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Overall Response Rate in Lymphoma Patients Unaffected By Addition of Rituximab
The study was designed with two distinct randomizations: the first, called the induction phase, randomized patients to receive either six-to-eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy alone, or CHOP in combination with four-to-five doses of Rituxan. Patients who responded to Rituxan plus CHOP or CHOP alone in the induction phase were then randomized for a second time to receive either Rituxan maintenance therapy (four doses of Rituxan weekly, every six months for two years) or no further therapy (observation).
For the analysis of the primary endpoint of the induction phase of the study -- time to treatment failure (TTF) -- the authors reported that patients who received Rituxan plus CHOP chemotherapy demonstrated a significant prolongation in TTF, as compared to patients receiving CHOP alone.
The addition of Rituxan to CHOP did not influence the overall response rate (ORR) in the induction phase. Complete and partial response information was not included in the abstract. Additionally, the authors concluded that -- at this time -- no statistically significant differences in overall survival (OS) were observed.
With regard to the primary endpoint for the maintenance phase of the study, patients treated with maintenance Rituxan for up to an additional two years had a significant prolongation in TTF, compared to patients who did not receive further treatment. This advantage appeared limited to patients who received CHOP alone during the induction phase of the study.
The abstract did not include safety information from the E4494 study. Updated results are scheduled for presentation in a plenary session at this year's ASH meeting on Sunday, December 7, 2003.
"While we are encouraged by the preliminary data on time to treatment failure in the induction arm of the study, we believe that the maintenance information is currently immature and require more clinical events in patients to be available for analysis to further understand the results," said Susan Desmond-Hellmann, M.D., MPH, Genentech's executive vice president, Development and Product Operations, and chief medical officer.
About the Phase III Study
Patients enrolled in the E4494 study had Stage I-IV diffuse large B-cell lymphoma, or primary mediastinal B-cell lymphoma. Patients were required to be at least 60 years old with measurable disease, no prior therapy and a performance status (PS) of 0-3.
Approximately 632 patients were randomly assigned to one of two treatment groups:
Arm A received CHOP plus Rituxan every 21 days for six-to-eight cycles. Two doses of Rituxan were given before the first cycle of CHOP and prior to cycles three and five. For patients who received eight cycles of CHOP chemotherapy, an additional dose of Rituxan was given prior to cycle seven.
Arm B received CHOP every 21 days for six-to-eight cycles. Patients with complete or partial responses were then randomized to one of two groups: Maintenance arm 1 received maintenance doses of Rituxan for four consecutive weeks every six months for two years beginning three weeks after their last CHOP chemotherapy dose.
Maintenance arm 2 served as the observation group as patients did not receive Rituxan maintenance therapy and were observed.
Additional Rituxan Studies to be Presented at ASH
In addition to the ECOG 4494 study, initial results from a randomized Phase III study evaluating Rituxan in combination with cyclophosphophamide, vincristine, and prednisolone (CVP) chemotherapy compared to CVP alone as a front-line therapy in patients with indolent lymphoma will be presented. The study met its primary endpoint of prolonging time to treatment failure in patients receiving Rituxan/CVP as compared to patients receiving CVP alone. Dr. Robert Marcus of Addenbrookes Hospital, Cambridge is scheduled to discuss these data at ASH in an oral presentation on Sunday, December 7, 2003.
Numerous other studies will be presented at ASH providing new and updated data on Rituxan in various disease settings, including:
Initial results from a randomized, Phase III study conducted by the German Low Grade Lymphoma Group Study (GSLG) in patients with follicular and mantle cell lymphoma;
Eight-year follow-up data on a Phase II study of Rituxan and CHOP in patients with indolent lymphoma;
Initial results from a randomized, Phase II study evaluating maintenance and retreatment with Rituxan in patients with indolent NHL; and Data from a retrospective study investigating the use of Rituxan in addition to fludarabine in previously-untreated chronic lymphocytic leukemia (CLL).
Rituxan Safety Profile
The majority of patients experience infusion-related symptoms with their first Rituxan infusion. These symptoms include but are not limited to, flu-like fever, chills/rigors, nausea, urticaria, headache, bronchospasm, angioedema and hypotension. These symptoms vary in severity and generally are reversible with medical intervention. In rare instances, severe and fatal infusion-related reactions have occurred, nearly all of which have been associated with the first Rituxan infusion. These events appear as manifestations of an infusion-related complex and include hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock and tumor lysis syndrome. Patients who develop clinically significant infusion-related cardiopulmonary events should have their Rituxan infusion discontinued and receive medical treatment.
In rare instances, severe mucocutaneous skin reactions have occurred that may be associated with Rituxan therapy. Many of these reactions have been described as paraneoplastic pemphigus and are known to be associated with various B-cell lymphomas, particularly NHL and CLL. Patients who develop a severe mucocutaneous skin reaction should have Rituxan discontinued and receive appropriate medical treatment including a skin biopsy to guide therapy.
Rituxan is a therapeutic antibody that binds to a particular protein – the CD20 antigen – on the surface of normal and malignant B-cells. It then recruits the body's natural defenses to attack and kill the marked B-cells. Stem cells (B-cell progenitors) in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.
Rituxan is indicated as a single-agent treatment for relapsed or refractory low-grade or follicular, CD20 positive, B-cell NHL. Rituxan, referred to as MabThera outside the United States, in combination with CHOP chemotherapy, received European approval to treat aggressive NHL in March 2002. More than 300,000 patients have been treated with Rituxan worldwide.
The Eastern Cooperative Oncology Group (ECOG) was established in 1955 as one of the first cooperative groups launched to perform multi-center cancer clinical trials. A cooperative group is a large network of researchers, physicians, and health care professionals at public and private institutions across the country who are members of the group. Funded primarily by the National Cancer Institute (NCI), ECOG has evolved from a five member consortium of institutions on the East Coast to one of the largest clinical cancer research organizations in the United States with almost 6000 physicians, nurses, pharmacists, statisticians, and clinical research associates (CRAs) from the United States, Canada, and South Africa.