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

Phase 2

• Conditions: Brain Metastases; Melanoma; Lung Cancer; Breast Cancer
• Interventions: Drug: Dexamethasone; Drug: Metformin

• Registration Number: NCT04001725
• Lead Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Brief Summary

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.

Detailed 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

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2019-06-04
• Study First Submitted QC: 2019-06-26
• Study First Posted: 2019-06-28
• Study Start: 2019-10-15
• Status Verified: 2019-11
• Last Update Submitted: 2019-11-10
• Last Update Posted: 2019-11-13
• Primary Completion: 2021-12-31
• Study Completion: 2022-03-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 110

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
A (Dexamethasone)	Dexamethasone	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
B (Dexamethasone and Metformin)	Dexamethasone	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).
B (Dexamethasone and Metformin)	Metformin	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).

Primary Outcome Measures

Name	Time	Method
Metformin in preventing precocious (14 days) dexamethasone-induced diabetes	14 days	To evaluate the efficacy of metformin in preventing precocious (14 days) dexamethasone-induced diabetes, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast cancer.

Secondary Outcome Measures

Name	Time	Method
Patient Quality of Life (QoL)	30 days	Patient QoL will be evaluated through the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) C-30 version 3.0. The EORTC QLQ.C30 instrument will be scored according to the EORTC guidelines.
Brain local control rate of disease	30 days	To evaluate the efficacy of metformin in modifying the local disease control rate (brain) in patients treated with radiation therapy (RT) plus dexamethasone at 1 month
Patient ECOG performance status (PS)	30 days	To test the impact of metformin on precocious modifycation of patient ECOG Performance Status (PS) at 1 month after initiation of dexamethasone therapy.
Dexamethasone-induced diabetes at 30 days	30 days	To study the efficacy of metformin in preventing dexamethasone-induced diabetes at 7 and 30 days after dexamethasone initiation, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast
Short-term mortality	90 days	To evaluate the efficacy of metformin in modifying short-term mortality (3 months) in patients taking high-dose dexamethasone
Activation status of immune cell populations	2 years	To investigate the potential impact of metformin on activated antitumor lymphocytes
Plasma lipids profile	30 days	To study the effect of metformin in modifying the plasma lipid profile at 30 days after treatment initiation
Systemic inflammatory parameters	2 years	To investigate the effect of metformin on systemic plasma cytokines (G-CSF, GM-CSF, CCL2, VEGFA)
GC-induced changes in gut microbiota populations	30 days	To evaluate the impact of high-dose GCs on gut microbiota populations (30 days)
Metformin-induced changes in gut microbiota populations	30 days	To evaluate the impact of metformin on gut microbiota populations (30 days)
Amino acid profile	14 days	To study the effect of metformin in modifying the plasma amino acid profile at 14 days after treatment initiation
Absolute counts of immune cell populations	2 years	To investigate the potential impact of metformin on absolute counts of immune cell populations
Relative counts of immune cell populations	2 years	To investigate the potential impact of metformin on relative counts and activation status of activated antitumor lymphocytes

Trial Locations

Locations (1)

Fondazione IRCCS Istituto Nazionale dei Tumori; 🇮🇹 Milan, Italy