A Phase 1b/2 Randomised Placebo Controlled Trial of Fulvestrant +/- AZD5363 in Postmenopausal Women With Advanced Breast Cancer Previously Treated With a Third Generation Aromatase Inhibitor
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 149
- 试验地点
- 21
- 主要终点
- Phase 1b primary outcome measure: Maximum Tolerated Dose of AZD5363 in combination with fulvestrant
研究概览
简要总结
This is a two stage study, with an initial dose escalation phase I study and subsequent double blind randomised phase II controlled trial. Eligible patients are post-menopausal women with metastatic ER+ breast cancer not suitable for surgical resection. Patients should be suitable for endocrine treatment, but have received no more than 3 previous lines of endocrine treatment and up to 1 line of chemotherapy for metastatic disease. They will also have had progressive disease during treatment with an aromatase inhibitor. Following the dose-escalation in stage 1, patients will be randomised to receive fulvestrant plus either placebo or 480mg (or maximum tolerated dose) of AZD5363 oral capsules or tablets taken once daily.
Patients will receive fulvestrant in combination with either placebo or AZD5363 until disease progression. Patients may continue to receive fulvestrant and AZD5363/placebo treatment even after the last trial visit.
详细描述
Phase 1 (n=9-12)
As fulvestrant and AZD5363 have not previously been administered to this population, we have incorporated an initial phase I dose escalation:
- 3 patients will receive fulvestrant 500mg on day 1 and 400mg AZD5363 oral capsules or tablets bd 4 days on and 3 days off. They will be assessed for dose limiting toxicity (DLT) on day 1, 15 and 28 of cycle 1. The safety review committee (SRC) will meet to review DLT reports when the third patient finishes cycle 1.
- If 400mg is tolerable (0/3-6 or 1-6 has a DLT) then the dose of AZD5363 will be escalated to 480mg.
- If 480mg is tolerable in a cohort of 6 patients then 480mg will be the Maximum tolerated dose (MTD).
- If 480mg is not tolerable (2/6 patients have a DLT), then the 400mg dose will be the MTD.
- If 400mg is not tolerable (2 or more patients have a DLT) then the dose will be reduced to 320mg for the next cohort of 6 patients.
- if 320mg is tolerable in a cohort of 6 patients, then 320mg will be the MTD.
- if 320mg is not tolerable, then the trial will not proceed. If patients are withdrawn for reasons other than toxicity during Stage 1 before DLT assessments then they will be replaced.
Phase 2 (n=136)
Recruitment in to Phase 2 will commence after all 6 patients in Stage 1 have completed at least 1 cycle of therapy and the SRC have given the go-ahead. Patients will be randomised to one of two arms:
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 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Post-menopausal Women
- •Life expectancy 3 months
- •Histological confirmation of ER+ breast cancer
- •Clinical or histological confirmation of metastatic or locally advanced disease not amenable to surgical resection
- •Measurable or non-measurable disease
- •Adequate bone marrow, renal and hepatic function
- •Eastern Cooperative Oncology Group (ECOG) performance status < or equal to 2
- •Progressive disease whilst receiving an aromatase inhibitor (AI) for metastatic breast cancer (MBC)
- •Relapsed with metastatic disease whilst receiving an AI in adjuvant setting
- •Up to 3 prior lines of endocrine therapy for Advanced Breast Cancer
- •Up to 1 line of chemotherapy for Advanced Breast Cancer
- •Patient willing to donate archival tumour sample
- •Patient willing to donate baseline blood sample
- •Suitable for further endocrine therapy
排除标准
- •Previous treatment with fulvestrant or PI3K/mTOR(mammalian target of rapamycin )/Akt inhibitor therapy
- •Treatment with chemotherapy, immunotherapy or targeted, biologic or tumour embolisation within 21 days of study drug administration
- •Palliative radiotherapy within 7 days of study drug
- •Clinically significant abnormalities in glucose metabolism
- •Rapidly progressive visceral disease not suitable for further endocrine therapy
- •Known brain or leptomeningeal metastases
- •Any co-existing medical condition precluding trial entry including significant cardiac disease (to be defined in the protocol)
- •Concomitant medication unsuitable for combination with trial medication
研究组 & 干预措施
AZD5363 plus fulvestrant
Fulvestrant 500mg and AZD5363 4 days on 3 days off at dose determined in safety run in (maximum 480mg and minimum 320mg bd)
干预措施: AZD5363 (Drug)
AZD5363 plus fulvestrant
Fulvestrant 500mg and AZD5363 4 days on 3 days off at dose determined in safety run in (maximum 480mg and minimum 320mg bd)
干预措施: Fulvestrant (Drug)
Placebo plus fulvestrant
Fulvestrant 500mg D1, D15 (cycle 1) and D1 of a 28 cycle thereafter. AZD5363 placebo 4 days on 3 days off
干预措施: Placebo (Drug)
Placebo plus fulvestrant
Fulvestrant 500mg D1, D15 (cycle 1) and D1 of a 28 cycle thereafter. AZD5363 placebo 4 days on 3 days off
干预措施: Fulvestrant (Drug)
结局指标
主要结局
Phase 1b primary outcome measure: Maximum Tolerated Dose of AZD5363 in combination with fulvestrant
时间窗: 6 months
To establish the MTD of AZD5363 in combination with fulvestrant and to establish a recommended phase 2 dose
Phase 2 primary outcome: Progression free survival (PFS)
时间窗: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months after the last patient is randomised
To establish the anti-tumour activity of the combination of AZD5363 with fulvestrant as measured by progression-free survival (PFS). This is the time from enrolment to any disease progression and/or any death, defined according to strict Response Evaluation Criteria in Solid Tumors(RECIST) v1.1 criteria. Lesions will be compared to baseline measurements to assess progression.
次要结局
- Number of patients with adverse events(Up to 12 months after the last patient is randomised)
- Objective response rate(Up to 12 months after the last patient is randomised)
- Overall survival(Up to 12 months after the last patient is randomised)
- Number of patients requiring dose modifications(Up to 12 months after the last patient is randomised)
- The influence of mutational status of PIK3CA and the presence of complete loss of PTEN on outcome in the two treatment groups(Up to 12 months after the last patient is randomised)
- Fulvestrant pharmacokinetics(Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 3 Day 1)
研究者
Dr Margherita Carucci
Clinical Trial Manager
Velindre NHS Trust