Standard of Care Alone or in Combination With Ad-CEA Vaccine and Avelumab in People With Previously Untreated Metastatic Colorectal Cancer QUILT-2.004

Background

- Colorectal cancer (CRC) is the fourth most common cancer diagnosis in the United States
and accounts for the second most cancer-related deaths.

- Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified
for its role in the maintenance of self-tolerance and prevention of autoimmunity.
Blockade of the interaction between PD-L1 on tumor cells and PD-1 on T cells is expected
to reverse T cell suppression within tumors. These agents are dependent on underlying T
cell activation against the tumor cell to be effective.

- Avelumab is a fully human IgG1 anti-PDL1 antibody that selectively binds to PD-L1 and
competitively blocks its interaction with PD-1.

- In ongoing phase 1 trials of avelumab, the agent has been well tolerated and has shown
clinical activity.

- Clinical trials with anti-PD-1/L1 agents in colorectal cancer have resulted in minimal
activity in patients who do not have mismatch repair deficiency (MMR-D)

- Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to
activate T cells against tumors.

- A novel adenovirus based, CEA-targeting vaccine has demonstrated cytolytic T cell
responses in patients with metastatic colorectal cancer.

- Standard of care agents in first line metastatic CRC have properties been associated
with improved immune response via immunologic cell death and immunogenic modulation.

Primary Objective

-To determine if there is an improvement progression free survival among patients with
metastatic colorectal cancer lacking a mismatch repair deficiency who are treated with
standard of care + anti- PDL1 monoclonal antibody + Ad-CEA therapeutic cancer vaccine
compared with standard of care alone.

Eligibility

- Subjects age 18 and older with previously untreated pathologically confirmed metastatic
or unresectable colorectal cancer; prior adjuvant therapy is acceptable

- ECOG performance status less than or equal to 2

- Normal organ and bone marrow function

- Subjects with active autoimmune diseases requiring treatment and subjects requiring
system steroids (except for physiologic doses for steroid replacement) are not allowed

- Tumor sample and whole blood sample must be available for proteomics, genomics and
transcriptomics analyses.

- Subjects with metastatic or unresectable colorectal cancer with mismatch repair
deficiency (MMR-D or MSI-High) will not be eligible

Design

- This is a randomized, multicenter phase II clinical trial designed to evaluate the
potential improvement in progression free survival (PFS) when Avelumab and Ad-CEA
vaccine are used in combination with standard of care therapy in metastatic or
unresectable /5-FUcolorectal cancer when compared with standard of care alone
(FOLFOX-A).

- A lead in cohort, comprising the first 6 evaluable subjects enrolled, will be treated
with avelumab + Ad- CEA vaccine + standard of care in order to assess the safety of the
combination.

- If no more than 1 subject in the lead in cohort experiences a dose limiting toxicity
attributable to the IND agents, 70 evaluable subjects will be randomized on a 1:1 basis
to receive either Avelumab + Ad-CEA vaccine + standard of care (Arm B) or standard of
care alone (Arm A).

- Standard of care therapy consists of 6 - 12 two week cycles of bevacizumab + FOLFOX
(5-FU, leucovorin, oxaliplatin) followed by two week cycles of bevacizumab +
capecitabine until disease progression.

- Subjects assigned to Arm A that have progressive disease will be offered Avelumab +
Ad-CEA vaccine in combination with a standard chemotherapy regimen.

- Kaplan-Meier curves and a two-tailed log-rank test will be the primary analysis methods.

- The accrual ceiling for the study is set at 97.

- INCLUSION CRITERIA:

- Subjects must have previously untreated metastatic or unresectable colorectal cancer
and have no contraindications to treatment with the standard of care regimen as
determined by the investigator. Prior adjuvant therapy is acceptable (including
immunotherapy), but must have been completed at least 6 months prior to metastatic
disease diagnosis.

- Patients should not be eligible for potentially curative surgical intervention in the
case of oligometastic disease at the time of enrollment or must have actively refused
after explicit discussion of potential benefit of this intervention with
multidisciplinary team.

- Histologically confirmed colorectal cancer

- Patients must have measurable disease by RECIST criteria.

- Age greater than or equal to18 years. Because safety data is not known with this agent
in patients less than 18 years old, children are excluded from this study.

- ECOG performance status less than or equal to 1.

- Patients must have normal organ and marrow function as defined below:

- Creatinine clearance (Cockroft-Gault calculated or 24-hour urine) greater than or
equal to 30 mL/min.

- Adequate hepatic function defined by a total bilirubin level less than or equal
to 1.5 (SqrRoot) the upper limit of normal range (ULN), an aspartate
aminotransferase (AST), level less than or equal to 2.5 (SqrRoot) ULN, and an
alanine aminotransferase (ALT) level less than or equal to 2.5 (SqrRoot) ULN or,
for subjects with documented metastatic disease to the liver, AST and ALT levels
less than or equal to 5 (SqrRoot) ULN.

- Hematological eligibility parameters (within16 days of enrollment):

- Granulocyte count greater than or equal to 1,500/mm^3

- Platelet count greater than or equal to 100,000/mm^3

- Hemoglobin greater than or equal to 9 g/dL

- The effects of Ad-CEA vaccine and Avelumab on the developing human fetus are unknown.
For this reason and because Ad-CEA vaccine and Avelumab as well as other therapeutic
agents used in this trial are known to be teratogenic, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry and for the duration of study
participation and for a period of 4 months after the last treatment with avelumab or 6
months after the last administration of bevacizumab, whichever occurs later. 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.

- Ability of subject to understand and the willingness to sign a written informed
consent document.

EXCLUSION CRITERIA:

- Metastatic or unresectable colorectal cancer with mismatch repair deficiency (MMR-D or
MSI-High).

- Concurrent treatment for cancer except agents specified within the treatment protocol.

- Prior surgery or gastrointestinal perforation within 28 days of enrollment.

- Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade > 1); however
alopecia, sensory neuropathy Grade <=2, or other Grade <=2 AEs not constituting a
safety risk based on investigator's judgment are acceptable.

- Known history of testing positive for HIV or known acquired immunodeficiency syndrome.

- Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)

- Any significant disease that, in the opinion of the investigator, may impair the
patient s tolerance of study treatment.

- Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid
diseases not requiring immunosuppressive treatment are eligible

- Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,
inhaled, topical steroids, or local steroid injection (e.g., intra-articular
injection); b. Systemic corticosteroids at physiologic doses less than or equal to 10
mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity
reactions (e.g., CT scan premedication).

- Patients who are receiving any other investigational agents within 28 days before
start of study treatment.

- Prior organ transplantation including allogenic stem-cell transplantation.

- Subjects with active central nervous system (CNS) metastases causing clinical symptoms
or metastases that require therapeutic intervention are excluded. Subjects with a
history of treated CNS metastases (by surgery or radiation therapy) are not eligible
unless they have fully recovered from treatment, demonstrated no progression for at
least 2 months, and do not require continued steroid therapy. Subjects with CNS
metastases incidentally detected during Screening which do not cause clinical symptoms
and for which standard of care suggests no therapeutic intervention is needed are
eligible.

- Active infection, requiring systemic therapy,

- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
prior to enrollment), unstable angina, congestive heart failure (greater than or equal
to New York Heart Association Classification Class II), or serious cardiac arrhythmia
requiring medication.

- Other severe acute or chronic medical conditions including immune colitis,
inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric
conditions including recent (within the past year) or active suicidal ideation or
behavior; or laboratory abnormalities that may increase the risk associated with study
participation or study treatment administration or may interfere with the
interpretation of study results and, in the judgment of the investigator, would make
the patient inappropriate for entry into this study.

- Pregnant women and breastfeeding mothers are excluded due to unknown impact on embryos
or infants.

- Known alcohol or drug abuse.

- Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v4.03 Grade greater than or equal to 3).

- Patients with a known hypersensitivity/allergy to any of the standard of care agents
used in this study or related compounds (e.g. platinum compounds) are excluded

- Prior history of hypertensive crisis or hypertensive encephalopathy.

- Serious, non-healing wound, active ulcer, or untreated bone fracture, including
tumorrelated pathological fracture.

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation).

- Patients being treated with medications with drug-drug interactions with study agents
will require evaluation by to determine if full doses of all study treatments can be
given safely. Significant drug-drug interactions will need to be addressed prior to
enrollment. Alternatively, the patient will not be eligible.

- Vaccination within 4 weeks of the first dose of avelumab and while on trials is
prohibited except for administration of inactivated vaccines