A Study of the Drug Casopitant for the Prevention of Nausea Caused By Cisplatin-Based Highly Emetogenic Chemotherapy

Condition(s) targeted: Nausea; Vomiting

Intervention: Oral Casopitant (GW679769) (Drug); IV Casopitant (GW679769) (Drug); IV ondansetron hydrochloride (Drug); Oral dexamethasone (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: GlaxoSmithKline

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

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.

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

Primary outcome: To demonstrate that triple therapy casopitant, ondansetron and dexamethasone provides an improved CR rate over ZOFRAN and dexamethasone alone during the 120 hours following a cisplatin-based HEC regimen.

Secondary outcome:

Complete response over 120 hours following subsequent chemotherapy cycles Use of rescue medication over 120 hours following all chemotherapy cycles Impact on daily life activities over 120 hours, assessed using a subject diary questionnaire

The proportion of subjects who achieve a complete response during the acute (0-24 hrs.) and the delayed (24-120 hrs.) phase following the first cycle of HEC

The proportion of subjects who achieve a complete response over the first 120 hours, during the acute (0-24 hrs.), the delayed (24-120 hrs.), and the overall (0-120 hrs.) phase following subsequent cycles of HEC.

Maximum nausea score (to assess the severity of nausea), as assessed by a Visual Analogue Scale (VAS) over the first 120 hours and in the acute and delayed phases following each cycle of HEC.

Time to first antiemetic rescue medication, defined as the time elapsed from the start of the HEC regimen to the first use of antiemetic rescue medication.

If a subject withdraws prematurely during the first 120 hours, then the time of withdrawal will be considered to be their time to first use of antiemetic rescue medications, and will be censored.

Time to first emetic event, defined as the time elapsed from the start of administration of HEC to the first emetic episode.

If a subject withdraws prematurely during the first 120 hours, then the time of withdrawal will be considered to be their first emetic episode, and will be censored.

The proportion of subjects who receive rescue medication.

The proportion of subjects reporting significant nausea defined as a maximum nausea score greater than or equal to 25 mm on the VAS.

The proportion of subjects reporting nausea defined as a maximum nausea score greater than or equal to 5 mm on the VAS.

The proportion of subject achieving total control, defined as complete responders who had no nausea.

The impact on subjects' daily life activities for the first 120 hours following the first cycle of chemotherapy as assessed by the FLIE questionnaire.

Subject satisfaction with the prophylactic antiemetic regimens, and the willingness of subjects to use the same treatment during future chemotherapy, as assessed by the Subject Satisfaction\Willingness Assessment in the Subject Diary.

Nausea as assessed by a categorical scale, over the first 120 hours following HEC administration.

Assessment of the safety and tolerability of casopitant through: routine physical exam, routine clinical laboratory tests, clinical monitoring and adverse events reporting.

The proportion of subjects who vomit/retch.

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

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

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.

GSK Clinical Trials Call Centre, Capital Federal C1405CUB, Argentina

GSK Clinical Trials Call Centre, Rosario 2000, Argentina

GSK Clinical Trials Call Centre, Tucuman 4000, Argentina

GSK Clinical Trials Call Centre, Ciudad Autonoma de Buenos Aires 1427, Argentina

GSK Clinical Trials Call Centre, Cordoba X5000JFK, Argentina

GSK Clinical Trials Call Center, Leuven 3000, Belgium

GSK Clinical Trials Call Center, Liege 4000, Belgium

GSK Clinical Trials Call Center, Edegem 2650, Belgium

GSK Clinical Trials Call Center, Sofia 1156, Bulgaria

GSK Clinical Trials Call Center, Varna 9000, Bulgaria

GSK Clinical Trials Call Centre, Zagreb 10000, Croatia

GSK Clinical Trials Call Centre, Zagreb, Croatia

GSK Clinical Trials Call Center, Varazdin 63900, Croatia

GSK Clinical Trials Call Center, Zagreb 10 000, Croatia

GSK Clinical Trials Call Centre, Tabor 390 19, Czech Republic

GSK Clinical Trials Call Centre, Jihlava 586 01, Czech Republic

GSK Clinical Trials Call Centre, Brno 639 00, Czech Republic

GSK Clinical Trials Call Center, Praha 150 06, Czech Republic

GSK Clinical Trials Call Centre, Brno 65691, Czech Republic

GSK Clinical Trials Call Center, Ostrava 708 52, Czech Republic

GSK Clinical Trials Call Centre, Turku 20520, Finland

GSK Clinical Trials Call Centre, Helsinki 00029, Finland

GSK Clinical Trials Call Center, Kangasala 36280, Finland

GSK Clinical Trials Call Center, Kavala 65403, Greece

GSK Clinical Trials Call Centre, Greece 15669, Greece

GSK Clinical Trials Call Centre, Thessaloniki 57010, Greece

GSK Clinical Trials Call Centre, Athens 13122, Greece

GSK Clinical Trials Call Centre, Thessaloniki 564 29, Greece

GSK Clinical Trials Call Centre, Szekesfehervar 8000, Hungary

GSK Clinical Trials Call Centre, Matrahaza 3233, Hungary

GSK Clinical Trials Call Centre, Budapest 1529, Hungary

GSK Clinical Trials Call Center, Nagpur 440027, India

GSK Clinical Trials Call Centre, Kochin 682026, India

GSK Clinical Trials Call Centre, Chennai 600020, India

GSK Clinical Trials Call Centre, Tirupati 517507, India

GSK Clinical Trials Call Centre, Lucknow 226014, India

GSK Clinical Trials Call Center, Wilton, Cork, Ireland

GSK Clinical Trials Call Centre, Cork, Ireland

GSK Clinical Trials Call Centre, Dublin 9, Ireland

GSK Clinical Trials Call Centre`, Tallaght 24, Ireland

GSK Clinical Trials Call Centre, Rome 00149, Italy

GSK Clinical Trials Call Centre, Monteforte Irpino 83024, Italy

GSK Clinical Trials Call Centre, Orbassano 10043, Italy

GSK Clinical Trials Call Centre, Pisa 56124, Italy

GSK Clinical Trials Call Centre, Rome 00184, Italy

GSK Clinical Trials Call Centre, Sassari 07100, Italy

GSK Clinical Trials Call Centre, Seoul 120-752, Korea, Republic of

GSK Clinical Trials Call Centre, Seoul 135-710, Korea, Republic of

GSK Clinical Trials Call Centre, Seoul 138-736, Korea, Republic of

GSK Clinical Trials Call Centre, Penang 11600, Malaysia

GSK Clinical Trials Call Centre, Sarawak 93586, Malaysia

GSK Clinical Trials Call Centre, Kubang Kerian 16150, Malaysia

GSK Clinical Trials Call Centre, Lahore, Pakistan

GSK Clinical Trials Call Centre, Islamabad 1590, Pakistan

GSK Clinical Trials Call Centre, Karachi 74800, Pakistan

GSK Clinical Trials Call Center, Lahore 54000, Pakistan

GSK Clinical Trials Call Center, Lahore, Pakistan

GSK Clinical Trials Call Center, Karachi, Pakistan

GSK Clinical Trials Call Centre, Lima Lima 34, Peru

GSK Clinical Trials Call Centre, Callao Callao 2, Peru

GSK Clinical Trials Call Centre, Lima Lima 13, Peru

GSK Clinical Trials Call Centre, Manila 1000, Philippines

GSK Clinical Trials Call Centre, Baguio City, Benquet 2600, Philippines

GSK Clinical Trials Call Center, Quezon City 1100, Philippines

GSK Clinical Trials Call Center, Bydgoszcz 85-796, Poland

GSK Clinical Trials Call Center, Krakow 31-115, Poland

GSK Clinical Trials Call Center, Bialystok 15-540, Poland

GSK Clinical Trials Call Centre, Poznan 60-569, Poland

GSK Clinical Trials Call Center, Poznan 61-866, Poland

GSK Clinical Trials Call Center, Olsztyn 10-357, Poland

GSK Clinical Trials Call Centre, Timisoara 300239, Romania

GSK Clinical Trials Call Centre, Iasi 700106, Romania

GSK Clinical Trials Call Centre, Bucuresti 022328, Romania

GSK Clinical Trials Call Centre, Poprad 058 87, Slovakia

GSK Clinical Trials Call Centre, Branska Bystrica 975 17, Slovakia

GSK Clinical Trials Call Centre, Bratislava 826 06, Slovakia

GSK Clinical Trials Call Centre, Madrid 28035, Spain

GSK Clinical Trials Call Centre, Avila 05071, Spain

GSK Clinical Trials Call Centre, Boadilla del Monte (Madrid) 28660, Spain

GSK Clinical Trials Call Centre, Madrid 28033, Spain

GSK Clinical Trials Call Centre, Badalona 08916, Spain

GSK Clinical Trials Call Centre, Cartagena 30392, Spain

GSK Clinical Trials Call Centre, Murcia 30008, Spain

GSK Clinical Trials Call Centre, Valencia 46009, Spain

GSK Clinical Trials Call Centre, Taichung 404, Taiwan

GSK Clinical Trials Call Centre, Tau-Yuan County 333, Taiwan

GSK Clinical Trials Call Center, Tau-Yuan County, Taiwan

GSK Clinical Trials Call Centre, Taichung 407, Taiwan

GSK Clinical Trials Call Centre, Chiang Mai 50200, Thailand

GSK Clinical Trials Call Centre, Bangkok 10400, Thailand

GSK Clinical Trials Call Centre, Ankara 6100, Turkey

GSK Clinical Trials Call Centre, Istanbul 34303, Turkey

GSK Clinical Trials Call Center, Istanbul, Turkey

GSK Clinical Trials Call Center, Sympheropol 95023, Ukraine

GSK Clinical Trials Call Center, Kharkiv 61024, Ukraine

GSK Clinical Trials Call Centre, Lvov, Ukraine

GSK Clinical Trials Call Center, Kyiv 03115, Ukraine

GSK Clinical Trials Call Center, Uzhorod 88014, Ukraine

GSK Clinical Trials Call Center, Birmingham, Alabama 35209, United States

GSK Clinical Trials Call Center, Greenbrae, California 94904, United States

Starting date: September 2006
Ending date: October 2007
Last updated: March 10, 2008