Time restricted Eating And Metformin (TEAM) in invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS). A randomized, phase IIb, window of opportunity presurgical trial.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ente Ospedaliero Ospedali Galliera Di Genova

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2024-11-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518402-40-00

EudraCT number

2021-000134-34

ClinicalTrials.gov

NCT05023967

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Primary interim objective: assess the safety of the experimental intervention based on the frequency of occurrence of a Dose Limiting Toxicity (DLT) in the first 14 participants assigned to the experimental treatment arm. A DLT is defined as a hypoglycemic event requiring permanent discontinuation of study treatment or any grade 3 or greater adverse event (AE) possibly, probably, or definitely related to the study drug.
Primary objective: assess the effect of the combination of prolonged nightly fasting (>=16 hours) and Metformin on the change of Ki67 labeling index (LI) in cancer tissue (IBC or DCIS, if IBC is absent) between pre-treatment biopsy and post treatment surgical specimen.
Co-primary objective: evaluate the difference in post-treatment Ki67 LI in cancer adjacent DCIS (in the presence of IBC) or IEN, defined as atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS), between the active treatment and the control group.

Conditions and MedDRA coding

Luminal (ER+ve and/or PgR+ve >=1%) invasive breast cancer or ductal carcinoma in situ

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Women with histologically confirmed ER+ve and/or PgR+ve ≥1% operable IBC (cT1-2, cN0-1, Mx) candidate to elective surgery and not to neo-adjuvant treatment. Women with larger tumors who refuse neo-adjuvant chemotherapy before surgery can also be eligible. ER+ve and/or PgR+ve ≥1% , HER2+ve (cT1, cN0) IBC and DCIS are also eligible.
2. Age ≥ 18 years
3. ECOG performance status ≤1 (Karnofsky ≥70%)
4. Participants must have normal organ and marrow function as defined below: Leukocytes ≥3,000/microliter Absolute neutrophil count ≥1,500/microliter Platelets ≥100,000/microliter AST (SGOT)/ALT (SGPT) ≤1.5 × institutional upper limit of normal Creatinine clearance estimated > 45 mL/min with Cockcroft-Gault formula
5. Female participants of child-bearing potential must agree to use contraception such as barrier method of birth control or abstinence, prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she has to inform her study physician immediately. The effects of Metformin Hydrochloride Extended Release on the developing human fetus at the recommended therapeutic dose are unknown.
6. Ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria 20

1. BMI < 18.5 Kg/m2.
2. Previous treatment for breast cancer including chemotherapy and endocrine therapy within the last 12 months.
3. Women who are planned to receive neoadjuvant therapy
4. Triple negative BC.
5. Patients with history of cancer within the last year. NOTE: Non melanoma skin cancer is allowed.
6. Documented history of symptomatic hypoglycemia.
7. Diabetic patients or participants with fasting glucose level ≥ 126 mg/dL.
8. Known hypersensitivity or intolerance to Metformin Hydrochloride Extended Release.
9. Participants should not be receiving any other investigational agents.
10. 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.
11. History of lactic acidosis.
12. Liver dysfunction including chronic active hepatitis and cirrhosis not compensated.
13. History of vitamin B12 deficiency or megaloblastic anemia.
14. Chronic use of large doses of diuretics (e.g., >80 mg furosemide)
15. Current use of oral hormonal contraceptives or female hormones in the last four weeks or 5 half-lives, excluding vaginal creams and IUDs.
16. Concomitant use of Topiramate or other carbonic anhydrase inhibitors (e.g., Zonisamide, Acetazolamide or Dichlorphenamide)
17. Concomitant use of GLP-1 medications (e.g. liraglutide, semaglutide, etc.).
18. Pregnant or lactating women. Pregnant women are excluded from this study because even though published data from post-marketing studies have not reported a clear association between Metformin Hydrochloride Extended Release and major birth defects, miscarriage, or adverse maternal or fetal outcomes when Metformin Hydrochloride Extended Release was used during pregnancy, these studies cannot definitely establish the absence of any Metformin Hydrochloride Extended Release associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with Metformin Hydrochloride Extended Release, breastfeeding should be discontinued if the mother is treated with Metformin Hydrochloride Extended Release. Moreover, prolonged fasting is not recommended in pregnant woman.
19. Women who practice any type of intermittent fasting program.
20. Women who will not have anyone available to assist them in case of need.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Frequency of occurrence of dose limiting toxicity in the first 14 patients in the experimental arm (interim endpoint); change in pre-post treatment immunohistochemical Ki67 LI in IBC or DCIS (in the absence of IBC) (primary) and difference in post-treatment adjacent DCIS (in the presence of IBC), if present, or IEN (defined as ADH/ALH/LCIS) Ki67 (co-primary) between arms.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ente Ospedaliero Ospedali Galliera Di Genova

Sponsor organisation

Ente Ospedaliero Ospedali Galliera Di Genova

Address

Mura Delle Cappuccine 14

City

Genoa

Postcode

16128

Country

Italy

Scientific contact point

Organisation

Ente Ospedaliero Ospedali Galliera Di Genova

Contact name

Andrea De Censi

Public contact point

Organisation

Ente Ospedaliero Ospedali Galliera Di Genova

Contact name

Andrea De Censi

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications