A Study Of IV Casopitant For The Prevention Of Chemotherapy Induced Nausea And Vomiting.
Condition: Nausea and Vomiting, Chemotherapy-Induced
MeSH terms: Nausea; Vomiting
Intervention: Casopitant; Dexamethasone; Placebo; Ondansetron
Intervention description: Experimental NK-1 receptor antagonist; Standard antiemetics; Placebo to match IV casopitant; Standard antiemetics
Intervention MeSH terms: Dexamethasone; Ondansetron; Casopitant
Phase: Phase 3
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 710.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: vomiting; colorectal cancer; nausea; oxaliplatin

Summary:

      This a Phase III trial designed to determine if IV casopitant plus dexamethasone and
      ondansetron is more effective in the prevention of vomiting and nausea then dexamethasone and
      ondansetrone alone following the administration of moderately emetogenic oxaliplatin-based
      chemotherapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  A subject will be considered eligible for initial inclusion in this study, and
             progression into subsequent cycles of therapy within the study, only if all of the
             following criteria apply:

          -  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.

          -  At least 18 years of age.

          -  Is scheduled to receive oxaliplatin at a dose between 85 mg/m² and 130 mg/m² in their
             first cycle of therapy for the treatment of colorectal cancer, administered as a
             single IV dose over 2-6 hours on Day 1 only, in combination with 5FU/LV, or in
             combination with capecitabine.

          -  An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

          -  Hematologic and metabolic status adequate for receiving an oxaliplatin-based
             moderately 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 alanine
             aminotransferase (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 1
                  and 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 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 on Cycle 1 Day 1. Women of childbearing
                       potential must also 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 the physician, are as follows:

          -  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 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 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 an
             acceptable 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 the
             following criteria apply, or will not be eligible for subsequent cycles of therapy if
             any 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 is
             permitted, provided that the last dose of adjuvant therapy was completed at least 6
             months prior to receiving the first dose of study medication or investigational
             product. 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 the
             protocol 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 study
             medication or investigational product and/or is scheduled to receive such radiation
             therapy in the 6 days following the first dose of study medication or investigational
             product in the first cycle of chemotherapy. Radiation therapy may be added in
             subsequent cycles of chemotherapy.

          -  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 investigational
             product for each cycle of chemotherapy.

          -  Has known central nervous system metastasis, unless previously successfully treated
             with excision or radiation, and has been stable for at least 1 week immediately prior
             to receiving the first dose of study medication or investigational product.

          -  Has increased intracranial pressure, hypercalcemia, an active systemic infection, 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 ondansetron, another 5-HT3
             receptor antagonist, dexamethasone, or any component of casopitant.

          -  Has received an NK-1 receptor antagonist prior to the first study cycle of
             chemotherapy.

          -  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 or
             investigational product, or is scheduled to receive any investigational drug other
             than casopitant/placebo during the study period.

          -  Has taken/received any medication of moderate or high emetogenic potential (including
             antineoplastic agents [see Appendix 2]) within the 48 hours prior to the first dose of
             study medication or investigational product in each cycle. However, opioid narcotics
             will be permitted if the subject has been on such medication for at least 7 days at a
             stable dose prior to the start of each cycle, and has not experienced emesis or nausea
             from the narcotics.

          -  Has taken/received any medication with known or potential antiemetic activity within
             the 24-hour period (unless otherwise stated) prior to receiving the first dose of
             study medication or investigational product or is expected to require use of such
             medication during the 120 hour assessment period for Cycle 1 of therapy only. This
             includes, but is not limited to:

               -  5-HT3 receptor antagonists (e.g., additional ondansetron, or granisetron,
                  dolasetron, tropisetron, ramosetron). Palonosetron is not permitted within 7 days
                  prior 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 or
                  anxiety and has been on a stable dose for at least 7 days prior to the first dose
                  of 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);

               -  butyrophenones (e.g., haloperidol, droperidol);

               -  corticosteroids within 72 hours prior to the first dose of study medication or
                  investigational product (e.g., dexamethasone, methylprednisolone); with the
                  exception that topical steroids for skin disorders including eye and ear drops,
                  and inhaled steroids for respiratory disorders at ≤ 10 mg prednisone daily or its
                  equivalent are permitted;

               -  anticholinergics (e.g., scopolamine); with the exception that anticholinergics
                  for the treatment of respiratory disorders and the management of diarrhea (e.g.,
                  ipratropium bromide, and hyoscyamine) and anticholinergic eye drops are
                  permitted;

               -  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 specified
             period prior to administration of investigational product in each cycle of therapy.

          -  Has taken/received inducers of CYP3A4 and CYP3A5 within 14 days prior to the
             administration of investigational product in each cycle of therapy.

          -  Is currently taking, or plans to take the following CYP2C8 substrates at any time
             during 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 any
             time during the study: astemizole, cisapride, pimozide, terfenadine.