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STUDIES SHOW ADDITIONAL PROMISE FOR NON-HODGKIN'S LYMPHOMA DRUG
Results Presented at The American Society of Clinical Oncology
BUFFALO, NY -- Preliminary results of a pilot and a Phase II study using Rituximab to treat non-Hodgkin's lymphoma (NHL) were presented at the American Society of Clinical Oncology (ASCO) meeting in Atlanta, GA. These studies show Rituximab to be effective when combined with Fludarabine (a chemotherapy) and when used alone dosed in an extended eight-infusion regimen. Both trials were conducted at Roswell Park Cancer Institute (RPCI) and other cancer centers.
Rituximab, marketed by Genentech, Inc. and by IDEC Pharmaceuticals as Rituxan, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of low-grade or follicular CD20-positive B-cell NHL in November 1997.
Non-Hodgkin's lymphoma is one of two cancers still on the rise and is the fifth leading cause of death from cancer in the United States. Data from ongoing studies is important to determine the optimal clinical utility of Rituximab in such areas as dosing and combination with chemotherapy.
Pilot Study of Rituximab in Combination with Fludarabine (Poster #61) In the completed pivotal trial, Rituximab, when used alone to treat relapsed or refractory, low-grade B-cell NHL patients, showed a 48% response rate using stringent response criteria. Fludarabine chemotherapy has proven antitumor activity as a single agent and in combination chemotherapy of CLL and low-grade B-cell NHL.
The rationale for the Rituximab plus Fludarabine (R&F) study includes: single agent efficacy against B-cells, non-cross-resistant mechanisms of action, no apparent overlapping toxicity, and in vitro studies suggesting additive/synergistic antitumor activity between Fludarabine and anti-CD 20 antibody.
Eighteen of the 40 patients planned have been enrolled to the R & F study at RPCI. Of the first 10 patients treated: seven have completed all therapy (6 complete remissions and 1 partial remission); 3 patients were taken off late in the study due to toxicity (hematologic, n=2; pulmonary, n=1). The last 8 patients are currently on therapy. No serious or opportunistic infections have been observed and mean quantitative immunoglobulin levels and natural killer cells are preserved. Non-hematologic toxicities have been minor. The study has been amended to allow the dose of Fludarabine to be reduced in cases of prolonged cytopenia. Combination chemoimmunotherapy of R & F appears to have significant antitumor activity in patients with low-grade B-cell NHL and study accrual to 40 patients will continue as planned.
Earlier as in vitro studies demonstrated the potential synergy of Rituximab with various chemotherapy agents and gave a scientific rationale for combination antibody plus drug trials.
"One of the main reasons we are interested in evaluating Rituximab in combination with Fludarabine is because of the compelling progression-free survival results we saw when evaluating Rituximab in combination with CHOP chemotherapy," says Myron Czuczman, MD, Administrative Director of the Lymphoma Service at RPCI and lead investigator on the study. "Rituximab in combination with CHOP represents one of the longest progression-free survival results of any NHL therapy to date with 28 of 38 evaluable (74%) patients still in remission with ongoing median duration of response being 39.1+ months." (Interim results of the Rituximab plus CHOP study were published in the Journal of Clinical Oncology, Jan. 1999).
New Rituximab Weekly Times Eight Dosing Regimen (Poster # 49) - Rituximab was studied in a new dosing regimen to evaluate whether higher cumulative doses and a prolonged course of Rituxan can increase clinical efficacy. This study was undertaken because of a statistically significant association between higher serum levels of Rituximab and patient response to therapy, as determined from the earlier pivotal Rituximab study.
This multi-institutional Phase II trial included 37 patients with relapsed low-grade follicular NHL treated with Rituximab over an eight-week period instead of the approved indication of four weekly infusions over a 22-day period. Evaluation of patients with the new dosing regimen revealed an overall response rate (ORR) of 57 percent (compared to 48 percent in the original dosing regimen) with median duration of response and median time to disease progression not yet reached at 13.4+ months and 19.4+ months, respectively.
This study suggests that dosing of Rituximab over a longer period of time may be associated with higher response rates and longer duration of response. Detailed results of the study will be published in the June 10th issue of the Annals of Oncology.
Adverse events were consistent with those previously described with Rituximab and included an infusion related syndrome of fever, chills, and less frequently nausea, tumor-related pain, a sensation of tongue or throat swelling, mild hypotension and/or bronchospasm. These events occurred with the first infusion and usually resolved in less than one to two hours. There was no incidence of HACA, an antibody response by the patient's immune system that may inhibit effectiveness of future antibody therapy.
"As a relatively new agent in a disease that has not had a new therapy in 11 years, Rituximab has already demonstrated potential as a highly flexible and durable therapy," says Dr. Czuczman. "We and many others world-wide continue to study the utility of Rituximab as part of numerous treatment protocols and are encouraged by the results presented at ASCO that show evidence of efficacy of Rituximab in combination with different chemotherapies and with different dosing regimens."
There are approximately 260,000 patients in the United States with B-cell non-Hodgkin's lymphomas, which are malignancies of the body's anitbody-producing immune system cells.
Roswell Park Cancer Institute, founded in 1898, is the nation's first and one of its largest cancer research, treatment and education centers, and is the only National Cancer Institute-designated comprehensive cancer center in Western New York.
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