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.
Status | Recruiting |
Enrollment | 28 |
Est. completion date | January 20, 2019 |
Est. primary completion date | January 20, 2019 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 99 Years |
Eligibility |
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. |
Country | Name | City | State |
---|---|---|---|
Singapore | National University Hospital Singapore | Singapore |
Lead Sponsor | Collaborator |
---|---|
National University Hospital, Singapore |
Singapore,
Massarweh S, Romond E, Black EP, Van Meter E, Shelton B, Kadamyan-Melkumian V, Stevens M, Elledge R. A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen receptor (ER)-positive breast cancer after aromatase inhibito — View Citation
Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011 Nov 20;29(33):4452-61. doi: 10.1200/JCO.2010.34.4879. Epub 2011 Oct 17. Review. — View Citation
Park IH, Ro J, Lee KS, Kim EA, Kwon Y, Nam BH, Jung SY, Lee S, Kim SW, Kang HS. Phase II parallel group study showing comparable efficacy between premenopausal metastatic breast cancer patients treated with letrozole plus goserelin and postmenopausal pati — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Clinical benefit rate (CBR) | 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. | 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 | Objective response rates (ORR) | a best overall response of CR or PR. | 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. | |
Secondary | Progression-free survival (PFS) | the time from the date of study enrollment until the first date of documented disease progression or death due to any cause, whichever occurs first. | 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. | |
Secondary | Presence of toxicities | as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0. | The presence of toxicies will be monitored through study completion, in an average of 2 years. |
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