Patients receiving the neurokinin 1 (NK1) antagonist aprepitant as part of a preparative regimen prior to stem-cell transplant had improved control of acute and delayed nausea and vomiting, and the drug did not interfere with antitumor efficacy, according to investigators from a prospective, randomized, double-blind, phase 3 trial.
"Everyone would have guessed that aprepitant would be effective as antiemesis, but we did not know whether it might negatively impact long-term survival," explained Mary Fox-Geiman, PharmD, of the Department of Pharmacy at Loyola University, Maywood, Illinois. The study's principal investigator was Patrick Stiff, MD, of Loyola's College of Medicine.
Aprepitant is known to interact with cytochrome P450 isoenzymes involved in the bioactivation of highdose cyclophosphamide and may also interfere with etoposide pharmacokinetics. Its impact on long-term survival as well as regimen-associated toxicity after hematopoietic stem-cell transplantation is unknown, she explained.
"Once you increase the cyclophosphamide in these regimens, you saturate the enzymes that normally metabolize the drug, and these enzymes are the same ones that are inhibited by aprepitant," she said, "so there is a theoretical possibility that aprepitant could inhibit the production of the active metabolites and thus decrease the effectiveness of the chemotherapy."
This possibility had to be conveyed to potential trial enrollees as part of informed consent, and this made it difficult to recruit patients to the trial. "We got 181 patients, but the study was begun in 2004 and we expected it to be completed within 15 months," she said. "The study population is highly skewed in favor of men, as they were more likely to consent."
As part of an ablative preparative regimen, patients scheduled for hematopoietic stem-cell transplant were randomized to placebo or aprepitant 125 mg orally on day 1, then 80 mg daily during the administration of chemotherapy and for 3 days after the regimen was completed. They all received oral ondansetron 8 mg every 8 hours plus intravenous dexamethasone daily during and for 1 day after the preparative regimen. Only as-needed lorazepam was permitted for nausea.
The aprepitant arm demonstrated a significant improvement in complete response rate, the primary end point. Complete responses (no emesis and no or mild nausea) were observed in 81.9% of patients taking aprepitant versus 65.8% receiving placebo, and 48.9% and 14.6%, respectively, met this end point for the entire study period, Fox-Geiman reported.
In addition, 73.3% of the aprepitant group never experienced a single episode of emesis during the study, versus 22.5% of the placebo group.
The greatest benefit was observed in the reduction of delayed vomiting, she emphasized.
Reassuringly, clinical outcomes were similar between the two groups, including days to engraftment (white blood cell or platelets), 30-day survival, progression-free survival, and overall survival, she reported.
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