Intratumoral Extracellular Metabolic Impact of DFMO and AMXT 1501
试验速览
- 阶段
- 早期 1 期
- 状态
- 招募中
- 发起方
- Mayo Clinic
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Change in the tumor/brain extracellular guanidinoacetate ratio
研究概览
简要总结
This early phase I trial studies brain tumor (glioma) metabolism in response to eflornithine (DFMO) and polyamine transport inhibitor AMXT-1501 dicaprate (AMXT 1501) in patients with diffused or high grade glioma. Brain tumors use and produce certain molecules to survive and grow. DFMO is an irreversible inhibitor of ornithine decarboxylase, the enzyme catalyzing polyamine synthesis. AMXT 1501 is a polyamine transport inhibitor which prevents uptake of polyamines from the extracellular environment. This trial is being done to analyze how DFMO and AMXT 1501 affect brain tumor metabolism based on the molecules in the tumor's fluid.
详细描述
PRIMARY OBJECTIVE:
I. Determine how polyamine depletion impacts extracellular guanidinoacetate abundance.
SECONDARY OBJECTIVES:
I. Determine the impact of polyamine depletion on polyamine abundance and the global extracellular metabolome within live human gliomas, in situ.
II. Assess the feasibility of longitudinal microdialysis to evaluate pharmacodynamic responses of in situ gliomas to therapeutic intervention in a post-operative setting.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
盲法说明
The patient and the principal investigator will be blinded to each patient's assignment until after the catheter has been placed. However, the clinical research coordinators and co-investigators will remain unblinded to facilitate study coordination and ensure protocol adherence.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >= 18 years
- •Clinical and radiographic evidence suggesting a diagnosis of a diffuse high grade glioma (HGG), or a prior diagnosis of a diffuse glioma
- •Planned subtotal resection or biopsy due to tumor location, size, or other clinical indication deemed appropriate by the surgeon
- •Provide written informed consent for the current study and the Neuro-Oncology biorepository for archiving of cerebrospinal fluid (CSF) and blood samples collected on this protocol. Willing to remain in the hospital at Mayo Clinic (Rochester, MN) for three days added to their standard post-operative stay to undergo longitudinal microdialysis
- •Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without transfusion within 7 days preceding the lab assessment (obtained =< 14 days prior to registration)
- •Platelet >= 100 x 10^9/L, without transfusion within 7 days preceding the lab assessment (obtained =< 14 days prior to registration)
- •Hemoglobin >= 9 g/dL, without transfusion support within 7 days preceding the lab assessment (obtained =< 14 days prior to registration)
- •Activated partial thromboplastin time or partial thromboplastin time (aPTT or PTT) =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration)
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (obtained =< 14 days prior to registration)
- •Total serum bilirubin =< 1.5 x ULN (obtained =< 14 days prior to registration)
- •The patient is clinically euthyroid [Thyroid Stimulating Hormone (TSH)]
- •Serum creatinine =< 1.5 x ULN or creatinine clearance >= 60 mL/min/1.73 m^2 for patients with serum creatinine levels above 1.5 x ULN (obtained =< 14 days prior to registration)
- •Negative serum or urine pregnancy test is required for female subjects of childbearing age < 14 days prior to registration
排除标准
- •Inappropriate surgical candidates due to current or past medical history or uncontrolled concurrent illness which limits safety of or compliance to study proceedings
- •Vulnerable populations: pregnant or nursing women, prisoners, mentally handicapped
- •Unable to swallow tablets or who are at risk for impaired absorption of oral medication. NOTE: This includes but not limited to, refractory vomiting, gastric resection/bypass, and duodenal/jejunal resection
- •Known hypersensitivity or allergy to DFMO or AMXT 1501
- •Contraindication to MRI or administration of gadolinium
研究组 & 干预措施
Arm I (MRI, resection, DFMO, AMXT 1501)
Patients undergo magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine PO in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Biospecimen Collection (Procedure)
Arm I (MRI, resection, DFMO, AMXT 1501)
Patients undergo magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine PO in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Computed Tomography (Procedure)
Arm I (MRI, resection, DFMO, AMXT 1501)
Patients undergo magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine PO in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Eflornithine (Drug)
Arm I (MRI, resection, DFMO, AMXT 1501)
Patients undergo magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine PO in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm I (MRI, resection, DFMO, AMXT 1501)
Patients undergo magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine PO in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Polyamine Transport Inhibitor AMXT-1501 Dicaprate (Drug)
Arm I (MRI, resection, DFMO, AMXT 1501)
Patients undergo magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine PO in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Resection (Procedure)
Arm I (MRI, resection, DFMO, AMXT 1501)
Patients undergo magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine PO in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Microdialysis (Device)
Arm I (MRI, resection, DFMO, AMXT 1501)
Patients undergo magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine PO in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Placement (Procedure)
Arm II (MRI, resection, placebo, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Biospecimen Collection (Procedure)
Arm II (MRI, resection, placebo, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Computed Tomography (Procedure)
Arm II (MRI, resection, placebo, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Eflornithine (Drug)
Arm II (MRI, resection, placebo, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm II (MRI, resection, placebo, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Polyamine Transport Inhibitor AMXT-1501 Dicaprate (Drug)
Arm II (MRI, resection, placebo, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Resection (Procedure)
Arm II (MRI, resection, placebo, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Microdialysis (Device)
Arm II (MRI, resection, placebo, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Placement (Procedure)
Arm III (MRI, resection, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine PO alone on days 1 and 2 post-surgery, then receive eflornithine PO in combination with AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Biospecimen Collection (Procedure)
Arm III (MRI, resection, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine PO alone on days 1 and 2 post-surgery, then receive eflornithine PO in combination with AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Computed Tomography (Procedure)
Arm III (MRI, resection, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine PO alone on days 1 and 2 post-surgery, then receive eflornithine PO in combination with AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Eflornithine (Drug)
Arm III (MRI, resection, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine PO alone on days 1 and 2 post-surgery, then receive eflornithine PO in combination with AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Arm III (MRI, resection, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine PO alone on days 1 and 2 post-surgery, then receive eflornithine PO in combination with AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Polyamine Transport Inhibitor AMXT-1501 Dicaprate (Drug)
Arm III (MRI, resection, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine PO alone on days 1 and 2 post-surgery, then receive eflornithine PO in combination with AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Resection (Procedure)
Arm III (MRI, resection, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine PO alone on days 1 and 2 post-surgery, then receive eflornithine PO in combination with AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Microdialysis (Device)
Arm III (MRI, resection, DMFO, AMXT 1501)
Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine PO alone on days 1 and 2 post-surgery, then receive eflornithine PO in combination with AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
干预措施: Placement (Procedure)
结局指标
主要结局
Change in the tumor/brain extracellular guanidinoacetate ratio
时间窗: Baseline up to 2 months
Targeted metabolomics will be performed using the microdialysate aliquot collected at each time point to quantify guanidinoacetate content. Fold change values will be calculated between each time point within a patient. Fold changes values between time points will be compared across the three arms for statistically significant differences using a Wilcoxon signed rank test; p \< 0.05 will be considered statistically significant.
次要结局
- Incidence of adverse events(Up to 2 months)
- Measured extracellular levels of glutamate in tumor and brain microdialysates(Up to 2 months)
- Central nervous system free drug levels from microdialysate - DFMO(Up to 2 months)
- Central nervous system free drug levels from microdialysate - AMXT 1501(Up to 2 months)
- AMXT 1501 brain/plasma ratio over time(Up to 2 months)
- Proportion of longitudinal microdialysis aliquots containing > 30 uL of microdialysate(Up to post-operative day 5)