Superenhancer Inhibitor Minnelide in Advanced Refractory Adenosquamous Carcinoma of the Pancreas (ASCP)

Background: Pancreatic cancer is one of the most lethal types of cancer. American Society for Clinical Pathology (ASCP) is a highly aggressive type of pancreatic cancer. It is very rare. Researchers want to see if a drug called Minnelide can be used to treat ASCP. Objective: To see if Minnelide is an effective treatment for ASCP. Eligibility: Adults ages 18 and older with ASCP whose cancer did not respond to previous treatments. Design: Participants will be screened with: Medical history Physical exam Blood and urine samples Evaluation of ability to do daily activities Electrocardiogram to test heart function Body and/or brain scans. For these, participants will lie in a machine that takes pictures of the body. They may have a contrast agent injected into a vein. Tumor sample. If one is not available, participants will have a tumor biopsy. The biopsy will be taken with a small needle put through the skin into the tumor. Treatment will be given in 28-day cycles, for up to 12 cycles. There is a 7-day resting period between cycles. Participants will take Minnelide by mouth every day for 21 days of each cycle. They will keep a medicine diary. Participants will have at least 1 study visit every cycle. They will review their medicine diary. They will repeat some screening tests. Participants may have optional tumor biopsies. Some participants may need to take birth control during the study and for up to 6 months after treatment. Participants will have an end-of-treatment visit 4 weeks after they stop taking the study drug. They will repeat some screening tests.

* INCLUSION CRITERIA: * Histological or cytological diagnosis of adenosquamous carcinoma of the pancreas (ASCP) or high suspicion for ASCP as confirmed by National Institutes of Health (NIH) Laboratory of Pathology. ASCP will be defined as \>=30% malignant squamous component in background of typical pancreatic ductal adenocarcinoma (PDA). If malignant squamous component is identified in the sample, but the pathologist is unable to determine whether it is \>= 30%, then the participant will be considered to have high suspicion for ASCP. Note: To meet this criterion, participant must be able to submit a suitable archival tumor specimen (primary or metastatic site) for review or currently have tumor in a location deemed low risk for core biopsy so that suitable tissue can be acquired for confirmation of diagnosis. Note that cytopathology specimens are not considered suitable for definitive diagnosis of ASCP but can be used to determine high suspicion for ASCP. * Participants with metastatic, recurrent or locally advanced unresectable disease and progression or intolerance to at least 1 prior systemic treatment regimen in the advanced disease setting. * Disease measurable by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. * Progressive disease as evidenced by increasing tumor size on radiologic assessment, increasing serum tumor marker (on last 2 measurements taken at least 1 week apart), increasing ascites, and/or worsening tumor-related symptoms such as weight loss, pain, gastrointestinal (GI) upset. * Age \>18 years. * Eastern Cooperative Oncology Group (ECOG) performance status \60%). * Be willing and able to provide written informed consent for the trial. * Participants must have adequate organ and marrow function as defined below: * absolute neutrophil count (ANC) \>= 1,500/microL * platelets \>= 100,000/microL * hemoglobin \>= 9.0 g/dL or \>= 5.6 mmol/La\* * Creatinine \= 45 mL/min for participant with creatinine levels \>1.5 x institutional upper limit of normal (ULN) * total bilirubin \