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

Sponsor

Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori (Other)

Overall Status

Completed

CT.gov ID

NCT02488564

Collaborator

(none)

Enrollment

Locations

Arm

63.5

Actual Duration (Months)

5.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
HER-2 Positive Breast Cancer	Drug: Liposomal doxorubicin Drug: Docetaxel Drug: Trastuzumab Drug: Metformin	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

49 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 17, 2014

Actual Primary Completion Date :

Oct 1, 2018

Actual Study Completion Date :

Apr 1, 2020

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

Pathologic complete response rate(pCR) [up to 36 months]
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

Secondary Outcome Measures

clinical response rate (RR) [up to 36 months]
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).
evaluation of toxicity [up to 36 months]
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)
conservative surgery rate [up to 36 months]
evaluation of the number of patients who underwent conservative surgery

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	IRST Oncologia medica	Meldola	FC	Italy	47014
2	Oncologia Medica AOU Ferrara	Ferrara	FE	Italy	44124
3	Oncologia Medica, Policlinico di Modena	Modena	MO	Italy	41100
4	Oncologia Medica Ospedale Guglielmo da Saliceto	Piacenza	PC	Italy	29121
5	Oncologia , IRCCS azienda ospedaliera S.Maria Nuova	Reggio Emilia	RE	Italy	42123
6	U.O Oncologia AUSLdella Romagna	Rimini	RN	Italy	47923
7	Day Hospital Oncologico, Ospedale Guastalla	Guastalla		Italy	42016
8	Oncologia Medica AUSL Imola	Imola		Italy	40133
9	Oncologia Medica AOU Parma	Parma		Italy	43100