Randomised, Phase II/III, 3 Stage Trial to Evaluate the Safety and Efficacy of the Addition of Olaparib to Platinum-based Neoadjuvant Chemotherapy in Breast Cancer Patients With TNBC and/or gBRCA.
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 780
- 试验地点
- 29
- 主要终点
- Stage 1 - Number of participants with treatment-related adverse events as assessed by NCI CTCAE v4.03.
研究概览
简要总结
This neoadjuvant trial for patients with TNBC and/or gBRCA breast cancer, aims to investigate the safety and efficacy (improvement in pathological Complete Response at surgery) of concurrent platinum-based chemotherapy with olaparib an inhibitor of the PARP enzyme (PARPi).
详细描述
Randomised, phase II/III 3 stage trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in breast cancer patients with TNBC and/or gBRCA.
Disease under investigation: Breast Cancer
Purpose of clinical trial: To establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for Triple Negative Breast Cancer (TNBC) and/or germline BRCA (gBRCA) breast cancer is safe and improves efficacy.
Trial Design: Open label, randomised, 3-stage Phase II/III
Sample Size: Minimum of 780 patients (including at least 220 gBRCA patients equally allocated to the control and the selected research arm).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 16 Years 至 70 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged between 16 and
- •Written informed consent, willing and able to comply with the Protocol for the duration of the trial including undergoing treatment and scheduled visits and examinations.
- •Histologically confirmed invasive breast cancer.
- •ER-negative*, and HER2-negative** breast cancer (TNBC). Patients will be eligible with any PR status but PR expression must be scored.
- •Germline BRCA (gBRCA) mutation positive, HER2 negative, and PgR / ER of any status.
- •T1, T2 or T3 tumours.
- •T4 tumour of any size with direct extension to (a) chest wall or (b) skin. OR Inflammatory carcinoma with tumour of any size. OR
- •Other Locally Advanced Disease:
- •Involvement of ipsilateral large or fixed axillary lymph nodes, or infra or supraclavicular nodes (>10mm diameter or clinical N2 or N3) and primary breast tumour of any diameter.
- •Involvement of ipsilateral large or fixed axillary lymph nodes, or infra or supraclavicular nodes (>10mm diameter, or clinical N2 or N3), without a primary breast tumour identified, the presence of breast cancer in a Lymph Node (LN) must be histopathologically confirmed by LN biopsy.
- •Multifocal tumour:
- •with at least one tumour with a size>10mm.
- •Patients with bilateral disease are eligible to enter the trial provided that both breast disease meets the above criteria.
- •Be fit to receive the trial chemotherapy regimen in the opinion of the responsible clinician:
- •Adequate bone marrow, hepatic, and renal function. ECOG performance status of 0, or
- •Treatment should be commenced within 6 weeks of the diagnostic biopsy. In uncommon circumstances, where medically acceptable, treatment is permitted to start within a maximum of 9 weeks of the diagnostic biopsy.
- •Availability of the Tumour Infiltrating Lymphocytes score is required.
- •Availability of CK 5/6 and EGFR +/- Androgen Receptor IHC score.
- •Availability of slides and paraffin embedded tissue blocks from pre-chemotherapy core biopsy and from primary surgical resection is required.
- •Women of child-bearing potential (WCBP), defined as not surgically sterilized or not post-menopausal for at least 24 consecutive months if age ≤55 year or 12 months if age >55 years, must have a negative serum or urine pregnancy test within 14 days prior to randomisation.
- •All WCBP and all sexually active male patients as well as their partners must be aware that they should not conceive during the treatment period and therefore should routinely use effective forms of contraception, throughout their participation in the trial and for at least 6 months after the last dose of trial treatment. Please follow the olaparib contraception guidelines.
排除标准
- •T0 tumour in absence of axillary node >10mm.
- •TNBC with a non-basal phenotype which strongly expresses Androgen Receptor.
- •Previous or concomitant chemotherapy or biological agents used for the treatment of cancer in the last 5 years.
- •Malignancy within the last 5 years except: adequately treated non-melanoma skin cancer; curatively treated in situ cancer of the cervix; ductal carcinoma in situ (DCIS); Stage 1, grade 1 endometrial carcinoma; or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years.
- •Patients with myelodysplastic syndrome/acute myeloid leukaemia.
- •Evidence of distant metastasis apparent prior to randomisation.
- •Patients with uncontrolled seizures.
- •Pre-existing sensory or motor neuropathy of CTCAE v4.03, grade ≥
- •Concomitant use of known potent CYP3A4 inhibitors and inducers. Consider wash-out periods.
- •Pregnant or breast feeding women.
- •Not suitable for neoadjuvant chemotherapy in the opinion of the responsible clinician.
- •Major surgery within 14 days of starting trial treatment and patients must have recovered from any effects of any major surgery.
- •Any evidence of other disease or any concomitant medical or psychiatric problems which in the opinion of the Investigator would prevent completion of treatment or follow-up. For example:
- •Evidence of severe or uncontrolled cardiac disease Uncontrolled ventricular arrhythmia Recent myocardial infarction (within 12 months) Active infection including Hepatitis B, Hepatitis C and Human Immunodeficiency virus (HIV). Screening for chronic conditions is not required.
- •ECG with mean resting QTc >470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
- •Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the trial medication
- •Known hypersensitivity to olaparib, carboplatin, paclitaxel or their excipients (including cremophor).
- •Whole blood transfusions in the last 120 days prior to blood sampling for BRCA test as it may interfere with the results (packed red blood cells and platelet transfusions are acceptable).
研究组 & 干预措施
Control
4 cycles of: Paclitaxel 80mg/m2 Day 1, 8 & 15, every 3 weeks, Carboplatin area under the curve (AUC) 5 Day 1, every 3 weeks
干预措施: Paclitaxel and Carboplatin (Drug)
Research 1
4 cycles of: Paclitaxel 80mg/m2 on Days 1, 8 & 15 every 3 weeks, Carboplatin AUC 5 Day 1, every 3 weeks, Olaparib oral 150mg twice daily, Day -2 to Day 10 every 3 weeks
干预措施: Olaparib (Drug)
Research 1
4 cycles of: Paclitaxel 80mg/m2 on Days 1, 8 & 15 every 3 weeks, Carboplatin AUC 5 Day 1, every 3 weeks, Olaparib oral 150mg twice daily, Day -2 to Day 10 every 3 weeks
干预措施: Paclitaxel and Carboplatin (Drug)
Research 2
4 cycles of: Paclitaxel 80mg/m2 on Days 1, 8 & 15 every 3 weeks, Carboplatin AUC 5 Day 1, every 3 weeks, Olaparib oral 150mg twice daily, Day 3 to Day 14 every 3 weeks
干预措施: Olaparib (Drug)
Research 2
4 cycles of: Paclitaxel 80mg/m2 on Days 1, 8 & 15 every 3 weeks, Carboplatin AUC 5 Day 1, every 3 weeks, Olaparib oral 150mg twice daily, Day 3 to Day 14 every 3 weeks
干预措施: Paclitaxel and Carboplatin (Drug)
结局指标
主要结局
Stage 1 - Number of participants with treatment-related adverse events as assessed by NCI CTCAE v4.03.
时间窗: 1 year - when first 25 patients in each research arm who had received at least one dose of Olaparib protocol treatment have completed their protocol treatment.
Primary outcome measure - safety of the addition of olaparib to three weekly carboplatin/weekly paclitaxel chemotherapy.
Stage 2 - pCR rate and completion rate of Olaparib treatment as per protocol.
时间窗: 15 months - when pathological complete response (pCR) is available for 53 patients in each of two research arms.
Primary outcome measure - pCR in each of the two research arms. At the end of stage 2, one of the research treatments will be dropped using the 'pick the winner' method.
Stage 3 - Efficacy analysis based on pCR at surgery. To be assessed by central review of pathology reports.
时间窗: 5.5 years - October 2021 approx.
Primary outcome measure - pCR at surgery after neoadjuvant treatment. pCR rates after neoadjuvant chemotherapy +/- olaparib, defined as no residual invasive carcinoma within the breast (Ductal Carcinoma in situ permitted) AND no evidence of metastatic disease within the lymph nodes.
次要结局
- pCR in breast alone(Up to 2 years after last patient is randomised)
- pCR at surgery - assessed by review of histopathology slides(Up to 2 years after last patient randomised)
- PARTNERing Pathway(2 cycles (each lasting 28 days))
- Distant disease-free survival(Up to 10 years after last patient is randomised)
- Residual Cancer Burden (RCB)(Up to 10 years after last patient is randomised)
- Breast cancer specific survival (BCSS)(Up to 10 years after last patient is randomised)
- Overall survival (OS)(Up to 10 years after last patient is randomised)
- Relapse-Free Survival (RFS)(Up to 10 years after last patient is randomised)
- Local recurrence-free survival(Up to 10 years after last patient is randomised)
- Time to second cancer (TTSC)(Up to 10 years after last patient is randomised)
- Treatment related toxicities - as assessed by CTCAE v4.03(Up to 10 years after last patient is randomised)
- Radiological response - as assessed by radiological response criteria as per RECIST v1.1(Up to 2 years after last patient is randomised)
- Quality of Life Questionnaire(Up to 10 years after last patient is randomised)
研究者
Prof. Jean Abraham
Professor
University of Cambridge