Pancreatic Ductal Adenocarcinoma
Conditions
Keywords
pancreatic ductal adenocarcinoma, mefloquine, TYMS
Brief summary
Pancreatic cancer (specifically pancreatic ductal adenocarcinoma, PDAC) is a very aggressive disease that is often diagnosed too late for surgery, and the medicines currently available, mainly two chemotherapy combinations called modified FOLFIRINOX (mFFX) and gemcitabine + nab-paclitaxel (GnP), can extend life but rarely cure patients. This study examines mefloquine, a well-studied antimalarial drug, as a new way to attack pancreatic cancer. Laboratory work has shown that mefloquine can block an enzyme (TYMS) that cancer cells need to make DNA, and unlike many existing drugs it does not cause the cancer cells to produce more of that enzyme and become resistant. In several mouse models, as well as tumors grown from human patients, oral mefloquine at doses that were well tolerated (up to 300 mg/kg) slowed tumor growth and helped the animals live longer. This trial aims to find a safe dose of mefloquine for PDAC patients. A classic "3 + 3" design will be used in three separate arms: one taking mFFX, one taking GnP, and one taking mefloquine as monotherapy after exhausting standard of care treatment options. The main goals are to determine the recommended Phase 2 dose and to collect early signals that the drug might help shrink tumors when combined with existing chemotherapy. If the trial shows that mefloquine can be given safely and hints at improved tumor control, it would pave the way for larger studies that could eventually add an established and already-approved drug to the existing treatment options for advanced pancreatic cancer.
Interventions
Subjects will receive gemcitabine and nab paclitaxel beginning on day 1. Dosing of gemcitabine and nab paclitaxel will be per standard of care guidelines and the treating physician's discretion.
DRUGMefloquine
Subjects will take a loading dose of 250 mg orally of mefloquine once daily on days -7, -6 and -5. Then, beginning on day 1, subjects will take 250 mg of mefloquine orally either once a week or once every 2 weeks. Dose assignment will follow a 3 + 3 design for each arm, with once a week dosing as the starting dose. Three subjects will enroll in weekly dosing; if none or only one experiences a dose-limiting toxicity DLT, the recommended Phase 2 dose for that arm will be 250 mg weekly after a loading dose. If more than one subject experiences a DLT, the dose will be reduced to once every 2 weeks, and the process will repeat. If 2 or more DLTs occur at the reduced dose level, dosing will cease. Treatment will continue for all subjects until unacceptable toxicity, patient preference or disease progression. For arms that include concurrent chemotherapy (modified FOLFIRINOX or gemcitabine and nab-paclitaxel), concurrent chemotherapy will start on day 1.
Subjects will receive modified FOLFIRINOX beginning on day 1. Dosing of modified FOLFIRINOX will be per standard of care guidelines and the treating physician's discretion.
Sponsors
University of Florida
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended phase 2 dose | During the first 28 days of study treatment | Determine the recommended phase 2 dose of mefloquine for each arm based on the number of patients who experience a dose-limiting toxicity (DLT) during the 28 day DLT assessment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate | 2 years | Determine the objective response rate for each arm. Objective response rate is define as the percentage of subjects who achieve either a complete or partial response per RECIST 1.1 criteria. |
| Progression-free survival | 2 years | Determine the progression-free survival for each arm. |
| Time to progression | 2 years | Determine the time to disease progression for each arm. |
| Overall survival | 2 years | Determine the overall survival for each arm. |
| Maximum serum concentration (Cmax) | 6 hours post dose of mefloquine on Days -7, 1 and 28 | Determine the maximum serum concentration of mefloquine. |
| Time to maximum serum concentration (Tmax) | 6 hours post dose of mefloquine on Days -7, 1 and 28 | Determine the time to maximum serum concentration for mefloquine. |
| Area under the serum concentration-time curve (AUC) | 6 hours post dose of mefloquine on Days -7, 1 and 28 | Determine the area under the serum concentration-time curve for mefloquine |
| Half-life | 6 hours post dose of mefloquine on Days -7, 1 and 28 | Determine the half-life of mefloquine. |
Outcome results
None listed