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

A Phase III Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel Group Study of the Efficacy and Safety of the Intravenous and Oral Formulations of the Neurokinin-1 Receptor Antagonist, Casopitant, Administered in Combination With ZOFRAN and Dexamethasone for Prevention of Chemotherapy-Induced Nausea and Vomiting in Cancer Subjects Receiving Highly Emetogenic Cisplatin-Based Chemotherapy

This is a Phase III trial designed to demonstrate that casopitant when added to dexamethasone and ondansetron is more effective in the prevention of vomiting then dexamethasone and ondansetron alone, in patients who receive a cisplatin-based highly emetogenic chemotherapy.

A Phase III Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel Group Study of the Efficacy and Safety of the Intravenous and Oral Formulations of the Neurokinin-1 Receptor Antagonist, Casopitant, administered in Combination with ZOFRAN and Dexamethasone for Prevention of Chemotherapy-Induced Nausea and Vomiting in Cancer Subjects Receiving Highly Emetogenic Cisplatin-Based Chemotherapy

Inclusion criteria:

• 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.

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

• 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 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 emetogenic cisplatin-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]) 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.

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

  • 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:

    1. 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)
    2. 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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Exclusion criteria:

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

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

• If female, is pregnant or lactating.

• Has received radiation therapy to the thorax, head & neck, 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 thorax, head & neck, abdomen or the pelvis in the 6 days following the first dose of study medication.

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

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

• 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.

• 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.

• Has a known hypersensitivity or contraindication to ZOFRAN, another 5-HT3 receptor antagonist, 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 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.

• 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.

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

• 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.

• 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.)

• 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 GW679769 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 or pemetrexed therapy)
  • 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
  • domperidone
  • mirtazapine
  • olanzapine
  • cannabinoids

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

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

• 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

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