Clinical trial NCT00601172: A Study Of IV Casopitant For The Prevention Of Chemotherapy Induced Nausea And Vomiting.
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Nausea and Vomiting, Chemotherapy-Induced
Keywords: vomiting
colorectal cancer
nausea
oxaliplatin
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2008-01-25
Enrollment: 710
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief 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.

Primary outcomes:
measure: Percentage of Participants Who Achieved a Complete Response in the Overall Phase (0-120 Hours) Following Initiation of the First Cycle of an Oxaliplatin Based Moderately Emetogenic Chemotherapy (MEC) Regimen
timeFrame: 0 to 120 hours in the first cycle of chemotherapy
Secondary outcomes:
measure: Percentage of Participants Who Achieved a Complete Response in the Acute Phase of Cycle 1
timeFrame: 0 to 24 hours in the first cycle of chemotherapy
measure: Percentage of Participants Who Achieved a Complete Response in the Delayed Phase of Cycle 1
timeFrame: 24 to 120 hours (delayed phase) in the first cycle of chemotherapy
measure: Percentage of Participants Who Achieved a Complete Response in the Overall Phase of Cycle 2
timeFrame: 0 to 120 hours in the second cycle of chemotherapy
measure: Maximum Nausea Score, Assessed by a Visual Analogue Scale (VAS)
timeFrame: 0 to 24 hours, 24 to 120 hours and 0 to 120 hours in the first cycle of chemotherapy
measure: Percentage of Participants Who Received Rescue Medication
timeFrame: 0 to 24 hours, 24 to 120 hours and 0 to 120 hours in the first cycle of chemotherapy
measure: Percentage of Participants Who Vomited and/or Retched
timeFrame: 0 to 24 hours, 24 to 120 hours and 0 to 120 hours in the first cycle of chemotherapy
measure: Percentage of Participants Who Reported Significant Nausea, Defined as a Maximum Score >= 25 mm on the VAS
timeFrame: 0 to 24 hours, 24 to 120 hours and 0 to 120 hours in the first cycle of chemotherapy
measure: Percentage of Participants Who Reported Nausea, Defined as a Maximum Score of >= 5 mm on the VAS
timeFrame: 0 to 24 hours, 24 to 120 hours and 0 to 120 hours in the first cycle of chemotherapy
measure: Percentage of Participants Who Achieved Complete Protection Defined as Complete Responders With no Significant Nausea
timeFrame: 0 to 24 hours, 24 to 120 hours and 0 to 120 hours in the first cycle of chemotherapy
measure: Percentage of Participants Who Achieved Total Control, Defined as Complete Responders Who Had no Nausea
timeFrame: 0 to 24 hours, 24 to 120 hours and 0 to 120 hours in the first cycle of chemotherapy
measure: Percentage of Participants Whose Daily Life Activities Were Impacted in the Overall Phase of Cycle 1, Assessed by Functional Living Index-Emesis (FLIE) Questionnaire
timeFrame: 0 to 120 hours in the first cycle of chemotherapy
measure: Severity of Nausea in the Overall, Acute, and Delayed Phases of Cycle 1 Assessed by a Categorical Scale
timeFrame: 0 to 24 hours, 24 to 120 hours and 0 to 120 hours in the first cycle of chemotherapy
measure: Single-dose Pharmacokinetic (PK) Parameters: Area Under the Curve (AUC) 0 to Infinity (0-∞), AUC 0 to t (0-t) and AUC 0 to 24 Hours (0-24) for Casopitant; AUC (0-t) and AUC (0-24) for Metabolites GSK525060, GSK517142 and GSK631832
timeFrame: Pre-dose, end of infusion and 0.5, 1, 3, 5, 8, 12, 16, 24 hours after the end of infusion
measure: Single-dose Pharmacokinetic Parameters: Maximum Observed Drug Concentration (Cmax) for Casopitant and Metabolites GSK525060, GSK517142 and GSK631832
timeFrame: Pre-dose, end of infusion and 0.5, 1, 3, 5, 8, 12, 16, 24 hours after the end of infusion
measure: Single-dose Pharmacokinetic Parameters: Time to Maximum Observed Drug Concentration (Tmax) and Observed Elimination Half-life (t1/2) for Casopitant and Metabolites GSK525060, GSK517142 and GSK631832
timeFrame: Pre-dose, end of infusion and 0.5, 1, 3, 5, 8, 12, 16, 24 hours after the end of infusion
measure: Single-dose Pharmacokinetic Parameters: Clearance (CL) for Casopitant
timeFrame: Pre-dose, end of infusion and 0.5, 1, 3, 5, 8, 12, 16, 24 hours after the end of infusion
measure: Single-dose Pharmacokinetic Parameters: Volume of Distribution (Vdss) for Casopitant
timeFrame: Pre-dose, end of infusion and 0.5, 1, 3, 5, 8, 12, 16, 24 hours after the end of infusion
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to 35 days
measure: Number of Participants With Hematology Toxicity Grade Shifts From Baseline to Toxicity Grade 3 and 4
timeFrame: Baseline (Day 1) to Day 24
measure: Number of Participants With Clinical Chemistry Toxicity Grade Shifts From Baseline to Toxicity Grade 3 and 4
timeFrame: Up to Day 24
measure: Evaluation of Vital Signs: Mean Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Up to End of Cycle for 6 cycles, an average of 24 days per cycle
measure: Evaluation of Vital Signs: Mean Heart Rate
timeFrame: Up to End of Cycle for 6 cycles, an average of 24 days per cycle
measure: Time to First Anti-emetic Rescue Medication
timeFrame: 0 to 120 hours in the first cycle of chemotherapy
measure: Time to First Emetic Event
timeFrame: 0 to 120 hours in the first cycle of chemotherapy
Other outcomes:
Locations:
city: Hot Springs
country: United States
facility: GSK Investigational Site
state: Arkansas
city: Corona
country: United States
facility: GSK Investigational Site
state: California
city: Fountain Valley
country: United States
facility: GSK Investigational Site
state: California
city: Riverside
country: United States
facility: GSK Investigational Site
state: California
city: Saint Petersburg
country: United States
facility: GSK Investigational Site
state: Florida
city: Tampa
country: United States
facility: GSK Investigational Site
state: Florida
city: Alexandria
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Baton Rouge
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Worcester
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Jefferson City
country: United States
facility: GSK Investigational Site
state: Missouri
city: Great Falls
country: United States
facility: GSK Investigational Site
state: Montana
city: Bronx
country: United States
facility: GSK Investigational Site
state: New York
city: Winston-Salem
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Hilton Head Island
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Mount Pleasant
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Sumter
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Corpus Christi
country: United States
facility: GSK Investigational Site
state: Texas
city: Corpus Christi
country: United States
facility: GSK Investigational Site
state: Texas
city: Duncanville
country: United States
facility: GSK Investigational Site
state: Texas
city: Ogden
country: United States
facility: GSK Investigational Site
state: Utah
city: Burlington
country: United States
facility: GSK Investigational Site
state: Vermont
city: Assebroek
country: Belgium
facility: GSK Investigational Site
city: Bonheiden
country: Belgium
facility: GSK Investigational Site
city: Gent
country: Belgium
facility: GSK Investigational Site
city: Ottignies
country: Belgium
facility: GSK Investigational Site
city: Shumen
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Varna
country: Bulgaria
facility: GSK Investigational Site
city: Sault Ste. Marie
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Thunder Bay
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Charlottetown
country: Canada
facility: GSK Investigational Site
state: Prince Edward Island
city: Greenfield Park
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Laval
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Rimouski
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Sherbrooke
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Chomutov
country: Czechia
facility: GSK Investigational Site
city: Havlickuv Brod
country: Czechia
facility: GSK Investigational Site
city: Praha 10
country: Czechia
facility: GSK Investigational Site
city: Praha 8
country: Czechia
facility: GSK Investigational Site
city: Semily
country: Czechia
facility: GSK Investigational Site
city: Freiburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Ulm
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Aschaffenburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Augsburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Hof
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Muenchen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Wuerzburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Bad Soden
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Kassel
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Braunschweig
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Recklinghausen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Wuerselen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Magdeburg
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Luebeck
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Pinneberg
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Jena
country: Germany
facility: GSK Investigational Site
state: Thueringen
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Gyula
country: Hungary
facility: GSK Investigational Site
city: Veszprém
country: Hungary
facility: GSK Investigational Site
city: Potenza
country: Italy
facility: GSK Investigational Site
state: Basilicata
city: Rionero In Vulture (PZ)
country: Italy
facility: GSK Investigational Site
state: Basilicata
city: Reggio Calabria
country: Italy
facility: GSK Investigational Site
state: Calabria
city: Avellino
country: Italy
facility: GSK Investigational Site
state: Campania
city: Benevento
country: Italy
facility: GSK Investigational Site
state: Campania
city: Napoli
country: Italy
facility: GSK Investigational Site
state: Campania
city: Genova
country: Italy
facility: GSK Investigational Site
state: Liguria
city: Sassari
country: Italy
facility: GSK Investigational Site
state: Sardegna
city: Catania
country: Italy
facility: GSK Investigational Site
state: Sicilia
city: Firenze
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Terni
country: Italy
facility: GSK Investigational Site
state: Umbria
city: Padova
country: Italy
facility: GSK Investigational Site
state: Veneto
city: Gyeonggi-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Songpa-gu, Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Kazan
country: Russian Federation
facility: GSK Investigational Site
city: Moscow Region
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Samara
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Banska Bystrica
country: Slovakia
facility: GSK Investigational Site
city: Bratislava
country: Slovakia
facility: GSK Investigational Site
city: Kosice
country: Slovakia
facility: GSK Investigational Site
city: Poprad
country: Slovakia
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Hesketh PJ, Wright O, Rosati G, Russo M, Levin J, Lane S, Moiseyenko V, Dube P, Kopp M, Makhson A. Single-dose intravenous casopitant in combination with ondansetron and dexamethasone for the prevention of oxaliplatin-induced nausea and vomiting: a multicenter, randomized, double-blind, active-controlled, two arm, parallel group study. Support Care Cancer. 2012 Jul;20(7):1471-8. doi: 10.1007/s00520-011-1235-4. Epub 2011 Aug 7.