Study of Myocet Plus Cyclophosphamide Plus Metformin Versus Myocet Plus Cyclophosphamide in First Line Treatment of HER2 Negative Metastatic Breast Cancer Patients

Overview[ - collapse ][ - ]

Purpose 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.
ConditionHER2-negative Metastatic Breast Cancer Patients
InterventionDrug: Metformin + Myocet + Cyclophosphamide
Drug: Myocet + Cyclophosphamide
PhasePhase 2
SponsorIstituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
Responsible PartyIstituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
ClinicalTrials.gov IdentifierNCT01885013
First ReceivedJune 19, 2013
Last UpdatedJune 21, 2013
Last verifiedJune 2013

Tracking Information[ + expand ][ + ]

First Received DateJune 19, 2013
Last Updated DateJune 21, 2013
Start DateSeptember 2010
Estimated Primary Completion DateApril 2014
Current Primary Outcome Measuresprogression-free survival (PFS) [Time Frame: 42 months] [Designated as safety issue: No]Clinical efficacy of the combination of Myocet / Cyclophosphamide plus Metformin compared to treatment with only Myocet / Cyclophosphamide, in terms of progression-free survival (PFS)
Current Secondary Outcome Measures
  • Objective response rate [Time Frame: 42 months] [Designated as safety issue: No]Objective Response Rate after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide
  • Overall survival [Time Frame: 42 months] [Designated as safety issue: No]Overall survival after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide
  • Progression free survival as function of Homa Index levels [Time Frame: 42 months] [Designated as safety issue: No]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
  • objective response rate as function of Homa Index levels [Time Frame: 42 months] [Designated as safety issue: No]Objective Response Rate after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide, as function of Homa Index levels
  • overall survival as function of Homa Index levels [Time Frame: 42 months] [Designated as safety issue: No]Overall survival after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide, as function of Homa Index levels
  • patient metabolic profile (metabolic syndrome) [Time Frame: 42 months] [Designated as safety issue: No]Characterization of the metabolic profile of patients: sensitivity in insulin levels

Descriptive Information[ + expand ][ + ]

Brief TitleStudy of Myocet Plus Cyclophosphamide Plus Metformin Versus Myocet Plus Cyclophosphamide in First Line Treatment of HER2 Negative Metastatic Breast Cancer Patients
Official TitleMYME: PHASE II COMPARATIVE STUDY OF MYOCET PLUS CYCLOPHOSPHAMIDE PLUS METFORMIN VERSUS MYOCET PLUS CYCLOPHOSPHAMIDE IN FIRST LINE TREATMENT OF HER2 NEGATIVE METASTATIC BREAST CANCER PATIENTS
Brief Summary
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.
Detailed DescriptionNot Provided
Study TypeInterventional
Study PhasePhase 2
Study DesignAllocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
ConditionHER2-negative Metastatic Breast Cancer Patients
InterventionDrug: Metformin + Myocet + Cyclophosphamide
Drug: Myocet + Cyclophosphamide
Study Arm (s)
  • Experimental: 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.
  • Active Comparator: 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

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment112
Estimated Completion DateApril 2014
Estimated Primary Completion DateApril 2014
Eligibility 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.
GenderFemale
Ages18 Years
Accepts Healthy VolunteersNo
ContactsContact: Oriana Nanni, PhD
+390543739266
o.nanni@irst.emr.it
Location CountriesItaly

Administrative Information[ + expand ][ + ]

NCT Number NCT01885013
Other Study ID NumbersIRST174.04
Has Data Monitoring CommitteeNo
Information Provided ByIstituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
Study SponsorIstituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
CollaboratorsNot Provided
Investigators Not Provided
Verification DateJune 2013

Locations[ + expand ][ + ]

P.O. M. Bufalini
Cesena, FC, Italy
Contact: Marina Faedi, MD
Principal Investigator: Marina Faedi, MD
Recruiting
Irccs Irst
Meldola (FC), FC, Italy, 47014
Contact: Oriana Nanni, PhD | +39 0543739266 | o.nanni@irst.emr.it
Principal Investigator: Dino Amadori, Prof.
Recruiting
Ospedale Civile degli Infermi
Faenza, RA, Italy
Contact: Stefano Tamberi, MD
Principal Investigator: Stefano Tamberi, MD
Recruiting
Ospedale Umberto I
Lugo, RA, Italy
Contact: Giorgio Cruciani, MD
Principal Investigator: Giorgio Cruciani, MD
Recruiting
Ospedale Civile Santa Maria delle Croci
Ravenna, RA, Italy
Contact: Giorgio Cruciani, MD
Principal Investigator: Giorgio Cruciani, MD
Recruiting
ULSS n.8 Asolo Ospedale di Castelfranco
Asolo, Italy
Contact: Paolo Manente, MD
Principal Investigator: Paolo Manente, MD
Recruiting
Centro di Riferimento Oncologico CRO
Aviano, Italy
Contact: Andrea Freschi, MD
Principal Investigator: Andrea Freschi, MD
Recruiting
Ospedale S.Martino
Belluno, Italy
Contact: Petros Giovanis, MD
Principal Investigator: Petros Giovanis, MD
Recruiting
Azienda Ospedaliera "Antonio Cardarelli"
Campobasso, Italy
Contact: Francesco Carrozza, MD
Principal Investigator: Francesco Carrozza, MD
Recruiting
P.O. "SS. Annunziata"
Chieti, Italy
Contact: Stefano Iacobelli, MD
Principal Investigator: Stefano Iacobelli, MD
Recruiting
Presidio Ospedaliero E. Profili
Fabriano, Italy
Contact: Rosa Rita Silva, MD
Principal Investigator: Rosa Rita Silva, MD
Recruiting
E.O. Galliera
Genova, Italy
Contact: Alessandra Gennari, MD
Principal Investigator: Alessandra Gennari, MD
Recruiting
Ospedale di Guastalla
Guastalla, Italy
Contact: Laura Scaltriti, MD
Principal Investigator: Laura Scaltriti, MD
Recruiting
Azienda per i Servizi Sanitari n.5 "Bassa Friulana"
Latisana, Italy
Contact: Aldo Iop, MD
Principal Investigator: Aldo Iop, MD
Recruiting
Presidio Ospedaliero "Vito Fazzi"
Lecce, Italy
Contact: Mariangela Ciccarese, MD
Principal Investigator: Mariangela Ciccarese, MD
Recruiting
ULSS n.13 di Mirano
Mirano, Italy
Contact: Mario Bari, MD
Principal Investigator: Mario Bari, MD
Recruiting
Arcispedale S. Maria Nuova
Modena, Italy
Contact: Massimo Federico, MD
Principal Investigator: Massimo Federico, MD
Recruiting
Azienda Ospedaliera S. Salvatore di Pesaro
Pesaro, Italy
Contact: Virginia Casadei, MD
Principal Investigator: Virginia Casadei, MD
Recruiting
Ospedale S. Spirito
Pescara, Italy
Contact: Marco Lombardo, MD
Principal Investigator: Marco Lombardo, MD
Recruiting
Ospedale Civile di Piacenza
Piacenza, Italy
Contact: Luigi Cavanna, MD
Principal Investigator: Luigi Cavanna, MD
Recruiting
Azienda Ospedaliera Santa Maria degli Angeli
Pordenone, Italy
Contact: Silvana Saracchini, MD
Principal Investigator: Silvana Saracchini, MD
Recruiting
Arcispedale S. Maria Nuova
Reggio E,milia, Italy
Contact: Corrado Boni, MD
Principal Investigator: Corrado Boni, MD
Recruiting
Ospedale Civile degli Infermi
Rimini, Italy
Contact: Lorenzo Gianni, MD
Principal Investigator: Lorenzo Gianni, MD
Recruiting
IRCCS Centro di riferimento Oncologico di Basilicata di Rionero in Vulture
Rionero in Vulture, Italy
Contact: Michele Aieta, MD
Principal Investigator: Michele Aieta, MD
Recruiting
Ospedale Nuovo Regina Margherita
Roma, Italy
Contact: Germano Zampa, MD
Principal Investigator: Germano Zampa, MD
Recruiting