A Study of the Drug Casopitant for the Prevention of Nausea Caused By Cisplatin-Based Highly Emetogenic Chemotherapy

Inclusion criteria:

• 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.

• Males or females of at least 18 years of age.

• Diagnosed with a malignant solid tumor and is scheduled to receive their first courseof 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 otherchemotherapeutic agents. For combination regimens, non-cisplatin agents of moderate tohigh emetogenic potential will be allowed, but must be administered following thecisplatin infusion and be completed no more than 6 hours after the initiation of thecisplatin infusion. Chemotherapy agents of minimal to low emetogenic potential may begiven on Day 1 following cisplatin or on any subsequent study day. Taxanes (e.g.paclitaxel, docetaxel) may be administered on study Day 1 only following cisplatin.

• Has an ECOG Performance Status of 0, 1, or 2.

• Hematologic and metabolic status must be adequate for receiving a highly emetogeniccisplatin-based regimen and meet the following criteria:

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

• Platelets ≥ 100,000/mm (Standard units: ≥100.0 x 10^9/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) = (140-age [yr]) xbody 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 upper limit of normal.

• With known liver metastases: AST and/or ALT ≤ 5.0 x upper limit of normal.

• Is willing and able to complete daily components of the subject diary for eachstudy cycle.

• Women of childbearing potential; must commit to consistent and correct use of anacceptable method of birth control; GSK acceptable contraceptive methods, whenused consistently and in accordance with both the product label and theinstructions of a physician, are as follows:

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 of cycle 1 day 1, and agrees to one of thefollowing:

• 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-barrier method of contraception consisting ofspermicide with either condom or diaphragm for a period after the trial to account fora potential drug interaction (minimum of six weeks)

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

• 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 theinvestigational product throughout the clinical trial, and for a period after thetrial 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 anacceptable method of birth control should they become sexually active. obstruction

Exclusion criteria:

• Has previously received cytotoxic chemotherapy. Previous biological or hormonaltherapy will be permitted.

• Is scheduled to receive cisplatin treatment on more than one day during a single cycleof therapy.

• If female, is pregnant or lactating.

• Has received radiation therapy to the thorax, head & neck, abdomen, or the pelvis inthe 10 days prior to receiving the first dose of study medication and/or will receiveradiation therapy to the thorax, head & neck, abdomen or the pelvis in the 6 daysfollowing the first dose of study medication.

• Emesis (i.e. vomiting and/or retching) experienced in the 24 hours prior to receivingthe first dose of study medication.

• Clinically significant nausea (e.g. ≥25 mm on a VAS) in the 24 hours prior toreceiving the first dose of study medication.

• A known central nervous system primary or malignancy metastatic to the CNS, unlesssuccessfully treated with excision or radiation and subsequently has been stable forat least 1 week prior to receiving the first dose of study medication.

• Has history of documented peptic ulcer disease (via endoscopy or x-ray), active pepticulcer disease, gastrointestinal obstruction, increased intracranial pressure,hypercalcemia, or any uncontrolled medical condition (other than malignancy) which inthe opinion of the Investigator may confound the results of the study, representanother potential etiology for emesis and nausea (other than CINV) or pose anunwarranted risk to the subject.

• Has a known hypersensitivity or contraindication to ZOFRAN, another 5-HT3 receptorantagonist, dexamethasone, or any component of casopitant.

• Has previously received an NK-1 receptor antagonist.

• 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 orpose 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.

• 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 aspremedication for a taxane. However, topical steroids and inhaled corticosteroids witha steroid dose of≤10 mg prednisone daily or its equivalent are permitted.

• Is scheduled to receive bone marrow transplantation and/or stem cell rescue with thiscourse of cisplatin therapy.

• Has received an investigational drug within the 30 days or five half-lives (whicheveris longer) prior to receiving the first dose of study medication, and/or is scheduledto receive any investigational drug during the study.

• Has received moderately and/or highly emetogenic medication within the 48 hours priorto the first dose of study medication. (Opioid narcotics for cancer pain will bepermitted if the subject has been on such medication for at least 7 days and has notexperienced nausea or emesis from the narcotics.)

• Has taken/received any medication with known or potential antiemetic activity withinthe 24-hour period prior to receiving study drug. This includes, but is not limitedto:

• 5-HT3 receptor antagonists (e.g., ondansetron, granisetron, dolasetron,tropisetron, ramosetron). Palonestron is not permitted within 7 days prior toadministration of 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 seven days prior to the firstdose of GW679769 investigational product; however, lorazepam is prohibited 24hours 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 oftopical steroids for skin disorders, inhaled steroids for respiratory disorders,and prophylactic treatment for taxane or pemetrexed therapy)

• anticholinergics (e.g., scopolamine with the exception of inhaledanticholingerics for respiratory disorders e.g., ipratropium bromide)

• antihistamines (e.g., cyclizine, hydroxyzine, diphenhydramine), except forprophylactic use for taxane therapy

• domperidone

• mirtazapine

• olanzapine

• cannabinoids

• Has taken/received strong or moderate inhibitors of CYP3A4 and CYP3A5 prior toadministration of casopitant (GW679769) investigational product

• Has taken/received inducers of CYP3A4 and CYP3A5 within fourteen days prior to theadministration of casopitant investigational product

• Is taking the anti-diabetic agent repaglinide or the diuretic torsemide. Investigatorsare advised to exercise caution if including patients taking the anti-diabetic agentsrosiglitazone or pioglitazone, or antimalarial agents such as chloroquine andamodiaquine, as the metabolite of casopitant is a potential inhibitor of CYP2C8

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