| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nausea and vomiting in cancer patients receiving moderately emetogenic theraphy |
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| 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 | 14.1 |
| 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 |
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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 |
| To compare the efficacy of a single oral dose of a fixed combination of netupitant and palonosetron (300 mg/0.50 mg) with oral dexamethasone versus oral palonosetron 0.50 mg with oral dexamethasone in terms of complete response in the delayed phase (25-120 hours) at cycle 1 |
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| E.2.2 | Secondary objectives of the trial |
To compare the efficacy, safety and tolerability of a single oral dose of a fixed combination of netupitant/palonosetron (300 mg/0.50 mg) with oral dexamethasone to oral palonosetron 0.50 mg with oral dexamethasone for the prevention of MEC induced nausea and vomiting in initial and repeat cycles.
To assess the population pharmacokinetics and pharmacodynamics of netupitant (and its metabolites M1, M2 and M3) and palonosetron in patients that have received the combination product. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PHARMACOKINETIC SUB STUDY: to obtain more information about the
concentration of netupitant (and its metabolites) and palonosetron in
the blood. Patients will separately consent before taking part in this sub study. SUB-STUDY TITLE: Population Pharmacokinetic and Pharmacodynamic Modeling of Netupitant (and its metabolites M1, M2 and M3) and Palonosetron: Pharmacokinetic Plan. SUB-STUDY CODE: NETU-10-02, AM1, version FINAL, 20 June 2011 |
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| 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 will be permitted. 4. Scheduled to receive first course of an anthracycline and cyclophosphamide containing moderately emetogenic chemotherapy (MEC) regimen for the treatment of a solid malignant tumor: cyclophosphamide I.V. (500 to 1500 mg/m2) and I.V. doxorubicin (greater or equal than 40 mg/m2) or cyclophosphamide I.V. (500 to 1500 mg/m2) and I.V. epirubicin (greater or equal than 60 mg/m2). 5. If scheduled to receive chemotherapy agents of minimal to low emetogenic potential they could be given on any day. 6. ECOG Performance Status of 0, 1, or 2. 7. 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 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. 8. Hematologic and metabolic status adequate for receiving a moderately emetogenic regimen and fulfilment 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 ULN; - with known liver metastases, AST and/or ALT less or equal than 5.0 x ULN; e. Serum Creatinine less or equal than 1.5 mg/dL (Standard units: less or equal than 132.6 MOL/L) or Creatinine Clearance greater or equal than 60 mL/min. 9. Able to read, understand, follow the study procedure and complete patient diary.
Inclusion Criteria (Multiple-Cycle Extension):
The following inclusion criteria must be checked prior inclusion at each cycle of the Multiple-Cycle Extension: 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. Satisfactory study compliance in the preceding cycle of chemotherapy and related study procedures. 3. Scheduled to receive the same chemotherapy regimen as cycle 1 as defined in Inclusion Criterion n. 4. 4. Adequate hematologic and metabolic status as defined by Inclusion Criterion n. 8.
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| E.4 | Principal exclusion criteria |
1. If female, pregnant or lactating. 2. Current use of illicit drugs or current evidence of alcohol abuse. 3. Scheduled to receive any highly emetogenic chemotherapy (HEC) from Day 1 to Day 5 or moderately emetogenic chemotherapy (MEC) from Day 2 to Day 5 following the allowed MEC regimen. 4. Received or is scheduled to receive radiation therapy to the abdomen or the pelvis within 1 week prior to Day 1 or between Days 1 to 5 in cycle 1. 5.Any vomiting, retching, or mild nausea (grade greater or equal than I as defined by National Cancer Institute) within 24 hours prior to Day 1. 6. Symptomatic primary or metastatic CNS malignancy. 7. Active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, hypercalcemia, an active infection or any uncontrolled medical condition (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-HT3 receptor antagonists (e.g., palonosetron, ondansetron, granisetron, dolasetron, tropisetron, ramosetron) or dexamethasone. 9. Previously received an NK1 receptor antagonist (e.g., aprepitant, casopitant). 10. Participation in a clinical trial involving oral netupitant administered in combination with palonosetron. 11. 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.
12. 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. 13. Scheduled to receive bone marrow transplantation and/or stem cell rescue therapy. 14. Any medication with known or potential antiemetic activity within 24 hours prior to Day 1 of cycle 1, including:
- 5 HT3 receptor antagonists (e.g. ondansetron, granisetron, dolasetron, tropisetron, ramosetron, palonosetron); - 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, chlorphenhyramine), except for prophylactic use for taxane therapy; - domperidone; - mirtazapine; - oolanzapine; - prescribed cannabinoides (e.g. tetrahydrocannabinol or nabilone). 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: terfenadine, cisapride, astemizole, pimozide. 17. Scheduled to receive any CYP3A4 inducer or its intake within 4 weeks prior to Day 1. 18. History or predisposition to cardiac conduction abnormalities, except for incomplete right bundle branch block. 19. History of risk factors for Torsade de Point (heart failure, hypokalemia, family history of Long QT Syndrome). 20. Severe 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) NYHA class III-IV, and severe uncontrolled arterial hypertension. 21. 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.
22. Concurrent medical condition that would preclude administration of dexamethasone such as systemic fungal infection or uncontrolled diabetes.
Exclusion Criteria (Multiple-Cycle Extension):
The following exclusion criteria must be checked prior inclusion at each cycle of the Multiple-Cycle Extension: 1. If female, pregnant or lactating, i.e. positive urine dipstick pregnancy test within 24 hours prior to Day 1. 2. Active infection or uncontrolled disease except for malignancy. 3. Started any of the restricted medications. 4. Any vomiting, retching, or mild nausea (grade greater or equal than I as defined by National Cancer Institute) within 24 hours prior to Day 1. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the proportion of patients with complete response (CR) (defined as no emesis, no rescue medication) in the time interval 25-120 hours after the start of the MEC administration at cycle 1. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time interval 25-120 hours after the start of the MEC administration at cycle 1 |
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| E.5.2 | Secondary end point(s) |
Key secondary efficacy endpoints are defined as the proportion of patients with: • complete response during the acute phase; • complete response during the overall phase.
Other secondary efficacy endpoints are defined as the proportion of patients with: • no emesis during the delayed, acute and overall phase; • no rescue medication during the delayed, acute and overall phase; • no significant nausea (maximum Visual Analogue Scale (VAS)<25 mm) during the delayed, acute and overall phase; • no nausea (maximum VAS<5 mm) during the delayed, acute and overall phase; • complete protection (no emetic episode, no rescue medication and no significant nausea), during the delayed, acute and overall phase; • total control (no emetic episode, no rescue medication and no nausea), during the delayed, acute and overall phase. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary efficacy endpoints: only if the primary objective is met, key secondary efficacy endpoints will be analyzed hierarchically (first acute and then overall) using the same CMH test adopted for the primary endpoint.
Other secondary efficacy endpoints: they will be analyzed in each phase (delayed, acute, overall) only if the superiority of the fixed combination in terms of complete response is demonstrated for that phase. |
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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 | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Argentina |
| Brazil |
| Bulgaria |
| Croatia |
| Germany |
| Hungary |
| India |
| Italy |
| Mexico |
| Poland |
| Romania |
| Russian Federation |
| 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. Each patient may participate in as many consecutive repeat cycles as long as they continue to fulfill the inclusion exclusion criteria for the Multiple-Cycle Extension. |
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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 | 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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