Biomarker Discovery Randomized Phase IIb Trial With Carboplatin-cyclophosphamide Versus Paclitaxel With or Without Atezolizumab as First-line Treatment in Advanced Triple Negative Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 304
- 试验地点
- 49
- 主要终点
- Validate the BRCA1-like test
研究概览
简要总结
Triple negative breast cancer (TNBC) is a difficult to treat molecular subtype with a poor survival. TNBC can be divided into at least two molecular entities; BRCA-like and non-BRCA-like. In this trial we would like to investigate whether a molecular subgroup exists within TNBCs that derives a benefit from atezolizumab added to first line chemotherapy.
详细描述
Atezolizumab, a humanized monoclonal antibody that targets human programmed death-ligand 1 (PD-L1) has shown activity in TNBC. Early clinical trials with anti-PD-(L)1 monotherapy have shown that the median duration to response in TNBC is remarkably long (18 weeks) compared to cytotoxic chemotherapy. Since advanced TNBC is characterized by rapid disease progression, most patients with TNBC may not have the opportunity to derive benefit from immunotherapy. We hypothesize that by combining atezolizumab with paclitaxel or carboplatin-cyclophosphamide the desired rapid tumor control will be obtained with chemotherapy and subsequently atezolizumab can result in durable responses in a significant subset of patients. It is unknown whether addition of atezolizumab to first line chemotherapy in TNBC is more beneficial than adding this antibody to a second line treatment schedule. Because of this and because of the poor outcome of patients with advanced TNBC experiencing disease progression after first line palliative chemotherapy, patients who were randomized to a chemotherapy only arm in this study will be offered the opportunity to cross over to the other chemotherapy regimen plus atezolizumab at disease progression.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Metastasized or locally advanced incurable triple negative breast cancer; patients with stage IV at diagnosis are eligible as well. If the primary lesion is the only measurable lesion according to RECIST criteria, every locoregional treatment must be mentioned to the investigators.
- •Histologically confirmed triple negative breast cancer (ER: < 10% nuclear staining of tumor cells on IHC; HER2: either score 0 or 1 at immunohistochemistry or negative at in situ hybridization [CISH or FISH] in case of score 2 or 3 on IHC)
- •Histological confirmation of triple negative breast cancer of a metastatic lesion is recommended
- •Histological or cytological confirmation of metastatic breast cancer is required in case of normal CA 15.3 levels
- •Primary tumor or metastasis tissue (10 x10 μm blank slides FFPE tumor material) sent to NKI-AVL for BRCA-like testing
- •Pretreatment histological biopsy of a metastatic lesion for the translational research questions (tumor tissue from bone metastases cannot be used).
- •No previous cytotoxic therapy for metastatic disease
- •Disease-free interval of at least 12 months after completion of adjuvant paclitaxel or platinum compound therapy
- •Disease-free interval of at least 6 months after completion of adjuvant docetaxel
- •Measurable disease according to RECIST v1.1
- •WHO performance status of 0 or 1
- •Adequate bone marrow function: neutrophils ≥ 1.5 x 10E9 cells/l, platelets ≥100 x 10E9 cells/l, Hb ≥ 6.2 mmol/l.
- •Normal liver function: bilirubin < 1.5 x upper limit of the normal range (ULN); alkaline phosphatase < 2.5 x ULN (< 5 x ULN in case of liver metastases, and < 7 x ULN in case of bone metastases); transaminases (ASAT/ALAT) < 2.5 x ULN (and < 5 x ULN in case of liver metastases).
- •Normal renal function:
- •> calculated (Cockcroft-Gault) or measured creatinine clearance > 50 mL/min
- •INR < 1.5 and APTT normal, unless patient is on stable anti-coagulant treatment for at least two weeks with a low molecular weight heparin or coumarin, then an INR within the target range (usually between 2 and 3) is allowed.
- •Written informed consent
排除标准
- •Receptor conversion to hormone receptor positive (defined as >= 10% positive ER or PgR tumor cells) or HER2 positive
- •Another cancer except basal-cell carcinoma of the skin or in situ cervical cancer within the previous 5 years
- •Other antitumor therapy within the previous 21 days with the exception of endocrine therapy. The patient should have stopped any endocrine therapy before start study treatment.
- •Radiotherapy with palliative intent within the previous 7 days before randomization.
- •Known CNS disease except for treated brain metastases.
- •Uncontrolled serious medical or psychiatric illness
- •Pre-existing peripheral neuropathy > grade 1 (NCI-CTC AE (version 4.03)) at inclusion
- •Severe infection within 4 weeks prior to randomization
- •received antibiotocs within 2 weeks prior to cycle 1, day 1
- •Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization or anticipation of need for major surgical procedure during the course of the study
- •New York Heart Association Class II or greater congestive heart failure. LVEF by MUGA, ultrasound or MRI must be ≥ 50% and should be performed within 4 weeks prior to randomization if cardiac failure is suspected.
- •History of myocardial infarction or unstable angina within 6 months prior to randomization
- •History of myocardial infarction or unstable angina or unstable arrhytmias within 3 months prior to randomization
- •futher criteria, see protocol
研究组 & 干预措施
Carbo/cyclo
Carboplatin AUC=5 Cyclophosphamide 600 mg/m2 Q 4 weeks
干预措施: Carbo/cyclo (Drug)
Carbo/cyclo + Atezolizumab
Carboplatin AUC=5 Cyclophosphamide 600 mg/m2 atezolizumab 840 mg d1,15 Q 4 weeks
干预措施: Carbo/cyclo + atezolizumab (Drug)
Paclitaxel
Paclitaxel 90 mg/m2 d1, 8, 15 Q 4 weeks
干预措施: Paclitaxel (Drug)
Paclitaxel + atezolizumab
Paclitaxel 90 mg/m2 d1, 8, 15 atezolizumab 840 mg d1,15 Q 4 weeks
干预措施: Paclitaxel + Atezolizumab (Drug)
结局指标
主要结局
Validate the BRCA1-like test
时间窗: assessed up to 120 months
Validate the BRCA1-like test in predicting differential PFS with first line alkylating and platinum agents (+/- antibody add-on) when compared to paclitaxel (+/- antibody add-on) in TNBC
次要结局
- Determine whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide for patients with PD-L1 positive tumors defined as combined positive score (CPS) 10 or higher (PFS1)(Assessed up to 120 months)
- Determine whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide (PFS1)(Assessed up to 120 months)
- Improvement of objective response by adding atezolizumab(assessed up to 120 months)
- PD-L1 status (immunohistochemistry) in tumor infiltrating immune cells(Assessed up to 120 months)
- Intratumoral CD8 and/or tumor-infiltrating lymphocytes (TIL)(Assessed up to 120 months)
- Compare PFS between alkylating-platinum regimen to paclitaxel as first line chemotherapy in BRCA1-like patients(Assessed up to 120 months)
- Compare PFS between alkylating-platinum regimen to paclitaxel as first line chemotherapy in non BRCA1-like patients(Assessed up to 120 months)
- TNBC molecular subtypes- based on RNA -expression analysis(Assessed up to 120 months)
- pretreatment LDH level(Assessed up to 120 months)
- Define predictive biomarkers for objective response gain(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 120 months)
- Define predictive biomarkers for PFS gain- chemotherapy(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 120 months)
- Define predictive biomarkers for PFS gain - atezolizumab(From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 120 months)
- Determine PFS in cross over(At 6 and 12 months and up to 120 months)
- Overal Response Rate (ORR)(Assessed up to 120 months)
- Benefit Atezolizumab(Assessed up to 120 months)
- Overall survival (OS)(assessed up to 120 months)
- Toxicity of all study regimens(Assessed at 1 year)
- Efficay in patients treated with or without Bevacizumab(Assessed up to 120 months)
- Determine PFS in BRCA like TNBC(From date of randomization until date of first documented progression or date of death, which ever comes first, assessed up to 120 months)
- putative predictive potential of BRCA1-like status(Assessed up to 120 months)