems to restore tamoxifen activity in some experimental systems. However, whether anti-HER-2 therapies will increase tamoxifen action and/or reverse this putative oncogene-mediated resistance in patients with estrogen receptor-positive, hormone-dependent tumors, is unclear. We are conducting a phase II trial of a humanized anti-HER-2 monoclonal antibody, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) in combination with tamoxifen in patients with estrogen receptor-positive metastatic breast cancer. Other prospective randomized clinical trials are needed to directly evaluate the contribution of HER-2 signaling to antiestrogen resistance in vivo.

Antibodies, Monoclonal↗
PubMed2000

Trastuzumab in combination with chemotherapy for the treatment of metastatic breast cancer.

Metastatic breast carcinoma still remains an incurable condition. The relentless search for novel agents that might prove useful for management has evolved toward monoclonal antibodies, in part because of a rapidly expanding understanding of breast cancer biology. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is a recombinant humanized monoclonal antibody against the HER-2 receptor that has shown antitumor activity as a single agent in phase I and II trials of patients with metastatic breast cancer overexpressing HER-2. The observation of increased antitumor activity between trastuzumab and some chemotherapeutic agents in preclinical models has prompted its use in combination with several drugs. Of particular interest is the use of trastuzumab with paclitaxel. Two trials were presented at the 1999 meeting of the American Society of Clinical Oncology that evaluated this combination. One multicenter phase III trial showed clinical benefit and increased survival for patients with HER-2-overexpressing metastatic breast cancer treated with chemotherapy plus trastuzumab. A phase II trial, reviewed in this report, evaluated the efficacy and safety of weekly paclitaxel plus trastuzumab for patients with metastatic breast carcinoma, including those overexpressing and nonoverexpressing HER-2.

Antibodies, Monoclonal↗
PubMed2000

The role of HER-2 expression in predicting response to therapy in breast cancer.

HER-2 expression may have predictive value regarding response to therapeutic interventions in breast cancer. A number of reports describe the interaction of HER-2 overexpression and tamoxifen, but data are inconclusive. Chemotherapy trials have supported an interaction between HER-2 overexpression and chemotherapy sensitivity (cyclophosphamide/methotrexate/5-fluorouracil resistance and doxorubicin sensitivity) which is compelling. More recently, HER-2 has been the target for Food and Drug Administration-approved antibody therapy, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA). The Clinical Trials Assay, a scoring system for tumor material, has been used successfully in the trastuzumab clinical development program. As many of the early studies evaluating the role of HER-2 were retrospective, controlled prospective studies are needed to best determine the value of trastuzumab in the adjuvant clinical setting.

Antibodies, Monoclonal↗
PubMed2000

HER-2/neu as a therapeutic target in non-small cell lung cancer, prostate cancer, and ovarian cancer.

HER-2/neu is overexpressed in most epithelial malignancies. Lung cancer, prostate cancer, and ovarian cancer are common epithelial tumors in which clinical trials are currently in progress to explore the potential therapeutic role for monoclonal antibodies to HER-2/neu (trastuzumab [Herceptin; Genentech, Inc, South San Francisco, CA]). In preclinical studies with tumor cell lines, trastuzumab was found to have additive and synergistic effects with some chemotherapeutic agents. Clinical trials investigating combination chemotherapy with trastuzumab and a variety of chemotherapeutic agents are already in progress in lung cancer.

Animals↗
PubMed2000

New insights into anti-HER-2 receptor monoclonal antibody research.

Abnormalities in the expression, structure, or activity of proto-oncogene products contribute to the development and maintenance of the malignant phenotype. For example, c-erbB-2 encodes the HER-2 receptor (also known as c-erbB-2 or c-neu) that is overexpressed, amplified, or both in a number of human malignancies including breast, ovarian, colon, lung, prostate, and cervical cancers. In addition to deregulation of cell-surface HER receptors, cancer cells often show excessive activation and/or nonattenuation of growth factor--inducible signaling components, as well as their downstream transcription factors. Current approaches to target HER-2 pathways include downregulation of HER-2 by the adenovirus 5E1A, antisense phosphothionate oligonucleotides, ribozyme, and targeting tyrosine kinase using specific inhibitors. Because growth factors regulate the proliferation of cancer cells by activating receptors on the surface of cells, one obvious approach to control cell proliferation is to interfere with the growth factor receptor-mediated autocrine/ paracrine growth stimulation by antireceptor-blocking monoclonal antibodies. Therefore, a large number of scientists are attempting to control the growth of cancer cells using agents that inhibit one or more of the above steps of growth factor action. Recently completed clinical trials established the usefulness of a humanized form of 4DS monoclonal antibody, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), against some forms of breast tumors overexpressing HER-2 receptors. Using in vitro models, recent studies have shown that HER-2 overexpression may not be a prerequisite for invasion of breast cancer cells, as HER-2 activation by heregulin, which binds to HER-3 or HER-4 and transphosphorylates HER in noninvasive breast cancer cells, could lead to increased motility, enhanced gelatinolytic activity, and invasion. Furthermore, these ligand-driven phenotypic changes were completely suppressed by trastuzumab, which also blocked interactions between HER-2 and HER-3 receptors in heregulin-treated breast cancer cells, and inhibited the phosphatidylinositol-3' kinase-dependent pathway, but not the mitogen-activated protein kinase pathway. These phenotypic effects of anti-HER-2 monoclonal antibody are of special interest, because they point to potential therapeutic effects of trastuzumab in inhibiting the invasion and metastasis of breast cancer with low receptor expression.

Animals↗
PubMed2000

Myocyte survival pathways and cardiomyopathy: implications for trastuzumab cardiotoxicity.

Recent clinical studies have documented the efficacy of trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) as a new biologically targeted therapy for erbB-2 receptor-positive forms of breast cancer. During the course of a large-scale clinical trial, a subset of patients reported the onset of symptoms and signs of cardiac failure that appeared to be aggravated by concomitant exposure to anthracyclines. The mechanisms responsible for this cardiac toxicity are unclear. However, new insights into the pathways that lead to other forms of heart failure have identified a pivotal role for myocyte survival pathways in preventing the onset of cardiomyopathy and associated heart failure in genetically engineered animal models of the disease. This mini-review highlights these recent findings and suggests the possibility that the loss of erbB-2 receptor-dependent myocyte survival pathways may create a susceptibility for the onset of heart failure in response to the cardiotoxicity of anthracycline treatment. The possibility exists that the divergent susceptibility for the onset of cardiotoxicity among patients who have received trastuzumab might ultimately reflect an inherent genetic susceptibility to the diverse mechanisms that initiate, promote, and suppress the complex pathways to heart failure.

Animals↗
PubMed2001

Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer.

HER2/neu amplification/overexpression confers more aggressive and malignant characteristics on breast cancer cells. Patients with HER2/neu-amplified breast cancer have a worse prognosis than those with normal HER2/neu expression. Over the past decade, the intracellular signaling pathways associated with this growth factor receptor have been elucidated. Multiple therapeutic strategies that target the HER2/neu oncoprotein are under development. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA), a humanized monoclonal antibody that binds to the extracellular domain of the HER2/neu receptor, has undergone phase I, II, and III clinical trials. These studies have shown that, as a single agent, trastuzumab has substantial and reproducible antitumor activity in HER2/neu-amplified metastatic breast cancer. In addition, when added to chemotherapy, trastuzumab improves antitumor efficacy as measured by time to progression, response rate, and survival. Additional chemotherapy/trastuzumab combinations are under active evaluation, and new schedules of administration are being tested. Thus, trastuzumab is the first successful example of molecularly targeted therapy in the management of metastatic breast cancer.

Antibodies, Monoclonal↗
PubMed2002

Rituximab: mechanism of action and resistance.

Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA)-mediated killing of CD20-positive tumor cells is likely caused by a combination of immune-mediated effects including complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity and direct effects induced by CD20 ligation. In vivo, the clearance of damaged or preapoptotic cells through specific receptors for phosphatidylserine translocated to the outer cell membrane may also be important. Direct effects, including growth inhibition and apoptosis, have been shown in vitro; however, their contribution to the clinical effect is not known. Currently, most data suggest that the predominant effector mechanism is antibody-dependent cell-mediated cytotoxicity, with a minor role of complement. With treatment, resistance to rituximab-mediated killing may emerge. Little is known regarding the molecular pathogenesis of this resistance. In rare cases, the CD20 antigen may be lost. Complement-resistance proteins may also increase, but it is not clear that this is the reason for loss of sensitivity. A better understanding of these mechanisms should allow combination therapy with agents capable of augmenting antibody-based killing.

Animals↗