Desloratadine to Prevent Taxane-induced Peripheral Neuropathy in Patients With Breast Cancer (DETOXp)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 116
- 试验地点
- 2
- 主要终点
- Change in Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group (GOG)-Neurotoxicity (NTX) Subscale Version 4 (FACT-GOG-NTX) neuropathy score
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Supportive Care
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Placebo
Paclitaxel or Docetaxel for 12 weeks and Placebo
干预措施: Placebo (Drug)
Desloratodine
Paclitaxel or Docetaxel for 12 weeks and Desloratadine
干预措施: Desloratodine (Drug)
结局指标
主要结局
Change in Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group (GOG)-Neurotoxicity (NTX) Subscale Version 4 (FACT-GOG-NTX) neuropathy score
时间窗: From baseline to after completion of 12 weeks of taxane chemotherapy
The patient-related-outcome based neurotoxicity will be assessed using the 11 items about neurotoxicity in the FACT/GOG-NTX questionnaire. For the FACT/GOG-NTX neuropathy, each item is scored from 0-4, and the neurotoxicity total score is the sum of the scores for the 11 items, and ranges from 0 to 44. Lower values of the FACT/GOG-NTX neurotoxicity total score indicate higher neurotoxicity. The FACT/GOG-NTX neurotoxicity total score will be analyzed as a continuous variable. Proper transformation to improve normality will be used if needed. Change in FACT/GOG-NTX neuropathy score will be defined as the difference in score values between baseline versus after 12 weeks of taxane chemotherapy.
次要结局
- Rate of grade 2-4 TIPN assessed by treating physician(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(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(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(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(12 weeks after the completion of taxane chemotherapy)
- Rate of permanent discontinuation of taxane due to TIPN(From baseline up to week 12 of taxane chemotherapy)
- Rate of taxane dose interruption or dose reduction due to TIPN(From baseline up to week 12 of taxane chemotherapy)
- Rate of pathological complete response (pCR)(After completion of 12 weeks of taxane chemotherapy)