This protocol will enroll patients with pancreatic adenocarcinoma and adenosquamous carcinoma (Cohort 1), gastrointestinal/pancreatic neuroendocrine neoplasms with Ki-67 > 20% (Cohort 2) and neuroendocrine prostate carcinoma (Cohort 3)). Each cohort will have its own interim analysis after enrollment of 10 patients.

Subjects will be given a one-month (28 day) supply of study drug (ESK981). Subjects will be instructed to take 4 capsules, with or without food, once per day for 5 consecutive calendar days, then take a drug holiday for 2 consecutive days before repeating the 5 days on-2 days off cycle in sets of 4 weeks or 28 calendar days. Subjects will be asked to keep a pill diary noting the date they take their study drug.

Eligibility Criteria:

• Patients with histological or cytological confirmation of advanced cancer per specific cohort.

  • Cohort 1: Pancreatic adenocarcinoma or adenosquamous carcinoma who have progressed or deemed intolerant of the standard of care chemotherapy regimens.

  • Cohort 2: Pancreatic or gastrointestinal neuroendocrine tumor or carcinoma with Ki-67 > 20% who have progressed or deemed intolerant of at least first-line standard of care systemic therapy.

  • Cohort 3: The subject has histologically proven prostate cancer who have progressed or deemed intolerant of at least first-line standard of care systemic therapy with radiologic evidence of metastases and at least one of the following:

    • Small cell or neuroendocrine morphology on the basis of tissue sample.
    • Prostate adenocarcinoma with IHC staining for neuroendocrine markers (e.g., chromogranin and synaptophysin).
    • Presence of visceral metastases or high-volume disease (> 4 sites of metastases) with a PSA ≤ 5.
    • Serum chromogranin A level ≥ 5x upper limit of normal (ULN) and/or serum neuron specific enolase (NSE) ≥ 2x ULN.
    • Trans-differentiated carcinoma or poorly-differentiated carcinoma

• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2

• Must be ≥ 18 years of age.

• Evaluable disease determined using guidelines of Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)

• Ability to understand and willingness to sign IRB-approved informed consent.

• Willing to provide archived tissue, if available, from a previous diagnostic biopsy.

• Must be able to tolerate CT and/or MRI with contrast.

• At least 4 weeks from major surgery with resolution of any sequela to date of enrollment

• Laboratory values ≤2 weeks during screening must be:

  • Platelet count ≥ 75,000 cells/mm3
  • Absolute neutrophil count ≥ 1500 cells/mm3
  • Hemoglobin ≥ 9 g/dL
  • AST/ALT ≤ 3x upper limit of normal [ULN], or (≤ 5x ULN if liver metastasis present)
  • Bilirubin ≤ 1.5x ULN, or (≤ 2.5 x ULN for subjects with Gilbert's syndrome)
  • Albumin ≥ 3 g/dL
  • Serum creatinine clearance CrCl ≥ 50 mL/min per Cockcroft-Gault Formula
  • INR ≤ 1.5 (or <2.0 if on anticoagulants)

• Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must agree to use acceptable highly effective contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive(s), intrauterine hormone releasing system (IUS), bilateral tubal occlusion or vasectomized partner) during and for 9 months after last study dose and must have a negative serum or urine pregnancy test during screening.

• Males with female partners (of childbearing potential) and female partners (of childbearing potential) with male partners must agree to use double barrier contraceptive measure (a combination of male condom with either cap, diaphragm or sponge with spermicide) in addition to oral contraception, or avoidance of intercourse during the study and for 6 months after last study dose is received.

• Female patients must not be pregnant, have a positive pregnancy test, breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 9 months after the last dose of study treatment.

• Male patients must be willing to abstain from donating sperm during treatment and for 6 months after completion of study treatment.

• No evidence of active infection and no serious infection within the past 30 days. Patient must have completed antibiotic course.

• No known cerebral metastasis, central nervous system (CNS), or epidural tumor (unless previously treated, asymptomatic and stable for at least 3 months).

• No active heart disease including but not limited to myocardial infarction that is <3 months prior to registration, symptomatic congestive heart failure (NYHA class 3 or 4), symptomatic coronary artery disease, symptomatic angina pectoris.

• No history of acute cerebrovascular disease, arterial or venous thromboembolism, percutaneous angioplasty, or coronary artery bypass surgery within 6 months prior to registration

• No pre-existing coagulopathy, or serious bleeding within 3 months prior to registration.

• No prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, in situ cancer, localized prostate cancer (Gleason score <8), or adequately treated cancer from which the patient has been disease-free for at least 3 years prior to registration.

• Must not have uncontrolled diarrhea at the time of enrollment.

• Patients must not use a chronic daily medication known to be a strong or moderate inhibitor of CYP1A2, CYP2C8 or CYP3A4 at registration (as per Appendix II).

• Patients must have recovered to baseline or ≤ grade 1 CTCAE v5.0 from toxicities related to any prior treatments, unless adverse event(s) is deemed clinically non-significant and/or stable on supportive therapy.

• Patients must not have uncontrolled hypertension defined as blood pressure >150/90 despite optimal medical management.

• No known hypersensitivity to gelatin or lactose monohydrate.