Effect of the Addition of Metformin Hydrochloride on the Prognosis of Patients With B-cell Precursor (Ph+ Negative) Acute Lymphoblastic Leukemia With High Expression of ABCB1 Gene
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 102
- 主要终点
- Effect of Metformin on first line treatment Refractoriness in high risk failure ALL patients
研究概览
简要总结
Metformin's Antitumor activity were identified from differens diabetic patients trials, mainly associated to its mechanism of action and protein - kinase AMPK (AMP-activated protein kinase) activation. According to Cancer and Diabetes International Consensus from 2012, diabetes increases the risk for developping cancer and metformin has an protector effect against cancer cells and has an impact on overall survival.
Chemotherapy drug resistance induces treatment fail in oncology. Metformin increases AMPK levels, blocks PI3K (phosphatidylinositol 3- kinase)/ AKT /mTOR(mammailian Target of Rapamycin) pathway but few evidence associated with drug resistance gene expression.
This is an, experimental one-center study that pretends to stablish the effect of adding metformin 850 mg PO three times a day over the multi-drug resistance gene expression (ABCB1) in de novo Acute Lymphoblastic Leukemia in one 7-days cycle with prednisone as pre-treatment- and on the induction remission treatment.
详细描述
The MDR (Multidrug-Resistance) Genes are implicated on the resistance of several types of cancer. The most important on leukemia are the ABCB1 and ABCG2- ABCB1 are implicated on resistance and severity on Acute Myeloid Leukemia and pediatric Acute Lymphoblastic Leukemia. Those transporters use ATP for use. Metformin decrease the intracellular ATP (Adenosine triphosphate) reserve the by the activation of AMPK. Recently on MCF7-Adr (Michigan Cancer Foundation 7, breast cancer cell line) cancer cell line, Metformin block the function of the P-glycoprotein by the inhibition of the Nuclear Factor -kappa-B.
The clinical evidence at this moment is limited, based on small clinical trials or observational studies. This study tries to evaluate the effect of the addition of Metformin to a standard chemotherapy regimen on patients who express high levels of expression of mRNA (messenger ribonucleic acid) ABCB1
Experimental protocol
The patients will be stratified on three groups: The high-expression, low expression and absent gene expression according the level mRNA of ABCB1 at diagnostic. The samples are obtained from mononuclear peripheral blood cells
Extraction of total RNA Total RNA was isolated by TRIzol® (Invtirogen Life Technologies) according to the manufacturer´s recomendations described by Chomczynski and Sacchi.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •> 18 years
- •de novo B-cell precursor Acute Lymphoblastic Leukemia
- •candidates to first line treatment protocol
- •ECOG (Eastern Cooperative Oncology Group) Scale of Performance Status 1/2
- •Informed Consent Form for genetic analysis samples
- •Precursor B Cell Acute Lymphoblastic Leukemia
排除标准
- •Diagnose of Acute Myelogenous Leukemia or Biphenotype Leukemia
- •Diagnose of type 2 Diabetes Mellitus
- •Previous use of Metformin
- •Relapsed Acute Leukemia that require treatment protocol to be started
- •Intolerance to prednisone
- •ECOG Scale of Performance Status 3/4
- •T-cell Acute Lymphoblastic Leukemia
- •Philadelphia positive Acute Lymphoblastic Leukemia
- •Tumor lysis syndrome at diagnose
- •Renal Failure (creatinine leve higher than 2mg/dl)
- •Several liver damage (>2 levels de upper normal limit of Aspartate transaminase (AST) and alanine transaminase (ALT)
- •Metabolic Acidosis or Lactic Acidosis at diagnose
- •Central nervous system infiltration at diagnose
- •Extramedullary disease (skin, pleura,eye)
- •Active GI bleeding
研究组 & 干预措施
metformin
Metformin 850mg PO three times a day, during the pre-induction with steroids, induction remission, consolidation and maintenance
干预措施: Metformin (Drug)
结局指标
主要结局
Effect of Metformin on first line treatment Refractoriness in high risk failure ALL patients
时间窗: 28 day induction remission treatment
Effect on the refractoriness frequency in high risk failure patients (High levels of ABCB1)
Effect of Metformin on relapse rate and survival of high risk failure ALL patients
时间窗: 12 months of follow up
Effect of Metformin on Relapse Free Survival (RFS) on patients with high risk failure (high levels of ABCB1 gene )
次要结局
未报告次要终点
研究者
Christian Ramos Penafiel
Principal Investigator
Hospital General de Mexico