Incidence of Chemotherapy-Induced Nausea and Vomiting Associated With Docetaxel-Cyclophosphamide in Early Breast Cancer.

Study Overview
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Brief Summary
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This is a prospective, multicenter, open label, non-comparative trial in Spain. The primary objective of this study is to determine the complete response, defined as no vomiting and no use of rescue treatment, in women with early-stage breast cancer treated with one cycle of Docetaxel-Cyclophosphamide and active therapy for the prevention of CINV (Chemotherapy-induced nausea and vomiting) day 1, 5-hydroxytryptamine 3 (5-HT3) antagonist plus 3 days of dexamethasone. A second step (efficacy phase) is designed to examine the efficacy and tolerability of aprepitant in the second cycle among patients who failed to the previous CINV prevention treatment. The study will focus on early-stage chemonaive breast cancer patients receiving docetaxel-cyclophosphamide and a 5-HT3 antagonist plus dexamethasone for the CINV prevention. The CINV incidence in those patients will be evaluated on the first cycle. All refractory patients, will be asked to participate in the second phase, where aprepitant on days 1, 2 and 3 will be added to their antiemetic regimen. Assuming a drop out of 5%, 212 patients will be included in the study. It is anticipated that around 48 patients will enter the efficacy phase. The duration of the study, from first patient visit to last patient visit will be approximately 21 months.

Detailed Description
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Sample size We want to obtain an estimation of the percent of the patients that we assume won't have a response to the treatment against vomiting. Reviewing bibliography, we think that the percent is approximately 25%. We are going to obtain an estimation of this percent with an accuracy of +/- 6%, with a bilateral confidence level of 95% bilateral. Whit all this premises it would be needed 201 patients. Assuming a drop out of 5%, 212 patients will be included in the study. A maximum of 212 patients will be included in the trial. It is anticipated that around 48 patients will enter the efficacy phase. APPROXIMATE DURATION OF THE STUDY. Inclusion period: 18 months approximately. Estimated follow-up: December 2012 Estimated date of end of study: June 2013

Official Title
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A Prospective, Open Label, Non-comparative Trial to Determine the Incidence of Chemotherapy-Induced Nausea and Vomiting (CINV) Associated With the Docetaxel-Cyclophosphamide Regimen in Early Breast Cancer Patients

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Aprepitant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patient ≥ 18 years of age. Patient has a histological confirmed early-stage (I to III) breast cancer. Patient is able to understand study procedures and agrees to participate in the study by giving written informed consent. Patient is naive to moderate or highly emetogenic chemotherapy per Hesketh criteria. Patient is scheduled to receive of chemotherapy with Docetaxel-Cyclophosphamide (Docetaxel 75mg/m2 and Cyclophosphamide 600mg/m2) administered every 21 days. Patient has a predicted life expectancy ≥ 4 months. Functional State 0-1 Eastern Cooperative Oncology Group (ECOG) Scale (see Appendix 12.2). Patient has an adequate organ function including the following: Bone marrow reserve: Absolute Neutrophil Count >1500/mm3 and white blood cell (WBC) count >3000/mm3; Platelet Count >100.000/mm3 Hepatic: aspartate aminotransferase (AST) <2.5 x upper limit of normal; alanine aminotransferase (ALT) <2.5 x upper limit of normal; Bilirubin within the normal limit. Renal: Creatinine <1.5 x upper limit of normal. Premenopausal female patients must demonstrate a negative serum and/or urine pregnancy test within 3 days of study drug administration, and agree to use a double-barrier form of contraception for at least 14 days prior to, throughout and for at least 14 days following the last dose of study medication. Women taking oral contraceptive agents must agree to add a barrier form of contraception. Abstinence is also considered an acceptable form of contraception. (Note: A female patient who is not of reproductive potential is eligible without requiring the use of contraception. A female patient who is not of reproductive potential is defined as one who has either: 1) reached natural menopause (defined as 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels in the postmenopausal range as determined by the laboratory, or 12 months of spontaneous amenorrhea); 2) 6 weeks post surgical bilateral oophorectomy with or without hysterectomy; or 3) bilateral tubal ligation.) Patient is able to read, understand and complete study questionnaires. Exclusion Criteria: Patient is scheduled to receive any chemotherapy treatment different to the Docetaxel-Cyclophosphamide chemotherapy. Patient has received or will receive radiation therapy to the abdomen, chest or pelvis in the month prior to the study enter. Patient has vomited in the 24 hours prior to Treatment Day 1. Patient has a history of treatment with emetogenic chemotherapy of moderate or high level per Hesketh (classification of emetogenic chemotherapy agents). Patient has an active infection (e.g., pneumonia) or any uncontrolled disease (e.g., diabetic ketoacidosis, gastrointestinal obstruction) except for malignancy which, in the opinion of the investigator, might confound the results of the study or pose unwarranted risk. Patient currently uses any illicit drugs, including marijuana, or has current evidence of alcohol abuse as determined by the investigator. Patient is mentally incapacitated or has a significant emotional or psychiatric disorder that, in the opinion of the investigator, precludes study entry. Patient has a history of any illness that, in the opinion of the investigator, might confound the results of the study or pose unwarranted risk. Patient has a history of hypersensitivity to aprepitant, 5-HT3 antagonists, or dexamethasone. Patient is pregnant or breast feeding. Patient has participated in a study with aprepitant or has taken a non approved (investigational) drug within the last 4 weeks. Patient is taking systemic corticosteroid therapy at any dose; topical and inhaled corticosteroids are permitted. Patient is taking, or will be taking within 28 days of Day 1 of cycle 2 (cycle in which patients will start taking aprepitant) the following CYP3A4 inducers: phenytoin or carbamazepine barbiturates rifampicin or rifabutin St. John's Wort Patient is taking, or will be taking within 7 days of Day 1 of cycle 2 the following CYP3A4 substrates: terfenadine cisapride astemizole pimozide Patient is taking, or will be taking within the 7 days of Day 1 of cycle 2 the following CYP3A4 inhibitors: clarithromycin ketoconazole, itraconazole Patient will be taking an antiemetic within 48 hours of Day 1 of cycle 2. Prohibited antiemetics include: 5-HT3 antagonists (ondansetron, granisetron, dolasetron, tropisetron or palonosetron) phenothiazines (e.g., prochlorperazine, fluphenazine, perphenazine, thiethylperazine, or chlorpromazine) butyrophenones (e.g., haloperidol or droperidol) benzamides (e.g., metoclopramide or alizapride) domperidone cannabinoids herbal therapies with potential antiemetic properties scopolamine cyclizine Patient has used benzodiazepines or opiates, except for single daily doses of triazolam, temazepam or midazolam in the 48 hours prior to Day 1 of cycle 2. Continuation of chronic benzodiazepines or opiate therapy is permitted provided it was initiated at least 48 hours before enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Patients that experiment emesis within the first cycle in spite of the administration of antiemetics, may opt to participate in a subsequent efficacy phase
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aprepitant<br>Observational phase (first cycle): Day 0 (Dexamethasone 8mg) Day 1 (5-HT3 antagonist, Ondansetron: 8 mg x2, Granisetron: 1mg x2,Tropisetron: 5 mg, Dexamethasone 24 mg) + Chemotherapy (Docetaxel 75mg/m2 and Cyclophosphamide 600mg/m2 ). Days 2 and 3 (Dexamethasone 16 mg). If not complete response: Efficacy phase (second cycle): Day 0 (Dexamethasone 8mg) Day 1 (Aprepitant: 125 mg,5-HT3 antagonist, Ondansetron: 8 mg x2, Granisetron: 1mg x2, Tropisetron: 5 mg, Dexamethasone 12 mg)+ Chemotherapy: Docetaxel 75mg/m2 and Cyclophosphamide 600mg/m2 . Days 2 and 3 (Aprepitant: 1 capsule of 80 mg daily, Dexamethasone 8 mg). | Drug: Aprepitant<br>* Efficacy phase (second cycle)<br>* Other names: - Domperidone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response (CR) | Complete response is defined as no vomiting and no use of rescue treatment within the first cycle of Docetaxel-Cyclophosphamide for the treatment of early-stage breast cancer patients. A vomiting episode is defined as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retches (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes are, by definition, separated by the absence of emesis and retching for at least 1 minute. The timing (date and time) of each vomiting episode will be recorded by the patient in each cycle diary at the time of occurrence. Assessments of efficacy will begin at the initiation of chemotherapy infusion (0 hours) until the morning of Day 6 (approximately 120 hours) after chemotherapy during 1-2 cycles. | Up to 21 days after cycle 1 of chemotherapy treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Response (CR) in Cycle 2 for Patient Without Complete Response in Cycle 1 | To evaluate in cycle 2 the efficacy of aprepitant (days 1, 2 and 3) as secondary prevention in patients without complete response in cycle 1. A vomiting episode is defined as one or more episodes of emesis (expulsion of stomach contents through the mouth) or retches (an attempt to vomit that is not productive of stomach contents). Distinct vomiting episodes are, by definition, separated by the absence of emesis and retching for at least 1 minute. The timing (date and time) of each vomiting episode will be recorded by the patient in each cycle diary at the time of occurrence. Assessments of efficacy will begin at the initiation of chemotherapy infusion (0 hours) until the morning of Day 6 (approximately 120 hours) after chemotherapy during 1-2 cycles. | Up to cycle 2, and average of 6 weeks | 
| Number of Participants With Treatment Related Adverse Events (AE) at Cycle 2 | Events are related to the primary end point, they were collected only in the diary during the period of diary data collection (Day 1 to the morning of Day 6) for the cycle 2, unless they meet the definition of a serious adverse event. | Cycle 2, and average of 3 weeks | 
| Total Impact of Chemotherapy-Induced Nausea and Vomiting on Daily Life by the Functional Living Index-Emesis Questionnaire in Cycle 1 | To determine the incidence of Chemotherapy-Induced Nausea and Vomiting associated with the Docetaxel-Cyclophosphamide regimen in early breast cancer patients, a Functional Living Index-Emesis (FLIE) questionnaire was collected on treatment Day 1 (prior to initiation of chemotherapy) and Day 6, which referenced the entire treatment period since the initiation of chemotherapy for non clinical responders (NCR) against clinical responders (CR). The FLIE questionnaire is a validated, patient-reported instrument to measure the impact of Chemotherapy-Induced Nausea and Vomiting on daily life. There are 18 items, each on a 7-point scale. Results are reported as a total score. For the purposes of this study, higher scores indicate less impairment on daily life as a result of nausea or vomiting (better outcome) (Maximum 126, Minimum 18). | Up to day 6 | 
| Impact of Chemotherapy-Induced Nausea on Daily Life by the Functional Living Index-Emesis Questionnaire in Cycle 1 | To determine the incidence of nausea associated with the Docetaxel-Cyclophosphamide regimen in early breast cancer patients, a Functional Living Index-Emesis (FLIE) questionnaire was collected on treatment Day 1 (prior to initiation of chemotherapy) and Day 6, which referenced the entire treatment period since the initiation of chemotherapy for non clinical responders (NCR) against clinical responders (CR). The FLIE questionnaire is a validated, patient-reported instrument to measure the impact of Chemotherapy-Induced Nausea and vomiting on daily life. There are 9 nausea-related items, each on a 7-point scale. Results are reported as a nausea score. For the purposes of this study, higher scores indicate less impairment on daily life as a result of nausea (better outcome) (Maximum 63, Minimum 9). | Up to day 6 | 
| Impact of Chemotherapy-Induced Vomiting on Daily Life by the Functional Living Index-Emesis Questionnaire in Cycle 1 | To determine the incidence of vomiting associated with the Docetaxel-Cyclophosphamide regimen in early breast cancer patients, a Functional Living Index-Emesis (FLIE) questionnaire was collected on treatment Day 1 (prior to initiation of chemotherapy) and Day 6, which referenced the entire treatment period since the initiation of chemotherapy for non clinical responders (NCR) against clinical responders (CR). The FLIE questionnaire is a validated, patient-reported instrument to measure the impact of vomiting on daily life. There are 9 vomiting-related items, each on a 7-point scale. Results are reported as a vomiting score. For the purposes of this study, higher scores indicate less impairment on daily life as a result of vomiting (better outcome) (Maximum 63, Minimum 9). | Up to day 6 | 
| Total Impact of Chemotherapy-Induced Nausea and Vomiting on Daily Life by the Functional Living Index-Emesis Questionnaire in Cycle 2 | To determine the total incidence of Chemotherapy-Induced Nausea and Vomiting associated with the Docetaxel-Cyclophosphamide regimen in early breast cancer patients, a Functional Living Index-Emesis (FLIE) questionnaire was collected on treatment Day 1 (prior to initiation of chemotherapy) and Day 6, which referenced the entire treatment period since the initiation of chemotherapy for non clinical responders (NCR) against clinical responders (CR). The FLIE questionnaire is a validated, patient-reported instrument to measure the impact of Chemotherapy-Induced Nausea and Vomiting on daily life. There are 18 items, each on a 7-point scale. Results are reported as a total score. For the purposes of this study, higher scores indicate less impairment on daily life as a result of nausea or vomiting (better outcome) (Maximum 126, Minimum 18). | Up to day 6 | 
| Impact of Chemotherapy-Induced Nausea on Daily Life by the Functional Living Index-Emesis Questionnaire in Cycle 2 | To determine the incidence of Nausea associated with the Docetaxel-Cyclophosphamide regimen in early breast cancer patients, a Functional Living Index-Emesis (FLIE) questionnaire was collected on treatment Day 1 (prior to initiation of chemotherapy) and Day 6, which referenced the entire treatment period since the initiation of chemotherapy for non clinical responders (NCR) against clinical responders (CR). The FLIE questionnaire is a validated, patient-reported instrument to measure the impact of Nausea on daily life. There are 9 items, each on a 7-point scale. Results are reported as a nausea score. For the purposes of this study, higher scores indicate less impairment on daily life as a result of nausea (better outcome) (Maximum 63, Minimum 9). | Up to day 6 | 
| Impact of Chemotherapy-Induced Vomiting on Daily Life by the Functional Living Index-Emesis Questionnaire in Cycle 2 | To determine the incidence of vomiting associated with the Docetaxel-Cyclophosphamide regimen in early breast cancer patients, a Functional Living Index-Emesis (FLIE) questionnaire was collected on treatment Day 1 (prior to initiation of chemotherapy) and Day 6, which referenced the entire treatment period since the initiation of chemotherapy for non clinical responders (NCR) against clinical responders (CR). The FLIE questionnaire is a validated, patient-reported instrument to measure the impact of vomiting on daily life. There are 9 items, each on a 7-point scale. Results are reported as a vomiting score. For the purposes of this study, higher scores indicate less impairment on daily life as a result of vomiting (better outcome) (Maximum 63, Minimum 9). | Up to day 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early-stage breast cancer patients