A Study of Liposomal Doxorubicin+Docetaxel+Trastuzumab+Metformin in Operable and Locally Advanced HER2 Positive Breast Cancer (met-HEReMYTA)

Clinical and Translational Phase II Study of Liposomal Doxorubicin Plus Docetaxel and Trastuzumab with Metformin As Primary Systemic Therapy for Operable and Locally Advanced Recombinant Human ErbB-2 (HER2) Positive Breast Cancer

It is a multicenter, open-label, two stage phase II trial, to assess activity, safety and potential early predictors of response in neoadjuvant setting. Patients with operable breast cancer (T1c and cytologically N1-2, or cT2-3, N0-N2, M0) or locally advanced breast cancer (T4a-d, N0-N2, M0) with overexpression or amplification of HER2 (AJCC 7th edition 2010) are included in the study.

The primary objective is to evaluate the pathological complete response rate (pCR).

The secondary objectives are:

• to evaluate the clinical response rate (RR).
• to evaluate the feasibility and systemic tolerance, with particular attention to cardiac toxicity.
• to evaluate the conservative surgery rate.

Total duration of the trial is 36 months; planned treatment are 6 cycles of chemotherapy. At every cycle (every 21 days) will be administered:

Day 1: Liposome-encapsulated doxorubicin, 50 mg/m2 IV 1 hour infusion; Day 2 and 9: Docetaxel, 30 mg/m2 IV 1 hour infusion; Day 2, 9 and 16: Trastuzumab 4 mg/kg for the first infusion loading dose, then 2 mg/kg/week for subsequent injections. Day -13 to 0: Metformin is administered as single agent. From day -13 to day -11, Metformin 1000 mg will be administered once a day; from day -10 Metformin 1000 mg will be administered twice a day continuously until end of the study treatment.

Study Overview

• Status: Completed
• Conditions: HER-2 Positive Breast Cancer
• Intervention / Treatment: Drug: Liposomal doxorubicin; Drug: Docetaxel; Drug: Trastuzumab; Drug: Metformin

Detailed Description

Multi-center, open-label phase II trial to assess activity of this chemotherapy scheme evaluated by pathologic complete response rate (pCR).

Planned treatment are 6 cycles of chemotherapy.

At every cycle (every 21 days) will be administered:

Day 1: Liposome-encapsulated doxorubicin, 50 mg/m2 IV 1 hour infusion; Day 2 and 9: Docetaxel, 30 mg/m2 IV 1 hour infusion; Day 2, 9 and 16: Trastuzumab 4 mg/kg for the first infusion loading dose, then 2 mg/kg/week for subsequent injections Day -13 to 0: Metformin is administered as single agent. From day -13 to day -11, Metformin 1000 mg will be administered once a day; from day -10 Metformin 1000 mg will be administered twice a day continuously until end of the study treatment.

Total duration of the trial: 36 months Enrollment period: 24 months Treatment: maximum of 6 cycles (5 months) per patient Follow-up for recurrence: every six months for 5 years, than once a year until 10 years after surgery.It's necessary to recruit 46 patients for clinical objectives evaluation.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Guastalla, Italy, 42016
    • Day Hospital Oncologico, Ospedale Guastalla
  • Imola, Italy, 40133
    • Oncologia Medica AUSL Imola
  • Parma, Italy, 43100
    • Oncologia Medica AOU Parma
  • FC
    • Meldola, FC, Italy, 47014
      • IRST Oncologia medica
  • FE
    • Ferrara, FE, Italy, 44124
      • Oncologia Medica AOU Ferrara
  • MO
    • Modena, MO, Italy, 41100
      • Oncologia Medica, Policlinico di Modena
  • PC
    • Piacenza, PC, Italy, 29121
      • Oncologia Medica Ospedale Guglielmo da Saliceto
  • RE
    • Reggio Emilia, RE, Italy, 42123
      • Oncologia , IRCCS azienda ospedaliera S.Maria Nuova
  • RN
    • Rimini, RN, Italy, 47923
      • U.O Oncologia AUSLdella Romagna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have histologically confirmed breast cancer
• HER2 overexpressing cancer
• Patients with operable breast cancer (T1c and cytologically N1-2, or cT2-3, N0-N2, M0) or locally advanced breast cancer (T4a-d, N0-N2, M0) (AJCC 7th edition 2010).
• No prior therapy for breast cancer
• Both sexes, age ≥ 18 years and < 75 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Life expectancy > 3 months
• Neutrophil count ≥ 2 x 109/ L, leukocytes count ≥ 3 x 109/ L and platelet count ≥ 100 x 109/ L
• Total bilirubin ≤ 1 upper-normal limits (UNL) of the Institutional normal values and alanine aminotransferase (ASAT (GOT) and/or alanine aminotransferase ALAT (GPT) ≤ 2.5 UNL, alkaline phosphatase ≤ 5 UNL. Patients with ASAT and/or ALAT > 1.5 UNL and alkaline phosphatase > 2.5 UNL aren't eligible for the trial.
• Creatinine ≤ 1.5 mg/dL
• Left ventricular ejection fraction (LVEF) ≥ 50% (evaluated by echocardiogram or multiple gated acquisition scan (MUGA) scan -only one method must be employed for each patient)
• Written informed consent
• Homa Index calculated using the Matthews'formula

EXCLUSION CRITERIA:

• Prior chemotherapy or radiotherapy for breast cancer.
• History of prior malignancy in the last 10 years (other than non-melanoma skin cancer or excised cervical carcinoma in situ).
• Other serious illness or medical condition
• Congestive heart failure or angina pectoris even if medically controlled. Previous history of myocardial infarction, uncontrolled high risk hypertension or arrhythmia
• History of significant neurologic or psychiatric disorders including dementia or seizures
• Active infection
• Concurrent treatment with other experimental drugs.
• Participation in another clinical trial with any investigational agents within 30 days prior to study screening.
• Geographic inaccessibility to treatment and followup
• Pregnant and lactating women
• Diabetes-insulin dependant and non-insulin dependant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Liposomal doxorubicin +Docetaxel+Trastuzumab+Metformin; Day 1: Liposome-encapsulated doxorubicin, 50 mg/m2 IV 1 hour infusion; Day 2 and 9: Docetaxel, 30 mg/m2 IV 1 hour infusion; Day 2, 9 and 16: Trastuzumab 4 mg/kg for the first infusion loading dose, then 2 mg/kg/week for subsequent injections. Day -13 to 0: Metformin is administered as single agent. From day -13 to day -11, Metformin 1000 mg will be administered once a day; from day -10 Metformin 1000 mg will be administered twice a day continuously until end of the study treatment.

Drug: Liposomal doxorubicin; 50 mg/m2 by intravenous infusion over a period of 1 hour on day 1 of each cycle repeated every 21 days. A final concentration of between 0.4 to 1.2 mg/ml doxorubicin hydrochloride, is required; Other Names: Myocet®; Drug: Docetaxel; 30 mg/m2 by intravenous infusion over a period of 1 hour on day 2 and 9, every 3 week.They will be given for 6 cycles.; Other Names: taxotere; Drug: Trastuzumab; 4 mg/kg for the first administration (day 2 cycle 1) and 2 mg/kg for subsequent administrations. Trastuzumab will be given weekly for the duration of chemotherapy (day 2, 9, 16), then will be administered at the dose of 6 mg/Kg every 3 weeks until completion of 52 weeks of treatment.; Other Names: herceptin; Drug: Metformin; It is administered as single agent from day -13 to 0. From day -13 to day -11, Metformin 1000 mg will be administered once a day; from day -10, Metformin 1000 mg will be administered twice a day continuously until end of the study treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic complete response rate(pCR)	Complete pathologic response will be defined as no invasive residuals in breast and axillary nodes. In situ tumor residuals are considered as complete response rate	up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clinical response rate (RR)	The clinical response rate (RR) will be including Pathological Complete Response, Clinical Complete Response and Clinical Partial Response (Response Evaluation Criteria in Solid Tumors (RECIST) criteria).	up to 36 months
evaluation of toxicity	All patients will be evaluable for toxicity from the time of their first treatment with Metformine. The toxicity will be recorded according to the CTC-AE, version 4.0 in the safety population until Follow-up is completed (36 months)	up to 36 months
conservative surgery rate	evaluation of the number of patients who underwent conservative surgery	up to 36 months

Collaborators and Investigators

• Sponsor: Istituto Romagnolo per lo Studio dei Tumori Dino Amadori IRST S.r.l. IRCCS
• Investigators: Principal Investigator: Anna Fedeli, MD, IRST IRCCS, Meldola-Cesena

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2014
• Primary Completion (Actual): October 1, 2018
• Study Completion (Actual): March 17, 2020

Study Registration Dates

• First Submitted: June 17, 2015
• First Submitted That Met QC Criteria: June 30, 2015
• First Posted (Estimated): July 2, 2015

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 30, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: pCR; locally advanced breast cancer; HER-2 Positive Breast Cancer; operable breast cancer; no prior therapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; Enzyme Inhibitors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Topoisomerase Inhibitors; Topoisomerase II Inhibitors; Docetaxel; Trastuzumab; Metformin; Doxorubicin; Liposomal doxorubicin
• Other Study ID Numbers: IRST174.09