Cetuximab and Pembrolizumab in Treating Patients With Colorectal Cancer That is Metastatic or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To estimate the objective response rate of patients with metastatic colorectal cancer
treated with pembrolizumab and cetuximab.

II. To estimate the 6-month progression free survival (PFS) rate of patients with metastatic
colorectal cancer treated with pembrolizumab and cetuximab.

III. To examine the adverse event profile of combining pembrolizumab and cetuximab.

SECONDARY OBJECTIVES:

I. To examine the PFS of patients with metastatic colorectal cancer treated with
pembrolizumab and cetuximab.

II. To determine the objective response rate by immune-related response criteria (irRC) of
patients with metastatic colorectal cancer.

III. To examine the overall survival of patients with metastatic colorectal cancer treated
with pembrolizumab and cetuximab.

EXPLORATORY OBJECTIVES:

I. Identify tumor and peripheral blood biomarkers of response and/or resistance to the study
treatment.

OUTLINE:

Patients receive cetuximab intravenously (IV) over 120 minutes on day 1, 8, and 15 (as
monotherapy for cycle 1 only) and pembrolizumab IV over 30 minutes on day 1. Treatment
repeats every 3 weeks for 24 months in the absence of disease progression or unacceptable
toxicity. Patients may continue pembrolizumab treatment for up to 1 year if they experience
disease progression.

After completion of the study treatment, patients are followed up every 3 months for up to 2
years.

Inclusion Criteria:

- Have a pathologically confirmed diagnosis of colorectal cancer, which is metastatic or
otherwise unresectable

- Have received at least 1 prior systemic therapy in the metastatic or unresectable
disease setting; patients who have recurred within six months of adjuvant chemotherapy
are not required to have received an additional line of chemotherapy

- Retrovirus-associated deoxyribonucleic acid (DNA) sequence (RAS) wild-type; v-Ki-ras2
Kirsten rat sarcoma viral oncogene homolog (KRAS) testing must be completed, with full
KRAS and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) testing strongly
advised; the presence of known mutations in KRAS or NRAS is exclusionary; primary
tumor or metastatic tumor may be tested; (note: in the case of multiple genomic
evaluations with conflicting results - e.g. KRAS mutant in one sample, but wild-type
in another - the patient may be included as RAS wild-type, if clinically justified,
after review with the principal investigator [PI])

- Naive to anti-EGFR therapy (cetuximab or panitumumab)

- Have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria present

- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion; newly-obtained is defined as a specimen obtained up to 30 days prior to
initiation of treatment on day 1; subjects for whom newly-obtained samples cannot be
provided (e.g. inaccessible or subject safety concern) may submit an archived specimen
only upon agreement from the principal investigator

- Hemoglobin >= 8 g/dL (performed within 14 days of treatment initiation)

- Absolute neutrophil count >= 1000/mm3 (performed within 14 days of treatment
initiation)

- Platelet count >= 100,000/mm3 (performed within 14 days of treatment initiation)

- Serum creatinine =< 2 upper limit of normal (ULN) or, >= 15 mL/min for participants
with creatinine levels > 2 ULN (performed within 14 days of treatment initiation)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5
ULN or, =< 5 ULN for participants with liver metastases (performed within 14 days of
treatment initiation)

- Female participants of childbearing potential are to have a negative serum pregnancy
test

- Female participants of child-bearing potential must agree to use an acceptable method
of birth control, be surgically sterile, or abstain from heterosexual activity for the
course of the study through 120 days after the last dose of study medication;
participants of childbearing potential are those who have not been surgically
sterilized or have not been free from menses for > 1 year; should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, she should inform her treating physician immediately

- Male participants 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

- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Participants who have had chemotherapy, targeted therapies, radiotherapy, or used an
investigational device within 2 weeks prior to the first dose of treatment or those
who have not recovered from adverse events (i.e., =< grade 1 or at baseline) due to
agents administered more than 2 weeks earlier; note: participants with =< grade 2
neuropathy are an exception to this criterion and may qualify for the study

- 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 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 known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; participants with previously treated brain metastases may participate
provided they are stable (without evidence of progression by imaging for at least four
weeks prior to the first dose of trial treatment and any neurologic symptoms have
returned to baseline), have no evidence of new or enlarging brain metastases, and are
not using steroids for at least 7 days prior to trial treatment; this exception does
not include carcinomatous meningitis which is excluded regardless of clinical
stability

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form
of systemic treatment

- Has known history of, or any evidence of active, non-infectious pneumonitis

- Uncontrolled clinically significant intercurrent illness including, but not limited
to, ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, unstable cardiac arrhythmia, or psychiatric illness, substance abuse
disorders or social situations that would limit compliance with study requirements

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment

- Has a known history of human immunodeficiency virus (HIV or HIV 1/2 antibodies);
testing not required

- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected); testing not required

- Has received a live vaccine within 30 days of planned start of study therapy (note:
seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and shingles are not allowed)

- Received an investigational agent within 30 days prior to starting study treatment

- 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

- Unwilling or unable to follow protocol requirements