Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Patients With Brain Metastases (OPTIMAL)

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Status and phase: Unknown; Phase 2

Conditions: Breast Cancer; Brain Metastases; Melanoma; Lung Cancer

Treatments: Drug: Dexamethasone; Drug: Metformin

Study type: Interventional

Funder types: Other

Identifiers

NCT04001725

INT31/19

B43C17000350001 (Other Grant/Funding Number)

2019-000105-73 (EudraCT Number)

Details and patient eligibility

About

This is a monocentric, open label, randomized Phase II study in patients with brain metastasis from melanoma, lung or breast cancer, who require treatment with high-dose dexamethasone, as defined as a minimum of 8 mg daily based on the clinician judgment, for at least three weeks, with or without radiation therapy. The aim is to investigate the metformin efficacy in preventing the onset of glucocorticoid-induced diabetes and other metabolic perturbations in patients with brain metastases from melanoma, lung or breast cancer.

Full description

The study will be conducted in approximately 110 adult patients. aim of the study is to evaluate the effect of oral metformin in preventing GC-induced alterations of systemic metabolism, and in particular GC-induced diabetes. Other clinical objectives of the study consist in investigating the impact of metformin on precocious mortality, deterioration of ECOG PS and local (brain) disease control rate at one month. As an exploratory analysis, the effect of dexamethasone plus/minus metformin on other metabolites or growth factors (including amino acids, fatty acids, ketone bodies, IGF-1), as well as on the number, activation status and metabolism of peripheral blood immune cell populations will be evaluated

Enrollment: 110 estimated patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Age ≥ 18 years and ≤ 75 years

2. Histologically confirmed diagnosis of melanoma, lung (SCLC or NSCLC) or breast cancer

3. Recent (28 days), radiologically documented (contrast-enhanced CT or MRI) diagnosis of measurable brain metastases requiring treatment with high-dose dexamethasone (at least 8 mg daily for at least 21 days) plus/minus radiation therapy (RT).

4. Any previous or ongoing antitumor systemic therapy; patients who have never received previous systemic therapy can be also included.

5. Fasting glycemia < 126 mg/dl at the baseline evaluation or random glycemia of less than 200 mg/dl if the patient has not fasted for at least 8 hours before blood sampling.

6. Adequate blood tests:

   • Hemoglobin ≥ 9 g/dl
   • Absolute neutrophil count (ANC) in the range between 1.5-10 x 103/μl
   • Total bilirubin ≤ 1.5 times the upper normal limit (UNL). For patients with Gilbert syndrome or known liver metastases, bilirubin levels ≤ 3 times the UNL are considered acceptable
   • AST, ALT ≤ 3 times the UNL
   • Alkaline phosphatase ≤ 2.5 times the UNL
   • Serum creatinine concentration ≤ 1.5 x UNL

7. ECOG Performance Status ≤ 2

8. Life expectancy > 6 weeks

9. Written informed consent

10. Ability to swallow metformin tablets

11. Patients of female gender with the potential of childbearing (neither surgically sterile nor 2 years postmenopausal) must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for at least 60 days after study conclusion. Acceptable methods of contraception include double barrier method [i.e. condom and occlusive cap (diaphragm or cervical vault caps)] spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, or injected) in conjunction with a barrier method.

12. Patients of male gender having female partners with childbearing potential must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 60 days after participation in the study

Exclusion criteria

1. Leptomeningeal carcinomatosis, either radiologically documented or cytologically confirmed
2. History of brain metastases
3. Diagnosis of other malignancies in the last 5 years, except for superficial, radically treated basal cell carcinomas of the skin or in situ carcinomas of the cervix
4. Previous or current use of metformin
5. Ongoing therapy with systemic glucocorticoids at a dosage that is higher than 10 mg prednisone equivalent. Previous GC treatment is allowed if stopped at least 2 months before enrollment. Inhaled or topical steroids are permitted.
6. Diagnosis of Type 1 or Type 2 diabetes mellitus
7. Known history of HBV- or HCV-related infection
8. Known liver cirrhosis, even in the absence of significant alterations in blood tests
9. Clinically uncontrolled disorders of the lung, kidney, liver or cardio-vascular apparatus
10. Known history of HIV infection
11. Serious neurological or psychiatric disorders
12. Absence of a caregiver for patients with an ECOG performance status of 2
13. Pregnancy or lactation
14. Body mass index < 18.5 kg/m2
15. Past or current alcohol abuse (> 36 grams/day for men and 24grams/day for women)
16. Documented metabolic acidosis from any cause in the last 5 years
17. History of allergy or hypersensitivity to study drug components

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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110 participants in 2 patient groups

A (Dexamethasone)

Active Comparator group

Description:

Patients subjected at a minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route (control arm). The total dose can either administered once a day or through a refracted schedule

Treatment:

Drug: Dexamethasone

B (Dexamethasone and Metformin)

Experimental group

Description:

Patients subjected at a minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route.The total dose can either administered once a day or through a refracted schedule. The same patients subjected at a metformin. Metformin initial dosage will be 850 mg per day, and will be escalated based on patient tolerability up to a maximum of 2550 mg daily (experimental arm).

Treatment:

Drug: Dexamethasone

Drug: Metformin