Efficacy and Safety of Intravenous Versus Oral 5-HT3 Antagonists Combined With NK-1 Receptor Antagonists for the Prevention of CINV in Breast Cancer

Study Overview
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Brief Summary
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Chemotherapy is one of the most common treatments for breast cancer, but the adverse effects can be severe enough to delay or make chemotherapy intolerable, thus affecting the efficacy of the disease. Women and younger patients are more likely to experience chemotherapy-induced nausea and vomiting (CINV) . Therefore, antiemetic drugs is a key way to reduce chemotherapy side effects, which ensures compliance, and maintain quality of life. CINV is usually induced by two pathways. The central pathway is mediated by neurokinin-1 (NK-1) receptors, where chemotherapeutic agents stimulate the secretion of substance-P (SP) from the vomiting center located in the medulla oblongata and nucleus accumbens, which binds to NK-1 receptors and induces vomiting. The peripheral pathway is mediated by 5-hydroxytryptamine 3 (5-HT3) receptors, and chemotherapy stimulates intestinal chromophores in the gastrointestinal mucosa to secrete 5-HT3, which binds to its receptors to induce vomiting. Most guidelines currently recommend the combination of 5-HT3 receptor antagonists, NK-1 receptor antagonists, and dexamethasone for high-emetogenic-risk chemotherapy regimens. Usually 5-HT3 receptor antagonists include granisetron, ondansetron, and palonosetron. Palonosetron is a second-generation 5-HT3 receptor antagonist with stronger affinity and higher efficacy than other antagonists. The commonly used NK-1 receptor antagonists are aprepitant and fosaprepitant. Fosaprepitant is an aprepitant prodrug that can be rapidly converted to aprepitant in the body, blocking the binding of substance P to NK-1 receptors for antiemetic purposes. Clinical trial has confirmed that the overall complete response (CR) rate of palonosetron 0.75 mg combined with fosaprepitant and dexamethasone was 54.9%, with 75.9% CR in the acute phase (0-24 h after chemotherapy) and 62.3% in the delayed phase (24-72 h after chemotherapy). Another clinical trial showed an acute phase CR of 89.8% and a delayed phase CR of 90.4% for oral aprepitant combined with intravenous palonosetron 0.75 mg and dexamethasone. The data suggests that both oral and intravenous administration are effective in preventing CINV, but there are no clinical trial results for oral versus intravenous administration. Oral administration is painless, has fewer side effects, and is a safer mode of administration, but bioavailability is different and drug absorption is affected by a variety of factors; whereas intravenous injection has rapid onset of action, but there are risks of injection reactions, phlebitis, and infection. Therefore, we hope to conduct a non-inferiority study on the efficacy of oral and intravenous 5-HT3 receptor antagonists combined with NK-1 receptor antagonists through this trial, which can provide more options for patients by combining the cost and administration methods.

Official Title
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Efficacy and Safety of Intravenous Versus Oral 5-HT3 Antagonists Combined With NK-1 Receptor Antagonists for the Prevention of Breast Cancer Chemotherapy-induced Nausea and Vomiting: a Single-center, Randomized Controlled Clinical Trial

Conditions
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Breast Cancer, Chemotherapy-induced Nausea and Vomiting

Intervention / Treatment
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* Drug: Aprepitant
* Drug: Palonosetron
* Drug: Fosaprepitant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female, age 18-70 years. Confirmed pathology suggested primary invasive breast adenocarcinoma; Presence of adjuvant chemotherapy or neoadjuvant chemotherapy indications according to clinical guidelines. No other malignant tumor or other chemotherapy No prior treatment for present breast cancer onset ECOG physical status score 0 to 1 Hematological examination before treatment should meet: white blood cell count (WBC) ≥ 4.0×10^9/L, neutrophil count (ANC) ≥ 1.5×10^9/L, platelet count (PLT) ≥ 100×10^9/L; hemoglobin (Hb) ≥ 90g/L; AST (sGOT), ALT (sGPT) ≤ 1.5 times the normal value upper limit, creatinine ≤ 1.5 times the upper limit of normal value, total bilirubin ≤ 1.5 times the upper limit of normal value. No serious impairment of heart, liver, kidney and other important organ functions. Exclusion Criteria: Unwilling or unable to use an acceptable method of contraception for up to and including 8 weeks after the final dose of the test drug. Women during pregnancy and breastfeeding after pregnancy. Women with proven distant metastases of breast cancer. Patients with proven sensory or motor nerve disease. Definite cardiovascular disease, severe co-morbidity or active infection, including known HIV infection. Patients who need long-term anticoagulant drugs for cardiovascular or thrombotic diseases. History of other tumors. Allergic to the study drug or its excipients, etc.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: oral group<br>patients receive oral palonosetron and aprepitant | Drug: Aprepitant<br>* oral aprepitant capsules 125mg for D1 before chemotherapy, 80mg for D2 and D3<br>Drug: Palonosetron<br>* oral palonosetron 0.5mg for D1 before chemotherapy; intravenous palonosetron 0.25mg for D1 before chemotherapy;<br>|
| Active Comparator: intravenous group<br>patients receive intravenous palonosetron and fosaprepitant | Drug: Palonosetron<br>* oral palonosetron 0.5mg for D1 before chemotherapy; intravenous palonosetron 0.25mg for D1 before chemotherapy;<br>Drug: Fosaprepitant<br>* intravenous fosaprepitant 150mg for D1 before chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complete response | No vomiting or additional antiemetic medication throughout the post-chemotherapy period (0-72 hours) | 0-72 hour after chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| delayed phase complete response | Delayed phase (24-72 hours after chemotherapy) without vomiting or additional antiemetic medication use | 24-72 hour after chemotherapy | 
| acute phase complete response | Acute phase (0-24 hours after chemotherapy) without vomiting or additional antiemetic medication use | 0-24 hour after chemotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, CINV, chemotherapy, oral versus intravenous