Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone.
OBJECTIVE
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.


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 (> 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.


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.


CONCLUSIONS
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.
Campos
D
D
Merck Research Laboratories, Rahway, NJ 07065, USA.
Pereira
J R
JR
Reinhardt
R R
RR
Carracedo
C
C
Poli
S
S
Vogel
C
C
Martinez-Cedillo
J
J
Erazo
A
A
Wittreich
J
J
Eriksson
L O
LO
Carides
A D
AD
Gertz
B J
BJ
D000328:Adult; D000368:Aged; D018687:Antidepressive Agents, Second-Generation / Q000008:administration & dosage / Q000494:pharmacology*; D000932:Antiemetics / Q000008:administration & dosage / Q000494:pharmacology*; D000077608:Aprepitant; D002945:Cisplatin / Q000009:adverse effects* / Q000627:therapeutic use; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D017829:Granisetron / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D014839:Vomiting / Q000139:chemically induced* / Q000517:prevention & control*
D018687:Antidepressive Agents, Second-Generation; D000932:Antiemetics; D000077608:Aprepitant; D002945:Cisplatin; D003907:Dexamethasone; D017829:Granisetron; D009025:Morpholines