Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Melanoma, breAst or Lung Cancer Patients With Brain Metastases: the Phase II OPTIMAL Study
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 110
- 试验地点
- 1
- 主要终点
- Metformin in preventing precocious (14 days) dexamethasone-induced diabetes
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
A (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
干预措施: Dexamethasone (Drug)
B (Dexamethasone and 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).
干预措施: Dexamethasone (Drug)
B (Dexamethasone and 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).
干预措施: Metformin (Drug)
结局指标
主要结局
Metformin in preventing precocious (14 days) dexamethasone-induced diabetes
时间窗: 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.
次要结局
- Brain local control rate of disease(30 days)
- Patient ECOG performance status (PS)(30 days)
- Patient Quality of Life (QoL)(30 days)
- Dexamethasone-induced diabetes at 30 days(30 days)
- Short-term mortality(90 days)
- Activation status of immune cell populations(2 years)
- Plasma lipids profile(30 days)
- Systemic inflammatory parameters(2 years)
- GC-induced changes in gut microbiota populations(30 days)
- Metformin-induced changes in gut microbiota populations(30 days)
- Amino acid profile(14 days)
- Absolute counts of immune cell populations(2 years)
- Relative counts of immune cell populations(2 years)
研究者
Filippo de Braud
Professor
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano