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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

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ClinicalTrials.gov Identifier: NCT03403712
Recruitment Status : Recruiting
First Posted : January 19, 2018
Last Update Posted : May 10, 2018
Sponsor:
Collaborators:
George Clinical Pty Ltd
PSI CRO AG
Information provided by (Responsible Party):
Helsinn Healthcare SA

Brief Summary:
Multicenter, randomized, double-blind, double-dummy, parallel group, stratified study assessing the safety and describing the efficacy of a single dose of intraveneous (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.

Condition or disease Intervention/treatment Phase
Chemotherapy-induced Nausea and Vomiting Drug: fosnetupitant/ palonosetron Drug: netupitant/palonosetron Drug: dexamethasone Phase 3

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: 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
Actual Study Start Date : March 16, 2018
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : October 2018

Resource links provided by the National Library of Medicine


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 Name: 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: netupitant/palonosetron
oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination
Other Name: Akynzeo capsules

Drug: dexamethasone
Oral dexamethasone (12 mg)




Primary Outcome Measures :
  1. treatment-emergent AEs at cycle 1 [ Time Frame: At the end of Cycle 1 (each cycle is 21 days) ]
  2. treatment-emergent AEs at cycle 2 [ Time Frame: At the end of Cycle 2 (each cycle is 21 days) ]
  3. treatment-emergent AEs at cycle 3 [ Time Frame: At the end of Cycle 3 (each cycle is 21 days) ]
  4. treatment-emergent AEs at cycle 4 [ Time Frame: At the end of Cycle 4 (each cycle is 21 days) ]

Secondary Outcome Measures :
  1. Emetic Episodes [ Time Frame: 120 hours after the start of AC chemotherapy administration ]
    one or more continuous vomits (expulsion of stomach contents through the mouth) or retches (an attempt to vomit that is not productive of stomach contents)

  2. Rescue Therapy [ Time Frame: 0-120 hour interval (Day 1 to Day 5) after the start of AC chemotherapy administration ]
    Rescue medication will be permitted on an as-needed basis. The patient will record in the patient diary the drug name, dosage and date/time of intake for each medication taken for the treatment of nausea and vomiting

  3. Severity of Nausea [ Time Frame: each day of the 0-120 hour interval (Days 1 to 5, inclusive) ]
    Severity of nausea will be evaluated by the patient in the patient diary for each day of the 0-120 hour interval using a 100-mm horizontal VAS. The left end of the scale (0 mm) will be labeled as 'no nausea' and the right end of the scale (100 mm) will be labeled as 'nausea as bad as it could be'

  4. Functional Living Index-Emesis (FLIE) Questionnaire [ Time Frame: cycle 1 and 2 ]
    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



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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).


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03403712


Contacts
Contact: Daniel Voisin +41 91 985 21 21 Daniel.Voisin@helsinn.com

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Sponsors and Collaborators
Helsinn Healthcare SA
George Clinical Pty Ltd
PSI CRO AG

Responsible Party: Helsinn Healthcare SA
ClinicalTrials.gov Identifier: NCT03403712     History of Changes
Other Study ID Numbers: NEPA-17-05
First Posted: January 19, 2018    Key Record Dates
Last Update Posted: May 10, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Vomiting
Nausea
Signs and Symptoms, Digestive
Signs and Symptoms
Dexamethasone acetate
Dexamethasone
BB 1101
Palonosetron
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Serotonin Antagonists
Serotonin Agents
Neurotransmitter Agents