INCLUSION CRITERIA: Histological or cytological diagnosis of ASCP as confirmed by NIH Laboratory of Pathology. ASCP will be defined as >= 30% malignant squamous component in background of typical PDA.  Note: To meet this criteria, 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 diagnosis of 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 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, GI upset. Age >18 years. ECOG performance status <2 (Karnofsky >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 <= 1.5 x ULN  OR  measured or calculated *bcreatinine clearance (GFR can also be used in place of creatinine or CrCl) >= 45 mL/min for participant with creatinine levels >1.5 x institutional ULN  total bilirubin <= 1.5 x ULN OR direct bilirubin <= ULN for participants with total bilirubin levels >1.5 x ULN AST (SGOT) and ALT (SGPT) <= 2.5 x ULN (<= 5 x ULN for participants with liver metastases)  International normalized ratio (INR) OR  prothrombin time (PT) activated partial thromboplastin time (aPTT):  <= 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants  ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR = glomerular filtration rate; ULN=upper limit of normal.  *a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC)  transfusion within last 2 weeks.  *b Creatinine clearance (CrCl) should be calculated per institutional standard.  Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.  -The effects of Minnelide on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months (women) and 3 months (men) after the last dose of trial treatment. Male participants must also refrain from donating sperm during this period. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.  EXCLUSION CRITERIA:  Has uncontrolled vomiting or medical condition which inhibits oral ingestion or digestion because the study treatment is administered orally. Pregnant and/or women who are breast feeding are excluded from this study because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Minnelide. Is currently participating and receiving trial therapy, or has participated in a trial of an investigational agent/therapy or used an investigational device within 3 weeks of the first planned treatment on this study. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1/Day 1 Requires use of ondansetron or another prohibited medication. Note that other 5-HT3 inhibitors are NOT prohibited. Has received major surgery within the last 4 weeks, minor endoscopic procedure such as biliary stenting within the last 2 weeks, or percutaneous procedure such as hepatic biopsy or celiac plexus block within 24 hours of planned treatment start date. Note: participant must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  Participants with previously treated brain metastases may participate if:  a) follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression at >= 4 weeks since treatment, AND b) participant has stability of baseline neurologic symptoms without receiving immunosuppressive-doses of systemic corticosteroid (physiologic replacement doses are permitted) x7 days or increases in other supportive medications that treat neurologic symptoms such as antiepileptics x14 days. Participants with carcinomatous meningitis are excluded regardless of clinical stability.  Has an active infection requiring systemic therapy. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant s participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Has known uncontrolled or poorly controlled human immunodeficiency virus (HIV) infection. HIV is considered uncontrolled or poorly controlled if an HIV-infected individual is not taking highly active anti-retroviral therapy or has a detectable viral load within the previous 6 months. Has active HBV or HCV or is currently under treatment for HBV or HCV. Active HBV or HCV does not include previously cleared HBV or HCV or successfully cured HBV or HCV through treatment Has received a live vaccine within 30 days of planned start of trial therapy.  Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist (Registered Trademark)) are live attenuated vaccines, and are not allowed.  -History of allergic reactions attributed to compounds of similar chemical or biologic composition to Minnelide