Myocet + Cyclophosphamide + Metformin Vs Myocet + Cyclophosphamide in 1st Line Treatment of HER2 Neg. Metastatic Breast Cancer Patients

Study Overview
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Brief Summary
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This is a phase II comparative randomized clinical trial. Eligible patients will be randomized (1:1) to: Arm A: Myocet plus Cyclofosfamide plus Metformin Arm B: Myocet plus Cyclofosfamide Statistical Considerations: In this randomized phase II study, the sample size was calculated basing on the primary end-point (PFS) and assuming an error α = 10% (2-tailed) with a power of 80%. To find an advantage of 4 months of median time to progression (6 months in the control arm B and 10 months in the experimental arm A) will be recruited 112 patients (98 events) for a period of 24 months and will be considered further 12-month of follow-up. The primary analysis of the study will be conducted in accordance with the intention to treat principle, the secondary analysis will be conducted in the per protocol population.

Detailed Description
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MULTICENTER, RANDOMIZED, COMPARATIVE STUDY OF MYOCET PLUS CYCLOPHOSPHAMIDE PLUS METFORMIN VERSUS MYOCET PLUS CYCLOPHOSPHAMIDE IN FIRST LINE TREATMENT OF HER2 NEGATIVE METASTATIC BREAST CANCER PATIENTS. The aim of this study is to determine if the addition of metformin to the regime Myocet / Cyclophosphamide improves disease-free survival in patients with HER2-negative metastatic breast cancer. The primary objective is the evaluation of the clinical efficacy of the combination of Myocet / Cyclophosphamide plus Metformin compared to treatment with only Myocet / Cyclophosphamide, in terms of progression-free survival (PFS). Clinical secondary objectives are: Objective response rate Overall survival Tolerability Progression-free survival, objective response rate and overall survival according to Homa Index levels. Secondary biological endpoint is the characterization of the metabolic profile of patients (sensitivity in insulin levels). Treatment Arm A (experimental treatment): Metformin 1000 mg, 2 times daily per os*. Myocet 60 mg/m2, intravenous infusion, on day 1, every 21 days Cyclophosphamide 600 mg/m2, intravenous infusion, at day 1 every 21 days. * During cycle 1, patients will assume only metformin from day 1 to day 13 and will begin chemotherapy from day 14. From day 1 to day 3, patients will assume Metformin 1000 mg once a day. Starting from day 4 patients will assume Metformin 1000 mg 2 times a day. Arm B (standard treatment): Myocet 60 mg/m2, intravenous infusion, on day 1, every 21 days Cyclophosphamide 600 mg/m2, intravenous infusion, on day 1, every 21 days Chemotherapy will be performed for 8 cycles. The treatment will be continued until progression of disease. Statistical Considerations: In this randomized phase II study, the sample size was calculated basing on the primary end-point (PFS) and assuming an error α = 10% (2-tailed) with a power of 80%. To find an advantage of 4 months of median time to progression (6 months in the control arm B and 10 months in the experimental arm A) will be recruited 112 patients (98 events) for a period of 24 months and will be considered further 12-month of follow-up. The primary analysis of the study will be conducted in accordance with the intention to treat principle, the secondary analysis will be conducted in the per protocol population.

Official Title
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Phase II Comparative Study of Myocet Plus Cyclophosphamide in First Line Treatment of HER2 Negative Metastatic Breast Patients

Conditions
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Human Epidermal Growth Factor 2 Negative Carcinoma of Breast

Intervention / Treatment
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* Drug: Metformin + Myocet + Cyclophosphamide
* Drug: Myocet + Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed breast cancer Metastatic disease HER2 negative disease, as measured by IHC or FISH Non endocrine responsive disease (negative hormonal status or failure of endocrine therapy for MBC) Patients with measurable and/or non-measurable disease according to RECIST Criteria (Version 1.1) Homa Index calculated according to Matthews' formula Prior endocrine therapy is allowed, in the adjuvant and/or metastatic setting Prior chemotherapy is allowed, only in adjuvant setting, provided it is terminated at least 12 months before study entry. Adjuvant anthracyclines are allowed if prior cumulative dose does not exceed 360 mg/m2 in case of epirubicin and 280 mg/m2 in case of doxorubicin. Adjuvant taxanes are allowed. Age 18-75 years Life expectancy of greater than 3 months ECOG performance status <2 Patients must have normal organ and marrow function: leukocytes >=3,000/μL absolute neutrophil count >=1,500/μL platelets >=100,000/μL total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) <=1.5 X institutional upper limit of normal creatinine within normal institutional limits Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF)>= 50% The effects of liposomal doxorubicin on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because anthracyclines as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. All women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study medication. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Known diabetes (type 1 or 2) Currently on metformin, sulfonylureas, thiazolidenediones or insulin for any reason (these drugs alter insulin levels) Current or previous congestive heart failure, renal failure or liver failure; history of acidosis of any type; habitual intake of 3 or more alcoholic beverages per day Creatinine above upper limit of normal for institution, AST above 1.5 times upper limit or normal for institution (to reduce risk of lactic acidosis) Hypersensitivity or allergy to metformin Participation in another clinical trial with any investigational agents within 30 days prior to study screening Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events History of allergic reactions attributed to compounds of similar chemical or biologic composition to Myocet or other agents used in the study Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin + Myocet + Cyclophosphamide<br>arm A : Metformin 1000 mg, 2 times daily per os*. Myocet 60 mg/m2, intravenous infusion, on day 1, every 21 days Cyclophosphamide 600 mg/m2, intravenous infusion, at day 1 every 21 days. * During cycle 1, patients will assume only metformin from day 1 to day 13 and will begin chemotherapy from day 14. From day 1 to day 3, patients will assume Metformin 1000 mg once a day. Starting from day 4 patients will assume Metformin 1000 mg 2 times a day. | Drug: Metformin + Myocet + Cyclophosphamide<br>* Metformin + Myocet + Cyclophosphamide: Metformin 1000 mg, 2 times daily per os*. Myocet 60 mg/m2, intravenous infusion, on day 1, every 21 days Chemotherapy will be performed for 8 cycles Cyclophosphamide 600 mg/m2, intravenous infusion, at day 1 every 21 days. * During cycle 1, patients will assume only metformin from day 1 to day 13 and will begin chemotherapy from day 14. From day 1 to day 3, patients will assume Metformin 1000 mg once a day. Starting from day 4 patients will assume Metformin 1000 mg 2 times a day.<br>* Other names: cyclofosfamide;|
| Active Comparator: Myocet + Cyclophosphamide<br>arm B : Myocet 60 mg/m2, intravenous infusion, on day 1, every 21 days Cyclophosphamide 600 mg/m2, intravenous infusion, on day 1, every 21 days | Drug: Myocet + Cyclophosphamide<br>* Myocet + Cyclophosphamide: Myocet 60 mg/m2, intravenous infusion, on day 1, every 21 days Cyclophosphamide 600 mg/m2, intravenous infusion, on day 1, every 21 days Chemotherapy will be performed for 8 cycles<br>* Other names: cyclofosfamide;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival (PFS) | Clinical efficacy of the combination of Myocet / Cyclophosphamide plus Metformin compared to treatment with only Myocet / Cyclophosphamide, in terms of progression-free survival (PFS) | 42 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Objective Response Rate after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide | 42 months | 
| Overall survival | Overall survival after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide | 42 months | 
| Progression free survival as function of Homa Index levels | Clinical efficacy of the combination of Myocet / Cyclophosphamide plus Metformin compared to treatment with only Myocet / Cyclophosphamide, in terms of progression-free survival (PFS) as function of Homa Index levels | 42 months | 
| objective response rate as function of Homa Index levels | Objective Response Rate after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide, as function of Homa Index levels | 42 months | 
| overall survival as function of Homa Index levels | Overall survival after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide, as function of Homa Index levels | 42 months | 
| patient metabolic profile (metabolic syndrome) | Characterization of the metabolic profile of patients: sensitivity in insulin levels | 42 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2 negative, metastatic breast cancer, non endocrine responsive disease