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

NCT05841849 | Not Yet Recruiting Phase 4 DMC

• 1 other identifier: 2023-0277
• Study Type: interventional
• Target: 1,028
• Locations: 1 country
• Sites: 1

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.

Conditions

Breast Cancer; Chemotherapy-induced Nausea and Vomiting

Keywords

breast cancer; CINV; chemotherapy; oral versus intravenous

Outcome Measures

Primary Outcomes (1)

• complete response

  No vomiting or additional antiemetic medication throughout the post-chemotherapy period (0-72 hours)

  0-72 hour after chemotherapy

Secondary Outcomes (2)

• delayed phase complete response

  24-72 hour after chemotherapy

• acute phase complete response

  0-24 hour after chemotherapy

Study Arms (2)

oral group

EXPERIMENTAL

patients receive oral palonosetron and aprepitant

Drug: Aprepitant; Drug: Palonosetron

intravenous group

ACTIVE COMPARATOR

patients receive intravenous palonosetron and fosaprepitant

Drug: Palonosetron; Drug: Fosaprepitant

Interventions

Aprepitant DRUG

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

oral group

Palonosetron DRUG

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

intravenous group; oral group

Fosaprepitant DRUG

intravenous fosaprepitant 150mg for D1 before chemotherapy

intravenous group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Second Affiliated Hospital, School of Medicine, Zhejiang University: lead

Study Sites (1)

the Second Affiliated Hospital of Zhejiang Univercity School of Medicine

Hanzhou, Zhejiang, China

Location

Related Publications (7)

• Navari RM, Aapro M. Antiemetic Prophylaxis for Chemotherapy-Induced Nausea and Vomiting. N Engl J Med. 2016 Apr 7;374(14):1356-67. doi: 10.1056/NEJMra1515442. No abstract available.

  PMID: 27050207 BACKGROUND

• Gupta K, Walton R, Kataria SP. Chemotherapy-Induced Nausea and Vomiting: Pathogenesis, Recommendations, and New Trends. Cancer Treat Res Commun. 2021;26:100278. doi: 10.1016/j.ctarc.2020.100278. Epub 2020 Dec 11.

  PMID: 33360668 BACKGROUND

• Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, Danso MA, Dennis K, Dupuis LL, Dusetzina SB, Eng C, Feyer PC, Jordan K, Noonan K, Sparacio D, Lyman GH. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020 Aug 20;38(24):2782-2797. doi: 10.1200/JCO.20.01296. Epub 2020 Jul 13.

  PMID: 32658626 BACKGROUND

• Navari RM. Palonosetron for the treatment of chemotherapy-induced nausea and vomiting. Expert Opin Pharmacother. 2014 Dec;15(17):2599-608. doi: 10.1517/14656566.2014.972366. Epub 2014 Oct 17.

  PMID: 25323946 BACKGROUND

• Garnock-Jones KP. Fosaprepitant Dimeglumine: A Review in the Prevention of Nausea and Vomiting Associated with Chemotherapy. Drugs. 2016 Sep;76(14):1365-72. doi: 10.1007/s40265-016-0627-7.

  PMID: 27510503 BACKGROUND

• Matsumoto K, Takahashi M, Sato K, Osaki A, Takano T, Naito Y, Matsuura K, Aogi K, Fujiwara K, Tamura K, Baba M, Tokunaga S, Hirano G, Imoto S, Miyazaki C, Yanagihara K, Imamura CK, Chiba Y, Saeki T. A double-blind, randomized, multicenter phase 3 study of palonosetron vs granisetron combined with dexamethasone and fosaprepitant to prevent chemotherapy-induced nausea and vomiting in patients with breast cancer receiving anthracycline and cyclophosphamide. Cancer Med. 2020 May;9(10):3319-3327. doi: 10.1002/cam4.2979. Epub 2020 Mar 13.

  PMID: 32168551 BACKGROUND

• Nakayama Y, Ito Y, Tanabe M, Takahashi S, Hatake K. A combination of aprepitant, palonosetron, and dexamethasone prevents emesis associated with anthracycline-containing regimens for patients with breast cancer. A retrospective study. Breast Cancer. 2015 Mar;22(2):177-84. doi: 10.1007/s12282-013-0472-4. Epub 2013 May 8.

  PMID: 23653153 BACKGROUND

MeSH Terms

Conditions

Breast Neoplasms; Vomiting

Interventions

Aprepitant; Palonosetron; fosaprepitant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinuclidines; Heterocyclic Compounds, Bridged-Ring; Isoquinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Central Study Contacts

Wei Tian, doctor

CONTACT

+86 13777825246; denyiweit@zju.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 23, 2023
• First Posted: May 3, 2023
• Study Start: July 1, 2023
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): July 1, 2029
• Last Updated: May 3, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)