A Phase Ib/Randomized Phase II Study of BEZ235 and Trastuzumab Versus Lapatinib and Capecitabine in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer Who Failed Prior to Trastuzumab
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Incidence of Dose Limiting Toxicities (DLT) in the first cycle - phase lb
研究概览
简要总结
This is a prospective, multi-center, open-label, phase Ib/ II study (two parts) with patients that have locally advanced or metastatic HER2+ breast cancer. The first part (phase Ib) will investigate the MTD/ RP2D of the combination therapy of BEZ235 BID and weekly trastuzumab using a Bayesian model. Once MTD/ RP2D is established the second part (phase II) will start. Phase II will evaluate the efficacy and the safety of weekly trastuzumab plus BEZ235 BID compared to capecitabine and lapatinib.
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Patient is a female ≥ 18 years of age
- •Patient has a histologically and/or cytologically confirmed diagnosis of HER2-positive invasive breast cancer with inoperable locally advanced or metastatic disease
- •Patients with controlled or asymptomatic CNS metastases are eligible
- •Patient has adequate bone marrow and organ functions, and has recovery from all clinically significant toxicities related to prior anti-neoplastic therapies
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- •Platelets ≥ 100 x 109/L
- •Hemoglobin (Hgb) ≥ 9.0 g/dL
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or ≤ 5.0 x ULN if liver metastases are present)
- •Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
- •Serum creatinine ≤ 1.5 x ULN
- •Fasting plasma glucose (FPG) ≤ 140mg/dL [7.8 mmol/L]
- •HbA1c ≤ 8%
- •Patient has received prior trastuzumab (alone or in combination) but NO more than 3 prior cytotoxic chemotherapy lines
- •Prior endocrine and radiotherapy allowed
- •Patient has ECOG performance status of 0-2 (Phase Ib) or 0-1 (Phase II)
- •Additional inclusion criteria for phase II:
- •Available tumor tissue (archival or fresh) for biomarker analysis; known PI3K activation status
- •At least one measurable lesion as per RECIST 1.1
- •Patient has received prior treatment with a taxane
- •Patient has "trastuzumab-resistance disease" defined as:
- •Recurrence while on trastuzumab (or T-DM1) or within 12 months since the last infusion in the adjuvant setting
- •Progression while on or within 4 weeks since the last infusion of trastuzumab (or T-DM1) in the locally advanced or metastatic setting
排除标准
- •Previous treatment with PI3K and/or mTOR inhibitors
- •Symptomatic/uncontrolled Central Nervous System (CNS) metastases
- •Concurrent malignancy or malignancy in the last 3 years prior to enrollment
- •Wide field radiotherapy ≤ 28 days or limited field radiation for palliation ≤ 14 days prior to starting study drug
- •Active cardiac disease (e.g. LVEF less than institutional lower limit of normal, QTcF > 480 msec, unstable angina pectoris, ventricular, supraventricular or nodal arrhythmias)
- •Inadequately controlled hypertension
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BEZ235
- •Treatment at start of study treatment with drugs with a known risk to induce Torsades de Pointes, moderate and strong inhibitors or inducers of isoenzyme CYP3A4, warfarin and coumadin analogues, LHRH agonists
- •Intolerance or contraindications to trastuzumab treatment
- •Pregnant or nursing (lactating) woman
- •Additional exclusion criteria for phase II:
- •Prior treatment with capecitabine and lapatinib
- •Intolerance or contraindications to capecitabine and lapatinib
- •Previous treatment with HER-2 targeted agents other than trastuzumab or T-DM1
- •Peripheral neuropathy ≥ Grade 2
研究组 & 干预措施
BEZ235 + Trastuzumab (Phase l /Phase ll)
Phase l: Eligible patients will receive increasing doses of oral BEZ235 administered on a continuous twice daily (BID) schedule + weekly trastuzumab at a fixed dose of 2 mg/kg. Treatment will be organized into cycles of 28 days.
Phase ll: Eligible patients will receive weekly trastuzumab (2 mg/kg) + oral BEZ235 on a continuous twice daily (BID schedule) at the MTD or RP2D.
Treatment will be organized into cycles of 21 days.
干预措施: BEZ235 + Trastuzumab Phase l/Phase ll) (Drug)
Lapatinib + Capecitabine (Phase II)
Eligible patients will receive lapatinib (1250 mg given orally once daily on days 1 through 21) in combination with capecitabine (2000 mg/m2/day administered orally in 2 doses approximately 12 hours apart on days 1 through 14). Treatment will be organized into cycles of 21 days .
干预措施: Lapatinib + Capecitabine (Phase II) (Drug)
结局指标
主要结局
Incidence of Dose Limiting Toxicities (DLT) in the first cycle - phase lb
时间窗: First treatment cycle (28 days)
DLT is defined as treatment-related toxicity (classified according Common Toxicity Criteria for Adverse Events (CTCAE) Version 4) occurring during the first 28 treatment days and meeting specific protocol-predefined criteria. The information will be integrated in a Bayesian logistic regression model with overdose control to estimate the maximum tolerated dose (MTD)
Progression Free Survival (PFS) based on local radiological assessment - phase ll
时间窗: Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months)
PFS is defined as the time from randomization until objective tumor progression or death from any cause. Radiological assessments will be performed every 6 weeks for the first 36 weeks after treatment start, then every 12 weeks.
次要结局
- Frequency and severity of Adverse Events - Phase lb(until 30 days after treatment discontinuation)
- BEZ235 plasma and trastuzumab serum concentrations - phase lb(Pre-dose (cycle 1 through 9) and 4-6 hours post-dose (cycle 1 and 2))
- Overall Response Rate (ORR) - phase ll(12 months)
- Duration of overall response (DR) - phase ll(12 months)
- Frequency and severity of adverse events (phase ll)(Until 30 days after treatment discontinuation)
- Efficacy in subgroups of patients with activated/non-activated PI3K pathway (phase ll)(12 months)
- Clinical Benefit Rate (CBR) - phase ll(12 months)
- Time to overall response (TTR) - phase ll(12 months)
- Median overall survival (OS) (phase ll)(Randomization, death (expected average:24 months))
- PFS based on central radiological assessment (phase ll)(Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months))
- Progression Free Survival (PFS) - Phase lb(Randomization, Randomization, disease progression or start of of new anti-neoplastic therapy (expected average: 12 months))
- Overall Response Rate (ORR)- Phase lb(12 months)
- Clinical Benefit Rate (CBR) (Phase lb)(12 months)