| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of nausea and vomiting due to first cycle of oxaliplatin based chemotherapy in patients with colorectal cancer receiving a combination with 5-fluorouracil and leucovorin, or in combination with capecitabine. |
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| MedDRA Classification |
| 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 |
| To demonstrate the superiority of triple therapy, single-dose 90 mg IV casopitant in combination with ondansetron and dexamethasone, over dual therapy ondansetron and dexamethasone for the prevention of emesis over the first 0-120 hours (overall phase) following initiation of the first cycle of oxaliplatin-based MEC. |
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| E.2.2 | Secondary objectives of the trial |
Determine whether the addition of single-dose 90 mg IV casopitant provides incremental improvement in:
- the prevention of emesis over the acute (0-24 hours) and delayed (24-120 hours) phases following initiation of the first cycle.
- the prevention of emesis over the overall (0-120 hours) phase following the second cycle.
- the control of nausea over the overall, acute and delayed phases following initiation of the first cycle.
Quantify the impact of the prophylactic anti-emetic regimens on daily life activities, as assessed by a FLIE during the first cycle.
Evaluate PK of single-dose IV casopitant and metabolites in a sub-set of subjects when given in combination with ondansetron and dexamethasone during the first cycle.
Determine the safety and tolerability of single-dose IV casopitant when given 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. At least 18 years of age.
3. 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. Refer to Section 4.1 for the list of chemotherapy agents that may be added to oxaliplatin.
4. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
5. 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 109/L)
• Platelets ≥100,000/mm3 (Standard units: ≥100.0 x 109/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.
6. Is willing and able to complete daily components of the Subject Diary for Cycle 1 and Cycle 2 without assistance from others.
7. A female subject is eligible to enter and participate in this study if she is of:
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 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.
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| E.4 | Principal exclusion criteria |
1. 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.
2. Scheduled to receive chemotherapy with any cytotoxic agents or biological agents other than the protocol allowed chemotherapy described in Inclusion Criterion 3.
3. Is a female subject who is pregnant or lactating.
4. 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.
5. Has experienced emesis or clinically significant nausea in the 24 hours preceding the first dose of study medication or investigational product for each cycle of chemotherapy.
6. 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.
7. 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.
8. Has a known hypersensitivity or contraindication to ondansetron, another 5-HT3 receptor antagonist, dexamethasone, or any component of casopitant.
9. Has received an NK-1 receptor antagonist prior to the first study cycle of chemotherapy.
10. 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.
11. Has taken/received any medication of moderate or high emetogenic potential 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.
12. 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 mdication during the 120 hour assessment period for Cycle 1 of therapy only. This includes, but is not limited to:
• 5-HT3 receptor antagonists. Palonosetron is not permitted within 7 days prior to administration of study medication or investigational product;
• benzamide / benzamide derivatives;
• 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;
• butyrophenones;
• corticosteroids within 72 hours prior to the first dose of study medication or investigational product; 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; 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; except for topical use which is permitted;
• domperidone;
• cannabinoids;
• mirtazapine;
• olanzapine.
13. 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
14. Has taken/received inducers of CYP3A4 and CYP3A5 within 14 days prior to the administration of investigational product in each cycle of therapy.
15. 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.
16. Is currently taking, or plans to take any of the following CYP3A4 substrates at any time during the study: astemizole, cisapride, pimozide, terfenadine.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the proportion of subjects who achieve a complete response (defined as no vomiting/retching and no rescue therapy) in the overall phase (0-120 hours) following initiation of the first cycle of an oxaliplatin-based MEC regimen, where the overall phase begins with the start of administration of the oxaliplatin infusion. |
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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 | Yes |
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
| E.8.5.1 | Number of sites anticipated in the EEA | 48 |
| 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 | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | 13 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 14 |
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