Netupitant/Palonosetron Hydrochloride and Dexamethasone With or Without Prochlorperazine or Olanzapine in Improving Chemotherapy-Induced Nausea and Vomiting in Patients With Breast Cancer

Study Overview
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Brief Summary
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This randomized phase III trial studies how well netupitant/palonosetron hydrochloride and dexamethasone with prochlorperazine or olanzapine work compared to netupitant/palonosetron hydrochloride and dexamethasone in improving chemotherapy-induced nausea and vomiting in patients with breast cancer. Antiemetic drugs, such as prochlorperazine and olanzapine, may help lessen nausea and vomiting in patients with breast cancer treated with chemotherapy.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if control of nausea at cycle 2 in participants who experienced chemotherapy-induced nausea and vomiting (CINV) at cycle 1 is improved by the addition of either prochlorperazine or olanzapine to the control arm of netupitant, palonosetron and dexamethasone. SECONDARY OBJECTIVES: I. To determine if olanzapine is more effective than prochlorperazine in controlling nausea at cycle 2 in participants who experienced CINV at cycle 1 when used in combination with netupitant, palonosetron and dexamethasone. II. To determine if control of vomiting at cycle 2 in patients who experienced CINV at cycle 1 is improved by the addition of either prochlorperazine or olanzapine to the control arm of netupitant, palonosetron and dexamethasone. III. To determine if olanzapine is more effective than prochlorperazine in controlling vomiting at cycle 2 in participants who experienced CINV at cycle 1 when used in combination with netupitant, palonosetron and dexamethasone. TERTIARY OBJECTIVES: I. To create an empirically-based algorithm predicting nausea from breast cancer chemotherapy regimens that takes into account not only state-of-the-art anti-emetic regimens but also participant factors such as age, race, education, ethnicity, quality of life (QOL), alcohol consumption, susceptibility to nausea, expectancy, anxiety, level of nausea on the day prior to treatment, and prior history of nausea. II. To compare the effects of the interventions on QOL, as assessed by the Functional Assessment of Cancer Therapy- General (FACT-G), by following the same procedures described under the primary aim and the first secondary aim, using change in the FACT-G scores as the response. III. To provide preliminary data on the frequency and severity of sleep disturbance, fatigue, anxiety, and dizziness, across treatment conditions. IV. To provide preliminary data on biological factors (e.g. glutathione [GSH] recycling, genetic markers) that may help identify a subgroup of patients at high risk for development of cancer-related or treatment-related side effects, or response to treatment. OUTLINE: PART I: Patients receive 1 cycle of standard of care chemotherapy. PART II: Patients with a nausea score >= 3 at least once on the diary at cycle 1 chemotherapy are randomized into 1 of 3 groups at cycle 2. GROUP I: Within 1 hour prior to chemotherapy, patients receive netupitant/palonosetron hydrochloride orally (PO) on day 1. Within 30 minutes prior to chemotherapy, patients also receive dexamethasone PO on days 1-4. Patients also receive placebo PO with chemotherapy every 8 hours (Q8H) on days 1-4. GROUP II: Patients receive netupitant/palonosetron hydrochloride and dexamethasone as in Group I. Patients also receive prochlorperazine PO Q8H and placebo PO with chemotherapy on days 1-4. GROUP III: Patients receive netupitant/palonosetron hydrochloride and dexamethasone as in Group I. Patients also receive olanzapine PO and placebo PO Q8H with chemotherapy on days 1-4. After completion of study treatment, patients are followed up for 30 days.

Official Title
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Treatment of Refractory Nausea

Conditions
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Breast Carcinoma

Intervention / Treatment
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* Drug: Dexamethasone
* Other: Laboratory Biomarker Analysis
* Drug: Netupitant/Palonosetron Hydrochloride
* Drug: Olanzapine
* Other: Placebo
* Drug: Prochlorperazine
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a diagnosis of breast cancer and be chemotherapy naive; NOTE: prior methotrexate for non-cancerous conditions is allowed Be scheduled to receive a single-day chemotherapy regimen that contains doxorubicin and/or cyclophosphamide and/or carboplatin. Single-day chemotherapy is defined as only one infusion or injection per cycle. Herceptin (trastuzumab) and other chemotherapy agents will be allowed with any of these regimens Be scheduled to receive an antiemetic regimen that does not contain Akynzeo; in addition, the antiemetic regimen must conform with American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines at cycle 1 Be able to read English Have the ability to give written informed consent Have Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 NOTE: patients 80 years of age or older must have approval from an oncologist or their designee to participate in this study NOTE: patients currently receiving warfarin must have approval from an oncologist or their designee to participate in this study Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, or abstinence) for the duration of the study and have a negative pregnancy test within 10 days prior to the initiation of chemotherapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately CYCLE II PORTION ONLY: Only participants with a nausea score >= 3 at least once on the diary assessment from cycle 1 can be randomized for cycle 2 CYCLE II PORTION ONLY: Participants must be scheduled to receive the same chemotherapy regimen as received at cycle 1 Exclusion Criteria: Have clinical evidence of current or impending bowel obstruction Have a known history of central nervous system disease (e.g., brain metastases or a seizure disorder) Have dementia Have uncontrolled diabetes mellitus or uncontrolled hyperglycemia Have severe hepatic impairment, severe renal impairment, or end-stage renal disease as determined by the treating physician Have had long term treatment (> 5 days within the past 30 days) with an antipsychotic agent such as risperidone, quetiapine, clozapine, a phenothiazine, or a butyrophenone within 30 days before enrollment or plans for such treatment during the study period; NOTE: participants could have received prochlorperazine and other phenothiazines as antiemetic therapy on a short term basis (i.e., =< 5 days) Have a known cardiac arrhythmia, uncontrolled congestive heart failure, or acute myocardial infarction within the previous 6 months Be taking benzodiazepines regularly (> 5 days within the past 30 days); pro re nata (PRN) use (=< 5 days) for the short-term relief of the symptoms of anxiety, anxiety associated with depressive symptoms, or as a rescue medication for breakthrough CINV is allowed Be taking anticholinergic medications Be receiving quinolone antibiotic therapy Be taking amifostine (Ethiofos) Have a known hypersensitivity to olanzapine or to phenothiazines CYCLE II PORTION ONLY: Must not have received Akynzeo at cycle 1 CYCLE II PORTION ONLY: Must still meet all the exclusion criteria for cycle 1

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I (netupitant/palonosetron hydrochloride, dexamethasone<br>Within 1 hour prior to chemotherapy, patients receive netupitant/palonosetron hydrochloride PO on day 1. Within 30 minutes prior to chemotherapy, patients also receive dexamethasone PO on days 1-4. Patients also receive placebo PO with chemotherapy Q8H on days 1-4. | Drug: Dexamethasone<br>* Given PO<br>* Other names: Visumetazone;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Netupitant/Palonosetron Hydrochloride<br>* Given PO<br>* Other names: Akynzeo;Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Group II (net/pal hydro, dexa, prochlorperazine, placebo)<br>Patients receive netupitant/palonosetron hydrochloride and dexamethasone as in Group I. Patients also receive prochlorperazine PO Q8H and placebo PO with chemotherapy on days 1-4. | Drug: Dexamethasone<br>* Given PO<br>* Other names: Visumetazone;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Netupitant/Palonosetron Hydrochloride<br>* Given PO<br>* Other names: Akynzeo;Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Drug: Prochlorperazine<br>* Given PO<br>* Other names: SKF-4657;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Group III (net/pal hydro, dexa, olanzapine, placebo)<br>Patients receive netupitant/palonosetron hydrochloride and dexamethasone as in Group I. Patients also receive olanzapine PO and placebo PO Q8H with chemotherapy on days 1-4. | Drug: Dexamethasone<br>* Given PO<br>* Other names: Visumetazone;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Netupitant/Palonosetron Hydrochloride<br>* Given PO<br>* Other names: Akynzeo;Drug: Olanzapine<br>* Given PO<br>* Other names: Zyprexa Zydis;Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average nausea defined as the average nausea rating across 15 assessment points (comparing prochlorperazine or olanzapine to control arm) | Will be measured on a 7-point scale anchored by not at all nauseated and extremely nauseated. | Up to day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average nausea defined as the average nausea rating across 15 assessment points (comparing olanzapine to prochlorperazine) | Will be measured on a 7-point scale anchored by not at all nauseated and extremely nauseated. | Up to day 4 | 
| Presence of any vomiting (yes or no) | Will assess presence of any vomiting (yes or no). | Up to day 4 |