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Prevention of Cisplatin-Induced Emesis by the Oral Neurokinin-1 Antagonist, MK-869, in Combination With Granisetron and Dexamethasone or With Dexamethasone Alone

From Merck Research Laboratories, Rahway, NJ; San Isidro Central Hospital, Buenos Aires, Argentina; Instituto de Enfermedades Neoplasicas, Lima, Peru; Instituto do Cancer, Arnaldo Vieira de Carvalho, Sao Paulo, Brazil; Ciudad Universitaria, Caracas, Venezuela; Fundacion Arturo Lopez Perez, Santiago, Chile; Instituto Nacional de Cancerologia; ISSSTE, Mexico City, Mexico.

Address reprint requests to Barry J. Gertz, MD, PhD, Clinical Pharmacology, RY33-600, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065; e-mail barry_gertz{at}merck.com

PURPOSE: The NK1-receptor antagonist MK-869 (L-754,030) has demonstrated antiemetic activity in humans receiving chemotherapy. Objectives of the present trial included the first assessment of oral MK-869 plus dexamethasone compared with a 5HT₃ antagonist plus dexamethasone for prevention of acute and delayed emesis after high-dose cisplatin. Furthermore, the study sought to confirm that addition of MK-869 to a 5HT₃ antagonist plus dexamethasone was more effective than just the 5HT₃ antagonist plus dexamethasone for prevention of acute and delayed emesis.

METHODS: This multicenter, double-blind, parallel-group trial in 351 cisplatin-naïve patients evaluated prevention of acute (0 to 24 hours) and delayed emesis (primary efficacy parameter; days 2 to 5) after cisplatin (70 mg/m²). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 µg/kg intravenously) pre-cisplatin followed by placebo on days 2 to 5 (group I) (n = 90; 90); granisetron and MK-869 (400 mg PO [by mouth]) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group II) (n = 86; 84); MK-869 (400 mg PO) the evening before and pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group III) (n = 89; 88); or MK-869 (400 mg PO) pre-cisplatin, followed by MK-869 (300 mg PO) on days 2 to 5 (group IV) (n = 86; 84). All patients also received dexamethasone (20 mg PO) before cisplatin. Additional medication was available to treat emesis or nausea at any time.

RESULTS: In the acute period, 57%, 80%, 46%, and 43% of patients were without emesis in groups I, II, III, and IV, respectively (P < .01 for group II v group I). In the delayed period, the proportion of patients without emesis in groups I, II, III, and IV was 29%, 63%, 51%, and 57%, respectively (P < .01 for groups II, III, and IV v group I). The distribution of nausea scores in the delayed period was lower when comparing group II with group I (P < .05 for days 1 to 5 and days 2 to 5). One serious adverse event (dizziness) was rated as possibly related to MK-869.

CONCLUSION: Once daily oral administration of MK-869 was effective in reducing delayed emesis and nausea after high-dose cisplatin. However, the combination of the 5HT3 antagonist plus dexamethasone was numerically superior to MK-869 plus dexamethasone in reducing acute emesis. Confirming and extending previous findings, the triple combination of a 5HT₃ antagonist, MK-869, and dexamethasone provided the best control of acute emesis.

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