Clinical trial NCT04001725: Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Patients With Brain Metastases
Official title: Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Melanoma, breAst or Lung Cancer Patients With Brain Metastases: the Phase II OPTIMAL Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Brain Metastases
Melanoma
Lung Cancer
Breast Cancer
Keywords: Metformin
Dexamethasone
Diabetes
Glucocorticoids
Phase II
Tumor
Immune system
Immunological Effects
Metabolic Effects
Anticancer Effects
Randomization
Quality of Life
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor class: OTHER
Collaborators: name: University of Milan
First posted: 2019-06-28
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: PREVENTION

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

Eligibility criteria: 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

Primary outcomes:
measure: Metformin in preventing precocious (14 days) dexamethasone-induced diabetes
timeFrame: 14 days
Secondary outcomes:
measure: Dexamethasone-induced diabetes at 30 days
timeFrame: 30 days
measure: Short-term mortality
timeFrame: 90 days
measure: Brain local control rate of disease
timeFrame: 30 days
measure: Patient ECOG performance status (PS)
timeFrame: 30 days
measure: Patient Quality of Life (QoL)
timeFrame: 30 days
measure: Absolute counts of immune cell populations
timeFrame: 2 years
measure: Relative counts of immune cell populations
timeFrame: 2 years
measure: Activation status of immune cell populations
timeFrame: 2 years
measure: Plasma lipids profile
timeFrame: 14 days
measure: Plasma lipids profile
timeFrame: 30 days
measure: Systemic inflammatory parameters
timeFrame: 2 years
measure: GC-induced changes in gut microbiota populations
timeFrame: 30 days
measure: Metformin-induced changes in gut microbiota populations
timeFrame: 30 days
measure: Amino acid profile
timeFrame: 14 days
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
Study officials:
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
name: Filippo De Braud, Professor
role: PRINCIPAL_INVESTIGATOR
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