Desloratadine to Prevent Taxane-induced Peripheral Neuropathy in Patients With Breast Cancer

Официальное название

Desloratadine to Prevent Taxane-induced Peripheral Neuropathy in Patients With Breast Cancer (DETOXp)

Обзор

This is a double-blinded randomized controlled clinical trial that aims to study if desloratadine can reduce rates of peripheral neuropathy development in patients with breast cancer receiving taxane chemotherapy. Researchers will compare desloratadine to a placebo (look-alike substance with no drug) and use validated neurotoxicity and quality of life questionnaires to determine if desloratadine can be used to prevent or make taxane induced peripheral neuropathy (TPIN) symptoms better.

Подробное описание

Taxanes are frequently incorporated in first line chemotherapy regimens for breast cancer. Although taxane induces peripheral neuropathy (TIPN) is among the most common side effects of taxane treatment, currently there are no therapies that have consistently proven to be effective in preventing TIPN. TIPN involves a complex interplay of mechanisms which are not yet fully understood. However, neuroinflammation has been shown to be a critical component of the pathophysiology of TIPN. As a result, the discovery of novel therapies that can safely and efficiently attenuate the inflammatory drivers of TIPN and thus prevent the onset of bothersome and potentially disabling neuropathy, represents a unique opportunity to make a meaningful impact on the lives of breast cancer patients.

Desloratadine has shown promise for preventing TIPN in animal models, but based on available information has not yet been tested in humans. This study aims to build on this research by investigating the efficacy of desloratadine in preventing and ameliorating TIPN symptoms as assessed by validated neurotoxicity and quality of life questionnaires. Additionally, this study seeks to expand current knowledge about the role of inflammatory biomarkers as predictive markers of TIPN development. This study will investigate a broad subset of pro and anti-inflammatory cytokines, many of which have been previously shown to be mediated by the Histamine H1 Receptor (HRH1) and 5-HT 2A /c-Fos/NLRP3/IL-1β pathways. This study will measure histamine and nitric oxide levels, which have been show in-vivo to induce neuroinflammation and be upregulated in TIPN. This study will also assess nerve growth factor (NGF) and neurofilament light polypeptide (NF-L), which have protective, regenerative, nociceptive, and structural function in neurons. These biomarkers have shown to correlate with severity of TIPN, but thus far predictive utility is lacking and merits more research. Finally, this study aims to build upon current research regarding the human microbiome and its role in mediating inflammation and the onset of TIPN. Based on current knowledge, no prior study has investigated whether attenuation of chemotherapy induced inflammation via an antihistamine can prevent dysbiosis and help minimize the effect altered gut flora has on promoting further inflammation.

Desloratadine is a safe and inexpensive drug. This study is using 5mg PO dosing, every other day, because this is the standard dose used clinically for allergic rhinitis and chronic urticaria. Based on the effectiveness of loratadine in improving patient reported outcomes from vinca alkaloid induced neuropathy, and because of promising results of desloratadine in preventing and alleviating TIPN in mouse models, it is hypothesized that desloratadine will be an effective therapy to prevent TIPN in patients with breast cancer who receive adjuvant taxane-based chemotherapy regimens. Furthermore, it is also hypothesized that inflammatory biomarkers and gut microbiome signatures are associated with the development of TIPN. The effect of desloratadine in modulating such biomarkers will be monitored.

This double-blinded randomized controlled trial design will help mitigate bias in patient reported outcomes and clinician assessments. If the primary objective is met, desloratadine could potentially represent a safe, cost effective, and accessible strategy to prevent TIPN.

Вмешательства

• Препарат Desloratodine
  Desloratadine 5mg PO every other day for 12 weeks. Desloratadine is a long- acting tricyclic histamine antagonist with selective H1-receptor histamine antagonist activity. Desloratadine inhibited histamine release from human mast cells.
• Препарат Placebo
  Placebo daily PO for 12 weeks. Placebo is a lactose filler covered by a capsule.

Первичные конечные точки

• Change in Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group (GOG)-Neurotoxicity (NTX) Subscale Version 4 (FACT-GOG-NTX) neuropathy score [Срок оценки: From baseline to after completion of 12 weeks of taxane chemotherapy]

Вторичные конечные точки (8)

• Rate of grade 2-4 TIPN assessed by treating physician [Срок оценки: After completion of 12 weeks of taxane chemotherapy and at 24 weeks and 12 months after completing taxane chemotherapy]
• Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) survey score [Срок оценки: After completion of 12 weeks of taxane chemotherapy]
• Change in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity (FACT-GOG-NTX) quality of life survey score [Срок оценки: From baseline to the completion of 12 weeks of taxane chemotherapy]
• Change in Patient-Reported Outcomes Measurement Information Systems (PROMIS) 29 v2.1 survey score [Срок оценки: From baseline to the completion of 12 weeks of taxane chemotherapy]
• European Organisation of Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) - Chemotherapy-induced Peripheral Neuropathy twenty-item scale (CIPN20) (EORTC QLQ CIPN20) survey score [Срок оценки: 12 weeks after the completion of taxane chemotherapy]
• Rate of permanent discontinuation of taxane due to TIPN [Срок оценки: From baseline up to week 12 of taxane chemotherapy]
• Rate of taxane dose interruption or dose reduction due to TIPN [Срок оценки: From baseline up to week 12 of taxane chemotherapy]
• Rate of pathological complete response (pCR) [Срок оценки: After completion of 12 weeks of taxane chemotherapy]

Критерии участия

Критерии включения

• Patients must have histologically confirmed breast cancer, stage I-III as per the American Joint Committee on Cancer (AJCC) 8th edition (Anatomic Staging)
• Patients must be planned to receive taxane-based regimen for breast cancer (Adjuvant or neoadjuvant) of at least 12 weeks duration. Patients planned to receive taxanes in combination with other chemotherapy drugs (including platinums) are eligible. Patients planned to receive taxanes plus single or dual antiher2 therapy are also eligible. Patients planned to receive taxane-based regimen with immune checkpoint inhibitors are also allowed
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥60%)
• Patients must have an adequate organ and marrow function as defined below:
• absolute neutrophil count ≥1,000/microliter (mcL)
• platelets ≥100,000/mcL
• total bilirubin ≤ institutional upper limit of normal (ULN)
• AST(SGOT)/ALT(SGPT) ≤3 × institutional ULN
• Creatinine ≤ institutional ULN
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with prior diagnosis of diabetes mellitus are allowed if the patient has no peripheral neuropathy
• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
• Patients must not have received prior taxane or platinum therapy
• Women of childbearing potential must have a negative pregnancy test: serum or urine beta human chorionic gonadotropin (hCG) within 14 days prior to first dose of study treatment
• Potential fertile subjects must agree to use adequate contraception (double barrier methods of birth control or abstinence) prior to start of treatment, for the duration of treatment, and 28 days after last study medication dose. If male, must also agree to refrain from donating sperm during this period

Критерии исключения

• Patients with prior diagnosis of peripheral neuropathy
• Patients who received chemotherapy for the current breast cancer diagnosis before the planned taxane-based regimen
• Patients who are receiving any other investigation agents
• Patients with concurrent use of antihistamines during or for 2 days prior to the study period
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to desloratadine
• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
• Pregnant or breastfeeding women are not allowed in the study
• Patients who are taking probiotics
• Patients who are using chronic laxatives or enema
• Patients who used antibiotics within 4 weeks of registration

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Поддерживающая терапия

Центры проведения

США · 1 центр

• Montefiore Medical Center — The Bronx

Публикации

• Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024 Jan-Feb;74(1):12-49. doi: 10.3322/caac.21820. Epub 2024 Jan 17. PMID 38230766
• Development of the World Health Organization WHOQOL-BREF quality of life assessment. The WHOQOL Group. Psychol Med. 1998 May;28(3):551-8. doi: 10.1017/s0033291798006667. PMID 9626712
• Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Electronic address: bc.overview@ctsu.ox.ac.uk; Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials. Lancet. 2023 Apr 15;401(10384):1277-1292. doi: 10.1016/S0 PMID 37061269
• Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1971 May 5;93(9):2325-7. doi: 10.1021/ja00738a045. No abstract available. PMID 5553076
• Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature. 1979 Feb 22;277(5698):665-7. doi: 10.1038/277665a0. No abstract available. PMID 423966
• Horwitz SB. Personal recollections on the early development of taxol. J Nat Prod. 2004 Feb;67(2):136-8. doi: 10.1021/np0304464. PMID 14987047
• Zasadil LM, Andersen KA, Yeum D, Rocque GB, Wilke LG, Tevaarwerk AJ, Raines RT, Burkard ME, Weaver BA. Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Sci Transl Med. 2014 Mar 26;6(229):229ra43. doi: 10.1126/scitranslmed.3007965. PMID 24670687
• Weaver BA. How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014 Sep 15;25(18):2677-81. doi: 10.1091/mbc.E14-04-0916. PMID 25213191

Идентификаторы

NCT: NCT07109817 · 2025-16651

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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