ORLANDO--Final results of a phase III trial show that monotherapy with IDEC-C2B8, a new chimeric monoclonal antibody being developed by IDEC Pharmaceuticals and Genentech, pro-duces favorable response rates in patients with relapsed low-grade or follicular non-Hodgkin's lymphoma (NHL).
ORLANDO--Final results of a phase III trial show that monotherapy withIDEC-C2B8, a new chimeric monoclonal antibody being developed by IDEC Pharmaceuticalsand Genentech, pro-duces favorable response rates in patients with relapsedlow-grade or follicular non-Hodgkin's lymphoma (NHL).
The results were reported by Peter McLaughlin, MD, of M.D. AndersonCancer Center, Myron Czuczman, MD, of Roswell Park Cancer Institute, andtheir colleagues, in two poster presentations at the 38th Annual Meetingof the American Society of Hematology (ASH).
Another phase II study presented at the ASH meeting demonstrates thatthe addition of IDEC-C2B8 to CHOP (cyclophosphamide, doxorubicin, Oncovin,and prednisone) chemotherapy is at least as effective as CHOP alone inpatients with newly diagnosed or relapsed low-grade or follicular lymphoma,and produces no significant additional toxicity.
In addition, Dr. Czuczman said, the combination appears to clear minimalresidual disease in blood and marrow, which has not been demonstrated byCHOP chemotherapy alone.
Phase III Trial Results
The phase III, open-label trial involved 166 patients with relapsedlow-grade or follicular lymphoma who were treated with single-agent IDEC-C2B8(375 mg/m² weekly for four infusions) on an outpatient basis at 30medical centers in the United States and Canada.
Half of the evaluable patients (76/151) responded to the MoAb. Of the76 responses, nine (6%) were complete and 67 (44%) were partial. Thesepatients had either proved unresponsive to previous treatment or had experiencedup to four relapses after prior therapy, including autologous bone marrowtransplantation (BMT), Dr. Czuczman told Oncology News International inan interview.
At a median follow-up of more than 9 months after IDEC-C2B8 therapy,the median time to progression has not yet been reached, and 70% of theresponding patients are still in remission, he said.
The most common side effects of the MoAb were mild, reversible flu-likesymptoms (fever, chills, nausea, and headache). These adverse effects occurredprimarily during the first infusion and decreased markedly in frequencyduring subsequent infusions.
The chimeric antibody, which binds a mouse component to a human IgG1backbone, showed low immunogenicity, Dr. Czuczman said. Only 1 of 166 patientshad a "clinically insignificant" elevation of human antichimericantibody (HACA). "Because patients don't mount a HACA response, theycould potentially be re-treated with the antibody," he said.
Unlike most MoAbs, IDEC-C2B8 has therapeutic activity in its own rightand does not have to be attached to a radioisotope or toxin to producean antitumor effect, Dr. Myron Czuczman told Oncology News Internationalat the ASH meeting (see article above).
IDEC-C2B8 binds selectively to the CD20 antigen, a protein found onthe surface of mature normal and malignant B-cells but not on B-cell precursorsor other cells in the body.
Once bound to the CD20 antigen, the MoAb activates both circulatingcomplement and antibody dependent cellular cytotoxicity.
This antibody may have other properties in addition to its immune responseactivity, Dr. Czuczman said. Research conducted by Dr. David Maloney, ofFred Hutchinson Cancer Center, and presented at ASH showed that the antibodyalso induces apoptosis and has antiproliferative effects in vitro.
Clearance of Tumor Marker
The presence of bcl-2, considered to be a marker of minimal residualdisease, in the peripheral blood and bone marrow was assessed by polymerasechain reaction (PCR) before and after single-agent IDEC-C2B8 therapy.
More than 70% of patients whose peripheral blood was positive for bcl-2at baseline became negative after therapy. Similarly, more than 50% ofpatients whose bone marrow was positive for bcl-2 at baseline revertedto negative.
Dr. Czuczman noted that IDEC-C2B8 therapy cleared the peripheral bloodand bone marrow of bcl-2 not only in responding patients but also in somepatients who did not exhibit a "nodal" response. This raisesthe possibility that the MoAb "could accomplish in vivo purging oflymphoma cells in those compartments," he said. "It would allowyou to collect and store bcl-2-negative blood or marrow, which could potentiallybe used in the future for transplantation."
IDEC-C2B8, CHOP Combination
Dr. Czuczman and his colleagues also studied IDEC-C2B8 in combinationwith CHOP chemotherapy in 38 patients with low-grade or follicular lymphoma,most of whom were previously untreated. In this phase II open-label trial,patients received six doses of 375 mg/m² of IDEC-C2B8 intravenouslyplus standard doses of CHOP every 3 weeks for six cycles.
"The overall response rate with combination therapy was at leastas good as has been described with CHOP alone," Dr. Czuczman said.Approximately 60% of patients experienced a complete response, and 37%had a partial response.
Researchers at Roswell Park also conducted PCR testing before and aftertherapy in 20 patients. In seven of the eight patients who were bcl-2 positiveat baseline, the tumor marker was no longer present in peripheral bloodand/or bone marrow after therapy with the combination regimen.
"The conversion of the baseline bcl-2 to PCR-negativity in theblood and marrow suggests clearing of residual disease, not previouslydemonstrated with CHOP chemotherapy alone," Dr. Czuczman said.
The overall toxicity profile of the MoAb-CHOP combination was similarto that of CHOP alone. Most of the toxic effects consisted of grade 1 or2 reactions, Dr. Czuczman said. The overall incidence of grade 3 or 4 toxicitywas approximately 17%, he added, and these adverse events were felt tobe associated primarily with CHOP chemotherapy. No HACA reactions wereobserved.