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

• Published in: Journal of clinical oncology Vol. 19; no. 6; pp. 1759 - 1767
• Main Authors: CAMPOS, Daniel, RODRIGUES PEREIRA, Jose, CARIDES, Alexandra D, GERTZ, Barry J, REINHARDT, Rick R, CARRACEDO, Carlos, POLI, Sergio, VOGEL, Conrado, MARTINEZ-CEDILLO, Jorge, ERAZO, Aura, WITTREICH, Johanna, ERIKSSON, Lars-Olof
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 15.03.2001; Lippincott Williams & Wilkins
• Subjects: Adult; Aged; Antidepressive Agents, Second-Generation - administration & dosage; Antidepressive Agents, Second-Generation - pharmacology; Antiemetics - administration & dosage; Antiemetics - pharmacology; Biological and medical sciences; Cisplatin - adverse effects; Cisplatin - therapeutic use; Dexamethasone - administration & dosage; Dexamethasone - pharmacology; Double-Blind Method; Drug Therapy, Combination; Drug toxicity and drugs side effects treatment; Female; Granisetron - administration & dosage; Granisetron - pharmacology; Humans; Male; Medical sciences; Middle Aged; Morpholines - administration & dosage; Morpholines - pharmacology; Neoplasms - drug therapy; Pharmacology. Drug treatments; Toxicity: digestive system; Vomiting - chemically induced; Vomiting - prevention & control; Antineoplastic agent; Chemoprophylaxis; Toxicity; Glucocorticoid; Prevention; Vomiting; Complication; Antagonist; Platinum II Complexes; Human; Corticosteroid; Drug combination; Granisetron; Dexamethasone; NK1 Tachykinin receptor; Substance P; Serotonin antagonist; Oral administration; Malignant tumor; Cisplatin; Alkylating agent; Chemotherapy; Treatment; 5-HT3 Serotonine receptor; Digestive diseases; Antiemetic
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2001.19.6.1759

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 5HT(3) 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 5HT(3) antagonist plus dexamethasone was more effective than just the 5HT(3) antagonist plus dexamethasone for prevention of acute and delayed emesis. 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 (> or =70 mg/m(2)). Patients were randomized to four groups (I to IV) (n = number randomized; number evaluable): granisetron (10 microg/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. 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. 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 5HT(3) antagonist, MK-869, and dexamethasone provided the best control of acute emesis.