This is a single arm Phase Ib/II, open label, safety, pharmacokinetic, pharmacodynamics and
efficacy study of ONC201 in combination with Opdivo (Nivolumab) in adult patients with
metastatic colorectal cancer, for whom no standard therapy is available. This study will
enroll adult patients with metastatic colorectal cancer who progressed after at least two
lines of therapy.
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
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
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
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
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
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.
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
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
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
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
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