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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Chemotherapy-Induced Nausea and Vomiting

Intervention / Treatment
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* Drug: Pro-netupitant/Palonosetron
* Drug: Netupitant/Palonosetron
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pro-netupitant/Palonosetron plus Dexamethasone<br>Intravenous Pro-netupitant/Palonosetron (260 mg/0.25 mg) powder for solution for infusion (on Day 1) with oral dexamethasone prior to each scheduled chemotherapy cycle | Drug: Pro-netupitant/Palonosetron<br> <br> * Other names: IV NEPA FDC;Drug: Dexamethasone<br> <br> |
| Active Comparator: Netupitant/Palonosetron plus Dexamethasone<br>Oral netupitant/palonosetron (300 mg/0.50 mg) hard capsule (on Day 1) with oral dexamethasone prior to each scheduled chemotherapy cycle | Drug: Netupitant/Palonosetron<br> <br> * Other names: Oral NEPA FDC;Drug: Dexamethasone<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Adverse Events | This is a safety study where Adverse Events is the primary outcome (defined by the current ICH Guideline for Good Clinical Practice). Patients are randomized according to a 1:1 ratio (IV NEPA FDC : oral NEPA FDC). No formal comparison is planned, the presence of a control in the same patient population helps interpret any unexpected safety finding in the experimental arm. It is expected that the number of patients randomized to the test group, i.e., 200, will allow approximately 100 patients to be treated with the test drug for 4 cycles. Based on 100 patients treated at Cycle 4 with the IV NEPA FDC , if a given Adverse Event (AE) is not observed, an AE incidence of 3% or greater can be excluded with 95% confidence. | Participants will be followed for the duration of the chemotherapy, an expected average duration of up to 14 weeks assuming a maximum of 4 chemotherapy cycles given every 3 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, in the Acute Phase |  | 0-24 hours | 
| Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, in the Delayed Phase |  | >24-120 hours | 
| Percentage of Patients With Complete Response (CR) Defined as no Emesis, no Rescue Medication, in the Overall Phase |  | 0-120 hours | 
| Percentage of Patients With no Emetic Episodes in the Acute Phase |  | 0-24 hours | 
| Percentage of Patients With no Emetic Episodes in the Delayed Phase |  | >24-120 hours | 
| Percentage of Patients With no Emetic Episodes in the Overall Phase |  | 0-120 hours | 
| Percentage of Patients With no Significant Nausea (VAS <25 mm) During the Acute Phase |  | 0-24 hours | 
| Percentage of Patients With no Significant Nausea (VAS <25 mm) During the Delayed Phase |  | >24-120 hours | 
| Percentage of Patients With no Significant Nausea (VAS <25 mm) During the Overall Phase |  | 0-120 hours |