LOS ANGELES--A second-generation topo-isomerase I inhibitor, RFS 2000, has led to significantly improved survival in patients with advanced pancreatic carcinoma, according to interim results of an ongoing phase II study presented at an ASCO poster session.
The study has enrolled 105 patients, but only those who received two or more courses of treatment were considered evaluable for efficacy (61 patients). "This is because preclinical research has shown that prolonged and continuous exposure to the drug is necessary to obtain a response," said John Stehlin, Jr., MD, of the Stehlin Foundation for Cancer Research at St. Joseph Hospital, Houston. "In order to fairly evaluate the efficacy of the drug in a clinical setting, we feel patients must receive a minimum of two courses (8 weeks)," he said.
The agent was given orally at a dose of 1 to 1.5 mg/m²/day for 5 consecutive days, followed by 2 days rest, for four cycles. Almost one-quarter of patients had stage IV disease (73%), and 47% had received prior treatment--radiotherapy or chemotherapy, usually with fluorouracil(Drug information on fluorouracil) or gemcitabine(Drug information on gemcitabine) (Gemzar). Of the evaluable patients, 45 had metastatic disease and 29 had failed conventional treatment.
Responses were evaluated by improvement in CT scan, the CA19-9 tumor marker, and clinical symptomatology (pain and general well-being). Using these criteria, 33% of patients were responders, with 30% having stable disease.
Dr. Stehlin said that responses correlated with improved Kaplan-Meier median survival, which was 16.2 months in responders, 9.7 months in those with stable disease, and 5.9 months for nonre-sponders. Median survival for the evaluable patients is 8.7 months, with 31% still alive at the time of the ASCO presentation.
There were no deaths attributable to RFS 2000. WHO grade 3/4 toxicities for the agent (reported for all 105 patients) were as follows: anemia, 20%; leu-kopenia, 13%; thrombocytopenia, 8%; nausea/vomiting, 17%; diarrhea, 6%; and cystitis, 0%. Grade 1 cystitis occurred in 8% of patients and grade 2 in 16%.
These toxicities were generally not clinically significant, Dr. Stehlin said, and all were reversible following either temporary discontinuation of the drug (during the two "rest" days) or a reduction in dosage. "We conclude that RFS 2000 shows promising activity against pancreatic adenocarcinoma at well-tolerated doses," Dr. Stehlin said.
No Other Options
The agent, a synthesized camptothe-cin known chemically as 9-nitro-20(S)-camptothecin-9N, is under development by SuperGen, San Ramon, California.
"The unmet medical need in pancreatic cancer is profound," said Dr. Joseph Rubinfeld, chief executive officer of SuperGen. "It is our responsibility to rapidly expand these human trials into additional sites and get data to the FDA with the greatest possible sense of urgency."
Dr. Rubinfeld said that the 16-month survival in responders is the longest reported in advanced pancreatic cancer patients. Because of these strong survival data and the fact that pancreatic cancer patients do not have other options, he said that phase II trials at other centers would be continued.
SuperGen will be meeting with the FDA, Dr. Rubinfeld said, to discuss proceeding with an expanded multisite phase III trial and possible fast-track approval of the agent.