Single-Dose Palonosetron Prevents Acute, Delayed Emesis

BOSTON—A single dose of a new long-acting 5-HT3 receptor antagonist called palonosetron matched the effectiveness of a single dose of dolasetron (Anzemet) against acute emesis and was more effective against delayed emesis in a phase III clinical trial conducted in patients receiving moderately emetogenic chemotherapy.

Steven M. Grunberg, MD, professor of medicine and pharmacology, University of Vermont, Burlington, reported the results in a late program addition at the 14th International Meeting of the Multinational Association for Supportive Care in Cancer (MASCC) and International Association for Oral Oncology.

MGI PHARMA Inc. of Minneapolis and its Swiss partner Helsinn Healthcare SA announced that they plan to submit a new drug application for palonosetron to the US Food and Drug Administration in the third quarter of this year.

According to MGI PHARMA, palonosetron has a stronger receptor binding affinity than the three widely used antiemetic agents: dolasetron, granisetron (Kytril), and ondansetron (Zofran). It has a 40-hour plasma half-life, which is significantly longer than the half-lives of the other agents and might make it more useful against delayed emesis. "When we find a family of compounds that are very similar, any small differences may lead to the next advance in antiemetic care," Dr. Grunberg said.

The lead consultant for the palonosetron project, Dr. Grunberg reported that 569 patients participated in the trial at 40 sites in the United States and 20 in Mexico. All had histologically confirmed cancer; 380 had not had chemotherapy before, and 467 were female. The most common regimens were carboplatin (Paraplatin), cisplatin (Platinol) at doses up to 50 mg/m², cyclophosphamide up to 1,500 mg/m², and more than 25 mg/m² of doxorubicin.

Although 5-HT3 antagonists are usually given just prior to chemotherapy and then as needed following chemotherapy, patients in this study received only one dose of palonosetron, 0.25 mg or 0.75 mg, or dolasetron, 100 mg, intravenously 30 minutes before chemotherapy. A complete response was defined as no vomiting and no need for a rescue medication.

Primary Endpoint Met

During the first 24 hours, 63% of patients receiving the lower dose of palonosetron, 57.1% of patients given the higher dose, and 52.9% of the dolasetron group had a complete response. This was the primary endpoint of the study—efficacy equal to that of an FDA-approved agent against acute emesis.

Palonosetron’s performance against delayed emesis was more striking. The higher dose prevented nausea and vomiting in 56.6% of patients (P < .001, compared with dolasetron) during a follow-up period defined as from 24 to 120 hours after chemotherapy. The lower dose was similarly effective, heading off delayed emesis in 54% of its cohort (P = .003, compared with dolasetron). In comparison, only 38.7% of the patients given dolasetron did not suffer from vomiting and did not require rescue medication after the first day.

Adverse events were mild for all three cohorts, with headaches and constipation the most common side effects.

"The overall protection for the full 5 days did appear to be better with this agent," Dr. Grunberg said. Palonosetron offered better protection than dolasetron on the second and third day, and similar protection on the fourth and fifth day. "This is not to say you wouldn’t have gotten the same effect if shorter-acting 5-HT₃ antagonists had been given once a day," he said, "but with this agent, you didn’t have to readminister the drug."