A study to evaluate the safety and efficacy of a combination of pro-netupitant/palonosetron intravenously administered for the prevention of chemotherapy-induced nausea and vomiting.

• Register: EUCTR
• Last refreshed on: 29 August 2016
• Main ID: EUCTR2015-001800-74-AT
• Date of registration: 26/06/2015
• Prospective Registration: Yes
• Primary sponsor: Helsinn Healthcare SA
• Public title: A study to evaluate the safety and efficacy of a combination of pro-netupitant/palonosetron intravenously administered for the prevention of chemotherapy-induced nausea and vomiting.
• Scientific title: 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
• Date of first enrolment: 17/08/2015
• Target sample size: 400
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001800-74
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: double dummy If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Croatia, Czech Republic, Germany, Israel, Italy, Poland, Serbia, South Africa, Spain, Ukraine, United States

Contacts

• Name: Medical Monitoring and Consulting
• Affiliation: PSI CRO AG

• Name: Medical Monitoring and Consulting
• Affiliation: PSI CRO AG

Key inclusion & exclusion criteria

Inclusion criteria:
Cycle 1:
The following inclusion criteria must be checked prior to inclusion at Cycle 1:
1. Signed written informed consent.
2. Male or female patient = 18 years of age.
3. Histologically or cytologically confirmed solid tumor malignancy.
4. Naïve to cytotoxic chemotherapy. Previous biological or hormonal therapy will be permitted.
5. 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)
* on Day 1, additional HEC or MEC chemotherapeutic agents have to be administered after the start of the reference chemotherapy administration and their administration must be completed no more than 6 hours after the start of reference
chemotherapy infusion. Low, minimally or not emetogenic chemotherapies can be administered at any time after the start of the reference HEC.
6. ECOG Performance Status of 0, 1, or 2
7. If a patient is female, she shall be:
a) of non-childbearing potential or
b) of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test.
8. Hematologic and metabolic status adequate for receiving a HEC regimen and fulfillment of the following criteria:
a. Total Neutrophils = 1500/mm3 (Standard units: = 1.5 x 10^9/L)
b. Platelets = 100,000/mm3 (Standard units: = 100.0 x 10^9/L)
c. Bilirubin = 1.5 x Upper Limit of Normal (ULN)
d. Liver enzymes:
ii. Without known liver metastases, Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) iii. With known liver metastases, AST and ALT e. Serum Creatinine 9. 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:
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 the same chemotherapy regimen as Cycle 1 or one of the reference chemotherapies as defined in Inclusion criterion # 5 for Cycle 1.
3. If a patient is female, she shall be:
a) of non-childbearing potential or
b) of childbearing potential using reliable contraceptive measures and having a negative urine pregnancy test.
4. Adequate hematologic and metabolic status according to the Investigator’s opinion.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 300
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100

Exclusion criteria:
to be checked prior to inclusion at Cycle 1:
1. Lactating woman.
2. Active infection or uncontrolled disease except for malignancy that may pose unwarranted risks in administering the study drugs to the patient.
3. Current use of illicit drugs or current evidence of alcohol abuse.
4. Scheduled to receive moderately or highly emetogenic chemotherapies from Day 2 to Day 5.
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.
6. 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.
7. Symptomatic primary or metastatic CNS malignancy.
8. Known hypersensitivity or contraindication to 5-HT3 receptor antagonists to dexamethasone or to NK-1 receptor antagonists.
9. Known contraindication to the IV administration of 50 mL 5% glucose solution.
10 . Previously received an NK-1 receptor antagonist.
11. Participation in a previous clinical trial involving IV pro-netupitant or oral netupitant administered alone or in combination with palonosetron.
12. 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.
13. Systemic corticosteroid therapy at any dose within 72 hours prior to the start of reference chemotherapy administration on Day 1. However, topical and inhaled corticosteroids are permitted.
14. Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy.
15. Scheduled to receive any strong or moderate inhibitor of CYP3A4 or its intake within 1 week prior to Day 1
16. Scheduled to receive any of the following CYP3A4 substrates within 1 week prior to Day 1: terfenadine, cisapride, astemizole, pimozide.
17. Received within 4 weeks prior to Day 1 or scheduled to receive any CYP3A4 inducer
18. 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:
a. 5-HT3 receptor antagonists
b. NK-1 receptor antagonists
c. benzamides
d. phenothiazines
e. benzodiazepines (except if the patient is receiving such medication for sleep or anxiety and has been on a stable dose for at least seven days prior to Day 1)
f. butyrophenones
g. anticholinergics
h. antihistamines
i. domperidone
j. mirtazapine
k. olanzapine
l. prescribed cannabinoides
m. Over The Counter (OTC) antiemetics, OTC cold or OTC allergy medications.
19. History or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block.
20. History of Torsade de Point or known history of risk factors for Torsade de Point
21. 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) NYHA class III-IV, and severe uncontrolled arterial hypertension.
22. 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.
23. Concurrent medical condition that would preclude administra

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

nausea and vomiting in cancer patients receiving highly emetogenic therapy
MedDRA version: 19.0 Level: LLT Classification code 10036899 Term: Prophylaxis against chemotherapy induced vomiting System Organ Class: 100000004865

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: pro-netupitant/palonosetron fixed dose combination
Product Code: IV NEPA FDC
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: PALONOSETRON
CAS Number: 135729-62-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.25-
INN or Proposed INN: not yet available
CAS Number: 1703748-89-3
Current Sponsor code: 08-PNET
Other descriptive name: 204-NETU
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 260-
Pharmaceutical form of the placebo: Powder for solution for infusion
Route of administration of the placebo: Intravenous use

Trade Name: Akynzeo
Product Name: oral netupitant/palonesetron fixed-dose combination
Product Code: Oral NEPA FDC
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: NETUPITANT
CAS Number: 290297-26-6
Current Sponsor code: 14-NETU
Other descriptive name: Roche Compound Code RO 0673189
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-
INN or Proposed INN: PALONOSETRON
CAS Number: 135729-62-3
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: The primary objective is to assess the safety and tolerability of a single dose of IV NEPA FDC (260 mg/0.25 mg) infused over 30 minutes, with oral dexamethasone, in initial and repeated cycles of HEC.

Timepoint(s) of evaluation of this end point: Assessments of safety parameters will be obtained in each cycle

Secondary Objective: The secondary objective is to describe the efficacy of a single dose of IV NEPA FDC (260 mg/0.25 mg) infused over 30 minutes, with oral dexamethasone, during the acute (0-24 hours), delayed (>24-120 hours) and overall (0-120 hours) phases of initial and repeated cycles of HEC.

Primary end point(s): Safety endpoints
• physical examination (PE)
• vital signs
• 12-lead electrocardiogram (ECG)
• laboratory test (hematology, blood chemistry, urinalysis)
• adverse events (AEs) assessment

Secondary Outcome(s)

Secondary end point(s): Efficacy endpoints
Proportion of patients:
• with complete response (no emetic episodes and no rescue medication) during the acute, delayed and overall phases;
• with no emetic episodes during the acute, delayed and overall phases;
• with no significant nausea (Visual Analogue Scale (VAS) <25 mm) during the acute, delayed, and overall phases (since VAS is assessed daily, for delayed and overall phases the maximum VAS value in the relevant phase will be considered).

Timepoint(s) of evaluation of this end point: Acute phase (time interval 0 to 24 hours after the start of reference HEC), delayed phase (>24 to 120 hours after the start of reference HEC), and overall phase (0 to 120 hours after the start of reference HEC).

Secondary ID(s)

NEPA-15-18

Source(s) of Monetary Support

Helsinn Healthcare SA