Phase II Trial Testing the Antiemetic Efficacy of a Single-day Low Dose Aprepitant (or Fosaprepitant) Added to a 5-HT3 Receptor Antagonist Plus Dexamethasone in Patients Receiving Carboplatin

Main predictive factor for the development of Chemotherapy-induced Nausea and Vomiting (CINV) is the emetic potential of a given chemotherapeutic agent. Carboplatin causes both acute and delayed emesis. Guideline groups have typically classified this agent as moderately emetic (MEC); however, its risk of inducing vomiting is at the upper range of this classification, and borders on highly emetic. The recommendation for prevention has been the use of a two-drug regimen (a 5-hydroxytryptamine receptor antagonist (5-HT3RA) plus dexamethasone). The recent randomized studies have shown that patients given only a 2-drug regimen have about a 50% likelihood of emesis if they are women, and about a 30% likelihood of emesis if they are men. Major improvements were reported when a neurokinin-1 receptor antagonist (NK1RA) Aprepitant was added. This improvement is of a similar magnitude to that seen in patients receiving cisplatin. Similar improvements were also seen in a trial in which the NK1RA antiemetic was Rolapitant rather than Aprepitant. The Tanioka and Yahata studies were conducted entirely in patients with gynecologic (GYN) malignancies, and it is not surprising that the control rates are lower in these all female groups.

The most commonly used NK1RA, Aprepitant, is generally given over 3 days. Most studies indicate that this class of agent gives similar results when given in just one day, or over multiple days. Recent studies conducted by Roila compared the efficacy of Aprepitant on day 1 at a low dose (125 mg) versus the full three day regimen totaling 285 mg in patients receiving either cisplatin or the combination of anthracyclines plus cyclophosphamide (AC). In both studies, those patients randomly assigned to just one day of lower dose Aprepitant had control of emesis equal to those receiving multiple days. In both of these trials, patients assigned to the single day Aprepitant arm also received additional antiemetics on days 2 and 3. However, recent studies have failed to show an advantage for continuing dexamethasone after day 1 in patients receiving AC (14) or in those receiving cisplatin. Additionally, a meta-analysis indicated that as long as dexamethasone is given on day 1, there is no advantage to adding a serotonin antagonist (such as ondansetron) after day 1, and ondansetron has been shown to be similar to metoclopramide in the delayed emesis phase. Similarly to studies conducted by Roila, Grunberg and colleagues showed non-inferiority of single-dose intravenous (IV) fosaprepitant (a phosphorylated analog of Aprepitant that is rapidly converted to Aprepitant after IV administration) in a randomized study of patients receiving cisplatin chemotherapy. Fosaprepitant 115 mg IV has been approved as an alternative to the 125-mg oral Aprepitant dose on day 1 of a 3-day regimen.

There is very little data regarding the efficacy of continued steroids after day 1 in patients receiving carboplatin. Recent trials fail to show benefit for continuing dexamethasone after the day of chemotherapy. Aapro and colleagues in a 300 patient trial, showed that dexamethasone in combination with a 5-HT3RA on day 1 gave similar CINV protection to a multiple-day dexamethasone. Similarly, a Japanese study showed no difference in antiemetic efficacy of a single day dexamethasone regimen when prospectively compared with a 3 day dexamethasone regimen; however, the 1 day regimen found significant reductions in steroid induced side effects. Additionally, a large multinational trial in patients receiving AC chemotherapy showed that a single dose of dexamethasone on day 1 along with a single day of NEPA (combination of 5-HT3RA palonosetron with NK1RA Netupitant) offers convenient single-day prophylaxis for both acute and delayed CINV.

Guideline groups are now starting to recommend a 3-agent preventive antiemetic regimen for patients receiving carboplatin, based on the evidence from the studies discussed above. However, not all guideline groups have yet made this recommendation. If it can be shown that a less expensive, more convenient (1-time administration), and potentially safer regimen performs in the same way for patients receiving carboplatin as it did for those receiving cisplatin or AC chemotherapy, and similarly to those receiving 3 days of Aprepitant with carboplatin in the recent randomized trials, a new standard may be established.

Objectives. Primary: To determine in patients receiving their first cycle of carboplatin-based chemotherapy, the complete control rate of emesis (acute and delayed; no vomiting and no use of rescue medications) with the addition of one dose of the oral Aprepitant or intravenous fosaprepitant to a combination of oral dexamethasone + an oral 5-HT3RA (ondansetron).