| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chemotherapy induced nausea and vomiting (CINV) due to Moderately Emetogenic Chemotherapy (MEC) |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008448 |
| E.1.2 | Term | Chemotherapy induced emesis prophylaxis |
|
| 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 demonstrate the superiority of triple therapy, casopitant, ZOFRAN and dexamethasone over dual therapy, ZOFRAN and dexamethasone in the prevention of emesis over the first 120 hours following the initiation of the first cycle of an anthracycline and cyclophosphamide containing MEC regimen. |
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| E.2.2 | Secondary objectives of the trial |
Determine if addition of casopitant provides incremental improvement in:
1) prevention of emesis in the acute (0-24 hrs.) and delayed (24-120 hrs.) phase following the first cycle of MEC
2) prevention of emesis in the acute, delayed and overall (0-120 hrs.) phase following subsequent cycles of MEC.
3) the control of nausea over the first 120 hours and in the acute and delayed phase following each cycle of MEC.
Quantify the impact of the antiemetic regimens on daily life activities, as assessed by a Functional Living Index-Emesis (FLIE) questionnaire following the first cycle of MEC.
Assess subject satisfaction with the prophylactic antiemetic regimen, and the willingness to use the same regimen during future chemotherapy treatments.
Determine the safety and tolerability of casopitant when administered as part of the antiemetic regimen outlined in this protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. A subject will be considered eligible for inclusion in this study only if all of the following criteria apply:
2. Subject understands the nature and purpose of this study and the study procedures and has signed an informed consent form for this study to indicate this understanding.
3. At least 18 years of age.
4. Is scheduled to receive their first course of an anthracycline and cyclophosphamide containing moderately emetogenic chemotherapy regimen for the treatment of a solid malignant tumor as outlined in Section 8.1.1.
5. Has an ECOG performance status of 0, 1, or 2.
6. Hematologic and metabolic status must be adequate for receiving a moderately emetogenic regimen and meet the following criteria:
• Total Neutrophils ≥ 1500/mm3 (Standard units : ≥1.5 x 109/L)
• Platelets ≥ 100,000/mm3 (Standard units: ≥100.0 x 109/L)
• Bilirubin ≤ 1.5 x ULN
• Liver enzymes must be below the following limits:
o Without known liver metastases: AST and/or ALT ≤ 2.5 x upper limit of normal.
o With known liver metastases: AST and/or ALT ≤ 5.0 x upper limit of normal.
7. Is willing and able to complete daily components of the subject diary for each study cycle.
8. Women of childbearing potential; must commit to consistent and correct use of an acceptable method of birth control; GSK acceptable contraceptive methods, when used consistently and in accordance with both the product label and the instructions of a physician, are as follows:
a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal. For purposes of this study, postmenopausal is defined as one year without menses)
b. child-bearing potential: must have a negative serum pregnancy test result or negative urine dipstick pregnancy test within 24 hours prior to the first dose of investigational product of Cycle 1, Day 1 and agrees to one of the following:
• male partner who is sterile prior to the female subject’s entry into the study and is the sole sexual partner for that female subject
• oral contraceptives (e.g., oral, injectable, or implantable) with double-barrier method of contraception consisting of spermicide with either condom or diaphragm for a period after the trial to account for potential drug interaction (minimum of six weeks)
• double-barrier method of contraception consisting of spermicide with either condom or diaphragm
• intra-uterine device (IUD) with a documented failure rate of less than 1% per year
• complete abstinence from intercourse for two weeks before exposure to the investigational product throughout the clinical trial, and for a period after the trial to account for elimination of the drug (minimum of three days),
• if subjects indicate they will remain abstinent during the period described above, they must agree to follow GSK guidelines for the consistent and correct use of an acceptable method of birth control should they become sexually active.
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|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Has previously received cytotoxic chemotherapy. A history of previous biological or hormonal therapy will be permitted.
2. Is a female subject who is pregnant or lactating.
3. Has received radiation therapy to the brain, abdomen, or pelvis in the ten days prior to the first dose of study medication or casopitant investigational product and/or will receive radiation therapy to the brain, abdomen, or the pelvis in the six days following the first dose of study medication (ZOFRAN and dexamethasone) or casopitant investigational product.
4. Is scheduled to receive taxane therapy during cycle 1. Note that subjects will be permitted to receive taxane therapy in conjunction with one of the allowed MEC regimens during subsequent cycles.
5. Has experienced emesis (i.e., vomiting and/or retching) or clinically significant nausea in the 24 hours preceding the first dose of study medication or casopitant investigational product.
6. Has a known central nervous system primary or metastatic malignancy, unless successfully treated with excision or radiation and has been medically stable for at least 1 week prior to receiving the first dose of study medication or casopitant investigational product.
7. Has history of documented peptic ulcer disease (via endoscopy or x-ray), active peptic ulcer disease, gastrointestinal obstruction, increased intracranial pressure, hypercalcemia, or any uncontrolled medical condition (other than malignancy) which in the opinion of the Investigator may confound the results of the study, represent another potential etiology for emesis and nausea (other than CINV) or pose an unwarranted risk to the subject.
8. Has a known hypersensitivity or contraindication to ZOFRAN, another 5-HT3 receptor antagonist, dexamethasone, or any component of casopitant.
9. Has previously received an NK-1 receptor antagonist.
10. Received an investigational drug in the previous 30 days or is scheduled to receive any investigational drug other than casopitant during the study period.
11. Has taken/received any medication of moderate or high emetogenic potential within the 48 hours prior to the first dose of study medication or casopitant investigational product. Opioid narcotics for cancer pain will be permitted if the subject has been on a stable dose and has not experienced emesis or nausea from the narcotics.
12. Has taken/received any medication with known or potential antiemetic activity within the 24-hour period prior to receiving study drug. This includes, but is not limited to:
• 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron, tropisetron, ramosetron). Palonestron is not permitted within 7 days prior to administration of investigational product.
• benzamide / benzamide derivatives (e.g., metoclopramide, alizapride)
• 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 the first dose of casopitant investigational product; however, lorazepam is prohibited 24 hours prior to receiving study drug regardless of reason for use)
• phenothiazines (e.g., prochlorperazine, promethazine, fluphenazine, perphenazine, thiethylperazine, chlorpromazine)
• butyrophenone (e.g., haloperidol, droperidol)
• corticosteroids (e.g., dexamethasone, methylprednisolone; with the exception of topical steroids for skin disorders, inhaled steroids for respiratory disorders, and prophylactic treatment for taxane therapy during subsequent cycles)
• anticholinergics (e.g., scopolamine, with the exception of inhaled anticholingerics for respiratory disorders e.g., ipratropium bromide)
• antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine), except for prophylactic use for taxane therapy during cycle 2-4
• domperidone
• cannabinoids
• mirtazpine
• olanzapine
13. Has taken/received strong or moderate inhibitors of CYP3A4 and CYP3A5 for a specified period prior to administration of casopitant investigational product
14. Has taken/received inducers of CYP3A4 and CYP3A5 within fourteen days prior to the administration of casopitant investigational product.
15. Is taking the anti-diabetic agent repaglinide or the diuretic torsemide. Investigators are advised to exercise caution if including patients taking the anti-diabetic agents rosiglitazone or pioglitazone, or antimalarial agents such as chloroquine and amodiaquine, as the metabolite of casopitant is a potential inhibitor of CYP2C8.
16. Is currently taking or plans to take the any of the following CYP3A4 substrates: astemizole, cisapride, pimozide, terfenadine. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be the proportion of subjects who achieve a complete response (defined as no vomiting/retching, and no rescue therapy) over the first 120 hours following the initiation of their first cycle of an anthracycline and cyclophosphamide containing MEC regimen. |
|
| 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 | Yes |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 78 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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