Preoperative Imatinib and Fampridine in KIT Mutant Gastrointestinal Stromal Tumor

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. Thus, the investigators aim to conduct this single site, prospective, open-label, non-randomized, single-arm phase 1 clinical trial in patients with KIT exon 11 mutant gastrointestinal stromal tumor to evaluate the safety and tolerability of the combination of imatinib plus fampridine in the preoperative setting (before surgery) to establish the dose of fampridine that can be used in a future phase 2 trial. The recommended phase 2 dose (RP2D) will be determined based on the rate of dose limiting toxicities (DLT) using the standard 3+3 phase 1 trial design with 3 dose levels.