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

Condition(s) targeted: Colorectal Cancer

Intervention: Casopitant (Drug); Dexamethasone and Ondansetron (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, MD, PhD, Study Director, Affiliation: GlaxoSmithKline

Overall contact:
US GSK Clinical Trials Call Center, Phone: 877-379-3718

This a Phase III trial designed to demonstrate that 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 chemotherapy.

Official title: A Study of Single Dose Intravenous Casopitant in Combination With Ondansetron and Dexamethasone for the Prevention of Oxaliplatin Induced Nausea and Vomiting.

Study design: Prevention, Randomized, Double-Blind, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Subject diary completed during cycle 1 to assess vomiting and the use of rescue medication.

Secondary outcome:

Subject diary completed during cycle 1 to assess nausea during the 120 hour assessment period; Subject diary completed to assess vomiting and use of rescue medication during cycle 2.

Assessed in the acute and delayed phases of Cycle 1: The proportion of subjects who achieve a complete response.

Assessed in the overall phase of Cycle 2: The proportion of subjects who achieve a complete response.

Assessed in the overall, acute and delayed phases of Cycle 1:

Maximum nausea score, assessed by a Visual Analogue Scale (VAS). • The proportion of subjects who receive rescue medication. • The proportion of subjects who vomit/retch. • The proportion of subjects reporting significant nausea, defined

The proportion of subjects reporting significant nausea, defined as a maximum nausea score ≥ 25 mm on the VAS. • The proportion of subjects reporting nausea, defined as a maximum nausea score ≥ 5 mm on the VAS.

The proportion of subjects achieving complete protection, defined as complete responders who had no significant nausea.

The proportion of subjects achieving total control, defined as complete responders who had no nausea. • Time to first anti-emetic rescue medication. • Time to first emetic event.

Time to event is defined as the time elapsed from the start of the oxaliplatin infusion to the first event.

If a subject withdraws prematurely or dies during the first 120 hours, then the time of withdrawal or death will be considered to be their time to first event, and will be censored.

Health Outcomes Endpoints assessed in Cycle 1: • The impact on subjects' daily life activities in the overall phase, as assessed by the FLIE questionnaire.

Severity of nausea in the overall, acute, and delayed phases assessed by a categorical scale.

PK Endpoints assessed in Cycle 1 (subset of subjects only)

Single-dose pharmacokinetic parameters: AUC(0-∞), AUC(0-t), Cmax, tmax, t1/2 for casopitant and metabolites GSK525060, GSK517142 and GSK631832; and CL and Vdss for casopitant only.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

US GSK Clinical Trials Call Center, Phone: 877-379-3718

GSK Investigational Site, Assebroek 8310, Belgium; Recruiting

GSK Investigational Site, Ottignies 1340, Belgium; Recruiting

GSK Investigational Site, Gent 9000, Belgium; Recruiting

GSK Investigational Site, Bonheiden 2820, Belgium; Recruiting

GSK Investigational Site, Sofia 1756, Bulgaria; Recruiting

GSK Investigational Site, Shumen 9700, Bulgaria; Recruiting

GSK Investigational Site, Plovdiv 4000, Bulgaria; Not yet recruiting

GSK Investigational Site, Varna 9010, Bulgaria; Recruiting

GSK Investigational Site, Praha 10 100 00, Czech Republic; Recruiting

GSK Investigational Site, Praha 8 180 00, Czech Republic; Recruiting

GSK Investigational Site, Semily 513 01, Czech Republic; Recruiting

GSK Investigational Site, Chomutov 430 12, Czech Republic; Recruiting

GSK Investigational Site, Brno 656 91, Czech Republic; Recruiting

GSK Investigational Site, Havlickuv Brod 580 22, Czech Republic; Recruiting

GSK Investigational Site, Brno 625 00, Czech Republic; Recruiting

GSK Investigational Site, Munich 81377, Germany; Withdrawn

GSK Investigational Site, Hamburg 22081, Germany; Recruiting

GSK Investigational Site, Hamburg 22457, Germany; Recruiting

GSK Investigational Site, Budapest 1106, Hungary; Recruiting

GSK Investigational Site, Budapest 1125, Hungary; Recruiting

GSK Investigational Site, Gyula 5700, Hungary; Recruiting

GSK Investigational Site, Veszprém 8200, Hungary; Recruiting

GSK Investigational Site, songpa-gu, Seoul 138-736, Korea, Republic of; Recruiting

GSK Investigational Site, Gyeonggi-do 411-769, Korea, Republic of; Recruiting

GSK Investigational Site, Seoul 135-710, Korea, Republic of; Recruiting

GSK Investigational Site, Seoul 120-752, Korea, Republic of; Recruiting

GSK Investigational Site, Moscow 129 128, Russian Federation; Recruiting

GSK Investigational Site, Moscow 115478, Russian Federation; Recruiting

GSK Investigational Site, Moscow Region 143 423, Russian Federation; Recruiting

GSK Investigational Site, Kazan 420029, Russian Federation; Recruiting

GSK Investigational Site, Samara 443066, Russian Federation; Recruiting

GSK Investigational Site, St. Petersburg 197758, Russian Federation; Recruiting

GSK Investigational Site, Bratislava 833 10, Slovakia; Recruiting

GSK Investigational Site, Kosice 041 91, Slovakia; Recruiting

GSK Investigational Site, Poprad 058 01, Slovakia; Recruiting

GSK Investigational Site, Banska Bystrica 975 17, Slovakia; Recruiting

GSK Investigational Site, Hot Springs, Arkansas 71913, United States; Recruiting

GSK Investigational Site, Freiburg, Baden-Wuerttemberg 79106, Germany; Recruiting

GSK Investigational Site, Ulm, Baden-Wuerttemberg 89081, Germany; Withdrawn

GSK Investigational Site, Potenza, Basilicata 85100, Italy; Recruiting

GSK Investigational Site, Rionero in Vulture (PZ), Basilicata 85028, Italy; Recruiting

GSK Investigational Site, Hof, Bayern 95028, Germany; Recruiting

GSK Investigational Site, Wuerzburg, Bayern 97070, Germany; Recruiting

GSK Investigational Site, Muenchen, Bayern 81241, Germany; Recruiting

GSK Investigational Site, Aschaffenburg, Bayern 63739, Germany; Recruiting

GSK Investigational Site, Fuerstenfeldbruck, Bayern 82256, Germany; Not yet recruiting

GSK Investigational Site, Augsburg, Bayern 86150, Germany; Withdrawn

GSK Investigational Site, Reggio Calabria, Calabria 89125, Italy; Recruiting

GSK Investigational Site, Corona, California 92879, United States; Recruiting

GSK Investigational Site, Fountain Valley, California 92708, United States; Recruiting

GSK Investigational Site, Riverside, California 92501, United States; Recruiting

GSK Investigational Site, Avellino, Campania 83100, Italy; Recruiting

GSK Investigational Site, Benevento, Campania 82100, Italy; Recruiting

GSK Investigational Site, Napoli, Campania 80131, Italy; Recruiting

GSK Investigational Site, Tampa, Florida 33614, United States; Recruiting

GSK Investigational Site, St Petersburg, Florida 33705, United States; Recruiting

GSK Investigational Site, Bad Soden, Hessen 65812, Germany; Recruiting

GSK Investigational Site, Kassel, Hessen 34117, Germany; Recruiting

GSK Investigational Site, Genova, Liguria 16132, Italy; Recruiting

GSK Investigational Site, San Remo (IM), Liguria 18038, Italy; Withdrawn

GSK Investigational Site, Alexandria, Louisiana 71301, United States; Recruiting

GSK Investigational Site, Baton Rouge, Louisiana 70809, United States; Recruiting

GSK Investigational Site, Baltimore, Maryland 21215-5271, United States; Active, not recruiting

GSK Investigational Site, Worcester, Massachusetts 01608, United States; Recruiting

GSK Investigational Site, Boston, Massachusetts 02135, United States; Recruiting

GSK Investigational Site, Jefferson City, Missouri 65109, United States; Recruiting

GSK Investigational Site, Great Falls, Montana 59405, United States; Withdrawn

GSK Investigational Site, Great Falls, Montana 59405, United States; Recruiting

GSK Investigational Site, Bronx, New York 10467, United States; Active, not recruiting

GSK Investigational Site, Braunschweig, Niedersachsen 38114, Germany; Recruiting

GSK Investigational Site, Hannover, Niedersachsen 30171, Germany; Recruiting

GSK Investigational Site, Wuerselen, Nordrhein-Westfalen 52146, Germany; Recruiting

GSK Investigational Site, Recklinghausen, Nordrhein-Westfalen 45657, Germany; Active, not recruiting

GSK Investigational Site, Essen, Nordrhein-Westfalen 45122, Germany; Completed

GSK Investigational Site, Winston-Salem, North Carolina 27103, United States; Recruiting

GSK Investigational Site, Canton, Ohio 44718, United States; Withdrawn

GSK Investigational Site, Sault Ste. Marie, Ontario P6A 2C4, Canada; Recruiting

GSK Investigational Site, Thunder Bay, Ontario P7B 6V4, Canada; Recruiting

GSK Investigational Site, Toronto, Ontario M5G 1X5, Canada; Recruiting

GSK Investigational Site, Charlottetown, Prince Edward Island C1A 8T5, Canada; Recruiting

GSK Investigational Site, Greenfield Park, Quebec J4V 2H1, Canada; Active, not recruiting

GSK Investigational Site, Laval, Quebec H7M 3L9, Canada; Recruiting

GSK Investigational Site, Montreal, Quebec H1T 2M4, Canada; Recruiting

GSK Investigational Site, Sherbrooke, Quebec J1H 5N4, Canada; Recruiting

GSK Investigational Site, Rimouski, Quebec G5L 5T1, Canada; Recruiting

GSK Investigational Site, Magdeburg, Sachsen-Anhalt 39104, Germany; Recruiting

GSK Investigational Site, Sassari, Sardegna 07100, Italy; Recruiting

GSK Investigational Site, Pinneberg, Schleswig-Holstein 25421, Germany; Completed

GSK Investigational Site, Luebeck, Schleswig-Holstein 23562, Germany; Recruiting

GSK Investigational Site, Catania, Sicilia 95125, Italy; Recruiting

GSK Investigational Site, Mt. Pleasant, South Carolina 29464, United States; Recruiting

GSK Investigational Site, Hilton Head Island, South Carolina 29926, United States; Recruiting

GSK Investigational Site, Sumter, South Carolina 29150, United States; Recruiting

GSK Investigational Site, Corpus Christi, Texas 78412, United States; Recruiting

GSK Investigational Site, Corpus Christi, Texas 78463-3069, United States; Recruiting

GSK Investigational Site, Duncanville, Texas 75137, United States; Recruiting

GSK Investigational Site, Jena, Thueringen 07743, Germany; Recruiting

GSK Investigational Site, Firenze, Toscana 50139, Italy; Recruiting

GSK Investigational Site, Terni, Umbria 05100, Italy; Recruiting

GSK Investigational Site, Ogden, Utah 84403, United States; Recruiting

GSK Investigational Site, Padova, Veneto 35128, Italy; Recruiting

GSK Investigational Site, Burlington, Vermont 05401, United States; Recruiting

Starting date: March 2008
Ending date: April 2009
Last updated: November 13, 2008