Role of Adding Metformin to Neoadjuvant Chemotherapy in Patients With Breast Cancer (METNEO) (METNEO)

Investigation of the Potential Beneficial Effect of Adding Metformin to Neoadjuvant Chemotherapy in Patients With Breast Cancer (METNEO)

Metformin, the widely prescribed oral hypoglycemic drug, is well known for its established efficacy, favorable safety profile, and low cost. Metformin has recently received increasing attention because of its potential antitumorigenic effects that are thought to be independent of its hypoglycemic effects. It has been extensively studied in preclinical models, which have implicated several molecular pathways in its antitumor activity.

Metformin was proved to have anti-proliferative and apoptotic effects on tumor cells.Moreover, metformin enhances the T-cell mediated immune response to tumor tissue and fights metastases. Also, epidemiological studies have shown that metformin, but not other antidiabetic drugs, reduces cancer incidence and improves survivability in diabetic cancer patients.

The proposed research in this application will investigate two prime questions with regards to the combined use of metformin together with traditional neoadjuvant chemotherapy in breast cancer patients. First, the hypothesis that the simultaneous use of metformin along with doxorubicin/cyclophosphamide/paclitaxel neoadjuvant protocol produces better antitumor outcomes will be tested. Second, the study will examine if the improved apoptotic effect of such regimen is paralleled by exaggerated stimulatory influences on apoptosis biomarkers.

Study Overview

• Status: Completed
• Conditions: Breast Cancer Female
• Intervention / Treatment: Drug: Metformin Hydrochloride 850 mg Tablets; Drug: AC-T chemotherapy regimen

Detailed Description

1. Ethical committee approval will be obtained from Ethics committee of Faculty of Pharmacy, Damanhour University.
2. All participants should agree to take part in this clinical study and will provide informed consent.
3. Sixty female breast cancer patients, who are candidates for neoadjuvant chemotherapy, will be recruited from the Medical Research Institute, Oncology department, Alexandria University, Alexandria.

4. The 60 participants will be randomly assigned into 2 arms:

   • Control arm (n=30): will be treated with AC-Taxol regimen (AC: Doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV) for 4 cycles every 3 weeks. Subsequent Taxol cycles (Paclitaxel 80mg/m2 IV) once weekly for 12 weeks.
   • Metformin arm (n=30): will be treated with the AC-Taxol regimen mentioned above together with Metformin 850 mg tablets orally twice per day (1700 mg/day).

5. All patients will be submitted to:

   • Full patient history and clinical examination.
   • Routine follow up before each chemotherapy cycle (complete blood picture, liver function tests, renal function tests).
   • Routine Echocardiography before each chemotherapy cycle.
6. All patients will be monitored for the incidence of chemotherapy toxicities during neoadjuvant therapy.
7. After completion of the neoadjuvant therapy, participants will undergo surgical tumor removal. The excised tumor will be collected, and the expression of apoptosis biomarkers and the pathologic complete response (pCR) will be assessed.
8. Patients demographic data will be recorded with respect to age, weight and disease history.
9. Statistical tests appropriate to the study design will be conducted to evaluate the significance of the results.
10. Results, conclusion, discussion and recommendations will be given.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• Egypt
  • Beheira, Egypt, 22511
    • Damanhour University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Females ≥ 18 years of age and < 65 years.
2. Unilateral or bilateral primary carcinoma of the breast confirmed.
3. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2.
4. Clinically measurable tumor size who are candidates for neoadjuvant therapy.
5. No evidence of distant metastasis.
6. Normal renal and liver functions.
7. Non-diabetics.

Exclusion Criteria:

1. Pregnant or breastfeeding women.
2. Prior cancer chemotherapy.
3. Heart disease or reduced cardiac output with left ventricular ejection fraction < 50%.
4. Metastatic breast cancer patients.
5. Patients with hepatic impairment.
6. Patients with renal impairment.
7. Diabetics.

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 group; Patients will receive AC-T neoadjuvant chemotherapy in addition to oral metformin HCl (850 mg tablets, twice per day, for 6 months) (n= 30)	Drug: Metformin Hydrochloride 850 mg Tablets; Oral administration of Metformin hydrochloride 850 mg tablets (1700 mg/day) daily until the completion of neoadjuvant chemotherapy cycles; Other Names: Cidophage 850 mg; Drug: AC-T chemotherapy regimen; AC: (Doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV) for 4 cycles every 3 weeks followed by Taxol cycles (Paclitaxel 80 mg/m2 IV) once weekly for 12 weeks.; Other Names: AC (doxorubicin [Adriamycin] + cyclophosphamide) followed by paclitaxel (Taxol)
ACTIVE_COMPARATOR: Control group; Patients will receive AC-T neoadjuvant chemotherapy alone (n= 30)	Drug: AC-T chemotherapy regimen; AC: (Doxorubicin 60 mg/m2 IV + cyclophosphamide 600 mg/m2 IV) for 4 cycles every 3 weeks followed by Taxol cycles (Paclitaxel 80 mg/m2 IV) once weekly for 12 weeks.; Other Names: AC (doxorubicin [Adriamycin] + cyclophosphamide) followed by paclitaxel (Taxol)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of the effect on tumor apoptosis	Tissue level of the apoptosis biomarker in the excised tumor.	6 months
Chemotherapy toxicities	Monitoring the incidence of chemotherapy toxicities during neoadjuvant therapy	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic complete response rate (pCR)	Pathologic complete response rate defined as the absence of residual invasive cancer in the resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy.	6 months

Collaborators and Investigators

• Sponsor: Damanhour University
• Collaborators: Alexandria University
• Investigators: Study Director: Mahmoud M El-Mas, PhD, Professor in Pharmacology, Faculty of Pharmacy, Alexandria University; Study Director: Yasser M El-Kerm, PhD, Professor in Clinical Oncology, Medical Research Institute,Alexandria University; Study Chair: Maged W Helmy, PhD, Professor in Pharmacology, Faculty of pharmacy, Damanhour University; Study Chair: Amira B Kassem, PhD, Lecturer in Clinical Pharmacy, Faculty of Pharmacy, Damanhour University; Study Chair: Noha A El-Bassiouny, PhD, Lecturer in Clinical Pharmacy, Faculty of Pharmacy, Damanhour University; Principal Investigator: Manar A Serageldin, Bachelor, Teaching assistant in Pharmacology, Faculty of Pharmacy, Alexandria University

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 29, 2019
• Primary Completion (ACTUAL): April 2, 2022
• Study Completion (ACTUAL): June 28, 2022

Study Registration Dates

• First Submitted: November 18, 2019
• First Submitted That Met QC Criteria: November 18, 2019
• First Posted (ACTUAL): November 20, 2019

Study Record Updates

• Last Update Posted (ACTUAL): September 10, 2022
• Last Update Submitted That Met QC Criteria: September 7, 2022
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: neoadjuvant; Metformin; locally advanced breast cancer
• 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; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Paclitaxel; Metformin; Doxorubicin
• Other Study ID Numbers: 919PP18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Summary of all relevant data will be shared

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No