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

Study Overview
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Brief Summary
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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
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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

Official Title
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Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Melanoma, breAst or Lung Cancer Patients With Brain Metastases: the Phase II OPTIMAL Study

Conditions
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Brain Metastases, Melanoma, Lung Cancer, Breast Cancer

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years and ≤ 75 years Histologically confirmed diagnosis of melanoma, lung (SCLC or NSCLC) or breast cancer 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). Any previous or ongoing antitumor systemic therapy; patients who have never received previous systemic therapy can be also included. 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. 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 ECOG Performance Status ≤ 2 Life expectancy > 6 weeks Written informed consent Ability to swallow metformin tablets 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. 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: Leptomeningeal carcinomatosis, either radiologically documented or cytologically confirmed History of brain metastases 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 Previous or current use of metformin 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. Diagnosis of Type 1 or Type 2 diabetes mellitus Known history of HBV- or HCV-related infection Known liver cirrhosis, even in the absence of significant alterations in blood tests Clinically uncontrolled disorders of the lung, kidney, liver or cardio-vascular apparatus Known history of HIV infection Serious neurological or psychiatric disorders Absence of a caregiver for patients with an ECOG performance status of 2 Pregnancy or lactation Body mass index < 18.5 kg/m2 Past or current alcohol abuse (> 36 grams/day for men and 24grams/day for women) Documented metabolic acidosis from any cause in the last 5 years History of allergy or hypersensitivity to study drug components

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible patients will be randomized in a 1:1 ratio. Randomization will be stratified by means of minimization technique according to the following factors: primary tumor (melanoma versus lung versus breast cancer), dexamethasone dosage (8-12 mg vs >12 mg daily), baseline (pre-enrollment) fasting glycemia (< 100 versus 100-125 mg/dl). Patients randomized to the experimental arm will discontinue metformin after 30 days, unless diabetes has developed in the meanwhile and the physician believes that metformin is still required for its management. Patients randomized to the control arm who develop steroid-induced diabetes will be prescribed metformin, unless contraindicated, as the preferred therapy option for the management of hyperglycemia. In both treatment arms, dexamethasone will be administered until necessary and at the required dosage in the judgment of the treating physician.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A (Dexamethasone)<br>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 | Drug: Dexamethasone<br>* A minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day.<br>|
| Experimental: B (Dexamethasone and Metformin)<br>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). | Drug: Dexamethasone<br>* A minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day.<br>Drug: Metformin<br>* A minimum daily dosage of Dexamethasone 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day and 2550 mg daily (maximum dose), oral administration (OS) of Metformin; starting dose will be 850 mg/day, to be progressively increased to 1700 mg/day on day 4 and 2550 mg/day on day 7, if well tolerated.<br>* Other names: METFORAL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metformin in preventing precocious (14 days) dexamethasone-induced diabetes | 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. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dexamethasone-induced diabetes at 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 | 30 days | 
| Short-term mortality | To evaluate the efficacy of metformin in modifying short-term mortality (3 months) in patients taking high-dose dexamethasone | 90 days | 
| Brain local control rate of disease | 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 | 30 days | 
| Patient ECOG performance status (PS) | To test the impact of metformin on precocious modifycation of patient ECOG Performance Status (PS) at 1 month after initiation of dexamethasone therapy. | 30 days | 
| Patient Quality of Life (QoL) | 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. | 30 days | 
| Absolute counts of immune cell populations | To investigate the potential impact of metformin on absolute counts of immune cell populations | 2 years | 
| Relative counts of immune cell populations | To investigate the potential impact of metformin on relative counts and activation status of activated antitumor lymphocytes | 2 years | 
| Activation status of immune cell populations | To investigate the potential impact of metformin on activated antitumor lymphocytes | 2 years | 
| Plasma lipids profile | To study the effect of metformin in modifying the plasma lipid profile at 14 days after treatment initiation | 14 days | 
| Plasma lipids profile | To study the effect of metformin in modifying the plasma lipid profile at 30 days after treatment initiation | 30 days | 
| Systemic inflammatory parameters | To investigate the effect of metformin on systemic plasma cytokines (G-CSF, GM-CSF, CCL2, VEGFA) | 2 years | 
| GC-induced changes in gut microbiota populations | To evaluate the impact of high-dose GCs on gut microbiota populations (30 days) | 30 days | 
| Metformin-induced changes in gut microbiota populations | To evaluate the impact of metformin on gut microbiota populations (30 days) | 30 days | 
| Amino acid profile | To study the effect of metformin in modifying the plasma amino acid profile at 14 days after treatment initiation | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metformin, Dexamethasone, Diabetes, Glucocorticoids, Phase II, Tumor, Immune system, Immunological Effects, Metabolic Effects, Anticancer Effects, Randomization, Quality of Life