Clinical trial NCT01885013: Myocet + Cyclophosphamide + Metformin Vs Myocet + Cyclophosphamide in 1st Line Treatment of HER2 Neg. Metastatic Breast Cancer Patients
Official title: Phase II Comparative Study of Myocet Plus Cyclophosphamide in First Line Treatment of HER2 Negative Metastatic Breast Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
Keywords: HER2 negative
metastatic breast cancer
non endocrine responsive disease
Lead sponsor: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS
Sponsor class: OTHER
First posted: 2013-06-24
Enrollment: 126
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

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.

Primary outcomes:
measure: progression-free survival (PFS)
timeFrame: 42 months
Secondary outcomes:
measure: Objective response rate
timeFrame: 42 months
measure: Overall survival
timeFrame: 42 months
measure: Progression free survival as function of Homa Index levels
timeFrame: 42 months
measure: objective response rate as function of Homa Index levels
timeFrame: 42 months
measure: overall survival as function of Homa Index levels
timeFrame: 42 months
measure: patient metabolic profile (metabolic syndrome)
timeFrame: 42 months
Other outcomes:
Locations:
city: Cesena
country: Italy
facility: P.O. M. Bufalini
state: FC
city: Meldola (FC)
country: Italy
facility: UO Oncologia Medica IRCCS IRST
state: FC
city: Faenza
country: Italy
facility: Ospedale Civile degli Infermi
state: RA
city: Lugo
country: Italy
facility: Ospedale Umberto I
state: RA
city: Ravenna
country: Italy
facility: Ospedale Civile Santa Maria delle Croci
state: RA
city: Asolo
country: Italy
facility: ULSS n.8 Asolo Ospedale di Castelfranco
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico CRO
city: Belluno
country: Italy
facility: Ospedale S.Martino
city: Campobasso
country: Italy
facility: Azienda Ospedaliera "Antonio Cardarelli"
city: Chieti
country: Italy
facility: P.O. "SS. Annunziata"
city: Fabriano
country: Italy
facility: Presidio Ospedaliero E. Profili
city: Genova
country: Italy
facility: E.O. Galliera
city: Guastalla
country: Italy
facility: Ospedale di Guastalla
city: Latisana
country: Italy
facility: Azienda per i Servizi Sanitari n.5 "Bassa Friulana"
city: Lecce
country: Italy
facility: Presidio Ospedaliero "Vito Fazzi"
city: Mirano
country: Italy
facility: ULSS n.13 di Mirano
city: Modena
country: Italy
facility: Arcispedale S. Maria Nuova
city: Pesaro
country: Italy
facility: Azienda Ospedaliera S. Salvatore di Pesaro
city: Pescara
country: Italy
facility: Ospedale S. Spirito
city: Piacenza
country: Italy
facility: Ospedale Civile di Piacenza
city: Pordenone
country: Italy
facility: Azienda Ospedaliera Santa Maria degli Angeli
city: Reggio Emilia
country: Italy
facility: Arcispedale S. Maria Nuova
city: Rimini
country: Italy
facility: Ospedale Civile degli Infermi
city: Rionero in Vulture
country: Italy
facility: IRCCS Centro di riferimento Oncologico di Basilicata di Rionero in Vulture
city: Roma
country: Italy
facility: Ospedale Nuovo Regina Margherita
Study officials:
affiliation: IRST IRCCS, Meldola
name: Dino Amadori, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.