NCT02988986已完成2 期
Open Label, Phase II Trial of Neoadjuvant TAK-228 Plus Tamoxifen in Patients With Estrogen Receptor (ER)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 28
- 试验地点
- 3
- 主要终点
- Ki67 Expression
研究概览
简要总结
This is an open label phase II clinical trial to determine the efficacy, toxicity, and safety of TAK-228 plus tamoxifen in patients with newly diagnosed ER-positive, HER2-negative breast cancer.
详细描述
The mTOR pathway is commonly dysregulated in ER-positive breast cancers and represents a key resistance mechanism to endocrine therapy such as tamoxifen. We plan to target the mTOR pathway with mTORC1/2 inhibitor TAK-228 to overcome tamoxifen resistance in early-stage ER-positive breast cancer. An open label phase II clinical trial will be conducted to determine the efficacy, toxicity, and safety of TAK-228 plus tamoxifen in patients with newly diagnosed ER-positive, HER2-negative breast cancer. TAK-228 (30 mg weekly) plus tamoxifen (20 mg daily) will be administered for 16 weeks. Patients will undergo tumor biopsy before starting the study treatment and after 6 weeks of study treatment. Blood samples for pharmacokinetics analysis will be obtained 1 hour before and after TAK-228 dosing on days 1 and 15 of the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 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
- •Female or male ≥ 18 years of age.
- •Newly diagnosed ER-positive, HER2-negative breast cancer. ER-positive is defined as ≥ 1% immunohistochemical (IHC) staining of any intensity. HER2 test result is negative if a single test (or both tests) performed show:
- •IHC 1+ or 0
- •In situ hybridization negative based on:
- •Single-probe average HER2 copy number < 4.0 signals/cell
- •Dual-probe HER2/CEP17 ratio < 2 with an average HER2 copy number < 4.0 signals/cell.
- •Patients with stage II-III breast cancer are eligible if they are deemed appropriate for neoadjuvant endocrine therapy by the referring or treating medical oncologist. Patients with stage I disease are eligible if they are deemed borderline candidates for breast conservation and the treating surgeon recommends preoperative therapy to increase the chances of breast conservation.
- •Eastern Cooperative Oncology Group performance status and/or other performance status of ≤
- •Female patients who:
- •Are postmenopausal for at least 1 year before the screening visit, OR
- •Are surgically sterile, OR
- •If they are of childbearing potential, agree to practice 1 effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the ICF through 90 days (or longer, as mandated by local labeling [e.g., United Surgical Partners International, summary of product characteristics, etc.] after the last dose of the study drugs, OR
- •Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condom should not be used together).
- •Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:
- •Agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of the study drugs, OR
- •Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient
- •Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of the study drugs.
- •Screening clinical laboratory values as specified below:
- •Bone marrow reserve consistent with: absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, and hemoglobin ≥ 9 g/dL (without transfusion) within 1 week preceding the administration of the study drugs;
- •Hepatic status: Serum total bilirubin ≤ 1 x upper limit of normal (ULN; in the case of known Gilbert's syndrome, a higher serum total bilirubin [< 1.5 x ULN] is allowed), aspartate aminotransferase and alanine aminotransferase ≤ 1.5 x ULN, and alkaline phosphatase ≤ 1.5 x ULN;
- •Renal status: Creatinine clearance ≥50 mL/min based on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour);
- •Metabolic status: HbA1c < 7.0%, fasting serum glucose ≤ 130 mg/dL, and fasting triglycerides ≤ 300 mg/dL.
- •Ability to swallow oral medications.
- •Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
- •Negative serum pregnancy test within 7 days prior to the administration of the study drugs for female patients of childbearing potential.
- •Patient must be accessible for treatment and follow-up.
- •Patient must be willing to undergo breast biopsies as required by the study protocol.
排除标准
- •Any patient with metastatic disease.
- •Other clinically significant comorbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise the patient's participation in the study.
- •Known human immunodeficiency virus infection.
- •Known hepatitis B surface antigen-positive or known or suspected active hepatitis C infection.
- •Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of the protocol-specified treatment.
- •Diagnosed or treated for another malignancy within 2 years before administration of the first dose of the study drugs or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
- •Breastfeeding or pregnant.
- •Manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal disease, or an unknown reason that may alter the absorption of TAK-
- •Patients with enteric stomata are also excluded.
- •Treatment with any investigational products within 2 weeks before administration of the first dose of the study drugs.
- •Poorly controlled diabetes mellitus (defined as HbA1c > 7%). Patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in the study if all other inclusion criteria and none of the other exclusion criteria are met.
- •History of any of the following within the last 6 months before administration of the first dose of the study drugs:
- •Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
- •Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures
- •Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, and ventricular tachycardia)
- •Placement of a pacemaker for control of rhythm
- •New York Heart Association Class III or IV heart failure
- •Pulmonary embolism
- •Significant active cardiovascular or pulmonary disease including:
- •Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg). Use of antihypertensive agents to control hypertension before week 1, day 1 is allowed.
- •Pulmonary hypertension
- •Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis or pulse oximetry on room air
- •Significant valvular disease, severe regurgitation, or stenosis by imaging independent of symptom control with medical intervention or history of valve replacement
- •Medically significant (symptomatic) bradycardia
- •History of arrhythmia requiring an implantable cardiac defibrillator
- •Baseline QTc prolongation (e.g., repeated demonstration of QTc interval > 480 milliseconds or history of congenital long QT syndrome or torsades de pointes)
- •Treatment with strong inhibitors and/or inducers of CYP3A4, CYP2C9, or CYP2C19 within 7 days preceding the first dose of the study drugs.
- •Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of the study drugs.
- •Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of the study drugs.
- •Patients unwilling or unable to comply with the study protocol.
- •Patients previously treated with hormonal therapy (tamoxifen, AI) or PI3K, AKT, dual PI3K/mTOR, TORC1/2, or mTORC1 inhibitors.
- •Patients who are currently being treated with cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) other than the trial therapy.
- •Patients with hypersensitivity to mTOR inhibitors or tamoxifen.
研究组 & 干预措施
TAK-228 Plus Tamoxifen
Experimental
TAK-228 will be orally administered at 30 mg weekly for 16 weeks.
Tamoxifen will be orally administered at 20 mg daily for 16 weeks.
干预措施: TAK-228 (Drug)
TAK-228 Plus Tamoxifen
Experimental
TAK-228 will be orally administered at 30 mg weekly for 16 weeks.
Tamoxifen will be orally administered at 20 mg daily for 16 weeks.
干预措施: Tamoxifen (Drug)
结局指标
主要结局
Ki67 Expression
时间窗: Baseline to 6 weeks
Ki67 expression change from baseline to 6 weeks
次要结局
- Number of Participants With Pathological Complete Response (pCR)(16 weeks)
- Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI)(16 weeks)
研究者
Jenny C. Chang, MD
Houston Methodist Cancer Center Director
The Methodist Hospital Research Institute
研究点 (3)
Loading locations...
相似试验
撤回
2 期
A Phase 2 Study of a Subcutaneous Injection of TAK-850 in Healthy Adult ParticipantsInfluenza PreventionNCT02713061Takeda
终止
2 期
TTAC-0001 Phase II Trial With Recurrent Glioblastoma Progressed on BevacizumabRecurrent GlioblastomaNCT03856099PharmAbcine19
已完成
1 期
A Phase 1/2 Study of a Intramuscular Injection of TAK-850 in Healthy Adult SubjectsInfluenzaNCT02111252Takeda55
撤回
2 期
TAK-700 in Castration Resistant Prostate CancerProstate CancerNCT01658527European Organisation for Research and Treatment of Cancer - EORTC
招募中
2 期
Phase II Open-label Trial of Neoadjuvant Immunochemotherapy for Resectable Non-metastatic Colon cancER: NICERStage I Colon CancerStage II Colon CancerStage III Colon CancerNCT05870800Baylor College of Medicine28