E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
nausea and vomiting in cancer patients receiving highly emetogenic therapy |
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E.1.1.1 | Medical condition in easily understood language |
nausea and vomiting in cancer patients receiving chemotherapy |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036899 |
E.1.2 | Term | Prophylaxis against chemotherapy induced vomiting |
E.1.2 | System Organ Class | 100000004865 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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) </= 2.5 x ULN
iii. With known liver metastases, AST and ALT </= 5.0 x ULN
e. Serum Creatinine </= 1.5 mg/dL (Standard units: </= 132.6 µMol/L) or Creatinine Clearance ≥ 60 mL/min.
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. |
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E.4 | Principal 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 administration of dexamethasone such as systemic fungal infection or uncontrolled diabetes.
to be checked prior to inclusion in each repeated cycle:
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. Started any of the restricted medications.
4. 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.
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. Symptomatic primary or metastatic CNS malignancy.
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 #3 and 5 need to be re-checked at Day 1 (Visit 2).
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E.5 End points |
E.5.1 | 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
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessments of safety parameters will be obtained in each cycle
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E.5.2 | 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).
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E.5.2.1 | 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). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Croatia |
Czech Republic |
Germany |
Israel |
Italy |
Poland |
Serbia |
South Africa |
Spain |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS (please see also study protocol, section 6.3 "Definition of Completion") |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |