Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: a randomised, active-controlled, double-blind, phase 3 trial.
BACKGROUND
Chemotherapy-induced nausea and vomiting is a common side-effect of many antineoplastic regimens and can occur for several days after treatment. We aimed to assess the neurokinin-1 receptor antagonist rolapitant, in combination with a serotonin (5-HT3) receptor antagonist and dexamethasone, for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide.


METHODS
We conducted a global, randomised, double-blind, active-controlled, phase 3 study at 170 cancer centres in 23 countries. We included patients with cancer aged 18 years or older, who had not received moderately or highly emetogenic chemotherapy before, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly allocate patients to receive either oral rolapitant (one 180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) 1-2 h before administration of moderately emetogenic chemotherapy. Patients were stratified by sex. All patients also received granisetron (2 mg orally) and dexamethasone (20 mg orally) on day 1 (except for patients receiving taxanes as part of moderately emetogenic chemotherapy, who received dexamethasone according to the package insert) and granisetron (2 mg orally) on days 2-3. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients received the same study drug they were assigned in cycle 1, unless they chose to leave the study or were removed at the treating clinician's discretion. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a study site compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (defined as no emesis or use of rescue medication) in the delayed phase (>24-120 h after initiation of chemotherapy) in cycle 1. This study is registered with ClinicalTrials.gov, number NCT01500226. The study has been completed.


RESULTS
Between March 5, 2012, and Sept 6, 2013, 1369 patients were randomised to receive either rolapitant (n=684) or active control (n=685). 666 patients in each group received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients receiving rolapitant had complete responses in the delayed phase than did those receiving active control (475 [71%] vs 410 [62%]; odds ratio 1·6, 95% CI 1·2-2·0; p=0·0002). The incidence of adverse events was similar in the rolapitant and control groups, with the most frequently reported treatment-related treatment-emergent adverse events being fatigue, constipation, and headache. For cycle 1, the most common grade 3-4 adverse event in the rolapitant versus active control groups was neutropenia (32 [5%] vs 23 [3%] patients). No serious adverse event was treatment-related, and no treatment-related treatment-emergent adverse event resulted in death.


CONCLUSIONS
Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the 5-day (0-120 h) at-risk period after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide.


BACKGROUND
TESARO, Inc.
The West Clinic, Memphis, TN, USA. Electronic address: lschwartzberg@westclinic.com.
Lee S
LS
Schwartzberg
ACRC/Arizona Clinical Research Center and Arizona Oncology, Tucson, AZ, USA.
Manuel R
MR
Modiano
The Medical Oncology Centre of Rosebank, Saxonwold, Johannesburg, South Africa.
Bernardo L
BL
Rapoport
The Ottawa Hospital Cancer Center, Ottawa, ON, Canada.
Martin R
MR
Chasen
Division of Medical Oncology, San Giuseppe Moscati Hospital, Avellino, Italy.
Cesare
C
Gridelli
Matrahaza Healthcare Center and University Teaching Hospital, Matrahaza, Hungary.
Laszlo
L
Urban
TESARO, Waltham, MA, USA.
Allen
A
Poma
TESARO, Waltham, MA, USA.
Sujata
S
Arora
Indiana University School of Medicine, South Bend, IN, USA.
Rudolph M
RM
Navari
Compass Oncology, US Oncology Research, Tualatin, OR, USA.
Ian D
ID
Schnadig
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000009:adverse effects; D003520:Cyclophosphamide / Q000009:adverse effects; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013141:Spiro Compounds / Q000008:administration & dosage*; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology
D018943:Anthracyclines; D013141:Spiro Compounds; D003520:Cyclophosphamide; C578834:rolapitant