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

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ClinicalTrials.gov Identifier: NCT01885013
Recruitment Status : Completed
First Posted : June 24, 2013
Last Update Posted : January 1, 2016
Sponsor:
Information provided by (Responsible Party):
Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Human Epidermal Growth Factor 2 Negative Carcinoma of Breast Drug: Metformin + Myocet + Cyclophosphamide Drug: Myocet + Cyclophosphamide Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 126 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Comparative Study of Myocet Plus Cyclophosphamide in First Line Treatment of HER2 Negative Metastatic Breast Patients
Study Start Date : September 2010
Actual Primary Completion Date : May 2015
Actual Study Completion Date : May 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Metformin + Myocet + Cyclophosphamide

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

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.

Other Names:
  • metformin
  • myocet
  • cyclofosfamide

Active Comparator: Myocet + Cyclophosphamide
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

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

Other Names:
  • myocet
  • cyclofosfamide




Primary Outcome Measures :
  1. progression-free survival (PFS) [ Time Frame: 42 months ]
    Clinical efficacy of the combination of Myocet / Cyclophosphamide plus Metformin compared to treatment with only Myocet / Cyclophosphamide, in terms of progression-free survival (PFS)


Secondary Outcome Measures :
  1. Objective response rate [ Time Frame: 42 months ]
    Objective Response Rate after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide

  2. Overall survival [ Time Frame: 42 months ]
    Overall survival after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide

  3. Progression free survival as function of Homa Index levels [ Time Frame: 42 months ]
    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

  4. objective response rate as function of Homa Index levels [ Time Frame: 42 months ]
    Objective Response Rate after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide, as function of Homa Index levels

  5. overall survival as function of Homa Index levels [ Time Frame: 42 months ]
    Overall survival after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide, as function of Homa Index levels

  6. patient metabolic profile (metabolic syndrome) [ Time Frame: 42 months ]
    Characterization of the metabolic profile of patients: sensitivity in insulin levels



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have histologically or cytologically confirmed breast cancer
  2. Metastatic disease
  3. HER2 negative disease, as measured by IHC or FISH
  4. Non endocrine responsive disease (negative hormonal status or failure of endocrine therapy for MBC)
  5. Patients with measurable and/or non-measurable disease according to RECIST Criteria (Version 1.1)
  6. Homa Index calculated according to Matthews' formula
  7. Prior endocrine therapy is allowed, in the adjuvant and/or metastatic setting
  8. 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.
  9. Age 18-75 years
  10. Life expectancy of greater than 3 months
  11. ECOG performance status <2
  12. 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
  13. Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF)>= 50%
  14. 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.
  15. Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  1. Known diabetes (type 1 or 2)
  2. Currently on metformin, sulfonylureas, thiazolidenediones or insulin for any reason (these drugs alter insulin levels)
  3. 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
  4. 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)
  5. Hypersensitivity or allergy to metformin
  6. Participation in another clinical trial with any investigational agents within 30 days prior to study screening
  7. 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
  8. History of allergic reactions attributed to compounds of similar chemical or biologic composition to Myocet or other agents used in the study
  9. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01885013


Locations
Italy
P.O. M. Bufalini
Cesena, FC, Italy
UO Oncologia Medica IRCCS IRST
Meldola (FC), FC, Italy, 47014
Ospedale Civile degli Infermi
Faenza, RA, Italy
Ospedale Umberto I
Lugo, RA, Italy
Ospedale Civile Santa Maria delle Croci
Ravenna, RA, Italy
ULSS n.8 Asolo Ospedale di Castelfranco
Asolo, Italy
Centro di Riferimento Oncologico CRO
Aviano, Italy
Ospedale S.Martino
Belluno, Italy
Azienda Ospedaliera "Antonio Cardarelli"
Campobasso, Italy
P.O. "SS. Annunziata"
Chieti, Italy
Presidio Ospedaliero E. Profili
Fabriano, Italy
E.O. Galliera
Genova, Italy
Ospedale di Guastalla
Guastalla, Italy
Azienda per i Servizi Sanitari n.5 "Bassa Friulana"
Latisana, Italy
Presidio Ospedaliero "Vito Fazzi"
Lecce, Italy
ULSS n.13 di Mirano
Mirano, Italy
Arcispedale S. Maria Nuova
Modena, Italy
Azienda Ospedaliera S. Salvatore di Pesaro
Pesaro, Italy
Ospedale S. Spirito
Pescara, Italy
Ospedale Civile di Piacenza
Piacenza, Italy
Azienda Ospedaliera Santa Maria degli Angeli
Pordenone, Italy
Arcispedale S. Maria Nuova
Reggio Emilia, Italy
Ospedale Civile degli Infermi
Rimini, Italy
IRCCS Centro di riferimento Oncologico di Basilicata di Rionero in Vulture
Rionero in Vulture, Italy
Ospedale Nuovo Regina Margherita
Roma, Italy
Sponsors and Collaborators
Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
Investigators
Principal Investigator: Dino Amadori, MD IRST IRCCS, Meldola

Responsible Party: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
ClinicalTrials.gov Identifier: NCT01885013     History of Changes
Other Study ID Numbers: IRST174.04
2009-014662-26 ( EudraCT Number )
First Posted: June 24, 2013    Key Record Dates
Last Update Posted: January 1, 2016
Last Verified: December 2015

Keywords provided by Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori:
HER2 negative
metastatic breast cancer
non endocrine responsive disease

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Metformin
Cyclophosphamide
Doxorubicin
Hypoglycemic Agents
Physiological Effects of Drugs
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors