Phosphatidylinositol 3-kinase (PI3K) Pathway Analysis in Tumor Tissue and Circulating DNA to Obtain Further Insight in the Efficacy of Everolimus When Combined With Exemestane: A Side-study Protocol Attached to Standard Treatment With Everolimus and Exemestane for Postmenopausal Patients With Hormone Receptor-positive Advanced Metastatic Breast Cancer, Who Have Progressed on Anastrozole or Letrozole
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 175
- 试验地点
- 28
- 主要终点
- Biomarker Evaluation from Primary Tumor Tissue, New Tumor Biopsies and Blood Samples
研究概览
简要总结
The purpose of this study is to determine whether biomarkers could be found to gain more insight in tumor characteristics in order to predict which patients will have a high chance of a long progression-free survival. Postmenopausal patients with advanced metastatic breast cancer who have progressed on anastrozole or letrozole will be eligible for this study.
详细描述
Rationale of study:
Everolimus combined with exemestane has shown to improve progression-free survival compared to exemestane monotherapy in patients with hormone receptor-positive breast cancer previously treated with non-steroidal aromatase inhibitors. Since January 1st, 2013, everolimus is being reimbursed for this category of patients. For many patients this means, that an interesting treatment possibility has become available. However, some patients do not benefit from everolimus and exemestane, while others have to deal with side-effects requiring adjustment of the dose or even discontinuation of treatment.
In this study proposal the investigators plan to gain more insight in tumor characteristics in order to predict which patients will have a high chance of a long progression-free survival.
Study objectives:
- It is proposed to compare progression-free survival on the combination of everolimus and exemestane between patients whose metastatic tumor expresses markers of phosphatidylinositol 3-kinase (PI3K) pathway activation versus patients whose metastatic tumor does not express PI3K pathway activation.
- It is proposed to carry out immunohistochemistry on activated members of the PI3K pathway in primary tumor tissue of patients treated with everolimus and exemestane and compare the findings with the outcome of treatment and more specifically, with the results from other studies.
- It is proposed to associate protein expression/ phosphorylation by proteomics in tumor biopsies to cancer mutations, PI3K pathway activation and progression-free survival on the exemestane and everolimus combination.
- It is proposed to establish the incidence of mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and protein kinase B (AKT) in peripheral blood of advanced breast cancer patients amenable for treatment with everolimus and exemestane and to explore whether the presence of such mutations is associated with outcome to treatment in these patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 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
- •Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.
- •Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer
- •Postmenopausal women. Postmenopausal status is defined either by:
- •Age ≥ 55 years and one year or more of amenorrhea
- •Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 40 pg/ml
- •Surgical menopause with bilateral oophorectomy
- •Disease refractory to NSAI, defined as:
- •a. Recurrence while on or within 12 months of end of adjuvant treatment with letrozole or anastrozole, or b. Progression while on or within one month of end of letrozole or anastrozole treatment for advanced breast cancer (locally advanced or metastatic )
- •Note: Letrozole or anastrozole do not have to be the last treatment prior to enrollment. Other prior anticancer therapy, e.g. tamoxifen, fulvestrant are allowed. Patients must have recovered to grade 1 or better from any adverse events (except alopecia) related to previous therapy prior to enrollment.
- •Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to enrollment.
- •Note: There are no restrictions as to the last systemic therapy prior to enrollment.
- •Adequate bone marrow and coagulation function as shown by:
- •Absolute neutrophil count (ANC) ≥ 1.5 ×109/L
- •Platelets ≥ 100 ×109/L
- •Hemoglobin (Hgb) ≥ 5.6 mmol/L
- •INR (international normalized ratio) ≤ 2.0
- •Adequate liver function as shown by:
- •Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN (upper limit of normal)(or ≤ 5 if hepatic metastases are present)
- •Total serum bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for patients known to have Gilbert Syndrome)
- •Adequate renal function as shown by:
- •Serum creatinine ≤ 1.5 × ULN
- •Fasting serum cholesterol ≤ 7.75 mmol/L and fasting triglycerides ≤ 2.5 × ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy or other lipid lowering drugs (eg fibrates), and when the above mentioned values have been achieved
- •Written informed consent obtained before any screening procedure and according to local guidelines.
排除标准
- •HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
- •Previous treatment with mTOR (mammalian target of rapamycin) inhibitors.
- •Radiotherapy within four weeks prior to enrollment except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to enrollment. Patients must have recovered from radiotherapy toxicities prior to enrollment.
- •Currently receiving hormone replacement therapy, unless discontinued prior to enrollment.
- •Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in cases outlined below:
- •Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways diseases), eye drops or local injections (e.g. intra-articular) are allowed.
- •Patients on stable low dose of corticosteroids for at least two weeks before enrollment are allowed in case of treatment of brain metastases.
- •Bilateral diffuse lymphangitic carcinomatosis or metastasis of the lung as the only manifestation of disease (>50% of lung involvement), evidence of metastases estimated as more than a third of the liver as defined by sonogram and/or CT scan.
- •Patients with a known history of HIV seropositivity.
- •Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin and acetylsalicylic acid or equivalent, as long as the INR is ≤ 2.0)
- •Any severe and / or uncontrolled medical conditions such as:
- •Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia
- •Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN
- •Acute and chronic, active infectious disorders (except for hepatitis B and C positive patients) and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy
- •Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
- •Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco (diffusing capacity of lung for carbon monoxide), O2 saturation at rest on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates.
- •Patients who test positive for hepatitis B (HBV) or C (HBC) (patients who test negative for HBV-DNA, HBsAg, and HBcAb, but positive for HBsAb with prior history of vaccination against Hepatitis B will be eligible - see also 1.4)
- •Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (rifabutin, rifampicin, clarithromycin, ketoconazole, itraconazole, voriconazole, ritonavir, telithromycin) within the last 5 days prior to enrollment
- •History of non-compliance to medical regimens
- •Patients unwilling to or unable to comply with the protocol
研究组 & 干预措施
Everolimus plus exemestane
Biomarker study in patients receiving standard treatment
干预措施: Everolimus plus Exemestane (Drug)
结局指标
主要结局
Biomarker Evaluation from Primary Tumor Tissue, New Tumor Biopsies and Blood Samples
时间窗: Before start therapy until progression (expected average until progression: 11 months)
Biomarker evaluation to gain more insight in tumor characteristics in order to predict which patients will have a high chance of a long progression-free survival. For biomarker evaluation, primary tumor tissue, new tumor tissue Biopsies and blood samples will be analysed for activated members of the PI3K pathway by immunohistochemistry and phosphoproteomics, and for the incidence of mutations in the PI3K pathway. The findings will be compared with the outcome of treatment and with the results from other studies.
Progression-free survival
时间窗: From start therapy until first reported progression (expected average until progression: 11 months)
Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression. Progressive disease will be assessed by radiological assessment or, if clearly stated in the patient's file, by clear clinical signs.
次要结局
- Number of Participants with Adverse Events as a Measure of Safety and Tolerability(From start therapy until 28 days after progression (expected average until progression: 11 months))
研究者
H.M.W. Verheul
Prof dr Verheul, MD
Amsterdam UMC, location VUmc