| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nausea and vomiting in cancer patients associated with chemotherapy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Nausea and vomiting in cancer patients receiving chemotheraphy |
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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 | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10054133 |
| E.1.2 | Term | Prophylaxis of nausea and vomiting |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 |
| To assess the safety and tolerability of a single oral dose of a fixed combination of netupitant and palonosetron (300 mg/0.50 mg) in initial and repeated cycles of chemotherapy |
|
| E.2.2 | Secondary objectives of the trial |
| To describe the efficacy of a single oral dose of a fixed combination of netupitant and palonosetron (300 mg/0.50 mg) with oral dexamethasone during the acute (0-24 hours), delayed (25-120 hours) and overall (0-120 hours) phases of initial and repeated cycles of chemotherapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1.Signed written informed consent; 2.Male or female patient greater or equal than 18 years of age; 3.Naïve to cytotoxic chemotherapy. Previous biological or hormonal therapy is permitted; 4.Diagnosed with a malignant tumor; 5.If scheduled to receive repeated consecutive courses of chemotherapy, a single dose of one or more of the following agents administered on Day 1 is allowed: - Highly emetogenic chemotherapy (HEC): any I.V. dose of cisplatin, mechlorethamine, streptozocin, cyclophosphamide greater or equal than 1500 mg/m2, carmustine, dacarbazine, - Moderately emetogenic chemotherapy (MEC): any I.V. dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin, cyclophosphamide I.V. (< 1500 mg/m2), cytarabine I.V. (> 1 g/m2), azacidine, alemtuzumab, bendamustine, or clofarabine; 6.If scheduled to receive combination regimens, the most emetogenic agent according to the MASCC/ESMO Antiemetic Guidelines 2010 is to be given as first on Day 1 and the infusion must be completed within 6 hours; 7.If scheduled to receive chemotherapy agents of minimal to low emetogenic potential (Appendix 4), they are to be given on Day 1 following the most emetogenic agent or on any subsequent study day; 8.ECOG Performance Status of 0, 1, or 2 (Appendix 5); 9.Female patients of either: a.non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is postmenopausal. For purposes of this study, postmenopausal is defined as 12 consecutive months of amenorrhea). In addition, postmenopausal definition has to be confirmed by consistent age and/or Follicle-Stimulating Hormone (FSH) levels) - b.child-bearing potential with a negative urine dipstick pregnancy test within 24 hours prior to the first dose of investigational product of Day 1 of each cycle and with a commitment to consistent and correct use throughout the clinical trial of one of the following contraceptive methods: - whose male partner is sterile prior to the female patient’s entry into the study and is the sole sexual partner, - using double-barrier method of contraception consisting of spermicide with either condom or diaphragm, also if taking any oral contraceptive, for a period after the trial to account for a potential drug interaction (minimum four weeks), - with intrauterine device (IUD), - with complete abstinence from intercourse for two weeks before exposure to the investigational product and throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum of twenty one days); should patients become sexually active during the period described above, they must agree to follow an acceptable method of birth control, as described above; 10.Hematologic and metabolic status adequate for receiving a chemotherapy regimen and fulfillment of the following criteria: a)Total Neutrophils greater or equal than 1500/mm3 (Standard units: greater or equal than 1.5 x 10^9/L), b)Platelets greater or equal than 100,000/mm3 (Standard units: greater or equal than 100.0 x 10^9/L), c)Bilirubin less or equal than 1.5 x Upper Limit of Normal (ULN), d)Liver enzymes: - Without known liver metastases, Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) less or equal than 2.5 x Upper Limit of Normal (ULN), - With known liver metastases, AST and/or ALT < 5.0 x Upper Limit of Normal (ULN), e)Serum Creatinine less or equal than 1.5 mg/dL (Standard units: less or equal than 132.6 microMOL/L) or Creatinine Clearance greater or equal than 60 mL/min; 11.Able to read, understand, follow the study procedure and complete patient diary |
|
| E.4 | Principal exclusion criteria |
| 1.If female, lactating or pregnant i.e. positive urine dipstick pregnancy test within 24 hours prior to Day 1 of each cycle; 2.Current use of illicit drugs or current evidence of alcohol abuse; 3. Scheduled to receive either: - a.cyclophosphamide I.V. (500 to 1500 mg/m2) and I.V. doxorubicin (greater or equal than 40 mg/m2), - b.cyclophosphamide I.V. (500 to 1500 mg/m2) and I.V. epirubicin (greater or equal than 60 mg/m2); 4. Scheduled to receive moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) from Day 2 to Day 5 following Day 1 chemotherapy administration; 5.Active infection or uncontrolled disease except for malignancy that may pose unwarranted risks in administering the study drugs to the patient; 6.Known hypersensitivity or contraindication to 5-HT3 receptor antagonists (e.g., palonosetron, ondansetron, granisetron, dolasetron, tropisetron, ramosetron) or dexamethasone; 7.Previously received an NK1 receptor antagonist (e.g., aprepitant, casopitant); 8.Participation in a clinical trial involving oral netupitant administered in combination with palonosetron; 9.Any investigational drugs taken within 4 weeks prior to Day 1 of cycle 1, and/or is scheduled to receive any investigational drug during the study; 10.Systemic corticosteroid therapy at any dose within 72 hours prior to Day 1 of cycle 1. However topical and inhaled corticosteroids with a steroid dose of less or equal than 10 mg of prednisone daily or its equivalent are permitted. Non-study drug dexamethasone as pre-medication in patients scheduled to receive taxanes is allowed; 11.Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy; 12.Scheduled to receive any strong or moderate inhibitor of CYP3A4 or its intake within 1 week prior to Day 1 (Appendix 1); 13.Scheduled to receive any of the following CYP3A4 substrates: terfenadine, cisapride, astemizole, pimozide; 14.Scheduled to receive any CYP3A4 inducer or its intake within 4 weeks prior to Day 1 (Appendix 1); 15.History or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block; 16.History of risk factors for Torsade de Point (heart failure, hypokalemia, family history of Long QT Syndrome); 17.Severe cardiovascular diseases within 3 months prior to Day 1, including myocardial infarction, unstable angina pectoris, significant valvular or pericardial disease, history of ventricular tachycardia, symptomatic Congestive Heart Failure (CHF) NYHA class III-IV (Appendix 6), and severe uncontrolled arterial hypertension; 18.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; 19.Concurrent medical condition that would preclude administration of dexamethasone for 4 days such as systemic fungal infection or uncontrolled diabetes |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The following efficacy endpoints are defined as the proportion of patients with: - complete response (no emetic episode, no rescue medication) during the delayed phase, acute and overall phase; - no significant nausea (maximum Visual Analogue Scale, VAS <25 mm) during the delayed, acute and overall phase. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Delayed phase, acute and overall phase |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| 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 |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| Bulgaria |
| Czech Republic |
| Germany |
| Hungary |
| India |
| Poland |
| Russian Federation |
| Serbia |
| Ukraine |
| United States |
|
| 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
|
| LVLS. While 2 to 5 weeks/cycle per patient are foreseen, there is no limit in the number of repeat consecutive cycles for each patient. The study will be closed after the last patient enrolled will have completed his/her last scheduled chemotherapy cycle |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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