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

Sponsor

Second Affiliated Hospital, School of Medicine, Zhejiang University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05841849

Collaborator

(none)

1,028

Enrollment

Location

Arms

Anticipated Duration (Months)

14.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Chemotherapy-induced Nausea and Vomiting	Drug: Aprepitant Drug: Palonosetron Drug: Fosaprepitant	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1028 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Anticipated Study Start Date :

Jul 1, 2023

Anticipated Primary Completion Date :

Jul 1, 2028

Anticipated Study Completion Date :

Jul 1, 2029

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: oral group

patients receive oral palonosetron and aprepitant

Drug: Aprepitant

oral aprepitant capsules 125mg for D1 before chemotherapy, 80mg for D2 and D3

Drug: Palonosetron

oral palonosetron 0.5mg for D1 before chemotherapy; intravenous palonosetron 0.25mg for D1 before chemotherapy;

Active Comparator: intravenous group

patients receive intravenous palonosetron and fosaprepitant

Drug: Palonosetron

oral palonosetron 0.5mg for D1 before chemotherapy; intravenous palonosetron 0.25mg for D1 before chemotherapy;

Drug: Fosaprepitant

intravenous fosaprepitant 150mg for D1 before chemotherapy

Outcome Measures

Primary Outcome Measures

complete response [0-72 hour after chemotherapy]
No vomiting or additional antiemetic medication throughout the post-chemotherapy period (0-72 hours)

Secondary Outcome Measures

delayed phase complete response [24-72 hour after chemotherapy]
Delayed phase (24-72 hours after chemotherapy) without vomiting or additional antiemetic medication use
acute phase complete response [0-24 hour after chemotherapy]
Acute phase (0-24 hours after chemotherapy) without vomiting or additional antiemetic medication use

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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.