Fampridine in Combination with Imatinib Mesylate before Surgery for the Treatment of KIT Exon 11 Mutant Gastrointestinal Stromal Tumor (GIST)

Inclusion Criteria

• Provision of written informed consent prior to any screening procedures
• Age ≥ 18 years
• Having been pathologically confirmed to have a KIT exon 11 mutant GIST assessed for KIT variant mutations by next-generation sequencing (NGS)
• Treatment naïve GIST
• Described as a primary localized GIST or a locally advanced GIST in any location that would benefit from neoadjuvant therapy before tumor surgical resection
• Has measurable or evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• Has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0–1
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 10^9/L
• Hemoglobin (Hgb) ≥ 11 g/dL
• Platelets ≥ 100 x 10^9/L
• Serum total bilirubin < 2.0 x ULN (upper limit of normal)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5 x ULN
• Plasma creatinine phosphokinase (CK) < 1.5 x ULN
• Serum creatinine ≤ 1.0 x ULN or calculated creatinine clearance (CrCl) ≥ 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

Exclusion Criteria

• Unwilling or unable to comply with the protocol
• KIT exon 9, 13, 14, 17, or 18 mutant GIST by NGS
• Non-KIT mutant GIST
• Newly diagnosed with metastatic GIST
• Have residual tumor following surgical debulking
• Have had major surgery within 4 weeks of initiation of study medication
• Of childbearing potential * Pregnant or breast feeding participants cannot be enrolled. Non-pregnant, non-breast-feeding participants of childbearing potential cannot be enrolled. Participants able to become pregnant need to be (1) surgically sterilized or (2) postmenopausal to participate in this study
• Received IM monotherapy prior to the first dose of study treatment with IM+4-AP and has demonstrated tumor shrinkage in CT assessment images
• Received 4-AP prior to the first dose of study treatment with IM+4-AP
• Use of compounded 4-AP 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], hepatic, or renal disease)
• Multiple sclerosis or other neurologic disorders
• 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 for Adverse Events (CTCAE) Grade ≥ 2 from previous anti-cancer therapy
• Allergy or sensitivity to 4-AP or known allergies to aminopyridine products, which, in the opinion of the investigator(s), suggest an increased potential for an adverse hypersensitivity to 4-AP
• Allergy to IM
• Any chronic liver disease including, but not limited to cirrhosis, non-alcoholic steatohepatitis (NASH), 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
• 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: IM 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 IM+4-AP
• Receiving other anti-neoplastic therapy (e.g., chemotherapy, targeted therapy, or radiotherapy) concurrently or within 4 weeks of starting study treatment with IM+4-AP
• 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 CYP3A4/5
• Receiving medications known to be strong inhibitors or inducers of CYP2E1 or medications metabolized by CYP2B6 or CYP2C9/19 that have narrow therapeutic index and that cannot be discontinued before starting study treatment