Single Arm Phase 2 Study of Metformin and Simvastatin in Addition to Fulvestrant in Metastatic Estrogen Receptor Positive Breast Cancer
试验速览
- 阶段
- 2 期
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Clinical benefit rate (CBR)
研究概览
简要总结
This is a prospective single arm open-label Phase 2 study utilising the combination of Fulvestrant, Metformin and Simvastatin in post-menopausal ER-positive metastatic breast cancer, with the primary endpoint being Clinical Benefit Rate (defined as complete response, partial response or stable disease, equal to or more than 24 weeks). The hypothesis is that the addition of Metformin and Simvastatin to Fulvestrant will improve the Clinical Benefit Rate from 40% (historical data from control arm of PALOMA-3 study) to 60%. A total of 28 patients will be enrolled over a period of 24 months. Eligible patients will receive 500 mg Fulvestrant by intramuscular injection on days 1 and 15 of cycle one and then on day one of each subsequent cycle (28 days). Patients will be given 850mg oral Metformin twice-a-day (based on xenograft models which showed that Metformin had anti-tumor effects at a minimum dose of 1500mg per day), and 20mg oral Simvastatin every night (drawing reference from the investigators' group's window-of-opportunity study), daily throughout the cycle. As part of the in-build safety and tolerability design, all patients will have a lead-in period of 7 days where they receive 850mg oral Metformin twice-a-day and 20mg oral Simvastatin every night. Special adverse events of interest include lactic acidosis, diarrhea, bloatedness, transaminitis and rhabdomyolysis. If no dose-limiting toxic effects (DLT) occur, Fulvestrant will be commenced, and considered the start of cycle 1. If DLT occurs in any of the patients, the combination of Metformin and Simvastatin will be modified for the affected patient as per protocol, with further monitoring for another 7 days. This combination will be deemed safe for that patient if no DLT occurs, following which cycle 1 can officially commence.
At the time of study entry, blood samples will be drawn to establish baseline physiological parameters including fasting insulin, glucose, lipids and Homeostasis Model Assessment 2 (HOMA2). In patients who have accessible tumor sites and are willing to provide tissue for translational research, pre- and post-treatment (at end of 8 weeks) biopsies will be taken for correlative biomarker studies. Patients will be evaluated on an 8-weekly basis for toxicities and efficacy assessments during the first 6 months of treatment, followed by 12-weekly thereafter until disease progression, unacceptable toxicities, or patient withdrawal.
详细描述
Endocrine therapy and acquired endocrine resistance in advanced breast cancer:
First-line treatment of metastatic estrogen receptor (ER) positive breast cancer with endocrine therapy such as Tamoxifen or aromatase inhibitors (AI) is efficacious, but development of secondary resistance is inevitable with median progression free survival of 9 months.1 Acquired resistance can be contributed by molecular cross-talk between estrogen receptors and other key survival and proliferative pathways. In particular, the PI3K/Akt/MAP kinase signaling pathway is upregulated with prolonged estrogen deprivation and is an important feature of progressive disease biology.2
The BOLERO-2 study showed an improvement in response rates and progression free survival with the addition of Everolimus, an mTOR-inhibitor to Exemestane in metastatic ER-positive breast cancer after failure on a non-steroidal AI.3 Synergy was also seen in a Phase 2 clinical trial with the combination of Fulvestrant and Everolimus in the second line setting.4 However, the clinical experience with Everolimus has been poor, with frequent adverse effects rendering the combination with endocrine therapy highly toxic. More recently, the PALOMA-1/3 studies have showed that targeting the CDK4/CDK6/E2F axis with Palbociclib is a feasible strategy with marked improvements in clinical endpoints when combined with Letrozole in the first line, and Fulvestrant after AI-failure.5,6 While the therapy was reasonably well-tolerated, Palbociclib remains prohibitively expensive, and is not widely used in countries where healthcare systems do not cover the cost of this novel combination.
Potential of Metformin and Simvastatin as anti-cancer agents:
It has been widely recognized that Metformin and Simvastatin, both commonly used medications in diabetes mellitus and dyslipidemia, have anti-cancer properties. Years of experience in the real world have shown that at standard doses, these 2 drugs can be used in combination with little toxicities. Metformin, a biguanide, results in activation of AMPK which consequently inhibits mTOR through phosphorylation of TSC2, as well as anti-proliferative effects through reduction in insulin receptor mediated mitogenesis and inhibition of cyclin dependent kinases.7,8 Pre-clinical studies in mouse xenograft models showed that at an equivalent dose of at least 1500mg per day, Metformin reduced the effective dosage of standard chemotherapeutic agents, and had preferential effects on tumor cells.9 Studies of Metformin in MCF7, an ER-positive breast cancer cell line, also showed that it resulted in significant reduction in protein synthesis as well as inhibition of the mTOR pathway.10 Simvastatin, a lipophilic HMGCoA reductase inhibitor, has been shown to interrupt oncogenic signaling by prenylation-dependent proteins including the RAS oncogene family, and attenuate PI3K signaling. In a recent window-of-opportunity study by the inverstigators' group, the investigators showed that at the usual prescribed dose of Simvastatin (20mg), a short course of therapy resulted in evident apoptosis and de-activation of the PI3K/Akt/mTOR and MAPK/ERK pathways in both clinical specimens as well as breast cancer cell lines.12
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Metformin/Simvastatin/Fulvestrant
7 days Lead-in period:
- Metformin: 850mg (one tablet) twice a day
- Simvastatin: 20mg (one tablet) once every night
Once the doctor has deemed that patients have tolerated Simvastatin and Metformin well, patients will receive Fulvestrant at standard doses:
- Cycle 1: 500mg (in the form of two injections, 1 in each buttock) at Day 1 and Day 15. Each cycle comprises of 28 consecutive days starting from Day 1.
- Cycle 2 and beyond: 500mg at Day 1 of each 28-day cycle.
干预措施: Metformin/Simvastatin/Fulvestrant (Drug)
结局指标
主要结局
Clinical benefit rate (CBR)
时间窗: The Clinical Benefit Rate will be assessed at 24 weeks of treatment with study drug. The time frame will be through study completion, in an average of 2 years.
the percentage achieving CR, PR and SD in patients with measurable disease or the absence of disease progression in patients with non-measurable disease, lasting at least 24 weeks.
次要结局
- Objective response rates (ORR)(The Objective Response Rate will be assessed from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed through study completion, in an average of 2 years.)
- Progression-free survival (PFS)(The progression-free survival will be assessed from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed through study completion, in an average of 2 years.)
- Presence of toxicities(The presence of toxicies will be monitored through study completion, in an average of 2 years.)