Metformin and Simvastatin in Addition to Fulvestrant
Keywords
Abstract
Description
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.
Dates
| Last Verified: | 12/31/2016 |
| First Submitted: | 02/05/2017 |
| Estimated Enrollment Submitted: | 06/15/2017 |
| First Posted: | 06/19/2017 |
| Last Update Submitted: | 06/15/2017 |
| Last Update Posted: | 06/19/2017 |
| Actual Study Start Date: | 01/19/2017 |
| Estimated Primary Completion Date: | 01/19/2019 |
| Estimated Study Completion Date: | 01/19/2019 |
Condition or disease
Intervention/treatment
Drug: Metformin/Simvastatin/Fulvestrant
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Experimental: 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. | Drug: 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.
Tumour biopsy at 8 weeks. Every 8 weeks for the first 6 months, every 12 weeks thereafter:
Performance status evaluation Medical history and physical examination Clinical tumor measurement Review of treatment-related side-effects Blood taking for research purpose and routine blood tests Routine scans |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | Eligibility criteria: - Women 18 years or older with metastatic or locally advanced disease, not amenable to curative therapy - Confirmed diagnosis of HR+/HER2- breast cancer - Any menopausal status - Progressed within 12 months from prior adjuvant or progressed within 1 month from prior advanced/metastatic endocrine breast cancer therapy - On an LHRH agonist for at least 28 days, if pre-/peri-menopausal*. - Measurable disease defined by RECIST version 1.1, or bone-only disease - Eastern Cooperative Oncology Group (ECOG) PS 0-2 and estimated life expectancy of at least 12 weeks - Adequate organ and marrow function, resolution of all toxic effects of prior therapy or surgical procedures - Signed informed consent - Pre-menopausal* females must have a negative serum pregnancy test within 21 days of study enrollment - Definition of Menopause: i. Age > 60 years, ii. Age < 60 years with amenorrhoea for > 12 months in the absence of endocrine therapy or chemotherapy iii. Bilateral oophorectomy Exclusion criteria: - Prior treatment with any CDK inhibitor, Fulvestrant, Everolimus, or agent that inhibits the PI3K-mTOR pathway - Patients with symptomatic visceral disease, or known uncontrolled or symptomatic CNS metastases - Patients who have not yet recovered from the toxicities of the previous anti-cancer therapy. - Concurrent administration of other anti-tumor therapies, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy are prohibited. Concomitant bone-modifying agents and gonadotropin-releasing hormone therapy are allowed. - Major surgery or radiotherapy within 2 weeks of randomization - Prior stem cell or bone marrow transplantation - Use of potent CYP3A4 inhibitors or inducers (Table 1); a washout period of 14 days is required for patients discontinuing these medications prior to study enrollment. - Currently on medications for diabetes (e.g. Metformin, sulphonylureas, insulin) or hypercholesterolaemia (statins or fibrates) - Renal impairment: Estimated glomerular filtration rate (eGFR) <60 mL/minute/1.73 m2 - Hepatic impairment: Aspartate transaminase (AST), Alanine Transaminase(ALT) ≥ 2.5 x upper limit of normal range (ULN), OR Total bilirubin ≥ 1.5 x ULN (subjects with Gilbert's syndrome can have bilirubin of up to 1.5 x ULN) - Pregnancy. - Breast feeding. - Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator. |
Outcome
Primary Outcome Measures
1. Clinical benefit rate (CBR) [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.]
Secondary Outcome Measures
1. 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.]
2. 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.]
3. Presence of toxicities [The presence of toxicies will be monitored through study completion, in an average of 2 years.]
