| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chemotherapy induced nausea and vomiting (CINV) due to Highly Emetogenic Chemotherapy (HEC) |
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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 |
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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 of this study is to demonstrate the superiority of triple therapy, casopitant, ZOFRAN and dexamethasone over dual therapy ZOFRAN and dexamethasone in prevention of emesis over the first 120 hours following the initiation of the first cycle of cisplatin-based highly emetogenic chemotherapy (HEC) regimen |
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| E.2.2 | Secondary objectives of the trial |
• Determine whether the addition of casopitant provides incremental improvement in the prevention of emesis in:
1) the acute (0-24 hrs.) and delayed (24-120 hrs.) phase following the first cycle of HEC.
2) the acute (0-24 hrs.), delayed (24-120 hrs.) and overall (0-120 hrs.) phases following subsequent cycles of HEC.
• Determine whether the addition of casopitant provides incremental improvement in the control of nausea over the first 120 hours and in the acute and delayed phases following each cycle of HEC.
• 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 HEC.
• Assess subject satisfaction with the prophylactic antiemetic regimen, and the willingness of subjects 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.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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.
2. Males or females of at least 18 years of age.
3. Diagnosed with a malignant solid tumor and is scheduled to receive their first course of cytotoxic chemotherapy with cisplatin administered as a single intravenous dose of . 70mg/m2 over 1-4 hours on study Day 1, either alone or in combination with other chemotherapeutic agents. For combination regimens, non-cisplatin agents of moderate to high emetogenic potential will be allowed, but must be administered following the cisplatin infusion and be completed no more than 6 hours after the initiation of the cisplatin infusion. Chemotherapy agents of minimal to low emetogenic potential may be given on or following study Day 1. Taxanes (e.g. paclitaxel, docetaxel) may be administered on study Day 1 only.
4. Has an ECOG Performance Status of 0, 1, or 2.
5. Hematologic and metabolic status must be adequate for receiving a highly emetogenic cisplatin-based 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
• Serum Creatinine ≤1.5 mg/dL (Standard units : ≤ 132.6 µMOL/L)
OR
• Creatinine clearance ≥ 60 mL/min
Creatinine clearance must be calculated using the Cockcroft-Gault formula:
Clcreat (ml/min) = (140-age [yr]) x body wt [kg]
72 x serum creatinine [mg/dl]
For females: multiply creatinine clearance by a factor of 0.85.
OR
Clcreat (ml/min) = K x (140-age [yr]) x body wt [kg]
serum creatinine [µmol/L]
K=1.05 for females
K=1.23 for males
• Liver enzymes must be below the following limits:
• Without known liver metastases: Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal.
•With known liver metastases: AST and/or ALT ≤ 5.0 x upper limit of normal.
6. Is willing and able to complete daily components of the subject diary for each study cycle.
7. 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 a 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 |
1. Has previously received cytotoxic chemotherapy. Previous biological or hormonal therapy will be permitted.
2. Is scheduled to receive cisplatin treatment on more than one day during a single cycle of therapy.
3. If female, is pregnant or lactating.
4. Has received radiation therapy to the thorax, abdomen, or the pelvis in the 10 days prior to receiving the first dose of study medication and/or will receive radiation therapy to the abdomen or the pelvis in the 6 days following the first dose of study medication.
5. Emesis experienced in the 24 hours prior to receiving the first dose of study medication.
6. Clinically significant nausea (e.g. >= 25 mm on a VAS) in the 24 hours prior to receiving the first dose of study medication.
7. A known central nervous system primary or malignancy metastatic to the CNS, unless successfully treated with excision or radiation and subsequently has been stable for at least 1 week prior to receiving the first dose of study medication.
8. Has history of documented peptic ulcer disease, active peptic ulcer disease, gastrointestinal obstruction, gastrointestinal carcinoma, 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.
9. Has a known hypersensitivity or contraindication to ZOFRAN, another 5-HT3 receptor antagonist, dexamethasone, or any component of casopitant.
10. Has previously received an NK-1 receptor antagonist.
11. An active systemic infection or any uncontrolled disease (other than malignancy) which, in the opinion of the investigator, may confound the results of the study or pose an unwarranted risk to the subject. Subjects with a previous, but not current, history of alcoholism may be permitted provided that, in the investigator’s opinion, the subject’s disease state will not confound the results of the study.
12. Receiving or planning to receive a systemic corticosteroid therapy at any dose within 72 hours prior to the first dose of study medication, except where indicated as premedication for a taxane. However, topical steroids and inhaled corticosteroids with a steroid dose of <= 10 mg prednisone daily or its equivalent are permitted.
13. Is scheduled to receive bone marrow transplantation and/or stem cell rescue with this course of cisplatin therapy.
14. Has received an investigational drug within the 30 days or five half-lives (whichever is longer) prior to receiving the first dose of study medication, and/or is scheduled to receive any investigational drug during the study.
15. Has received moderately and/or highly emetogenic medication within the 48 hours prior to the first dose of study medication. (Opioid narcotics for cancer pain will be permitted if the subject has been on such medication for at least 7 days and has not experienced nausea or emesis from the narcotics.)
16. Has taken/received any medication with known or potential antiemetic activity within the 24-hour period prior to receiving study drug.
17. Has taken/received strong or moderate inhibitors of CYP3A4 and CYP3A5 prior to administration of casopitant (GW679769) investigational product
18. Has taken/received inducers of CYP3A4 and CYP3A5 within fourteen days prior to the administration of casopitant investigational product
19. 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 |
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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 a cisplatin-based highly emetogenic chemotherapy regimen |
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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 | 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 |
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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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| 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 | 4 |
| 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 | 4 |
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