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

Chemotherapy-induced Nausea and Vomiting Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03403712
• Other study ID #: NEPA-17-05
• Status: Completed
• Phase: Phase 3
• Start date: March 16, 2018
• Est. completion date: September 19, 2018

Study information

• Verified date: May 2020
• Source: Helsinn Healthcare SA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 404
• Est. completion date: September 19, 2018
• Est. primary completion date: September 19, 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Chemotherapy-induced Nausea and Vomiting
• Nausea
• Vomiting

Intervention

Drug:
• fosnetupitant/ palonosetron
intravenous fosnetupitant/ palonosetron (260 mg/0.25 mg) fixed-dose combination
• netupitant/palonosetron
oral netupitant/palonosetron (300 mg/0.50 mg) fixed-dose combination
• dexamethasone
Oral dexamethasone (12 mg)

Locations

Country	Name	City	State
Georgia	JSC Saint Nikolozi Surgery and Oncological Centre	Kutaisi
Georgia	LTD Institute of Clinical Oncology	Tbilisi
Georgia	LTD S.Khechinashvili University Hospital	Tbilisi
Georgia	LTD Tbilisi Oncology Dispensary	Tbilisi
United States	Pacific Cancer Medical Center, Inc.	Anaheim	California
United States	Ashland-Bellefonte Cancer Center	Ashland	Kentucky
United States	University Cancer & Blood Center, LLC	Athens	Georgia
United States	CBCC Global Research, INC at Comprehensive Blood and Cancer Center	Bakersfield	California
United States	Mercy Medical Center, Medical Oncology and Hematology	Baltimore	Maryland
United States	Cheyenne Regional Medical Center	Cheyenne	Wyoming
United States	Mid Ohio Oncology/Hematology Inc. DBA The Mark H. Zangmeister Center	Columbus	Ohio
United States	The Oncology Tnstitute of Hope and Innovation	Corona	California
United States	Cancer Center of !\!Iiddle Georgia	Dublin	Georgia
United States	Trinitas Cancer Center	Elizabeth	New Jersey
United States	San Juan Oncology Associates	Farmington	New Mexico
United States	Fort Wayne Medical Oncology and Hematology, Inc.	Fort Wayne	Indiana
United States	The West Clinic, PC dba West Cancer Center	Germantown	Tennessee
United States	Hattiesburg Clinic Hematology Oncology	Hattiesburg	Mississippi
United States	Uptimum Medical Group Inc.	Inglewood	California
United States	Cornell-Beshore Cancer Institute	Joplin	Missouri
United States	TU Health Arnett Cancer Center	Lafayette	Indiana
United States	Watson Clinic LLP	Lakeland	Florida
United States	Carti Cancer Center	Little Rock	Arkansas
United States	The Oncology Institute of Hope and Innnovation	Long Beach	California
United States	Hao Wei Zhang M.D.	Los Angeles	California
United States	Monongahela Valley Hospital	Monongahela	Pennsylvania
United States	Baptist Health Cancer Center	New Albany	Indiana
United States	Mid Florida Hematology and Oncology Center	Orange City	Florida
United States	Emad Ibrahim, MD, INC.	Redlands	California
United States	Carolina Blood and Cancer Care Associates, P.A.	Rock Hill	South Carolina
United States	Harbin Clinic	Rome	Georgia
United States	Summit Cancer Care	Savannah	Georgia
United States	CHRISTUS Cancer Treatment Center	Shreveport	Louisiana
United States	Edward H. Kaplan MD & Associates	Skokie	Illinois
United States	Presence Infusion Care - Skokie	Skokie	Illinois
United States	Cox Mcdical ·Centers	Springfield	Missouri
United States	Toledo Clinic Cancer Center - Toledo	Toledo	Ohio
United States	Cotton O'Neil Clinical Res. Ctr., Hematology & Oncology	Topeka	Kansas
United States	The Oncology Inst. Of Hope and Innovation	Tucson	Arizona
United States	Cancer Center of Kansas	Wichita	Kansas

Sponsors (3)

Lead Sponsor	Collaborator
Helsinn Healthcare SA	George Clinical Pty Ltd, The Physicians' Services Incorporated Foundation

Countries where clinical trial is conducted

United States,  Georgia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Treatment-emergent AEs at Cycle 1		At the end of Cycle 1 (each cycle is 21 days)
Primary	Number of Participants With Treatment-emergent AEs All Cycles		At the end of Cycle 4 (each cycle is 21 days)
Primary	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)
Primary	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	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
Secondary	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
Secondary	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
Secondary	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