Rituximab Research Aims to Increase Efficacy

NEW YORK—IDEC, the developer of rituximab (Rituxan), the first monoclonal antibody approved by the FDA for cancer therapy, is pushing ahead with research to increase the agent’s effectiveness in non-Hodgkin’s lymphoma.

Antonio J. Grillo-López, MD, chief medical officer and senior vice president for Medical and Regulatory Affairs at IDEC Pharmaceuticals, San Diego, outlined several of these efforts at Current Concepts in Cancer Therapy II, a scientific symposium sponsored by Long Ridge Associates. They include increased and repeated dosages and combinations with other therapeutic entities.

It has proved safe, Dr. Grillo-López reported, to double the treatment schedule used in the trials that led to FDA approval of the agent in 1997 for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. The adverse events profile with 8 weekly infusions of 375 mg/m², he said, was “very similar” to that with 4 weekly infusions.

The overall response rate of 60% in the 35 evaluable patients was higher than the 48% response rate in the earlier trial in 166 patients but was not significant because of the small study population. The median duration of response, he said, has not yet been reached more than 19.5 months into the follow-up period.

Rituximab Retreatment

Retreatment of patients who relapse after responding to rituximab proved safe in a study of a second round of therapy, Dr. Grillo-López reported. “The adverse events profile,” he said, “was the same as in the initial studies.” In all, 40% of the 57 evaluable patients responded to retreatment. “Some patients in the company’s ongoing research have been treated successfully up to four times,” he added, and some in a Stanford University study have been treated five times.

Duration of response and time to disease progression turned out to be longer after patients’ second successful treatment with rituximab. “This was a surprise to us,” Dr. Grillo-López said, but he cautioned that the observation has no statistical significance.

A 100% response rate was seen in the first study combining rituximab with another treatment modality, CHOP chemotherapy. In this study in low-grade follicular non-Hodgkin’s lymphoma, 31 of the 40 patients had received no prior therapy for their disease. The protocol combined six CHOP cycles with six rituximab infusions, two given before the start of chemotherapy, two in midcourse, and two at the end.

Complete responses were seen in 63% of the patients and partial responses in 37%. “A median duration of response has not been reached at 39.1+ months,” Dr. Grillo-López said. The median for time to progression likewise has not been reached, and observation time now exceeds 40 months, with some patients at 54.5+ months. “The combination of modalities,” he added, “actually does clear bcl2 from peripheral blood and bone marrow,” which CHOP alone does not.

The combination of rituximab and CHOP therapy is being more intensively studied in a randomized trial by the Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, and Southwest Oncology Group, with a planned enrollment of 630 patients. Half of the patients who respond will receive four infusions of rituximab every 6 months for 2 years, and the other half will simply be observed.

In another combination trial, rituxi-mab was paired with interferon alfa-2a, a biologic agent known to have some antilymphoma activity. During a 12-week course of interferon alfa-2a, rituximab was given during the middle 4 weeks. The response rate in the 38 evaluable patients was 45%.

“Frankly, this was a bit disappointing because that’s about the response rate that we had with Rituxan alone,” Dr. Grillo-López said. “Nevertheless, the duration of those responses was prolonged. In fact, we have not reached the median time to progression at 25+ months at this point.”

The response rate was markedly higher in a phase I/II study in which rituximab was administered in conjunction with radioimmunotherapy using Zevalin, formerly known as IDEC-Y2B8 (ibritu-momab tiuxetan). The overall response rate in the total group of 51 patients was 67%, and in the 34 with low-grade lymphoma, 82%. The response rate in the 14 patients with intermediate-grade lymphoma was only 43%, however, and none of the 3 patients with mantle cell lymphoma responded.

In this study, rituximab was administered before the radiolabeled antibody (Zevalin) and an indium-labeled antibody used for imaging and dosimetry. “Zevalin,” Dr. Grillo-López explained, “incorporates a murine antibody that is the parent of Rituxan (a chimeric antibody).” It is linked to yttrium-90 in a stable bond.

In the phase III trial now underway, rituximab is infused on days 1 and 7, and Zevalin is administered on day 7.

“B cell lymphomas,” Dr. Grillo-López observed, “may be especially suited for radioimmunotherapy due to the accessibility of malignant cells in the blood, bone marrow, spleen, and lymph nodes.”