Inclusion Criteria:

          1. Patients must have a histologically/cytologically -confirmed primary colorectal tumor,
             with confirmation of being microsatellite stable.

          2. Radiographic or clinical evidence of metastatic disease that has progressed after at
             least 2 prior regimens. Prior bevacizumab, cetuximab, trifluridine and tipiracil , or
             regorafenib is allowed, prior FOLFIRI and FOLFOX treatment is required. (Treatment
             with a FOLFIRINOX regimen will count as 2 regimens). Prior treatment does not have to
             have been in the metastatic setting.

          3. Patients must have measurable disease by RECIST criteria

          4. All patients must have a tumor(s) located in an area that that can be biopsied as
             confirmed by treating physician

          5. All patients must submit representative tissue from their malignancy if it is
             confirmed there is enough tissue from prior surgery or most recent biopsy.

          6. All previous therapies for cancer, including radiotherapy, major surgery and
             investigational therapies must be discontinued for ≥ 14 days before the first dose of
             ONC201

          7. All clinically significant adverse events related to any prior therapy must have
             resolved to Grade ≤ 1 Common Terminology Criteria for Adverse Events (CTCAE v5.0),
             except alopecia or parameters defined in this eligibility list.

          8. Age ≥ 18 years.

          9. ECOG performance status ≤ 2.

         10. Adequate organ and marrow function as defined below:

               1. Absolute neutrophil count ≥1,000/mm3 without growth factor use ≤ 7 days prior to
                  treatment

               2. Platelets ≥75,000/mm3 without platelet transfusion ≤ 7 days prior to treatment

               3. Hemoglobin>8.0 mg/dL without red blood cell transfusion ≤ 7 days prior to
                  treatment

               4. Total serum bilirubin<1.5 X upper limit of normal (ULN)

               5. AST (SGOT)/ALT (SGPT)≤2 X ULN; ≤ 5 X ULN if liver dysfunction is felt to be
                  secondary to tumor burden within 14 days prior to treatment, Serum creatinine ≤
                  1.5 X ULN (OR creatinine clearance ≥ 60 mL/min/1.73 m2) within 14 days prior to
                  treatment

               6. Serum or urine pregnancy test (for females of childbearing potential) negative ≤7
                  days of treatment

         11. Ability to understand and the willingness to sign a written informed consent document
             and comply with the study scheduled visits, treatment plans, laboratory tests and
             other procedures.

         12. Female patients of child-bearing potential must be practicing an effective form of
             contraception from the time of informed consent and for the duration of the study
             treatment through 5 months after the last dose of drug (ONC201 or Nivolumab, whichever
             is administered last). The decision of effective contraception will be based on the
             judgment of the principal investigator or a designated associate.

         13. Male patients must be surgically sterile (provide date of surgery) or must agree to
             use effective contraception from the time of informed consent and for the duration of
             the study treatment through 7 months after the last dose of drug (ONC201 or Nivolumab,
             whichever is administered last). The decision of effective contraception will be based
             on the judgment of the principal investigator or a designated associate.

         14. Patients must agree to the required tumor biopsies to enroll in the trial.

        Exclusion Criteria:

          1. Patients with symptomatic brain metastases are excluded. Patients with asymptomatic
             and treated CNS metastases may participate in this trial. The patient must have
             completed any prior treatment for CNS metastases > 28 days prior to registration,
             including radiotherapy or surgery. Steroids for the treatment of brain metastasis are
             not permitted.

          2. Patients with prior treatment with ONC201 will be excluded

          3. Active inflammatory gastrointestinal disease such as severe chronic diarrhea (unless
             related to underlying malignancy), gastrointestinal perforation, or intra-abdominal
             abscess within 6 months prior to study registration. Gastroesophageal reflux disease
             under controlled treatment with proton pump inhibitors is allowed.

          4. Pregnant or breast feeding.

          5. Current active treatment in another clinical study (treatment trial) within 14 days of
             D-7.

          6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection requiring IV antibiotics, hepatitis, active rheumatologic or collagen
             vascular disease, symptomatic congestive heart failure, unstable angina pectoris,
             clinically significant cardiac arrhythmia, or psychiatric illness/social situations
             that would limit compliance with study requirements.

          7. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
             (AIDS)-related illness. (testing is not required for eligibility).

          8. Any of the following in the previous 3 months: myocardial infarction, severe/unstable
             angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure,
             cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism
             as defined by treating physician.

          9. Other severe acute or chronic medical or psychiatric condition or laboratory
             abnormality that may increase the risk associated with study participation or study
             drug administration, or may interfere with the interpretation of study results, or in
             the judgment of the investigator would make the patient inappropriate for entry into
             the study.

         10. Participants with an active, known or suspected autoimmune disease. Participants with
             type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin
             disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment,
             or conditions not expected to recur in the absence of an external trigger are
             permitted to enroll.

         11. Participants with a condition requiring systemic treatment with either corticosteroids
             (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
             days of day 1 of treatment. Inhaled or topical steroids, and adrenal replacement
             steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of
             active autoimmune disease

         12. Patients with a history of other invasive malignancies, with the exception of
             non-melanoma skin cancer are excluded if there is any evidence of other malignancy
             being present within the last three years (2 years for invasive breast cancer).
             However, patients with a malignancy that is non-likely to require treatment, as per
             the treating physician, in the next 2 years, such as a completely resected, early
             stage breast cancer, or other malignancies treated with curative intent are eligible.
             Patients are also excluded if their previous cancer treatment contraindicates this
             protocol therapy.

         13. Prior treatment with immunotherapy for any cancer, including immune checkpoint
             inhibitors or anti-CTLA4 agents

         14. Participants who have received a live / attenuated vaccine within 30 days of first
             treatment.