Aprepitant for Prevention of Acute and Delayed Nausea and Vomiting in Patients Receiving a High-emetogenic Dose of Cyclophosphamide for Peripheral Blood Stem Cells Harvesting (PG-APRE1)

Title of the study Aprepitant for prevention of acute and delayed nausea and vomiting: a phase III, double-blind, randomized, placebo-controlled trial in patients receiving a high-emetogenic dose of cyclophosphamide for peripheral blood stem cells harvesting

Objective(s) Primary objective: to confirm and extend the investigators preliminary data on the efficacy and safety of combined aprepitant, palonosetron and dexamethasone in preventing CINV after high emetic therapy with cyclophosphamide 3 g/m2 compared with the palonosetron and dexamethasone regimen.

Secondary objective: to monitor peripheral blood stem cell harvest. Methodology Single centre, randomized, double-blind, placebo-controlled phase III trial Endpoints Primary endpoint: the complete response (CR) rate defined as the number of patients with no emetic episodes and no rescue medication in the first 120 hours post-chemotherapy.

Secondary endpoints:

• CR rates for acute (0-24 h) and delayed (24-120 h) phases;
• complete control rate (CC) defined as no emetic episode, no rescue medication use and no more than mild nausea;
• number of emetic episodes;
• severity of nausea;
• impact of CINV on daily life as measured by the Functional Living Index-Emesis (FLIE) (total score > 108 = no impact);
• peripheral blood stem cell harvest;
• tolerability (adverse events, drug-related adverse events, serious adverse events; discontinuation of treatment due to an adverse event). Adverse events will be classified using NCI Common Toxicity Criteria.

Number of patients A total of 120 patients will be enrolled Inclusion criteria - Male or female patients ≥ 18 years of age

• Patient is able to understand study procedure and agrees to participate in the study by giving written informed consent.
• Patient is scheduled to receive a highly emetogenic cyclophosphamide IV chemotherapy (3 g/m2) for autologous PBSC harvesting
• Karnofsky score ≥60
• Normal laboratory values
• Normal ECG
• HBV-, HCV- and HIV- negative
• Negative urine pregnancy test for women of childbearing age Treatment Eligible patients will be randomized to receive oral doses of Aprepitant (125 mg day 1, 80 mg days 2 and 3), dexamethasone (8 mg/day for 3 days) and a single intravenous dose of palonosetron (0.25 mg on day 1) versus placebo plus dexamethasone (8 mg/day for 3 days) and a single intravenous dose of palonosetron (0.25 mg on day 1) Duration of study 3 years Criteria for evaluation Efficacy and safety data will be obtained using the patient's daily diary (days 1 through 5) reporting the number of episodes of retching and vomiting, severity of nausea (using a categorical scale of none, mild, moderate or severe), and overall quality of life. The FLIE 8 questionnaire will be completed on days 1 (before starting chemotherapy) and 6 (after chemotherapy). All side effects attributed to this combination therapy will be recorded daily.

Safety parameters: medical history, clinical examination and weight, vital signs, laboratory tests (hematology, chemistry, urine analysis and urine pregnancy test for women of childbearing age).

Statistical aspects Sample size was defined assuming the cumulative incidence rate of the primary endpoint to be 68% in the treatment group and 41% in the control group. With balanced allocation in the two groups, considering a two sided test with α=0.05 and ß=0.20 a total of 110 patients is needed. As few withdrawals and drop-outs are expected a total of 120 patients will be enrolled.

Intention to treat approach will be used for all efficacy analysis. The primary endpoint will be analysed by binomial logistic models. The dependent variable will be vomiting yes/no during the first 120 hours after chemotherapy. Anti-emetic treatment, gender and age will enter as explicative variables.

Dichotomous secondary endpoints will also be analysed by binomial logistic models. Multinomial logistic models will analyze the severity of nausea, stratified in 4 classes.

Generalized Linear Models will investigate quantitative variables such as number of retching or vomiting episodes and peripheral blood stem cell harvest.

In all tests, p value <0.05 will be considered statistically significant. No interim analyses are planned.