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

Nausea and Vomiting, Chemotherapy-Induced Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00431236
• Other study ID #: NKV102551
• Status: Completed
• Phase: Phase 3
• First received: February 2, 2007
• Last updated: August 21, 2017
• Start date: November 6, 2006
• Est. completion date: October 9, 2007

Study information

• Verified date: August 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 810
• Est. completion date: October 9, 2007
• Est. primary completion date: October 9, 2007
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Nausea
• Nausea and Vomiting, Chemotherapy-Induced
• Vomiting

Intervention

Drug:
• Oral Casopitant (GW679769)

• IV Casopitant (GW679769)

• IV ondansetron hydrochloride

• Oral dexamethasone

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Capital Federal	Buenos Aires
Argentina	GSK Investigational Site	Cordoba	Córdova
Argentina	GSK Investigational Site	Rosario	Santa Fe
Argentina	GSK Investigational Site	Tucuman
Belgium	GSK Investigational Site	Edegem
Belgium	GSK Investigational Site	Leuven
Belgium	GSK Investigational Site	Liège
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Varna
Croatia	GSK Investigational Site	Zagreb
Croatia	GSK Investigational Site	Zagreb
Croatia	GSK Investigational Site	Zagreb
Czechia	GSK Investigational Site	Brno
Czechia	GSK Investigational Site	Brno
Czechia	GSK Investigational Site	Jihlava
Czechia	GSK Investigational Site	Ostrava
Czechia	GSK Investigational Site	Praha 5
Czechia	GSK Investigational Site	Tabor
Finland	GSK Investigational Site	Helsinki
Finland	GSK Investigational Site	Kangasala
Finland	GSK Investigational Site	Turku
Greece	GSK Investigational Site	Athens
Greece	GSK Investigational Site	Kavala
Greece	GSK Investigational Site	Papagos, Athens
Greece	GSK Investigational Site	Thessaloniki
Greece	GSK Investigational Site	Thessaloniki
Hungary	GSK Investigational Site	Budapest
Hungary	GSK Investigational Site	Mátraháza
Hungary	GSK Investigational Site	Székesfehérvár
India	GSK Investigational Site	Kochi
India	GSK Investigational Site	Tirupati
Ireland	GSK Investigational Site	Dublin
Ireland	GSK Investigational Site	Tallaght, Dublin
Ireland	GSK Investigational Site	Wilton, Cork
Italy	GSK Investigational Site	Monteforte Irpino	Campania
Italy	GSK Investigational Site	Pisa	Toscana
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Roma	Lazio
Italy	GSK Investigational Site	Sassari	Sardegna
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Malaysia	GSK Investigational Site	Kubang Kerian
Malaysia	GSK Investigational Site	Penang
Malaysia	GSK Investigational Site	Sarawak
Pakistan	GSK Investigational Site	Islamabad
Pakistan	GSK Investigational Site	Karachi
Pakistan	GSK Investigational Site	Karachi
Pakistan	GSK Investigational Site	Lahore
Pakistan	GSK Investigational Site	Lahore
Philippines	GSK Investigational Site	Baguio City, Benguet
Philippines	GSK Investigational Site	Manila
Philippines	GSK Investigational Site	Quezon City
Poland	GSK Investigational Site	Bialystok
Poland	GSK Investigational Site	Bydgoszcz
Poland	GSK Investigational Site	Krakow
Poland	GSK Investigational Site	Olsztyn
Poland	GSK Investigational Site	Poznan
Poland	GSK Investigational Site	Poznan
Romania	GSK Investigational Site	Bucuresti
Romania	GSK Investigational Site	Iasi
Romania	GSK Investigational Site	Timisoara
Slovakia	GSK Investigational Site	Banska Bystrica
Slovakia	GSK Investigational Site	Bratislava
Slovakia	GSK Investigational Site	Poprad
Spain	GSK Investigational Site	Avila
Spain	GSK Investigational Site	Badalona
Spain	GSK Investigational Site	Madrid
Spain	GSK Investigational Site	Murcia
Spain	GSK Investigational Site	Valencia
Taiwan	GSK Investigational Site	Taichung
Taiwan	GSK Investigational Site	Taichung
Taiwan	GSK Investigational Site	TaoYuan Hsien
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Chiang Mai
Ukraine	GSK Investigational Site	Kharkiv
Ukraine	GSK Investigational Site	Kyiv
Ukraine	GSK Investigational Site	Lvov
Ukraine	GSK Investigational Site	Sympheropol
Ukraine	GSK Investigational Site	Uzhgorod

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Argentina,  Belgium,  Bulgaria,  Croatia,  Czechia,  Finland,  Greece,  Hungary,  India,  Ireland,  Italy,  Korea, Republic of,  Malaysia,  Pakistan,  Philippines,  Poland,  Romania,  Slovakia,  Spain,  Taiwan,  Thailand,  Ukraine, 

References & Publications (1)

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 pati — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants who achieved complete response	Complete response was defined as no vomiting/retching and no rescue therapy) over the first 120 hours following the initiation of their first cycle of a cisplatin-based HEC regimen. Vomiting was defined as the forceful expulsion of gastrointestinal contents through the mouth or nose. Retching was defined as the labored, spasmodic, rhythmic contraction of the respiratory and abdominal muscles in an attempt to vomit, that was not productive of gastrointestinal contents (also known as "dry heaves").	Up to 120 hours of cycle 1 of HEC
Secondary	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	Complete response was defined as no vomiting/retching and no rescue therapy over the first 120 hours following the initiation of their first cycle of a cisplatin-based HEC regimen. Vomiting was defined as the forceful expulsion of gastrointestinal contents through the mouth or nose. Retching was defined as the labored, spasmodic, rhythmic contraction of the respiratory and abdominal muscles in an attempt to vomit, that was not productive of gastrointestinal contents (also known as "dry heaves").	Up to 120 hours of cycle 1 of HEC
Secondary	Number of participants who achieved a complete response during the overall (0-120 hours) phase following subsequent cycles of HEC	Complete response was defined as no vomiting/retching and no rescue therapy over the first 120 hours following the initiation of their first cycle of a cisplatin-based HEC regimen. Vomiting was defined as the forceful expulsion of gastrointestinal contents through the mouth or nose. Retching was defined as the labored, spasmodic, rhythmic contraction of the respiratory and abdominal muscles in an attempt to vomit, that was not productive of gastrointestinal contents (also known as "dry heaves").	Up to 120 hours of cycle of HEC 2 to 6
Secondary	Maximum nausea score (to assess the severity of nausea), as assessed by a visual analogue scale (VAS)	Nausea was defined as a subjectively unpleasant sensation associated with the awareness of the urge to vomit; the desire to vomit without the presence of expulsive muscular movements. The participants were asked to rate the level of nausea he/she has experienced over the previous 24 hours for a period of 120 hours on a 100-point VAS scale (millimeters [mm]) where, 0: no nausea and 100: nausea as bad as it could be. Higher score indicates more severity. The maximum nausea score (to assess the severity of nausea) was assessed by a VAS during the acute (0-24 hour), delayed (24-120 hour) and overall (0-120 hour) phase.	Up to 120 hours of each HEC cycle (up to 24 months)
Secondary	Number of participants who use of anti-emetic rescue medication	Anti-emetic rescue medication was defined as any medication, other than the protocol prescribed agents, given specifically for the treatment or prophylaxis of nausea and/or emesis during the 120 hour assessment phase of each study cycle. The time to the first anti-emetic rescue medication was defined as the length of time from initiation of HEC until the time of first use of anti-emetic rescue medication.	Up to 120 hours of each HEC cycle (up to 24 months)
Secondary	Number of participants with first emetic event	Vomiting was defined as the forceful expulsion of gastrointestinal contents through the mouth or nose and retching was defined as the labored, spasmodic, rhythmic contraction of the respiratory and abdominal muscles in an attempt to vomit, that is not productive of gastrointestinal contents (also known as "dry heaves"). The time to first emetic event was defined as the length of time from initiation of HEC until the time of the first emetic event (example: retch/vomiting).	Up to 120 hours of each HEC cycle (up to 24 months)
Secondary	Number of participants who received anti-emetic rescue medication	Anti-emetic rescue medication was defined as any medication, other than the protocol prescribed agents, given specifically for the treatment or prophylaxis of nausea and/or emesis during the 120 hour assessment phase of each study cycle. The time to the first anti-emetic rescue medication was defined as the length of time from initiation of HEC until the time of first use of anti-emetic rescue medication. If no event had occurred at the end of the 120 hour time period, then the observation was censored for the purpose of this analysis.	Up to 120 hours of cycle 1 of HEC
Secondary	Number of participants who vomited/retched	The forceful expulsion of gastrointestinal contents through the mouth or nose. The laboured, spasmodic, rhythmic contraction of the respiratory and abdominal muscles in an attempt to vomit, that was not productive of gastrointestinal contents (also known as "dry heaves"). It was assessed during the acute (0-24 hour), delayed (24-120 hour) and overall (0-120 hour) phase. The odds ratio indicated a reduction in the likelihood of vomiting in the single dose oral group and in the 3-Day IV/oral group compared with the control group.	Up to 120 hours of cycle 1 of HEC
Secondary	Number of participants who reported significant nausea (>=25 mm on the VAS)	Nausea was defined as a subjectively unpleasant sensation associated with the awareness of the urge to vomit; the desire to vomit without the presence of expulsive muscular movements. The participants were asked to rate the level of nausea he/she has experienced over the previous 24 hours for a period of 120 hours on a 100-point VAS scale (mm) where, 0: no nausea and 100: nausea as bad as it could be. Higher score indicates more severity. The maximum nausea score (to assess the severity of nausea) was assessed by a VAS during the acute (0-24 hour), delayed (24-120 hour) and overall (0-120 hour) phase.	Up to 120 hours of cycle 1 of HEC
Secondary	Number of participants who reported nausea (>=5 mm on the VAS)	Nausea was defined as a subjectively unpleasant sensation associated with the awareness of the urge to vomit; the desire to vomit without the presence of expulsive muscular movements. The participants were asked to rate the level of nausea he/she has experienced over the previous 24 hours for a period of 120 hours on a 100-point VAS scale (mm) where, 0: no nausea and 100: nausea as bad as it could be. Higher score indicates more severity. The maximum nausea score (to assess the severity of nausea) was assessed by a VAS during the acute (0-24 hour), delayed (24-120 hour) and overall (0-120 hour) phase.	Up to 120 hours of cycle 1 of HEC
Secondary	Number of participants who achieved complete protection, defined as no vomiting/retching, no significant nausea and no rescue medication	Complete protection was defined as no vomiting/retching, no rescue therapy and no significant nausea (<25 mm on VAS). It was assessed during the acute (0-24 hour), delayed (24-120 hour) and overall (0-120 hour) phase.	Up to 120 hours of cycle 1 of HEC
Secondary	Number of participants who achieved total control, defined as no vomiting/retching, no nausea and no rescue medication	Total control was defined as no vomiting, no retching, no rescue therapy and no nausea (<5 mm on VAS). It was assessed during the acute (0-24 hour), delayed (24-120 hour) and overall (0-120 hour) phase.	Up to 120 hours of each HEC cycle (up to 24 months)
Secondary	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	The FLIE was a self-administered questionnaire consisting of 18 items indicating impact of nausea and vomiting on daily activities: physical, social and emotional function, and the ability to enjoy meals. Questions are divided into two domains: nausea 1-9; vomiting 10-18. Each item was scored on a VAS from 1: not at all to 7: a great deal; higher score indicates more severity. The initial score for each question was calculated by measuring the distance from the left hand end to the point where the participant had placed the mark. For questions 1, 2, 4, 5, 7-10, 12-14, 16 and 17, the final score: subtracting the initial score from 100 and for questions 3, 6, 11, 15 and 18, final score was the one provided in the dataset. The score for the nausea/vomiting domain was the sum of the individual scores divided by the number actually answered multiplied by 9. This sum was then multiplied by 0.06 and 9 added. The score ranged from 9-63 for each nausea and vomiting and sum both is provided.	Up to 120 hours of each HEC cycle (up to 24 months)
Secondary	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	The FLIE was a self-administered questionnaire consisting of 18 items indicating impact of nausea and vomiting on daily activities: physical, social and emotional function, and the ability to enjoy meals. Questions are divided into two domains: nausea questions 1-9; vomiting questions 10-18. Each item was scored on a VAS from 1: not at all to 7: a great deal. Higher scores indicate less impairment on daily life as a result of nausea or vomiting. No impact on daily life was defined as an average item score of >6 on the 7-point scale. The total score for no impact of chemotherapy induced nausea and vomiting (CINV) daily life, defined as a FLIE total score of >108 (range: 18-126). The same method was applied to vomiting and nausea subscores: no impact of vomiting (nausea) on daily life was defined as a FLIE total score of >54 (range: 9-63). The FLIE total score, as well as the vomiting and nausea subscores, for each treatment arm was calculated at Baseline and Day 6-10.	Up to 120 hours of each HEC cycle (up to 24 months)
Secondary	Participant satisfaction with the prophylactic anti-emetic regimens, as assessed by the participant satisfaction questionnaire	A participant satisfaction questionnaire was included in the participants diary card. At Day 6-10 of cycle 1, participants were asked to rate overall satisfaction with study medications in preventing chemotherapy induced nausea and vomiting, using the 5-point scale: 1: very satisfied; 2: somewhat satisfied; 3: neither satisfied nor dissatisfied; 4: somewhat dissatisfied and 5: very dissatisfied, where higher score indicates greater dissatisfaction.	Up to 120 hours of each HEC cycle (up to 24 months)
Secondary	The willingness of participant to use the same treatment during future chemotherapy, as assessed by the participant willingness questionnaire	A participant willingness questionnaire was included in the participants diary card. Participants completed this assessment on Day 6 - 10. Participants were asked to rate overall willingness to use study medications in preventing chemotherapy induced nausea and vomiting, using the 5-point scale: 1: definitely would be willing; 2: probably would be willing; 3: not certain; 4: probably would not be willing and 5: definitely would not be willing.	Up to 120 hours of each HEC cycle (up to 24 months)
Secondary	Number of participants with nausea as assessed by a categorical scale, over the first 120 hours following HEC	Nausea was defined as a subjectively unpleasant sensation associated with the awareness of the urge to vomit; the desire to vomit without the presence of expulsive muscular movements. The categorical scale assessed the participant's severity of his/her nausea using the descriptions; none: no nausea, mild: queasiness/upset stomach that was manageable and minimally (if at all) affects daily activities; moderate: increased queasiness, sometimes with the feeling of having to vomit/throw up (but not vomiting), that has significant negative effect on the daily activities (for example, being unable to work, eat and drink, prepare food, care for children or others) and severe: feeling sick and vomiting or feeling like you are going to vomit and unable to perform most daily activities.	Up to 120 hours of each HEC cycle (up to 24 months)
Secondary	Number of participants with adverse events (AE) and serious adverse events (SAE)	An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.	Up to 24 month after last dose of investigational product
Secondary	Number of participants with abnormalities of Grade 3 and 4 in laboratory parameters (clinical chemistry and hematology)	Grade shifts from Baseline were assessed as shift from any Grade to Grade 3 or Grade 4 in any cycle. Toxicities were graded according to the National Cancer Institute common toxicity criteria for adverse events (NCI-CTCAE), version 3.0. Grade refers to the severity of the toxicity. The NCI-CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on the following general guideline: Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE and Grade 5: Death related to AE. It was assessed on Day 1, during day 6-10 and end of cycle. Clinical chemistry parameters assessed included: alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, creatinine, blood urea nitrogen (BUN), chloride, glucose, potassium, sodium and urea. Hematology parameters assessed included: hemoglobin, hematocrit, total neutrophils, platelets and white blood cells (WBC).	Up to end of cycle (approximately 28 days per cycle); maximum up to 24 months
Secondary	Summary of abnormal electrocardiogram findings	It was assessed on Day 1, during day 6-10 and end of cycle. Electrocardiogram data clinically significant change from Baseline (worse, improved and no change) is presented.	Up to end of cycle (approximately 28 days per cycle); maximum up to 24 months
Secondary	Summary of mean systolic blood pressure (SBP) and diastolic blood pressure (DBP)	It was assessed on Day 1, during day 6-10 and end of cycle in cycle 1 while on Day 1 and end of cycle in subsequent cycles 2 to 6. Summary of mean SBP and DBP is presented.	Up to end of cycle (approximately 28 days per cycle); maximum up to 24 months
Secondary	Summary of mean respiratory rate	It was assessed on Day 1, during day 6-10 and end of cycle in cycle 1 while on Day 1and end of cycle in subsequent cycles 2 to 6. Summary of mean respiratory rate is presented.	Up to end of cycle (approximately 28 days per cycle); maximum up to 24 months
Secondary	Summary of mean heart rate	It was assessed on Day 1, during day 6-10 and end of cycle in cycle 1 while on Day 1and end of cycle in subsequent cycles 2 to 6. Summary of mean heart rate is presented.	Up to end of cycle (approximately 28 days per cycle); maximum up to 24 months