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

Human Epidermal Growth Factor 2 Negative Carcinoma of Breast Clinical Trial

— MYME  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01885013
• Other study ID #: IRST174.04
• Secondary ID: 2009-014662-26
• Status: Completed
• Phase: Phase 2
• First received: June 19, 2013
• Last updated: December 31, 2015
• Start date: September 2010
• Est. completion date: May 2015

Study information

• Verified date: December 2015
• Source: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 126
• Est. completion date: May 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 75 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Human Epidermal Growth Factor 2 Negative Carcinoma of Breast

Intervention

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.
• 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

Locations

Country	Name	City	State
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. M. Bufalini	Cesena	FC
Italy	P.O. "SS. Annunziata"	Chieti
Italy	Presidio Ospedaliero E. Profili	Fabriano
Italy	Ospedale Civile degli Infermi	Faenza	RA
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	Ospedale Umberto I	Lugo	RA
Italy	UO Oncologia Medica IRCCS IRST	Meldola (FC)	FC
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	Ospedale Civile Santa Maria delle Croci	Ravenna	RA
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

Sponsors (1)

Lead Sponsor	Collaborator
Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Objective response rate	Objective Response Rate after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide	42 months	No
Secondary	Overall survival	Overall survival after treatment with Myocet/Cyclophosphamide/Metformin compared with after therapy with Myocet/Cyclophosphamide	42 months	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	patient metabolic profile (metabolic syndrome)	Characterization of the metabolic profile of patients: sensitivity in insulin levels	42 months	No