A Study Of IV Casopitant For The Prevention Of Chemotherapy Induced Nausea And Vomiting.

Inclusion Criteria:

• A subject will be considered eligible for initial inclusion in this study, andprogression into subsequent cycles of therapy within the study, only if all of thefollowing criteria apply:

• Subject understands the nature and purpose of this study and the study procedures andhas signed an informed consent form for this study to indicate this understanding.

• At least 18 years of age.

• Is scheduled to receive oxaliplatin at a dose between 85 mg/m² and 130 mg/m² in theirfirst cycle of therapy for the treatment of colorectal cancer, administered as asingle IV dose over 2-6 hours on Day 1 only, in combination with 5FU/LV, or incombination with capecitabine.

• An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

• Hematologic and metabolic status adequate for receiving an oxaliplatin-basedmoderately emetogenic regimen and meeting the following criteria:

• Total Neutrophils ≥1500/mm³ (Standard units : ≥1.5 x 10^9/L)

• Platelets ≥100,000/mm³ (Standard units: ≥100.0 x 10^9/L)

• Bilirubin ≤1.5 x upper limit of normal (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 alanineaminotransferase (ALT) ≤2.5 x ULN.

• With known liver metastases: AST and/or ALT ≤5.0 x ULN.

• Is willing and able to complete daily components of the Subject Diary for Cycle 1and Cycle 2 without assistance from others.

• A female subject is eligible to enter and participate in this study if she is of:

1. non-childbearing potential (i.e., physiologically incapable of becomingpregnant, including any female who is post-menopausal. For purposes of thisstudy, postmenopausal is defined as one year without menses)

2. child-bearing potential: must have a negative serum pregnancy test result ornegative urine dipstick pregnancy test within 24 hours prior to the firstdose of investigational product on Cycle 1 Day 1. Women of childbearingpotential must also commit to consistent and correct use of an acceptablemethod of birth control. GSK acceptable contraceptive methods, when usedconsistently and in accordance with both the product label and theinstructions of the physician, are as follows:

• male partner who is sterile prior to the female subject's entry into the study and isthe sole sexual partner for that female subject;

• oral contraceptives (e.g., oral, injectable, or implantable) with double-barriermethod of contraception consisting of spermicide with either condom or diaphragm for aperiod after the trial to account for a potential drug interaction (minimum of sixweeks);

• double-barrier method of contraception consisting of spermicide with either condom ordiaphragm;

• intra-uterine device with a documented failure rate of less than 1% per year;

• complete abstinence from intercourse for two weeks before exposure to theinvestigational product throughout the clinical trial, and for a period after thetrial to account for elimination of the drug (minimum of 3 days);

• if subject indicates they will remain abstinent during the period described above,they must agree to follow GSK guidelines for the consistent and correct use of anacceptable method of birth control should they become sexually active.

Exclusion Criteria:

• A subject will not be eligible for initial inclusion in this study if any of thefollowing criteria apply, or will not be eligible for subsequent cycles of therapy ifany of the following criteria become applicable:

• Has received cytotoxic chemotherapy prior to the first study cycle of chemotherapy,with the exception that previous adjuvant therapy with 5FU/LV or capecitabine ispermitted, provided that the last dose of adjuvant therapy was completed at least 6months prior to receiving the first dose of study medication or investigationalproduct. Previous biological or hormonal therapy completed at any time is permitted.

• Scheduled to receive chemotherapy with any cytotoxic agents (e.g., irinotecan,gemcitabine) or biological agents (e.g., cetuximab, panitumimab) other than theprotocol allowed chemotherapy described in Inclusion Criterion 3.

• Is a female subject who is pregnant or lactating.

• Has received radiation therapy in the 10 days prior to the first dose of studymedication or investigational product and/or is scheduled to receive such radiationtherapy in the 6 days following the first dose of study medication or investigationalproduct in the first cycle of chemotherapy. Radiation therapy may be added insubsequent cycles of chemotherapy.

• Has experienced emesis (i.e., vomiting and/or retching) or clinically significantnausea in the 24 hours preceding the first dose of study medication or investigationalproduct for each cycle of chemotherapy.

• Has known central nervous system metastasis, unless previously successfully treatedwith excision or radiation, and has been stable for at least 1 week immediately priorto receiving the first dose of study medication or investigational product.

• Has increased intracranial pressure, hypercalcemia, an active systemic infection, orany uncontrolled medical condition (other than malignancy) which in the opinion of theInvestigator may confound the results of the study, represent another potentialetiology for emesis and nausea (other than CINV) or pose an unwarranted risk to thesubject.

• Has a known hypersensitivity or contraindication to ondansetron, another 5-HT3receptor antagonist, dexamethasone, or any component of casopitant.

• Has received an NK-1 receptor antagonist prior to the first study cycle ofchemotherapy.

• Has received an investigational drug within the previous 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study medication orinvestigational product, or is scheduled to receive any investigational drug otherthan casopitant/placebo during the study period.

• Has taken/received any medication of moderate or high emetogenic potential (includingantineoplastic agents [see Appendix 2]) within the 48 hours prior to the first dose ofstudy medication or investigational product in each cycle. However, opioid narcoticswill be permitted if the subject has been on such medication for at least 7 days at astable dose prior to the start of each cycle, and has not experienced emesis or nauseafrom the narcotics.

• Has taken/received any medication with known or potential antiemetic activity withinthe 24-hour period (unless otherwise stated) prior to receiving the first dose ofstudy medication or investigational product or is expected to require use of suchmedication during the 120 hour assessment period for Cycle 1 of therapy only. Thisincludes, but is not limited to:

• 5-HT3 receptor antagonists (e.g., additional ondansetron, or granisetron,dolasetron, tropisetron, ramosetron). Palonosetron is not permitted within 7 daysprior to administration of study medication or investigational product;

• benzamide / benzamide derivatives (e.g., metoclopramide, alizapride);

• benzodiazepines (except if the subject is receiving such medication for sleep oranxiety and has been on a stable dose for at least 7 days prior to the first doseof investigational product; however, lorazepam is prohibited 24 hours prior toreceiving study drug regardless of reason for use);

• phenothiazines (e.g., prochlorperazine, promethazine, fluphenazine, perphenazine,thiethylperazine, chlorpromazine);

• butyrophenones (e.g., haloperidol, droperidol);

• corticosteroids within 72 hours prior to the first dose of study medication orinvestigational product (e.g., dexamethasone, methylprednisolone); with theexception that topical steroids for skin disorders including eye and ear drops,and inhaled steroids for respiratory disorders at ≤ 10 mg prednisone daily or itsequivalent are permitted;

• anticholinergics (e.g., scopolamine); with the exception that anticholinergicsfor the treatment of respiratory disorders and the management of diarrhea (e.g.,ipratropium bromide, and hyoscyamine) and anticholinergic eye drops arepermitted;

• first-generation antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine;see Appendix 4); except for topical use which is permitted;

• domperidone;

• cannabinoids;

• mirtazapine;

• olanzapine.

• Has taken/received strong or moderate inhibitors of CYP3A4 and CYP3A5 for a specifiedperiod prior to administration of investigational product in each cycle of therapy.

• Has taken/received inducers of CYP3A4 and CYP3A5 within 14 days prior to theadministration of investigational product in each cycle of therapy.

• Is currently taking, or plans to take the following CYP2C8 substrates at any timeduring the study: the anti-diabetic agent repaglinide or the diuretic torsemide.

• Is currently taking, or plans to take any of the following CYP3A4 substrates at anytime during the study: astemizole, cisapride, pimozide, terfenadine.