A Phase I/II Study of AZD5363 Combined With Paclitaxel in Patients With Advanced or Metastatic Breast Cancer. Comprising a Safety Run-In and a Placebo-controlled Randomised Expansion in ER+ve Patients Stratified by PIK3CA Mutation Status
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 148
- 试验地点
- 1
- 主要终点
- Dose-limiting Toxicity (DLT) Events - Part A
研究概览
简要总结
The purpose of this study is to investigate the safety and efficacy of different doses and schedules of AZD5363, when in combination with paclitaxel, in treatment of patients with advanced or metastatic breast cancer. Also to investigate a selected dose and schedule of AZD5363 in combination with paclitaxel vs. paclitaxel in combination with placebo in treatment of patients with estrogen receptor-positive advanced or metastatic breast cancer, including a subgroup who have the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) tumour mutation.
详细描述
This is a Phase I/II multicentre, study investigating the safety, tolerability and efficacy of a twice-daily oral formulation of AZD5363 when combined with a weekly intravenous paclitaxel infusion in patients with advanced or metastatic breast cancer. Study treatment is given in 28-day cycles, comprising three weeks on-therapy followed by one week off-therapy.
The study will be conducted in two parts:
Part A. Approximately 40 patients will be recruited to this Phase I multiple ascending-dose safety run-in evaluation of each of two intermittent dosing schedules (2 days per week or 4 days per week) of AZD5363 given in combination with weekly paclitaxel. The study population is female patients, 18 years or older, with advanced or metastatic breast cancer.
The purpose of Part A is to assess the comparative safety, tolerability, pharmacokinetics and preliminary efficacy of both schedules to determine one dose and schedule of AZD5363 to take forward to study Part B in combination with weekly paclitaxel.
Part A assessments will be made in dose-escalating cohorts of 3 to 6 patients to determine a recommended dose in each of the schedules. A total of 6 patients must be evaluated at a selected dose level for it to be confirmed as the recommended dose. All dose evaluations and recommendations will be conducted by a Safety Review Committee.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Provision of informed consent.
- •Female patient.
- •Aged at least 18 years.
- •Histological or cytological confirmation of breast cancer with evidence of advanced or metastatic disease (must be ER+ve, HER2-ve, in Part B).
- •World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.
排除标准
- •Clinically significant abnormalities of glucose metabolism.
- •Spinal cord compression or brain metastases unless asymptomatic, treated and stable (not requiring steroids).
- •Evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses or active infections including hepatitis B, C and HIV.
- •Any prior exposure to agents which inhibit AKT as the primary pharmacological activity.
- •Part A: more than two prior courses of chemotherapy (including taxanes) for advanced or metastatic breast cancer.
- •Part B: any prior chemotherapy for advanced or metastatic breast cancer.
研究组 & 干预措施
Part A: Intermittent schedule (2/5)
See intervention description below.
干预措施: AZD5363 when combined with weekly paclitaxel. (Drug)
Part A: Intermittent schedule (4/3)
See intervention description below.
干预措施: AZD5363 when combined with weekly paclitaxel. (Drug)
Part B: AZD5363 combined with paclitaxel
See intervention description below.
干预措施: AZD5363when combined with weekly paclitaxel. (Drug)
Part B: paclitaxel combined with placebo
See intervention description below.
干预措施: A placebo in combination with weekly paclitaxel. (Drug)
结局指标
主要结局
Dose-limiting Toxicity (DLT) Events - Part A
时间窗: During Part A DLT evaluation period (Cycle 1, up to 28 days)
An Adverse Event (AE) or laboratory abnormality considered to be related to study drug, that starts at any time during the DLT evaluation period (Cycle 1) and is dose limiting
Progression Free Survival (PFS) - Part B
时间窗: From randomisation date to date of objective disease progression or death (by any cause) whichever came first, assessed every 12 wks (median total treatment duration AZD5363=325.5 days; Placebo=245 days)
Time from randomisation to date of objective disease progression or death (by any cause in the absence of progression). Progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a \>= 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, and an absolute increase of \>=5mm, or progression of non-target lesions or the appearance of new lesions.
次要结局
- Best Objective Response (BOR)(From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).)
- Overall Objective Response Rate(From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).)
- Change in Tumour Size at 12 Weeks(RECIST tumour assessments every 12 weeks)
- Durable Response Rate (DRR) - Part B(From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).)
- Overall Survival - Part B(From date of randomisation, assessed every 12 weeks, up until the time of final statistical analysis. (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).)
- Objective Response Rate (ORR) at Week 12(RECIST tumour assessments every 12 weeks)
- Number of Subjects Without Progression Disease at Week 12 - Part A(up to 12 weeks)
- Duration of Response (DOR) - Part B(From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).)