Clinical trial NCT00431236: A Study of the Drug Casopitant for the Prevention of Nausea Caused By Cisplatin-Based Highly Emetogenic Chemotherapy
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Nausea and Vomiting, Chemotherapy-Induced
Keywords: cisplatin
CINV
highly emetogenic
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-02-05
Enrollment: 810
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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

Eligibility criteria: 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.

obstruction

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.

Primary outcomes:
measure: Number of participants who achieved complete response
timeFrame: Up to 120 hours of cycle 1 of HEC
Secondary outcomes:
measure: Number of participants who achieved complete response during the acute (0-24 hours) and the delayed (24-120 hours) phase following the first cycle of HEC
timeFrame: Up to 120 hours of cycle 1 of HEC
measure: Number of participants who achieved a complete response during the overall (0-120 hours) phase following subsequent cycles of HEC
timeFrame: Up to 120 hours of cycle of HEC 2 to 6
measure: Maximum nausea score (to assess the severity of nausea), as assessed by a visual analogue scale (VAS)
timeFrame: Up to 120 hours of each HEC cycle (up to 24 months)
measure: Number of participants who use of anti-emetic rescue medication
timeFrame: Up to 120 hours of each HEC cycle (up to 24 months)
measure: Number of participants with first emetic event
timeFrame: Up to 120 hours of each HEC cycle (up to 24 months)
measure: Number of participants who received anti-emetic rescue medication
timeFrame: Up to 120 hours of cycle 1 of HEC
measure: Number of participants who vomited/retched
timeFrame: Up to 120 hours of cycle 1 of HEC
measure: Number of participants who reported significant nausea (>=25 mm on the VAS)
timeFrame: Up to 120 hours of cycle 1 of HEC
measure: Number of participants who reported nausea (>=5 mm on the VAS)
timeFrame: Up to 120 hours of cycle 1 of HEC
measure: Number of participants who achieved complete protection, defined as no vomiting/retching, no significant nausea and no rescue medication
timeFrame: Up to 120 hours of cycle 1 of HEC
measure: Number of participants who achieved total control, defined as no vomiting/retching, no nausea and no rescue medication
timeFrame: Up to 120 hours of each HEC cycle (up to 24 months)
measure: The impact on participants daily life activities for the first 120 hours following the first cycle of chemotherapy as assessed by the Functional Living Index-Emesis (FLIE) questionnaire-Score
timeFrame: Up to 120 hours of each HEC cycle (up to 24 months)
measure: Percentage of participants with impact on daily life activities for the first 120 hours following the first cycle of chemotherapy as assessed by the FLIE questionnaire-interpretation
timeFrame: Up to 120 hours of each HEC cycle (up to 24 months)
measure: Participant satisfaction with the prophylactic anti-emetic regimens, as assessed by the participant satisfaction questionnaire
timeFrame: Up to 120 hours of each HEC cycle (up to 24 months)
measure: The willingness of participant to use the same treatment during future chemotherapy, as assessed by the participant willingness questionnaire
timeFrame: Up to 120 hours of each HEC cycle (up to 24 months)
measure: Number of participants with nausea as assessed by a categorical scale, over the first 120 hours following HEC
timeFrame: Up to 120 hours of each HEC cycle (up to 24 months)
measure: Number of participants with adverse events (AE) and serious adverse events (SAE)
timeFrame: Up to 24 month after last dose of investigational product
measure: Number of participants with abnormalities of Grade 3 and 4 in laboratory parameters (clinical chemistry and hematology)
timeFrame: Up to end of cycle (approximately 28 days per cycle); maximum up to 24 months
measure: Summary of abnormal electrocardiogram findings
timeFrame: Up to end of cycle (approximately 28 days per cycle); maximum up to 24 months
measure: Summary of mean systolic blood pressure (SBP) and diastolic blood pressure (DBP)
timeFrame: Up to end of cycle (approximately 28 days per cycle); maximum up to 24 months
measure: Summary of mean respiratory rate
timeFrame: Up to end of cycle (approximately 28 days per cycle); maximum up to 24 months
measure: Summary of mean heart rate
timeFrame: Up to end of cycle (approximately 28 days per cycle); maximum up to 24 months
Other outcomes:
Locations:
city: Capital Federal
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Cordoba
country: Argentina
facility: GSK Investigational Site
state: Córdova
city: Rosario
country: Argentina
facility: GSK Investigational Site
state: Santa Fe
city: Tucuman
country: Argentina
facility: GSK Investigational Site
city: Edegem
country: Belgium
facility: GSK Investigational Site
city: Leuven
country: Belgium
facility: GSK Investigational Site
city: Liège
country: Belgium
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Varna
country: Bulgaria
facility: GSK Investigational Site
city: Zagreb
country: Croatia
facility: GSK Investigational Site
city: Zagreb
country: Croatia
facility: GSK Investigational Site
city: Zagreb
country: Croatia
facility: GSK Investigational Site
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Brno
country: Czechia
facility: GSK Investigational Site
city: Jihlava
country: Czechia
facility: GSK Investigational Site
city: Ostrava
country: Czechia
facility: GSK Investigational Site
city: Praha 5
country: Czechia
facility: GSK Investigational Site
city: Tabor
country: Czechia
facility: GSK Investigational Site
city: Helsinki
country: Finland
facility: GSK Investigational Site
city: Kangasala
country: Finland
facility: GSK Investigational Site
city: Turku
country: Finland
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Kavala
country: Greece
facility: GSK Investigational Site
city: Papagos, Athens
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Thessaloniki
country: Greece
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Mátraháza
country: Hungary
facility: GSK Investigational Site
city: Székesfehérvár
country: Hungary
facility: GSK Investigational Site
city: Kochi
country: India
facility: GSK Investigational Site
city: Tirupati
country: India
facility: GSK Investigational Site
city: Dublin
country: Ireland
facility: GSK Investigational Site
city: Tallaght, Dublin
country: Ireland
facility: GSK Investigational Site
city: Wilton, Cork
country: Ireland
facility: GSK Investigational Site
city: Monteforte Irpino
country: Italy
facility: GSK Investigational Site
state: Campania
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Roma
country: Italy
facility: GSK Investigational Site
state: Lazio
city: Sassari
country: Italy
facility: GSK Investigational Site
state: Sardegna
city: Pisa
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Seoul
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: Kubang Kerian
country: Malaysia
facility: GSK Investigational Site
city: Penang
country: Malaysia
facility: GSK Investigational Site
city: Sarawak
country: Malaysia
facility: GSK Investigational Site
city: Islamabad
country: Pakistan
facility: GSK Investigational Site
city: Karachi
country: Pakistan
facility: GSK Investigational Site
city: Karachi
country: Pakistan
facility: GSK Investigational Site
city: Lahore
country: Pakistan
facility: GSK Investigational Site
city: Lahore
country: Pakistan
facility: GSK Investigational Site
city: Baguio City, Benguet
country: Philippines
facility: GSK Investigational Site
city: Manila
country: Philippines
facility: GSK Investigational Site
city: Quezon City
country: Philippines
facility: GSK Investigational Site
city: Bialystok
country: Poland
facility: GSK Investigational Site
city: Bydgoszcz
country: Poland
facility: GSK Investigational Site
city: Krakow
country: Poland
facility: GSK Investigational Site
city: Olsztyn
country: Poland
facility: GSK Investigational Site
city: Poznan
country: Poland
facility: GSK Investigational Site
city: Poznan
country: Poland
facility: GSK Investigational Site
city: Bucuresti
country: Romania
facility: GSK Investigational Site
city: Iasi
country: Romania
facility: GSK Investigational Site
city: Timisoara
country: Romania
facility: GSK Investigational Site
city: Banska Bystrica
country: Slovakia
facility: GSK Investigational Site
city: Bratislava
country: Slovakia
facility: GSK Investigational Site
city: Poprad
country: Slovakia
facility: GSK Investigational Site
city: Avila
country: Spain
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Murcia
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Taichung
country: Taiwan
facility: GSK Investigational Site
city: Taichung
country: Taiwan
facility: GSK Investigational Site
city: TaoYuan Hsien
country: Taiwan
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Chiang Mai
country: Thailand
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Kyiv
country: Ukraine
facility: GSK Investigational Site
city: Lvov
country: Ukraine
facility: GSK Investigational Site
city: Sympheropol
country: Ukraine
facility: GSK Investigational Site
city: Uzhgorod
country: Ukraine
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Grunberg SM, Rolski J, Strausz J, Aziz Z, Lane S, Russo MW, Wissel P, Guckert M, Wright O, Herrstedt J. Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009 Jun;10(6):549-58. doi: 10.1016/S1470-2045(09)70109-3. Epub 2009 May 8.