NCT05252988进行中（未招募）2 期
A Randomized Phase II Study to Evaluate the Incidence of Discontinuations Due to Diarrhoea at 3 Cycles in Patients With Early-stage HER2-positive (HER2+), Hormone Receptor-positive (HR+) Breast Cancer Treated With Neratinib Plus Loperamide Prophylaxis Versus Neratinib With Initial Dose Escalation Plus PRN Loperamide Prophylaxis Versus Neratinib Plus Loperamide Plus Colesevelam Prophylaxis "DIANER Study"
适应症
干预措施
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 177
- 试验地点
- 55
- 主要终点
- The incidence of neratinib discontinuations due to diarrhoea at the end of 3 cycles (1 cycle= 28 days) of neratinib treatment.
研究概览
简要总结
A Randomized Phase II Study to Evaluate the Incidence of Discontinuations due to Diarrhoea at 3 Cycles in patients with Early-stage HER2-positive (HER2+), Hormone Receptor-positive (HR+) Breast Cancer treated with Neratinib plus Loperamide prophylaxis versus Neratinib with Initial Dose Escalation plus PRN Loperamide prophylaxis versus Neratinib plus Loperamide plus Colesevelam prophylaxis.
详细描述
This is an international, multicenter, prospective, controlled, randomized, adaptative, phase II study to evaluate the incidence of discontinuations due to diarrhoea within the first 3 cycles in patients with early-stage HER2+ and HR+ breast cancer treated with neratinib plus loperamide prophylaxis for the first 2 cycles versus neratinib with initial 2-week dose escalation plus PRN loperamide versus neratinib and loperamide plus colesevelam prophylaxis for 28 days.
After the preplanned therapy, prophylaxis or treatment for diarrhoea will be given as clinically indicated following the standard of care by the treating physician.
Approximately 315 patients will be enrolled in the study.
All enrolled patients will receive neratinib orally once daily for 13 cycles, continuously. Eligible patients will be randomly assigned in a 1:1:1 ratio to one of the diarrhoea prophylaxis arms, using an interactive response technology (IRT) module within the electronic data capture (EDC) system. Patients will be stratified according to menopausal status (premenopausal versus postmenopausal) and prior anti-HER2 therapy (trastuzumab only versus trastuzumab plus pertuzumab).
Baseline assessments will be performed prior to C1D1 dosing. During the first 3 cycles of treatment, safety data will be collected during the cycle visits. After the first 3 cycles, all patients will enter in a follow-up period to complete approximately 1 year of neratinib treatment. During this follow-up period, safety data will be collected every 3 months. An End-of-Treatment (EOT) Visit is planned on cycle 13 day 28 for all treatment arms (unless patient discontinues earlier), followed by a Safety Follow-up Visit (30 +/-5 days after the last dose of neratinib). This will be the core phase of the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
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 are eligible to be enrolled in the study only if they meet all of the following criteria:
- •Male or female patient ≥18 years of age at signing of informed consent.
- •Histologically confirmed Stage I B through Stage III C primary adenocarcinoma of the breast.
- •Documented HER2-positive disease based on local laboratory determination according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2018 criteria.
- •Documented HR+ disease, defined as oestrogen receptor (ER) and/or progesterone receptor (PR) ≥1% based on local laboratory determination.
- •Patients must have completed prior neoadjuvant/adjuvant trastuzumab-based therapy (eg, trastuzumab-based treatments including trastuzumab-emtansine [T-DM1]) or experienced side effects that resulted in early discontinuation of trastuzumab-based therapy that have since resolved (pertuzumab therapy is accepted but not mandatory).
- •The last dose of trastuzumab-based therapy must have been given to the patient >2 weeks and ≤1 year (365 days) before first dose of neratinib.
- •Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
- •Eastern Cooperative Oncology Group (ECOG) status of 0 or
- •Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause. [Women are considered postmenopausal if they are ≥ 12 months without menses, in the absence of endocrine or anti-endocrine therapies].
- •Women of childbearing potential must agree and commit to the use of a highly effective non-hormonal method of contraception, ie, intrauterine device, bilateral tubal ligation, vasectomized partner, or abstinence (only when it is the preferred lifestyle of the patient), from the time of informed consent until 30 days after the last dose of the medicinal products. Male patient with female partner of childbearing potential must agree and commit to use condom, and the female partner must agree and commit to use a highly effective method of contraception (ie, any of the above methods, or for females, hormonal contraception associated with inhibition of ovulation) while on treatment and for 3 months after last dose of medicinal products.
- •Recovery (ie, to Grade 1 or baseline) from all clinically significant AEs related to prior therapies (excluding alopecia, neuropathy, and nail changes).
- •Provide written, informed consent to participate in the study and follow the study procedures.
排除标准
- •Patients will be excluded from the study if they meet any of the following criteria:
- •Clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or at the time of study entry.
- •Currently receiving chemotherapy, radiation therapy, immunotherapy, or biological therapy for breast cancer (adjuvant endocrine therapy is allowed).
- •Major surgery within <30 days of starting treatment or received chemotherapy, investigational agents, or other cancer therapy <14 days prior to the initiation of investigational products.
- •Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrolment, or ventricular arrhythmia.
- •Corrected QT interval (QTc) interval >0.450 seconds (males) or >0.470 (females), or known history of QTc prolongation or Torsade de Pointes (TdP).
- •Screening laboratory assessments outside the following limits:
- •Absolute neutrophil count (ANC) ≤1,000/μl (≤1.0 x 109/L), Platelet count ≤100,000/μl (≤100 x 109/L), Hemoglobin ≤9 g/dL, Total bilirubin >1.5 x institutional upper limit of normal (ULN) (in case of known Gilbert's syndrome, <2 x ULN is allowed), Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x institutional ULN, Creatinine clearance <30 mL/min (as calculated by Cockcroft-Gault formula a or Modification of Diet in Renal Disease (MDRD) formula).
- •Active, unresolved infections.
- •Patients with a second malignancy, other than adequately treated non-melanoma skin cancers, in situ melanoma or in situ cervical cancer. Patients with other non-mammary malignancies must have been disease-free for at least 5 years.
- •Currently pregnant or breast-feeding.
- •Significant chronic gastrointestinal disorder with diarrhoea as a major symptom (eg, Crohn's disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 5.0 [CTCAE v.5.0] diarrhoea of any etiology at baseline); or gastroparesis, dysphagia, or swallowing disorder.
- •Clinically active infection with hepatitis B or hepatitis C virus.
- •Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that could, in the Investigator's judgment, make the patient inappropriate for this study.
- •Known hypersensitivity to any component of the investigational products; known allergies to any of the medications or components of medications used in the trial.
- •Unable or unwilling to swallow tablets.
研究组 & 干预措施
Arm A
Experimental
- Neratinib 240 mg (six 40mg tablets) orally once daily for 13 cycles (C) (1 C = 28 days), unless patient discontinues earlier.
- Mandatory loperamide 4 mg (2 tablets/capsules) orally, 3 times a day (total 12 mg a day) starting Day (D) 1 of neratinib and for the first 14 days. Then, 4 mg (2 tablets/capsules) orally, 2 times a day (total 8 mg a day) until the end of C2 (D56); thereafter, loperamide will be administered PRN (without exceeding 16 mg per day).
干预措施: Loperamide (Drug)
Arm A
Experimental
- Neratinib 240 mg (six 40mg tablets) orally once daily for 13 cycles (C) (1 C = 28 days), unless patient discontinues earlier.
- Mandatory loperamide 4 mg (2 tablets/capsules) orally, 3 times a day (total 12 mg a day) starting Day (D) 1 of neratinib and for the first 14 days. Then, 4 mg (2 tablets/capsules) orally, 2 times a day (total 8 mg a day) until the end of C2 (D56); thereafter, loperamide will be administered PRN (without exceeding 16 mg per day).
干预措施: Neratinib (Drug)
Arm B
Experimental
- Neratinib 120 mg for Week 1 (C1D1 - C1D7), followed by 160 mg neratinib for Week 2 (C1D8 - C1D14), followed by 240 mg neratinib for Week 3 and thereafter for 13 cycles inclusive, until cycle 13 day 28 (unless patient discontinues earlier).
- Loperamide to be administered PRN only (without exceeding 16 mg per day).
干预措施: Neratinib (Drug)
Arm B
Experimental
- Neratinib 120 mg for Week 1 (C1D1 - C1D7), followed by 160 mg neratinib for Week 2 (C1D8 - C1D14), followed by 240 mg neratinib for Week 3 and thereafter for 13 cycles inclusive, until cycle 13 day 28 (unless patient discontinues earlier).
- Loperamide to be administered PRN only (without exceeding 16 mg per day).
干预措施: Loperamide (Drug)
Arm C
Experimental
- Neratinib 240 mg (six 40-mg tablets) orally once daily for 13 C, unless patient discontinues earlier.
- Mandatory loperamide 4 mg (2 tablets/capsules) orally, 3 times a day (total 12 mg a day) for the first 14 days. After the first 14 days, 4 mg (2 tablets/capsules) orally, 2 times a day (total 8 mg a day) to complete a total of 28 days.
- Mandatory colesevelam 1,875 mg (three 625-mg capsules orally), 2 times a day for the first month (28 days). After day 28, any prophylaxis or treatment for diarrhoea could be administered PRN, if loperamide not to exceed 16 mg per day.
干预措施: Neratinib (Drug)
Arm C
Experimental
- Neratinib 240 mg (six 40-mg tablets) orally once daily for 13 C, unless patient discontinues earlier.
- Mandatory loperamide 4 mg (2 tablets/capsules) orally, 3 times a day (total 12 mg a day) for the first 14 days. After the first 14 days, 4 mg (2 tablets/capsules) orally, 2 times a day (total 8 mg a day) to complete a total of 28 days.
- Mandatory colesevelam 1,875 mg (three 625-mg capsules orally), 2 times a day for the first month (28 days). After day 28, any prophylaxis or treatment for diarrhoea could be administered PRN, if loperamide not to exceed 16 mg per day.
干预措施: Loperamide (Drug)
Arm C
Experimental
- Neratinib 240 mg (six 40-mg tablets) orally once daily for 13 C, unless patient discontinues earlier.
- Mandatory loperamide 4 mg (2 tablets/capsules) orally, 3 times a day (total 12 mg a day) for the first 14 days. After the first 14 days, 4 mg (2 tablets/capsules) orally, 2 times a day (total 8 mg a day) to complete a total of 28 days.
- Mandatory colesevelam 1,875 mg (three 625-mg capsules orally), 2 times a day for the first month (28 days). After day 28, any prophylaxis or treatment for diarrhoea could be administered PRN, if loperamide not to exceed 16 mg per day.
干预措施: Colesevelam (Drug)
结局指标
主要结局
The incidence of neratinib discontinuations due to diarrhoea at the end of 3 cycles (1 cycle= 28 days) of neratinib treatment.
时间窗: Up to 3 months
The proportion of patients who discontinue the treatment with neratinib due to diarrhoea within this time period.
次要结局
- Time to neratinib discontinuations due to any TEAE (treatment-emergent adverse event).(Up to 13 months)
- Cumulative duration of diarrhoea (Grade 2/3/4).(Up to 13 months)
- Incidence of neratinib discontinuation (for any reason).(Up to 13 months)
- Incidence of TEAEs and SAEs that include AESIs (ie, hepatic, cardiac, pulmonary, reproductive and developmental).(Up to 13 months)
- Cumulative dose of neratinib.(Up to 13 months)
- Neratinib relative dose intensity.(Up to 13 months)
- Incidence of hospitalisations due to any reason and diarrhoea.(Up to 13 months)
- Neratinib dose intensity.(Up to 13 months)
- Incidence of diarrhoea of any grade/grade 3 or higher.(Up to 13 months)
- Time to first episode of diarrhoea.(Up to 13 months)
- Time to neratinib discontinuation/neratinib treatment duration.(Up to 13 months)
- Patient reported outcomes (PRO) of health related quality of life measured by Systemic Therapy-Induced Diarrhea Assessment Test (STIDAT)(Up to 13 months)
- Incidence of neratinib discontinuations due to any TEAE (treatment-emergent adverse event).(Up to 13 months)
- Patient reported outcomes (PRO) of health related quality of life measured by FACT B.(Up to 13 months)
- Patient reported outcomes (PRO) of health related quality of life measured by EQ5D-5L(Up to 13 months)
研究者
研究点 (55)
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