An Efficacy and Safety Study of Oral Netupitant and Palonosetron for the Prevention of Nausea and Vomiting

A Phase III Multicenter, Randomized, Double-blind, Double-dummy, Active-controlled, Parallel Group Study of the Efficacy and Safety of Oral Netupitant Administered in Combination With Palonosetron and Dexamethasone Compared to Oral Palonosetron and Dexamethasone for the Prevention of Nausea and Vomiting in Cancer Patients Receiving Moderately Emetogenic Chemotherapy

NETU-08-18 is a two-arm clinical study assessing efficacy and safety of a single oral dose of netupitant and palonosetron, two antiemetic drugs, versus oral palonosetron, both given with oral dexamethasone. The objective of the study is to demonstrate that netupitant and palonosetron are more effective than palonosetron alone, to prevent nausea and vomiting induced by moderately emetogenic cancer chemotherapy after administration of repeated cycles of chemotherapy.

NETU-08-18 is a two-arm clinical study assessing efficacy and safety of a single oral dose of netupitant and palonosetron, two antiemetic drugs, versus oral palonosetron, both given with oral dexamethasone. Study is organised in two phases: cycle-1 and a multi-cycle extension. Safety assessment is performed separately in cycle 1 (arm 1 and arm 2) and in multi-cycle extension (arm 3 and arm 4).

Inclusion Criteria:

• Naïve to cytotoxic chemotherapy. Previous biological or hormonal therapy will be permitted.
• Scheduled to receive first course of an anthracycline and cyclophosphamide containing moderately emetogenic chemotherapy (MEC) regimen for the treatment of a solid malignant tumor: cyclophosphamide I.V. (500 to 1500 mg/m2) and I.V. doxorubicin (more or equal to 40 mg/m2) or cyclophosphamide I.V. (500 to 1500 mg/m2) and I.V. epirubicin (more or equal to 60 mg/m2).
• If scheduled to receive chemotherapy agents of minimal to low emetogenic potential they could be given on any day.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2.
• Female patients of either non-childbearing potential or child-bearing potential with a commitment to use contraceptive methods throughout the clinical trial
• Hematologic and metabolic status adequate for receiving a moderately emetogenic regimen based on laboratory criteria (Total Neutrophils,Platelets, Bilirubin, Liver enzymes, Serum Creatinine or Creatinine Clearance)

The following inclusion criteria must be checked prior inclusion at each cycle of the Multiple-Cycle Extension:

• Participation in the study during the next cycle of chemotherapy is considered appropriate by the investigator Satisfactory study compliance in the preceding cycle of chemotherapy and related study procedures.
• Scheduled to receive the same chemotherapy regimen as cycle 1
• Adequate hematologic and metabolic status as defined for cycle 1

Exclusion Criteria:

• If female, pregnant or lactating.
• Current use of illicit drugs or current evidence of alcohol abuse.
• Scheduled to receive any highly emetogenic chemotherapy (HEC) from Day 1 to Day 5 or moderately emetogenic chemotherapy (MEC) from Day 2 to Day 5 following the allowed MEC regimen.
• Received or is scheduled to receive radiation therapy to the abdomen or the pelvis within 1 week prior to Day 1 or between Days 1 to 5 in cycle 1.
• Any vomiting, retching, or mild nausea within 24 hours prior to Day 1.
• Symptomatic primary or metastatic central nervous system (CNS) malignancy.
• Active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, hypercalcemia, an active infection or any uncontrolled medical condition (other than malignancy) that, in the opinion of the investigator, may confound the results of the study, represent another potential etiology for emesis and nausea (other than chemotherapy-induced nausea and vomiting, CINV) or pose unwarranted risks in administering the study drugs to the patient.
• Known hypersensitivity or contraindication to 5-HT3 receptor antagonists or dexamethasone.
• Previously received a neurokin-1 (NK1) receptor antagonist
• Participation in a clinical trial involving oral netupitant administered in combination with palonosetron.
• Any investigational drugs taken within 4 weeks prior to Day 1 of cycle 1, and/or is scheduled to receive any investigational drug during the study.
• Systemic corticosteroid therapy at any dose within 72 hours prior to Day 1 of cycle 1.
• Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy.
• Any medication with known or potential antiemetic activity within 24 hours prior to Day 1 of cycle 1
• Scheduled to receive any strong or moderate inhibitor of cytocrome P450 3A4 (CYP3A4) or its intake within 1 week prior to Day 1.
• Scheduled to receive any of the following CYP3A4 substrates: terfenadine, cisapride, astemizole, pimozide.
• Scheduled to receive any CYP3A4 inducer or its intake within 4 weeks prior to Day 1.
• History or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block.
• History of risk factors for Torsade de Point (heart failure, hypokalemia, family history of Long QT Syndrome).
• Severe cardiovascular diseases, including myocardial infarction within 3 months prior to Day 1, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic Congestive Heart Failure (CHF) New York Heart Association (NYHA) class III-IV, and severe uncontrolled arterial hypertension.
• Any illness or condition that, in the opinion of the investigator, may confound the results of the study or pose unwarranted risks in administering the investigational product to the patient.
• Concurrent medical condition that would preclude administration of dexamethasone such as systemic fungal infection or uncontrolled diabetes.

The following exclusion criteria must be checked prior inclusion at each cycle of the Multiple-Cycle Extension:

• If female, pregnant or lactating
• Active infection or uncontrolled disease except for malignancy.
• Started any of the restricted medications.
• Any vomiting, retching, or mild nausea within 24 hours prior to Day 1.