A Study of Enhancing Response to MK-3475 in Advanced Colorectal Cancer

This study is being done to test the safety and effectiveness of the combination of
intravenous (IV) romidepsin and/or oral CC - 486 with IV MK-3475 in people with
microsatellite stable advanced colorectal cancer.

The use of CC - 486 in this research study is investigational. The word "investigational"
means that the oral form of CC - 486 is not approved for marketing by the U.S. Food and Drug
Administration (FDA). Oral CC - 486 has only been given to a very small number of people so
far, and this combination has never before been given together to people.

Romidepsin has been approved by the FDA for the treatment of cutaneous T-cell lymphoma (blood
cancer). It is not approved by the FDA for use in other cancers.

MK-3475 is an antibody. Antibodies are proteins that the immune system uses to fight
infection. Researchers have designed MK-3475 to block PD-1. PD-1 is a molecule that can shut
down an immune response to infection or a cancer cell. An antibody to PD-1 can stop it from
turning off an immune response and may be able to boost the immune system against the cancer.

People with advanced colorectal tumors that are microsatellite stable (MSS) may join this
study. Tumors that are MSS positive are not deficient in repair of DNA.

This is a pilot study that will look at different ways of making MSS colorectal tumors
sensitive to MK-3475 by giving 14 or 21 days of an epigenetic agent (oral CC - 486 and/or
romidepsin).

Participants will be randomly assigned (by chance, like drawing numbers from a hat) to one of
three study drug combinations:

A. Oral CC - 486 taken daily for 21 days (and later shortened to 14 days if there are side
effects) and IV MK-3475 given every 2 weeks.

B. IV romidepsin given once weekly for 3 weeks and IV MK-3475 given every 2 weeks C. Oral CC
- 486 taken daily for 21 days (and later shortened to 14 days if there side effects) and IV
romidepsin given every 2 weeks and IV MK-3475 given every 2 weeks.

Each arm is repeated every 28 days and will continue until the point that the study drug are
no longer working. It will not be possible to cross over onto another arm if a participant's
disease does not respond to the study drugs.

In this study investigators are looking for the following information:

- What effects, good and/or bad, the combination of oral CC - 486 and/or romidepsin in
combination with MK-3475 has on participants' cancer; and

- If the genetic and chemical make-up of participants' blood and tumor cells play a role
in a response to oral CC - 486 and/or romidepsin in combination with MK-3475.

Inclusion Criteria:

1. Have histologically confirmed microsatellite stable metastatic colorectal cancer and
have received at least one line of treatment for metastatic colorectal cancer
including fluoropyrimidines, oxaliplatin and/or irinotecan

2. Be willing and able to provide written informed consent/assent for the trial

3. Be 18 years of age on day of signing informed consent

4. Have measurable disease

5. Have biopsiable disease. If biopsy is attempted and unsuccessful (the patient
undergoes an invasive procedure), the patient may still be treated

6. Have a performance status of 0 or 1 on the ECOG Performance Scale at study entry

7. Demonstrate adequate organ function

8. Female subject of childbearing potential must have a negative urine or serum pregnancy
test within 72 hours prior to receiving the first dose of study medication

9. Female subjects of childbearing potential must be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication

10. Male subjects must agree to use an adequate method of contraception starting with the
first dose of study therapy through 120 days after the last dose of study therapy

11. In patients with liver metastases, there should be <50% involvement of the liver.

12. Patients must have had < 3 prior therapies in the metastatic setting.

Exclusion Criteria:

1. Patients whose tumors have progressed at the first restaging during first line therapy

2. Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of treatment

3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment

4. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not
recovered from adverse events due to agents administered more than 4 weeks earlier

5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 4 weeks (6 weeks for nitrosureas or mitomycin C) prior to study Day 1 or who
has not recovered from adverse events due to a previously administered agent

6. Has a known additional malignancy that is progressing or requires active treatment

7. Has known central nervous system (CNS) metastases and/or carcinomatous meningitis

8. Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents.

9. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

10. Has an active infection requiring systemic therapy.

11. Any clinical or radiological ascites or pleural effusions

12. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator

13. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

14. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial

15. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137,
anti-OX-40, anti-CD40, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)
antibody (including ipilimumab or any other antibody or drug specifically targeting
T-cell co-stimulation or checkpoint pathways). Prior therapies with other
immunomodulatory agents must be reviewed by the PI and may be cause for ineligibility

16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

17. Has known active Hepatitis B or Hepatitis C

18. Has received a live vaccine within 30 days prior to the first dose of trial treatment

19. Any known cardiac abnormalities