Breast Cancer Clinical Trial
Official title:
Single Arm Phase 2 Study of Metformin and Simvastatin in Addition to Fulvestrant in Metastatic Estrogen Receptor Positive Breast Cancer
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.
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
The investigators believe that there is untapped potential in the usage of Metformin and
Simvastatin in targeting the PI3K/Akt/mTOR pathway which is upregulated in metastatic
ER-positive breast cancer after progression on first-line endocrine therapy, and that this
inexpensive and non-toxic combination will show synergy with Fulvestrant in the second-line
(and beyond) setting.
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