New Topoisomerase-I Inhibitor Tested in Pancreatic Cancer

NEW YORK—Although no complete responses occurred in patients with advanced pancreatic cancer in a study of DX-8951F (exatecan mesylate, Daiichi Pharmaceuticals), those who were treatment-naïve survived longer than usual, and stable disease was observed in 39%, Eileen M. O’Reilly, MD, reported at the Chemotherapy Foundation Symposium XVIII.

The phase II open-label study of the topoisomerse-I inhibitor enrolled 39 patients at three centers, said Dr. O’Reilly, of the Department of Medicine, Memorial Sloan-Kettering Cancer Center. Other participating institutions were the Cancer Therapy & Research Center, San Antonio, and Johns Hopkins.

Median survival for US patients with pancreatic cancer "is less than 6 months," Dr. O’Reilly said, "and for people with bulky metastatic disease, just several months." In the 18 patients not previously treated with radiation or chemotherapy, median survival was 9.1 months.

Median survival for the entire study group of 39 patients was 5.3 months, "which is similar to that for patients who receive gemcitabine [Gemzar]," she said. Median survival for those who had prior therapy was 3.8 months. In the treatment-naïve subset, 74% of the patients were alive at 6 months.

The study was limited to patients with pancreatic cancer of epithelial origin with measurable metastatic disease outside the pancreas, Dr. O’Reilly said. "The majority of patients had liver metastases," she said, "but about 10% had exclusively peritoneal or lung metastases."

One course of prior treatment, radiation, chemotherapy, or chemoradiation, was permitted. Enrollment ended early in 1999. The median age of the group was 57 years.

Laboratory Studies

In laboratory studies, Dr. O’Reilly said, the in vitro activity of DX-8951F was about three times greater than that of the active metabolite of irinotecan (Camp-tosar) and 10 to 20 times more potent than topotecan (Hycamtin) and campto-thecan. "The rationale for looking at this drug in pancreatic cancer," she said, "relates to the fact that it has activity in irinotecan-resistant human pancreatic cell graft models."

Under the study protocol, DX-8951F was to be administered at a dose of 0.5 mg/m² for 5 days every 3 weeks. "There was an option for dose escalation for patients who had no hematologic toxicity and no nonhematologic toxicity greater than grade 1," Dr. O’Reilly said. Dose attenuation to 0.4 mg/m² was made for any toxicity greater than grade 3.

The median number of treatment cycles was three, Dr. O’Reilly reported, with 87% of the patients receiving two or more cycles. The highest number of cycles per patient was 20. Dose escalation was possible in only one patient, while attenuation was needed in 26%. Two patients continue on the DX-8951F regimen.

Clinical Responses

Tumor assessments were performed every 6 weeks, Dr. O’Reilly said, and two patients achieved a durable partial response. One of these patients remains on the therapy, she said, and the other was treated for 16 months. In all, 15 patients had stable disease, "defined as four or more cycles of therapy," she reported. Disease progression occurred in 20.

Two patients left the study, one to pursue unconventional treatment options after receiving only one cycle of DX-8951F. The other was taken off study because he developed hemoptysis in the setting of grade 2 thrombocytopenia.

Grade 3-4 neutropenia occurred in 56% of the patients. "About 10% had grade 3-4 thrombocytopenia," Dr. O’Reilly said. "Other toxicities were nausea and vomiting, which were manageable, and fatigue."

One patient had grade 3 diarrhea, probably due to pancreatic insufficiency rather than drug toxicity. Five patients had thrombotic episodes, but these were considered to be due to the disease rather than treatment, Dr. O’Reilly said. One person had a pulmonary embolus.

Nine patients were hospitalized a total of 11 times. Of these, 3 were for neutropenia, 1 for neutropenic fever of unclear etiology, 3 for ascending cholangitis, and 4 for abdominal pain that was attributed to tumor progression.

Because DX-8951F showed some activity in advanced pancreatic cancer in this study, Dr. O’Reilly suggested that it merits further development. Ongoing studies, she noted, are defining gemcita-bine doses to be used in conjunction with DX-8951F in a randomized phase III trial that will compare the doublet with gemcitabine alone.

"It remains to be seen," she said, "whether it is worth looking at DX-8951F as a single agent as first-line or second-line therapy in advanced pancreatic cancer."