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).
The results were reported by Peter McLaughlin, MD, of M.D. Anderson Cancer Center, Myron Czuczman, MD, of Roswell Park Cancer Institute, and their colleagues, in two poster presentations at the 38th Annual Meeting of the American Society of Hematology (ASH).
Another phase II study presented at the ASH meeting demonstrates that the addition of IDEC-C2B8 to CHOP (cyclophosphamide, doxorubicin(Drug information on doxorubicin), Oncovin, and prednisone(Drug information on prednisone)) chemotherapy is at least as effective as CHOP alone in patients 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 minimal residual disease in blood and marrow, which has not been demonstrated by CHOP chemotherapy alone.
Phase III Trial Results
The phase III, open-label trial involved 166 patients with relapsed low-grade or follicular lymphoma who were treated with single-agent IDEC-C2B8 (375 mg/m² weekly for four infusions) on an outpatient basis at 30 medical centers in the United States and Canada.
Half of the evaluable patients (76/151) responded to the MoAb. Of the 76 responses, nine (6%) were complete and 67 (44%) were partial. These patients had either proved unresponsive to previous treatment or had experienced up to four relapses after prior therapy, including autologous bone marrow transplantation (BMT), Dr. Czuczman told Oncology News International in an 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 the responding patients are still in remission, he said.
The most common side effects of the MoAb were mild, reversible flu-like symptoms (fever, chills, nausea, and headache). These adverse effects occurred primarily during the first infusion and decreased markedly in frequency during subsequent infusions.
The chimeric antibody, which binds a mouse component to a human IgG1 backbone, showed low immunogenicity, Dr. Czuczman said. Only 1 of 166 patients had a "clinically insignificant" elevation of human antichimeric antibody (HACA). "Because patients don't mount a HACA response, they could potentially be re-treated with the antibody," he said.
MoAb Has Multiple Mechanisms of Action
Unlike most MoAbs, IDEC-C2B8 has therapeutic activity in its own right and does not have to be attached to a radioisotope or toxin to produce an antitumor effect, Dr. Myron Czuczman told Oncology News International at the ASH meeting (see article above).
IDEC-C2B8 binds selectively to the CD20 antigen, a protein found on the surface of mature normal and malignant B-cells but not on B-cell precursors or other cells in the body.
Once bound to the CD20 antigen, the MoAb activates both circulating complement and antibody dependent cellular cytotoxicity.
This antibody may have other properties in addition to its immune response activity, Dr. Czuczman said. Research conducted by Dr. David Maloney, of Fred Hutchinson Cancer Center, and presented at ASH showed that the antibody also induces apoptosis and has antiproliferative effects in vitro.
Clearance of Tumor Marker
The presence of bcl-2, considered to be a marker of minimal residual disease, in the peripheral blood and bone marrow was assessed by polymerase chain reaction (PCR) before and after single-agent IDEC-C2B8 therapy.
More than 70% of patients whose peripheral blood was positive for bcl-2 at baseline became negative after therapy. Similarly, more than 50% of patients whose bone marrow was positive for bcl-2 at baseline reverted to negative.
Dr. Czuczman noted that IDEC-C2B8 therapy cleared the peripheral blood and bone marrow of bcl-2 not only in responding patients but also in some patients who did not exhibit a "nodal" response. This raises the possibility that the MoAb "could accomplish in vivo purging of lymphoma cells in those compartments," he said. "It would allow you to collect and store bcl-2-negative blood or marrow, which could potentially be used in the future for transplantation."
IDEC-C2B8, CHOP Combination
Dr. Czuczman and his colleagues also studied IDEC-C2B8 in combination with 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 intravenously plus standard doses of CHOP every 3 weeks for six cycles.
"The overall response rate with combination therapy was at least as 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 after therapy in 20 patients. In seven of the eight patients who were bcl-2 positive at baseline, the tumor marker was no longer present in peripheral blood and/or bone marrow after therapy with the combination regimen.
"The conversion of the baseline bcl-2 to PCR-negativity in the blood and marrow suggests clearing of residual disease, not previously demonstrated with CHOP chemotherapy alone," Dr. Czuczman said.
The overall toxicity profile of the MoAb-CHOP combination was similar to that of CHOP alone. Most of the toxic effects consisted of grade 1 or 2 reactions, Dr. Czuczman said. The overall incidence of grade 3 or 4 toxicity was approximately 17%, he added, and these adverse events were felt to be associated primarily with CHOP chemotherapy. No HACA reactions were observed.