Phase I Study of Preoperative Therapy Imatinib Mesylate and Fampridine in KIT Mutant Gastrointestinal Stromal Tumor (GIST)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 18
- 试验地点
- 2
- 主要终点
- Recommended phase 2 dose
研究概览
简要总结
The goal of this clinical trial is to learn what dose of the drug fampridine can be given safely together with imatinib (Gleevec) in patients with gastrointestinal stromal tumor (GIST) with a DNA mutation in exon 11 of the KIT gene.
The main questions this study aims to answer are:
- What is the maximum dose of fampridine that can be given safely together with imatinib (Gleevec)?
- Is the combination of the two drugs efficacious against the tumor?
Participants will:
- Take the drugs before tumor surgery (preoperative treatment) for at least 2 months with the option to continue for a longer period of time if treatment seems safe and effective.
- Visit the clinic at the scheduled appointments for checkups and tests.
详细描述
Gastrointestinal stromal tumor (GIST) is the most common form of sarcoma. Surgical resection is the current main form of treatment, however preoperative medical therapies are also often necessary.
The majority of gastrointestinal stromal tumor (approximately 60-70%) are caused by gain-of-function mutations in the KIT oncogene. Since KIT is a tyrosine kinase, it is not surprising that four of five Food and Drug Administration (FDA)-approved therapies for this condition are tyrosine kinase inhibitors that target the KIT oncogene. Among these compounds, imatinib is considered the standard first line treatment. However, tumor response to tyrosine kinase inhibitors is suboptimal and more efficacious therapies are needed.
There are data that demonstrate lack of KIT protein expression in some KIT mutant gastrointestinal stromal tumor cells (cell not expressing KIT are referred to as KITnegative/low). Therefore, these cells do not have the cellular machinery that would allow them to respond to tyrosine kinase inhibitors.
The study investigators have discovered that the mRNA for the beta subunit of the voltage-gated potassium channels (VGKCs), Kvβ1.1, is expressed at high levels in KITnegative/low tumor cells. Previous studies have also shown that inhibition of the voltage-gated potassium channels (VGKCs) can inhibit cell proliferation and migration/invasion, as well as induce apoptosis in various cancer types. This led to the hypothesis that inhibitors of voltage-gated potassium channels (VGKCs) may have antitumor activity in KITnegative/low gastrointestinal stromal tumor cells.
A voltage-gated potassium channels inhibitor, fampridine, is FDA-approved for multiple sclerosis. The investigators hypothesize that voltage-gated potassium channels (VGKCs) blockade with fampridine may represent a novel strategy for treating KITnegative/low gastrointestinal stromal tumor. The investigators performed preclinical studies that suggest that the combination imatinib plus fampridine may lead to cell killing in an additive and/or synergistic manner in vitro. In addition, they showed that imatinib synergizes with fampridine to decrease tumor mass in vivo in a genetically engineered mouse model of GIST that carry KIT exon 11 Val-558 deletion.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •Provision of written informed consent prior to any screening procedures
- •Age ≥ 18 years
- •Having been pathologically confirmed to have a KIT exon 11 mutant gastrointestinal stromal tumor assessed for KIT variant mutations by next generation sequencing
- •Treatment naïve gastrointestinal stromal tumor
- •Described as a primary localized, locally advanced, or metastatic gastrointestinal stromal tumor in any location that would benefit from preoperative therapy before tumor surgical resection
- •Has measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors v1.
- •Has Eastern Cooperative Oncology Group Performance Status of 0-1
- •Has adequate hematologic, hepatic, and renal function: Absolute Neutrophil Count ≥ 1.5 x 10^9/L; Hemoglobin ≥ 11 g/dL; Platelets ≥ 100 x 10^9/L; Serum total bilirubin < 2.0 x upper limit of normal; Aspartate aminotransferase and alanine aminotransferase ≤ 5 x upper limit of normal; Plasma creatinine phosphokinase < 1.5 x upper limit of normal; Serum creatinine ≤ 1.0 x upper limit of normal or calculated creatinine clearance ≥ 50ml/min based upon the Cockcroft-Gault Equation
- •Life expectancy of ≥ 5 years
- •Participants able to cause pregnancy agree to use an adequate method of contraception starting with the first dose of study therapy and for 120 days after the last dose
排除标准
- •Unwilling or unable to comply with the protocol
- •KIT exon 9, 13, 14, 17, or 18 mutant gastrointestinal stromal tumor by next generation sequencing.
- •Non-KIT mutant gastrointestinal stromal tumor
- •Have residual tumor following surgical debulking
- •Have had major surgery within 4 weeks of initiation of study medication.
- •Of childbearing potential
- •Pregnant or nursing.
- •Received imatinib monotherapy prior to the first dose of study treatment with imatinib plus fampridine and has demonstrated tumor shrinkage in computed tomography assessment images.
- •Received fampridine prior to the first dose of study treatment with imatinib plus fampridine.
- •Use of compounded fampridine or other forms of fampridine.
- •Known brain metastases and any other progressive neurologic dysfunction should be excluded from this clinical trial because of their poor prognosis and because their progressive neurologic dysfunction would confound the evaluation of neurologic and other adverse events.
- •Evidence of severe or uncontrolled systemic diseases (e.g., unstable, or uncompensated respiratory, cardiac [including life threatening arrhythmias] disease).
- •Presence of cardiac impairment defined as:
- •Prior history of cardiovascular disease including heart failure that meets New York Heart Association (NYHA) class III and IV definitions; OR
- •History of myocardial infarction/active ischemic heart disease within one year of study entry; OR
- •Uncontrolled dysrhythmias; OR
- •Poorly controlled angina.
- •Unresolved toxicity Common Terminology Criteria Adverse Events (CTCAE) Grade ≥ 2 from previous anti-cancer therapy.
- •Allergy or sensitivity to fampridine or known allergies to aminopyridine products, which in the opinion of the investigator(s) suggests an increased potential for an adverse hypersensitivity to fampridine.
- •Allergy to imatinib.
- •Any chronic liver disease including, but not limited to cirrhosis, non-alcoholic steatohepatitis, alcohol-related liver disease, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, hepatic, or biliary autoimmune disorders (i.e., primary biliary cholangitis, autoimmune hepatitis). Exception: Patients aged ≤ 65 years with non-alcoholic fatty liver disease detected by imaging are acceptable if adequate hepatic function as defined in the inclusion criteria is confirmed. Note: Patients aged > 65 years with non-alcoholic fatty liver disease are excluded from the study.
- •Any evidence or history of hepatitis B and/or hepatitis C.
- •Medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease that, in the opinion of the investigator(s), would make this study unreasonably hazardous for the patient.
- •Any other disease or clinically significant abnormality in laboratory parameters, including serious medical or psychiatric illness/condition, which in the judgment of the investigator(s) likely might compromise the safety of the participant or the integrity of the study, interfere with the participant participation in the trial, or compromise the trial objectives.
- •History of seizures.
- •Cannot swallow oral formulations of the medications or lack physical integrity of the upper gastrointestinal tract, or has known malabsorption syndromes. Note: imatinib tablets can be dissolved in water or apple juice if participants have difficulty swallowing.
- •Have taken part in an experimental drug study within 4 weeks of initiating study treatment with imatinib plus fampridine
- •Receiving other anti-neoplastic therapy (e.g., chemotherapy, targeted therapy, or radiotherapy) concurrently or within 4 weeks of starting study treatment with imatinib plus fampridine
- •Receiving medications that inhibit the renal Organic Cation Transporter 2 (OCT2), such as cimetidine and quinidine, because of possible drug-drug interactions.
- •Receiving medications known to be strong inhibitors or inducers of CYP3A4/
- •Receiving medications known to be strong inhibitors or inducers of cytochrome CYP2E1 or medications metabolized by cytochrome CYP2B6 or CYP2C9/19 that have narrow therapeutic index and that cannot be discontinued before starting study treatment.
研究组 & 干预措施
Imatinib plus Fampridine
Imatinib in combination with fampridine at one of three dose levels (10 mg every other day, or 10 mg every day, or 10 mg twice a day) after a 7-day run-in period with imatinib monotherapy.
干预措施: Imatinib (Drug)
Imatinib plus Fampridine
Imatinib in combination with fampridine at one of three dose levels (10 mg every other day, or 10 mg every day, or 10 mg twice a day) after a 7-day run-in period with imatinib monotherapy.
干预措施: Fampridine (Drug)
结局指标
主要结局
Recommended phase 2 dose
时间窗: 28 days
Recommended phase 2 dose (RP2D) of imatinib plus fampridine determined by the dose-limiting toxicities and maximum tolerated dose via assessment of adverse events as defined by CTCAE version 5.0 during the first cycle (28 days) of therapy.
次要结局
未报告次要终点
研究者
Paul Fanta
Clinical professor, medical oncology
University of California, San Diego