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

Background: * Adenosquamous carcinoma of the pancreas (ASCP) is a highly aggressive variant of pancreatic ductal adenocarcinoma (PDA), the most common type of pancreas cancer. * ASCP is estimated to account for 0.5-4% of the 55,000 people who are diagnosed with pancreatic cancer in the United States (U.S.) each year, making it a very rare tumor type. * No prospective clinical trials specific to ASCP have ever been performed. * Preclinical data in ASCP models indicate that an activated superenhancer network drives epigenetic changes which cause the prognostically unfavorable squamous differentiation. * Genomic analysis of ASCP tumors identifies frequent amplification of MYC. * Minnelide is a small molecule anti-superenhancer drug that inhibits MYC. * The recommended dose of Minnelide has previously been established through clinical testing for other indications. Primary Objective: -To determine the single agent antitumor activity (disease control rate) of the anti-superenhancer agent Minnelide in participants with advanced, previously treated ASCP Eligibility: * Age \>= 18 years * Histologically confirmed ASCP or high suspicion for ASCP based on histologic analysis for squamous markers * Participants with metastatic or locally advanced unresectable disease and progression on at least 1 prior treatment regimen Design: * This is a phase II single cohort clinical trial with one arm. * The number of evaluable participants needed for the primary endpoint is 25; maximum accrual set at 55 participants (accounting for screen failures and inevaluable participants). * initial participants will receive Minnelide at 2 mg/day by mouth (PO) on Days 1-21 of a 28-day cycle. * Later participants will receive a higher dose of 2.5 mg/day PO on the same schedule. * Treatment will be continued for up to 12 cycles (1 year) in the absence of disease progression or unacceptable toxicity. * Treatment response will be assessed by imaging every 2 cycles (8 weeks). * Optional tumor biopsies will be requested mid-cycle 1 and at time of progression. * A disease control rate of \>= 40% in this highly refractory population would constitute a positive study. Up to 12 participants will be treated initially. If 3 of the 12 participants have a response, then up to 13 additional participants will be entered to determine the true response rate.