A Safety Study of Intravenous Pro-Netupitant and Palonosetron Combination for the Prevention of Nausea and Vomiting

A Phase 3, Multicenter, Randomized, Double-blind, Active Control Study to Evaluate the Safety and Efficacy of IV Pro-netupitant/Palonosetron (260 mg/0.25 mg) Combination for the Prevention of Chemotherapy-induced Nausea and Vomiting in Repeated Chemotherapy Cycles in Patients Receiving Highly Emetogenic Chemotherapy

NEPA-15-18 is a clinical study assessing safety of pro-netupitant and palonosetron, two antiemetic drugs, given with oral dexamethasone. The objective of the study is to evaluate if pro-netupitant and palonosetron are safe when administered to prevent nausea and vomiting after administration of repeated cycles of chemotherapy.

Inclusion Criteria:

Cycle 1

• Signed written informed consent
• Histologically or cytologically confirmed solid tumor malignancy.
• Naïve to cytotoxic chemotherapy. Previous biological or hormonal therapy will be permitted.
• Scheduled to receive at least 4 repeated consecutive cycles of the following highly emetogenic reference chemotherapies (HEC), alone or in combination with other chemotherapeutic agents on Day 1: cisplatin administered as a single IV dose of ≥ 70 mg/m2; cyclophosphamide ≥1500 mg/m2; carmustine (BCNU) >250mg/m2; dacarbazine (DTIC); mechloretamine (nitrogen mustard)
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 .
• If a patient is female, she shall be of non-childbearing potential or of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test.
• Hematologic and metabolic status adequate for receiving an highly emetogenic regimen based on laboratory criteria (Total Neutrophils,Platelets, Bilirubin, Liver enzymes, Serum Creatinine or Creatinine Clearance)
• Able to read, understand, follow the study procedure and complete patient diary.

Cycles 2 to 4:

The following inclusion criteria must be checked prior to inclusion at each repeated cycle:

• Participation in the study during the next cycle of chemotherapy is considered appropriate by the Investigator and does not pose unwarranted risk to the patient.
• Scheduled to receive the same chemotherapy regimen as Cycle 1 or one of the reference chemotherapies as defined in Inclusion criterion 5 for Cycle 1.
• If a patient is female, she shall be of non--childbearing potential or of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test.
• Adequate hematologic and metabolic status according to the Investigator's opinion.

Exclusion Criteria:

Cycle 1

• Lactating woman.
• Active infection or uncontrolled disease except for malignancy that may pose unwarranted risks in administering the study drugs to the patient.
• Current use of illicit drugs or current evidence of alcohol abuse.
• Scheduled to receive moderately or highly emetogenic chemotherapies from Day 2 to Day 5.
• Received or is scheduled to receive radiation therapy to the abdomen or the pelvis within 1 week prior to the start of the reference chemotherapy administration on Day 1 or between Days 1 to 5.
• Any vomiting, retching, or nausea (grade ≥ 1 as defined by National Cancer Institute) within 24 hours prior to the start of the reference chemotherapy administration on Day 1.
• Symptomatic primary or metastatic CNS malignancy.
• Known hypersensitivity or contraindication to 5-HT3 receptor antagonists, to dexamethasone or to NK-1 receptor antagonists.
• Known contraindication to the IV administration of 50 mL 5% glucose solution.
• Previously received an NK-1 receptor antagonist.
• Participation in a previous clinical trial involving IV pro-netupitant or oral netupitant administered alone or in combination with palonosetron.
• Any investigational drugs (other than those given in this study) taken within 4 weeks prior to Day 1, and/or is scheduled to receive any investigational drug during the present study.
• Systemic corticosteroid therapy at any dose within 72 hours prior to the start of reference chemotherapy administration on Day 1. Topical and inhaled corticosteroids are permitted.
• Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy.
• Scheduled to receive any strong or moderate inhibitor of CYP3A4 or its intake within 1 week prior to Day 1.
• Scheduled to receive any of the following CYP3A4 substrates within 1 week prior to Day 1: terfenadine, cisapride, astemizole, pimozide.
• Received within 4 weeks prior to Day 1 or scheduled to receive any CYP3A4 inducer.
• Any medication with known or potential antiemetic activity within 24 hours prior to the start of reference chemotherapy administration on Day 1 of Cycle 1, including but not limited to 5-HT3 receptor antagonists and NK-1 receptor antagonists
• History or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block
• History of Torsade de Point or known history of risk factors for Torsade de Point (heart failure, hypokalemia, family history of Long QT Syndrome).
• Severe cardiovascular diseases diagnosed within 3 months prior to Day 1 of first cycle, including myocardial infarction, 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.

Cycles 2 to 4:

The following exclusion criteria must be checked prior to inclusion in each repeated cycle:

• Lactating woman.
• Active infection or uncontrolled disease except for malignancy that may pose unwarranted risks in administering the study drugs to the patient.
• Started any of the restricted medications.
• Any vomiting, retching, or nausea (grade ≥ 1 as defined by National Cancer Institute) within 24 hours prior to the start of reference chemotherapy administration on Day 1.
• Received or is scheduled to receive radiation therapy to the abdomen or the pelvis within 1 week prior to the start of the reference chemotherapy administration on Day 1 or between Days 1 to 5.
• Symptomatic primary or metastatic CNS malignancy.