Pembrolizumab + Poly-ICLC in MRP Colon Cancer

Mismatch repair genes normally serve to fix the small glitches that occur when DNA is copied
as cells divide. In 1993, researchers discovered that mutations in human mismatch repair
genes play a key role in the development of certain forms of colorectal cancer; individuals
who are deficient in these mismatch repair genes are at high risk for colorectal cancer.
Accumulating evidence has shown that immunotherapy may be most effective against these
cancers.

Programmed cell death protein 1, also known as PD-1, functions as an immune checkpoint,
down-regulating the immune system by preventing the activation of T-cells, which in turn
reduces autoimmunity and promotes self-tolerance. A new class of immunotherapy drugs that
block PD-1, the PD-1 inhibitors, activate the immune system to attack tumors and are
therefore used with varying success to treat some types of cancer.

Current clinical trials are showing that patients whose tumors are mismatch repair deficient
are more likely to respond to immune-boosting anti-PD-1 drugs—such as pembrolizumab—than
those with tumors proficient in mismatch repair. The idea is that the greater the number of
DNA glitches in a tumor cell, the more abnormal proteins it will produce—and the more
abnormal proteins that are generated, the greater the odds that the body's immune cells will
regard the tumor cells as "foreign" and target them for destruction. Thus far, PD-1
inhibitors have shown great promise for mismatch repair deficient cancer patients, but not
for mismatch repair proficient (MRP) cancer patients.

In this clinical trial, the investigators hypothesize that treating MRP colon cancer patients
with immunostimulating agent poly-ICLC will generate an inflammatory response, increasing
epitope recognition and development of tumor reactive T-cells at the tumor site. However,
interferon alpha and gamma produced by the poly-ICLC will increase PD-L1 expression and limit
new T-cell development. Thus, PD1 blockade will increase the effectiveness of treatment with
pembrolizumab.

Diagnosis/Condition for Entry into the Trial Phase 1 - Presence of histologically confirmed
malignancy that has progressed following at least one therapy and able to be visualized on
imaging. Measurable disease is not required. Patients with known targetable mutations must
have progressive disease on the appropriated targeted drug therapy.

Phase 2 - Presence of MRP colon cancer that has progressed following at least two lines of
therapy. Ten patients will be included who have disease that can be biopsied pre- and
post-therapy.

Inclusion Criteria:

- Be willing and able to provide written informed consent for the trial

- Have measurable disease based on RECIST 1.1 (Phase 2)

- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion

- Have a performance status of 0 or 1 on the ECOG Performance Scale

- Have adequate organ function, according to screening labs performed within 10 days of
treatment initiation

- Subjects of childbearing potential must be willing to use an adequate method of
contraception for the course of the study through 120 days after the last dose of
study medication

Exclusion Criteria:

- Currently participating/previously participated in a therapeutic study and received
study therapy or used an investigational device within 4 weeks of the first dose of
treatment

- 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

- Has a known history of active TB (Bacillus Tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients

- 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 received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active
Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is
detected).

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

- Has active autoimmune disease that has required systemic treatment in the past 2 years