Clinical Trials /

Metformin and Simvastatin in Addition to Fulvestrant

NCT03192293

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Unknown status

Phase:

Phase 2

Trial Eligibility

Document

Title

    <li>Brief Title: Metformin and Simvastatin in Addition to Fulvestrantli><li>Official Title: Single Arm Phase 2 Study of Metformin and Simvastatin in Addition to Fulvestrant in Metastatic Estrogen Receptor Positive Breast Cancerli>

Clinical Trial IDs

    <li>ORG STUDY ID: BR03/10/16li><li>SECONDARY ID: 2016/01178li><li>NCT ID: NCT03192293li>

Conditions

    <li>Breast Cancerli>

Interventions

<td>Metformin/Simvastatin/Fulvestranttd><td/><td>Metformin/Simvastatin/Fulvestranttd>
DrugSynonymsArms

Purpose

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.

Detailed 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.
    

Trial Arms

<td>Metformin/Simvastatin/Fulvestranttd><td>Experimentaltd><td>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 Fulvestrantat 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.td><td>
    <li>Metformin/Simvastatin/Fulvestrantli>
td>
NameTypeDescriptionInterventions

Eligibility 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.
      
<td>Maximum Eligible Age:td><td>99 Yearstd><td>Minimum Eligible Age:td><td>18 Yearstd><td>Eligible Gender:td><td>Alltd><td>Healthy Volunteers:td><td>Notd>

Primary Outcome Measures

<td>Measure:td><td>Clinical benefit rate (CBR)td><td>Time Frame:td><td>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.td><td>Safety Issue:td><td/><td>Description:td><td>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.td>

Secondary Outcome Measures

<td>Measure:td><td>Objective response rates (ORR)td><td>Time Frame:td><td>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.td><td>Safety Issue:td><td/><td>Description:td><td>a best overall response of CR or PR.td>
<td>Measure:td><td>Progression-free survival (PFS)td><td>Time Frame:td><td>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.td><td>Safety Issue:td><td/><td>Description:td><td>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.td>
<td>Measure:td><td>Presence of toxicitiestd><td>Time Frame:td><td>The presence of toxicies will be monitored through study completion, in an average of 2 years.td><td>Safety Issue:td><td/><td>Description:td><td>as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0.td>

Details

<td>Phase:td><td>Phase 2td><td>Primary Purpose:td><td>Interventionaltd><td>Overall Status:td><td>Recruitingtd><td>Lead Sponsor:td><td>National University Hospital, Singaporetd>

Last Updated

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