A Study to Assess the Safety and the Efficacy of IV Fosnetupitant/Palonosetron (260 mg/0.25 mg) Combination Compared to Oral Netupitant/Palonosetron (300 mg/0.5 mg) Combination for the Prevention of CINV in AC Chemotherapy in Women With Breast Cancer

A Multicenter, Randomized, Double-blind, Double-dummy, Active-controlled, Parallel Group Phase 3b Study to Assess the Safety and to Describe the Efficacy of IV Fosnetupitant/Palonosetron (260 mg/0.25 mg) Combination (IV NEPA FDC) Compared to Oral Netupitant/Palonosetron (300 mg/0.5 mg) Combination (Akynzeo®) for the Prevention of Chemotherapy-induced Nausea and Vomiting in Initial and Repeated Cycles of Anthracycline-cyclophosphamide (AC) Chemotherapy in Women With Breast Cancer

Multicenter, randomized, double-blind, double-dummy, parallel group, stratified study assessing the safety and describing the efficacy of a single dose of intravenous (IV) fosnetupitant/palonosetron (260 mg/0.25 mg) infusion [test] versus oral netupitant/palonosetron (300 mg/0.5 mg) combination [control]; each administered with oral dexamethasone prior to initial and repeated cycles of AC chemotherapy in female breast cancer patients.

Study Overview

• Status: Completed
• Conditions: Chemotherapy-induced Nausea and Vomiting
• Intervention / Treatment: Drug: fosnetupitant/ palonosetron; Drug: dexamethasone; Drug: netupitant/palonosetron

• Study Type: Interventional
• Enrollment (Actual): 404
• Phase: Phase 3

Contacts and Locations

Study Locations

• Georgia
  • Kutaisi, Georgia, 4600
    • JSC Saint Nikolozi Surgery and Oncological Centre
  • Tbilisi, Georgia, 0159
    • LTD Institute of Clinical Oncology
  • Tbilisi, Georgia, 0159
    • LTD Tbilisi Oncology Dispensary
  • Tbilisi, Georgia, 0179
    • LTD S.Khechinashvili University Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85745
      • The Oncology Inst. Of Hope and Innovation
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • CARTI Cancer Center
  • California
    • Anaheim, California, United States, 92801
      • Pacific Cancer Medical Center, Inc.
    • Bakersfield, California, United States, 93309
      • CBCC Global Research, INC at Comprehensive Blood and Cancer Center
    • Corona, California, United States, 92882
      • The Oncology Tnstitute of Hope and Innovation
    • Inglewood, California, United States, 90305
      • Uptimum Medical Group Inc.
    • Long Beach, California, United States, 90805
      • The Oncology Institute of Hope and Innnovation
    • Los Angeles, California, United States, 90033
      • Hao Wei Zhang M.D.
    • Redlands, California, United States, 92373
      • Emad Ibrahim, MD, Inc.
  • Florida
    • Lakeland, Florida, United States, 33805
      • Watson Clinic LLP
    • Orange City, Florida, United States, 32763
      • Mid Florida Hematology and Oncology Center
  • Georgia
    • Athens, Georgia, United States, 30607
      • University Cancer & Blood Center, LLC
    • Dublin, Georgia, United States, 31021
      • Cancer Center of !\!Iiddle Georgia
    • Rome, Georgia, United States, 30165
      • Harbin Clinic
    • Savannah, Georgia, United States, 31404
      • Summit Cancer Care
  • Illinois
    • Skokie, Illinois, United States, 60076
      • Edward H. Kaplan MD & Associates
    • Skokie, Illinois, United States, 60077
      • Presence Infusion Care - Skokie
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Fort Wayne Medical Oncology and Hematology, Inc.
    • Lafayette, Indiana, United States, 47904
      • TU Health Arnett Cancer Center
    • New Albany, Indiana, United States, 47150
      • Baptist Health Cancer Center
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Cotton O'Neil Clinical Res. Ctr., Hematology & Oncology
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas
  • Kentucky
    • Ashland, Kentucky, United States, 41101
      • Ashland-Bellefonte Cancer Center
  • Louisiana
    • Shreveport, Louisiana, United States, 71105
      • Christus Cancer Treatment Center
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center, Medical Oncology and Hematology
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Hattiesburg Clinic Hematology Oncology
  • Missouri
    • Joplin, Missouri, United States, 64804
      • Cornell-Beshore Cancer Institute
    • Springfield, Missouri, United States, 65807
      • Cox Mcdical ·Centers
  • New Jersey
    • Elizabeth, New Jersey, United States, 07207
      • Trinitas Cancer Center
  • New Mexico
    • Farmington, New Mexico, United States, 87401
      • San Juan Oncology Associates
  • Ohio
    • Columbus, Ohio, United States, 43219
      • Mid Ohio Oncology/Hematology Inc. DBA The Mark H. Zangmeister Center
    • Toledo, Ohio, United States, 43623
      • Toledo Clinic Cancer Center - Toledo
  • Pennsylvania
    • Monongahela, Pennsylvania, United States, 15063
      • Monongahela Valley Hospital
  • South Carolina
    • Rock Hill, South Carolina, United States, 29732
      • Carolina Blood and Cancer Care Associates, P.A.
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • The West Clinic, PC dba West Cancer Center
  • Wyoming
    • Cheyenne, Wyoming, United States, 82001
      • Cheyenne Regional Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

Cycle 1:

The following inclusion criteria must be checked prior to inclusion at Cycle 1:

1. Patient read, understood and signed the written informed consent before any study related activity, agreeing to participate in the study and to comply with study requirements.
2. Female patient of at least 8 years of age.
3. Histologically or cytologically confirmed breast cancer, including recurrent or metastatic.
4. Naïve to moderately or highly emetogenic antineoplastic agents.

5. Scheduled to receive at least 4 consecutive cycles of an AC combination regimen.

   Notes:

   1. additional not emetogenic, minimally or low emetogenic antineoplastic agents are permitted at any time after start of AC combination on Day 1.
   2. additional highly or moderately emetogenic antineoplastic agents are only allowed on Day 1 after the start of AC combination, provided their administration is completed within 6 hours from the start of the AC combination administration.
6. ECOG Performance Status of 0 or 1.

7. Patient shall be: a) of non-childbearing potential or b) of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test within 24 hours prior to dose of investigational product.

   Notes:

   1. Female patients of non-childberaring potential are defined as being in post-menopausal state since at least 1 year; or having documented surgical sterilization or hysterectomy at least 3 months before study participation.
   2. Reliable contraceptive measures include implants, injectables, combined oral contraceptives, intrauterine devices, vasectomized partner or complete (long term) sexual abstinence;
8. Hematologic and metabolic status adequate for receiving a cycle of AC chemotherapy based on investigator's assessment.
9. If the patient has a known hepatic or renal impairment, she may be enrolled in the study at the discretion of the Investigator.
10. Able to read, understand, follow the study procedure and complete the patient diary.

All inclusion criteria will be checked at screening visit (Visit 1 of Cycle 1); inclusion criteria 7 will be re-checked at Day 1 (Visit 2).

Cycles 2 to 4:

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

1. 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.
2. Scheduled to receive an AC chemotherapy regimen or AC chemotherapy together with other chemotherapies as defined in Inclusion criterion #5 for Cycle 1.
3. Patient shall be: a) of non-childbearing potential or b) of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test within 24 hours prior to dosing of investigational product.
4. Adequate hematologic and metabolic status for receiving a cycle of AC chemotherapy according to the Investigator's opinion.

All inclusion criteria will be checked at screening visit (Visit 1); inclusion criterion #3 will be re-checked at Day 1 (Visit 2).

Exclusion Criteria:

Cycle 1:

The following exclusion criteria must be checked prior to inclusion at Cycle 1:

1. Lactating patient.
2. Current use of illicit drugs or current evidence of alcohol abuse.
3. Scheduled to receive moderately or highly emetogenic antineoplastic agent in addition to the AC regimen, from 6 hours after the start of the AC chemotherapy on Day 1 and up to Day 1 of Cycle 2.
4. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis within 1 week prior to the start of AC chemotherapy administration on Day 1 or between Days 1 to 5, inclusive.
5. Any vomiting, retching, or nausea (grade 1 as defined by National Cancer Institute) within 24 hours prior to the start of AC chemotherapy administration on Day 1.
6. Symptomatic primary or metastatic central nervous system (CNS) malignancy.
7. Active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, hypercalcemia, an active infection or any illness or medical conditions (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.
8. Known hypersensitivity or contraindication to 5 hydroxytryptamine type 3 (5-HT3) receptor antagonists (e.g., palonosetron, ondansetron, granisetron, dolasetron, tropisetron, ramosetron), to dexamethasone, or to neurokinin-1 (NK1) receptor antagonists (e.g., aprepitant, rolapitant).
9. Known contraindication to the IV administration of 50 mL 5% glucose solution.
10. Participation in a previous clinical trial involving IV fosnetupitant or oral netupitant administered alone or in combination with palonosetron.
11. Any investigational drugs taken within 4 weeks prior to Day 1, and/or is scheduled to receive any investigational drug (other than those planned by the study protocol) during the present study.
12. Systemic corticosteroid therapy within 72 hours prior to the start of AC chemotherapy administration on Day 1, except the dexamethasone provided as additional study drug. However, topical and inhaled corticosteroids are permitted.
13. Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy during the study participation.

14. Other than as administered as part of the study protocol, any medication with known or potential antiemetic activity within 24 hours prior to the start of AC chemotherapy administration on Day 1, including:

    • 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, ramosetron, palonosetron)
    • NK1 receptor antagonists (e.g., aprepitant, fosaprepitant, rolapitant or any other new drug of this class)
    • benzamides (e.g., metoclopramide, alizapride)
    • phenothiazines (e.g., prochlorperazine, promethazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine)
    • benzodiazepines (except if the subject is receiving such medication for sleep or anxiety and has been on a stable dose for at least seven days prior to Day 1).
    • butyrophenones (e.g., haloperidol, droperidol)
    • anticholinergics (e.g., scopolamine, with the exception of inhaled anticholinergics for respiratory disorders, e.g., ipratropium bromide)
    • antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine, chlorpheniramine)
    • domperidone
    • mirtazapine
    • olanzapine
    • prescribed cannabinoids (e.g., tetrahydrocannabinol or nabilone)
    • Over The Counter (OTC) antiemetics, OTC cold or OTC allergy medications.
15. Scheduled to receive any strong or moderate inhibitor of CYP3A4 during the efficacy assessment period (Day 1 to Day 5, inclusive) or its intake within 1 week prior to Day 1.
16. Scheduled to receive any CYP3A4 inducer during the efficacy assessment period (Day 1 to Day 5, inclusive) or its intake within 4 weeks prior to Day 1, with the exception of corticosteroids (for which exclusion criterion #12 applies).
17. History or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block.
18. History of risk factors for Torsades de Pointes (heart failure, hypokalemia, family history of Long QT Syndrome).
19. Severe or uncontrolled 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.

All exclusion criteria with the exception of criteria #5, #12, and #14 will be checked at screening visit (Visit 1). Exclusion criteria #5, #12, and #14 will be checked at Day 1 (Visit 2) only.

Exclusion criteria #3, #4, #7, #11, #13, #15, and #16 need to be re-checked at Day 1 (Visit 2).

Cycles 2 to 4:

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

1. Scheduled to receive moderately or highly emetogenic antineoplastic agent in addition to the AC regimen, from 6 hours after the start of the AC chemotherapy on Day 1 of current cycle and up to Day 1 of the next cycle.
2. Active infection or uncontrolled disease that may pose unwarranted risks in administering the study drugs to the patient.
3. Started any of the prohibited medications.
4. Any vomiting, retching, or nausea (grade ≥ 1 as defined by National Cancer Institute) within 24 hours prior to the start of AC chemotherapy administration on Day 1.
5. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis within 1 week prior to the start of AC chemotherapy administration on Day 1 or between Days 1 to 5.
6. Symptomatic primary or metastatic CNS malignancy.
7. Any illness or medical condition that, in the opinion of the investigator, may confound the results of the study or pose unwarranted risks in administering the investigational product or dexamethasone to the patient.

All exclusion criteria, with exception of criterion #4, will be checked at screening visit (Visit 1). Exclusion criterion #4 will be checked at Day 1 (Visit 2) only. Exclusion criteria #2, #3 and #5 need to be re-checked at Day 1 (Visit 2).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Test group; intravenous fosnetupitant/ palonosetron (260 mg/0.25 mg) fixed-dose combination, administered as a 30-minute infusion of a 50 mL solution, on Day 1 of each cycle. Oral dexamethasone will be administered on Day 1 of each cycle (12 mg)	Drug: fosnetupitant/ palonosetron; intravenous fosnetupitant/ palonosetron (260 mg/0.25 mg) fixed-dose combination; Other Names: IV NEPA FDC; Drug: dexamethasone; Oral dexamethasone (12 mg)
Active Comparator: Control group; oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination on Day 1 of each cycle. Oral dexamethasone will be administered on Day 1 of each cycle (12 mg)	Drug: dexamethasone; Oral dexamethasone (12 mg); Drug: netupitant/palonosetron; oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination; Other Names: Akynzeo capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants With Treatment-emergent AEs at Cycle 1	At the end of Cycle 1 (each cycle is 21 days)
Number of Participants With Treatment-emergent AEs All Cycles	At the end of Cycle 4 (each cycle is 21 days)
Number of Participants With Severe (i.e., CTCAE Grade ≥3) TEAEs Reported for ≥2% of Patients in Either Treatment Group and Overall Throughout the Study	At the end of Cycle 4 (each cycle is 21 days)
Number of Participants With Study-Drug-Related TEAEs Reported for ≥2% of Patients in Either Treatment Group Throughout the Study	At the end of Cycle 4 (each cycle is 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Response in Cycle 1 During the Acute Phase	defined as no emetic episodes [vomit or retch] and no rescue medication	24 hours after the start of AC chemotherapy administration
Complete Response in Cycle 1 During the Delayed Phase	defined as no emetic episodes [vomit or retch] and no rescue medication	120 hour after the start of AC chemotherapy administration
Complete Response in Cycle 1 During the Overall Phase	defined as no emetic episodes [vomit or retch] and no rescue medication	0-120 hours after the start of AC chemotherapy
Overall Percentage of Patients With NIDL Based on FLIE Scores for Cycles 1	Percentage (including two-sided 95% CI using Wilson score method) of patients with NIDL based on FLIE scores (overall, by domain, and by individual item) are summarized by treatment group. NIDL was defined as a score greater than 108 points, 54 points, and 6 points for total FLIE score, domain score, and single item score, respectively. Differences between treatment groups for total FLIE score and domain scores (nausea and vomiting) were presented with two-sided 95% CIs using the CMH method adjusted for region and age class strata and also using Newcombe-Wilson's method without strata adjustment. No Impact on Daily Life (NIDL) Based on Functional Living Index-Emesis (FLIE) Scores. The FLIE is a nausea and vomiting specific self report instrument comprised of two domains (nausea and vomiting) with nine identical items in each domain	cycle 1

Collaborators and Investigators

• Sponsor: Helsinn Healthcare SA
• Collaborators: The Physicians' Services Incorporated Foundation; George Clinical Pty Ltd

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2018
• Primary Completion (Actual): September 19, 2018
• Study Completion (Actual): September 19, 2018

Study Registration Dates

• First Submitted: January 4, 2018
• First Submitted That Met QC Criteria: January 10, 2018
• First Posted (Actual): January 19, 2018

Study Record Updates

• Last Update Posted (Actual): June 1, 2020
• Last Update Submitted That Met QC Criteria: May 15, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Nausea; Vomiting; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Serotonin Agents; Serotonin Antagonists; Serotonin 5-HT3 Receptor Antagonists; Dexamethasone; Palonosetron
• Other Study ID Numbers: NEPA-17-05

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No