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

Inclusion Criteria:

• Naïve to cytotoxic chemotherapy. Previous biological or hormonal therapy will bepermitted.

• Scheduled to receive first course of an anthracycline and cyclophosphamide containingmoderately emetogenic chemotherapy (MEC) regimen for the treatment of a solidmalignant tumor: cyclophosphamide I.V. (500 to 1500 mg/m2) and I.V. doxorubicin (moreor 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 potentialthey 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 acommitment to use contraceptive methods throughout the clinical trial

• Hematologic and metabolic status adequate for receiving a moderately emetogenicregimen based on laboratory criteria (Total Neutrophils,Platelets, Bilirubin, Liverenzymes, Serum Creatinine or Creatinine Clearance) The following inclusion criteria must be checked prior inclusion at each cycle of theMultiple-Cycle Extension:

• Participation in the study during the next cycle of chemotherapy is consideredappropriate by the investigator Satisfactory study compliance in the preceding cycleof 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 ormoderately emetogenic chemotherapy (MEC) from Day 2 to Day 5 following the allowed MECregimen.

• Received or is scheduled to receive radiation therapy to the abdomen or the pelviswithin 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 intracranialpressure, hypercalcemia, an active infection or any uncontrolled medical condition (other than malignancy) that, in the opinion of the investigator, may confound theresults of the study, represent another potential etiology for emesis and nausea (other than chemotherapy-induced nausea and vomiting, CINV) or pose unwarranted risksin administering the study drugs to the patient.

• Known hypersensitivity or contraindication to 5-HT3 receptor antagonists ordexamethasone.

• Previously received a neurokin-1 (NK1) receptor antagonist

• Participation in a clinical trial involving oral netupitant administered incombination with palonosetron.

• Any investigational drugs taken within 4 weeks prior to Day 1 of cycle 1, and/or isscheduled 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 toDay 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 incompleteright bundle branch block.

• History of risk factors for Torsade de Point (heart failure, hypokalemia, familyhistory of Long QT Syndrome).

• Severe cardiovascular diseases, including myocardial infarction within 3 months priorto Day 1, unstable angina pectoris, significant valvular or pericardial disease,history of ventricular tachycardia, symptomatic Congestive Heart Failure (CHF) NewYork Heart Association (NYHA) class III-IV, and severe uncontrolled arterialhypertension.

• Any illness or condition that, in the opinion of the investigator, may confound theresults of the study or pose unwarranted risks in administering the investigationalproduct to the patient.

• Concurrent medical condition that would preclude administration of dexamethasone suchas systemic fungal infection or uncontrolled diabetes. The following exclusion criteria must be checked prior inclusion at each cycle of theMultiple-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.