Repurposing Mefloquine for Pancreatic Cancer Treatment

• Adults (≥ 18 years old) with histologically confirmed, unresectable or metastatic PDAC.
• Subjects must have measurable disease per RECIST 1.1.
• Subjects must be about to initiate a treatment regimen containing either mFFX or GnP, OR (for monotherapy arm) have relapsed/refractory disease following standard therapies, not candidates for standard-of-care therapies, or are intolerant of such therapies.
• Subjects must plan to continue cancer care at UF Health for at least the next three months.
• Subjects with known or suspected Gilbert's disease must be formally tested for UGT1A1*28 with results available to study team prior to treatment initiation

• Adequate organ and hematologic function, as defined by:

  1. Serum total bilirubin within 1.5 upper limit of normal (ULN) for the institution, with a trend downwards (biliary drainage is allowed for biliary obstruction)
  2. AST and ALT ≤ 2.5 × ULN
  3. Albumin ≥ 3.0 g/dL
  4. Serum creatinine ≤ 1.5 × ULN
  5. ANC > 1,500 cells/µl without the use of hematopoietic growth factors
  6. Platelets ≥ 100,000/mm³
  7. Hemoglobin ≥ 9 g/dL (blood transfusions are permitted for patients with hemoglobin levels below 9 g/dL)
  8. Normal ECG or ECG without any clinically significant findings as defined by the treating physician

• Subjects of childbearing potential (SOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for at least 7 months after the last dose of study drug (and for at least 9 months after the last dose of Oxaliplatin, for those receiving mFOLFIRINOX) to minimize the risk of pregnancy. Prior to study enrollment, SOCBP must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. SOCBP include any participant who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:

  • Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or
  • For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.
• Because of the potential for serious adverse reactions in nursing infants from study treatment, participants must not breastfeed during study participation and for 6 months after the End of Treatment Visit.
• Partners of SOCBP must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 6 months following the last dose of study drug.
• Subjects must not have more than one active invasive malignancy at the time of enrollment (Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen or primary endpoint [as determined by the treating physician and approved by the PI] are eligible for this trial).
• Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures.
• ECOG Performance Status of 0-2

Exclusion Criteria:

• Patients with unstable or active CNS metastases
• Patients with swallowing problems or any gastrointestinal disorder or malabsorption that may affect a patient's ability to take and absorb an oral medication
• Known hypersensitivity to Mefloquine or related compounds (e.g., quinine and quinidine), or to any of the excipients contained in the formulation.
• Use of strong CYP3A4 inhibitors or inducers which cannot be discontinued prior to study entry.
• Known history of psychosis, major depression, major anxiety disorder or other psychiatric disorder that the PI believes will place the patient at higher risk of psychiatric toxicity
• Any history of seizures, even if actively treated or remote in history
• Planned Ketoconazole or Halofantrine use within 15 weeks of the last dose of Mefloquine
• Current use of anticonvulsant medication at time of enrollment, including valproic acid, carbamazepine, phenobarbital, or phenytoin
• Current use of quinine (Qualaquin) or quinidine at time of enrollment
• History of, or active, epilepsy or chronic seizures per medical record or patient report.
• Participant has had a myocardial infarction or unstable angina within 6 months prior to the start of study intervention, an LVEF \< 50% as determined by MUGA scan or ECHO or currently has an uncontrolled illness including, but not limited to symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, obligate use of a cardiac pacemaker, known family history of sudden cardiac death or long QT syndrome. ECHO or MUGA may be considered at the treating physician's discretion based upon clinical symptomatology or concerns for reduced LVEF even if the above criteria are not present.
• Participant has a corrected QT interval (single ECG) using Fridericia's formula (QTcF) > 450 msec (men) or > 470 msec (women) during screening.
• Participant requires treatment with concomitant drugs, herbal supplements or dietary products that are strong inhibitors or inducers of CYP3A4. If taking any of these, must be discontinued >14 days prior to start of investigational therapy.
• Uncontrolled diarrhea, active infection requiring systemic antibiotics, known interstitial lung disease or other medical condition that precludes safe administration of this combination therapy consistent with manufacturer recommendations.
• Unwilling/unable to comply with birth control requirements while on study.
• Subjects who are confirmed to be pregnant
• Known dihydrypyrimidine (DPD) deficiency
• History of any other disease, metabolic dysfunction, clinical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician and as confirmed by the PI.
• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.