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

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

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.

Study Overview

• Status: Completed
• Conditions: Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
• Intervention / Treatment: Drug: Metformin + Myocet + Cyclophosphamide; Drug: Myocet + Cyclophosphamide

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
• Enrollment (Actual): 126
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Publications and helpful links

General Publications

• Gennari A, Foca F, Zamarchi R, Rocca A, Amadori D, De Censi A, Bologna A, Cavanna L, Gianni L, Scaltriti L, Rossi E, Facchinetti A, Martini V, Bruzzi P, Nanni O. Insulin-like growth factor-1 receptor (IGF-1R) expression on circulating tumor cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial. Breast Cancer Res Treat. 2020 May;181(1):61-68. doi: 10.1007/s10549-020-05596-4. Epub 2020 Mar 21.

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (ACTUAL): May 1, 2015
• Study Completion (ACTUAL): May 1, 2015

Study Registration Dates

• First Submitted: June 19, 2013
• First Submitted That Met QC Criteria: June 21, 2013
• First Posted (ESTIMATE): June 24, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): January 1, 2016
• Last Update Submitted That Met QC Criteria: December 31, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: HER2 negative; metastatic breast cancer; non endocrine responsive disease
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Metformin; Doxorubicin
• Other Study ID Numbers: IRST174.04; 2009-014662-26 (EUDRACT_NUMBER)