Neoadjuvant Biomarker ResearcH Study of Palbociclib Combined With Endocrine Therapy in Estrogen Receptor Positive/HER2 Negative Breast CAncer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 100
- 试验地点
- 5
- 主要终点
- To identify biomarkers of resistance to a 4-month preoperative treatment of palbociclib plus endocrine therapy defined as stable or progressive disease by ultrasound (based on WHO criteria) using RNA-seq of the baseline tumour biopsy
研究概览
简要总结
This is an open-label, single arm, phase 2 trial that will include pre or post-menopausal female subjects, that have ER-positive, HER2-negative early breast cancer. Subject will receive 4 cycles of palbociclib 125 mg (each cycle of palbociclib consists of treatment from D1 to D21 followed by a week of rest) combined with endocrine therapy given continuously (each cycle of endocrine therapy consists of treatment from D1 to D28).
The endocrine therapy will be determined according to the menopausal status of the subject evaluated at the study screening.
详细描述
This is an open-label, single arm, phase 2 trial that will include pre or post-menopausal female subjects, that have ER-positive, HER2-negative early breast cancer. Subject will receive 4 cycles of palbociclib 125 mg (each cycle of palbociclib consists of treatment from D1 to D21 followed by a week of rest) combined with endocrine therapy given continuously (each cycle of endocrine therapy consists of treatment from D1 to D28).
The endocrine therapy will be determined according to the menopausal status of the subject evaluated at the study screening.
For post-menopausal subjects: endocrine therapy will consist of letrozole 2.5 mg continuously.
For pre-menopausal or peri-menopausal subjects: endocrine therapy will consist of tamoxifen 20 mg continuously, combined or not with goserelin 3.6 mg monthly at the local investigator's discretion.
Endocrine therapy for both groups should continue until the last day of palbociclib treatment (i.e. the day before surgery).
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
- Female
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years
- •Histological diagnosis of breast adenocarcinoma that is estrogen receptor-positive, and HER2- negative as per the updated American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines according to local testing.
- •Multifocal unilateral or bilateral breast adenocarcinoma tumours are allowed provided that all tested foci are ER-positive and HER2-negative.
- •ER-positive (ER+ is defined as having a IHC of 1% or more and/or and Allred of 2 or more and HER2-negative.
- •HER2 negative (HER2 negative is defined as having an IHC of 1+ without ISH OR IHC 2+ and ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells OR ISH non-amplified with ratio less than 2.0 and if reported, average HER2 copy number < 4 signals/cells (without IHC)
- •A primary non metastatic or locally advanced tumour of more than 2 cm (T2 or T3), N0 or N1 without prior treatment candidate for preoperative treatment
- •ECOG Performance Status (PS) 0 or
- •Adequate Bone Marrow Function including:
- •Absolute Neutrophil Count (ANC) ≥1500/μL or ≥1.5 x109/L;
- •Platelets ≥100000/μL or ≥100 x 109/L;
- •Hemoglobin ≥ 9 g/dL.
- •Adequate Renal Function including: Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥ 60 ml/min as calculated using the method standard for the institution.
- •Adequate Liver Function, including all of the following parameters:
- •Total serum bilirubin ≤ 1.0 x ULN unless the subject has documented Gilbert syndrome (in which case up to 3 x ULN is acceptable) ;
- •Aspartate and Alanine Aminotransferase (AST and ALT) ≤ 1.5 x ULN;
- •Alkaline phosphatase ≤ 2.5 x ULN.
- •Signed consent form
- •Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests, radiological exams, tumour and blood specimen collection and other procedures.
- •Women who are not postmenopausal or have not undergone hysterectomy must have documented negative pregnancy test (serum) prior to inclusion.
- •Female subjects of child bearing potential and their partners, who are sexually active, must agree to the use of two highly effective forms of contraception in combination throughout the period of taking study treatment and for at least 90 days after last dose of study drug, or they must totally/truly abstain from any form of sexual intercourse. Use of oral hormonal contraceptive agents in this study is not permitted.
排除标准
- •Clinical T4 disease including inflammatory breast cancer.
- •Prior history of invasive cancer including breast cancer except basal or squamous cell carcinoma of skin that has been definitively treated.
- •Known hypersensitivity to the study drugs or excipients.
- •Any illness or medical condition that is unstable or could jeopardize the safety of the subject or her compliance with study requirements.
- •Subjects unable to swallow oral medications.
- •Prior intake of letrozole, or any CDK inhibitor or anti-cancer therapy.
- •Concurrent treatment with any of the drugs not permitted, i.e. strong CYP3A inhibitors/inducers and drugs known to cause QTc interval prolongation (see section 5.7 for specific instructions).
- •QTc exceeding 480 msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP).
- •Uncontrolled diabetes, according to investigator's clinical judgment.
- •Pregnant or lactating women.
研究组 & 干预措施
Palbociclib with Endocrine Therapy
All subjects will receive palbociclib 125 mg for 4 cycles, orally, once a day, for 21 days followed by 7 days of rest (4 cycles of 28 day long). After the final rest week (therefore post cycle 4), subjects will receive 3 to 7 additional days of palbociclib, as necessary, at the same dose and posology, until the day before curative intent surgery. Depending upon the menopausal status, the patient will receive either letrozole or tamoxifen continuously during the palbociclib treatment (which consists of 4 cycles of 28 days).
干预措施: Palbociclib (Drug)
结局指标
主要结局
To identify biomarkers of resistance to a 4-month preoperative treatment of palbociclib plus endocrine therapy defined as stable or progressive disease by ultrasound (based on WHO criteria) using RNA-seq of the baseline tumour biopsy
时间窗: 4 Months
• Baseline transcriptomic profile of resistance to 4 months of palbociclib and endocrine therapy defined as stable or progressive disease by ultrasound based on WHO criteria
次要结局
- To identify biomarkers of resistance to a 4-month preoperative treatment of palbociclib plus endocrine therapy defined as residual disease burden, RCB of 3 using RNA-seq of the baseline tumour biopsy(4 Months)
- To understand mechanisms of resistance to the combination of endocrine therapy and palbociclib by comparing the transcriptome of tumours at baseline and at surgery using RNA-seq(4 Months)
- To identify biomarkers of resistance to a 4-month preoperative treatment of endocrine therapy and palbociclib defined as GGI high by RNA-seq of the residual tumour at surgery using RNA-seq of the baseline tumour biopsy(4 Months)
- To evaluate the safety of the combination of palbociclib plus endocrine therapy as assessed by the NCI-CTCAE version 4.03(4 Months)
- To determine the effect of a pre-operative treatment with endocrine therapy and palbociclib on anti-tumour immune response(4 Months)
- To refine an 11-gene expression signature associated with response/resistance to palbociclib and endocrine treatment(4 Months)
- To identify biomarkers of resistance to a 4-month preoperative treatment of endocrine therapy and palbociclib by correlating tumour response by ultrasound (mandatory) or magnetic resonance (optional) imaging(4 Months)
- The role of plasma ctDNA in monitoring response/resistance to pre-operative treatment with endocrine therapy and palbociclib(4 Months)
- To determine the effect of a pre-operative treatment with endocrine therapy and palbociclib on tumour senescence(4 Months)