NEW YORKIDEC, the developer of rituximab (Rituxan), the first
monoclonal antibody approved by the FDA for cancer therapy, is
pushing ahead with research to increase the agents
effectiveness in non-Hodgkins 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-Hodgkins 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.
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 companys 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-Hodgkins 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
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 thats 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
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.