Pembrolizumab, Capecitabine, and Bevacizumab in Treating Patients With Microsatellite Stable Colorectal Cancer That Is Locally Advanced, Metastatic, or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD) of
capecitabine when administered with pembrolizumab and bevacizumab. (Safety Lead-In Cohort)
II. To evaluate the overall response rate (ORR) to pembrolizumab plus capecitabine and
bevacizumab (complete or partial response rate per Response Evaluation Criteria in Solid
Tumors [RECIST] 1.1) in subjects with metastatic or locally advanced unresectable
microsatellite stable (MSS)/mismatch repair proficient (pMMR) colorectal carcinoma (CRC) that
is stable or progressing on fluorouracil (5FU)-based therapy. (Phase II Expansion Cohort)

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of pembrolizumab in combination with capecitabine
and bevacizumab.

II. To evaluate ORR per immune-related RECIST (irRECIST). III. To evaluate duration of
response (DOR), disease control rate (DCR) and progression-free survival (PFS) per RECIST 1.1
and irRECIST and overall survival (OS).

TERTIARY OBJECTIVES:

I. Correlation of outcomes to line of therapy; stable disease or progression on a prior
regimen containing infusional 5-FU or capecitabine; prior exposure to bevacizumab; and
primary tumor location.

II. To explore baseline immune profiles via PD-L1, and multiplex IHC (immunohistochemistry)
for identification of potentially predictive biomarkers in patients with metastatic or
locally advanced, unresectable CRC treated with pembrolizumab-based combination therapy.

III. To characterize the change in the populations of tumor-infiltrating immune cells (TIICs)
by IHC induced by pembrolizumab-based combination therapy in paired pre- and on-treatment
tumor biopsies from patients with metastatic or locally advanced, unresectable MSS/pMMR CRC.

IV. To determine the change in T cell repertoire via next generation sequencing (NGS) within
blood and tumor biopsy samples induced by pembrolizumab-based combination therapy in patients
with metastatic or locally advanced, unresectable MSS/pMMR CRC.

V. To establish human immune system (HIS) patient-derived xenograft (PDX) models from
pre-treatment biopsies to a) analyze change in immune cell profiles HIS PDX models using the
same techniques as described for corresponding patients, above and b) correlate response to
pembrolizumab-containing therapy in patients and HIS PDX.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, bevacizumab IV
over 30-90 minutes on day 1, and capecitabine orally (PO) twice daily (BID) on days 1-14.
Treatment repeats every 3 weeks for up to 35 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 9 weeks until
disease progression or start of new anti-cancer therapy, and then every 12 weeks thereafter.

Inclusion Criteria:

- Have histologically confirmed, locally advanced unresectable or metastatic (stage IV)
colorectal adenocarcinoma

- Have locally confirmed MSS or pMMR CRC; MSS is defined as 0-1 allelic shifts among 3-5
tumor microsatellite loci using a PCR-based assay; pMMR is defined as presence of
protein expression of 4 MMR enzymes (MLH1, MSH2, MSH6 and PMS2) by
immunohistochemistry

- Have stable disease or progression on a prior regimen containing infusional 5-FU or
capecitabine according to the interpretation of the treating provider

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

- Have measurable disease based on RECIST 1.1

- Be willing to provide tissue from a newly obtained core or excisional biopsy of a
tumor lesion (phase II dose expansion cohort only); newly-obtained is defined as a
specimen obtained up to 6 weeks (42 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
Sponsor

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
performance scale

- Absolute neutrophil count (ANC) >= 1,500 /mcL (performed within 10 days of treatment
initiation)

- Platelets >= 100,000 / mcL (performed within 10 days of treatment initiation)

- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO)
dependency (within 7 days of assessment) (performed within 10 days of treatment
initiation)

- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated
creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 X
institutional ULN (performed within 10 days of treatment initiation) (glomerular
filtration rate [GFR] can also be used in place of creatinine or creatinine clearance
[CrCl])

- Creatinine clearance should be calculated per institutional standard

- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total
bilirubin levels > 1.5 ULN (performed within 10 days of treatment initiation)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X
ULN OR =< 5 X ULN for subjects with liver metastases (performed within 10 days of
treatment initiation)

- Albumin >= 2.5 mg/dL (performed within 10 days of treatment initiation)

- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic
range of intended use of anticoagulants (performed within 10 days of treatment
initiation)

- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving
anticoagulant therapy; as long as PT or PTT is within therapeutic range of intended
use of anticoagulants (performed within 10 days of treatment initiation)

- Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication; if
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required

- Female 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

- Male subjects of childbearing potential 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

- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment

Exclusion Criteria:

- 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 tuberculosis (TB) (Bacillus Tuberculosis)

- Hypersensitivity to pembrolizumab or any of its excipients

- Hypersensitivity/intolerance to capecitabine, infusional 5-flurouracil, or bevacizumab

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
due to agents administered more than 4 weeks earlier

- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at
baseline) from adverse events due to a previously administered agent

- Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study

- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting therapy

- 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 known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects 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, etc.) is not considered a
form of systemic treatment

- Has known history of (non-infectious) pneumonitis that required steroids or current
pneumonitis

- Has an active infection requiring systemic therapy

- 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

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

- 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 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)

- 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)

- Requires therapeutic anticoagulation with warfarin at baseline

- Patients must be off warfarin or warfarin-derivative anti-coagulants for at least
7 days prior to starting study drug, however, therapeutic or prophylactic therapy
with low-molecular weight heparin is allowed

- Has history of known coagulopathy that increases risk of bleeding or a history of
clinically significant hemorrhage within 12 months of start of study drug

- Bleeding risk including serious hemorrhage or hemoptysis within the last 3 months;
major surgery within the past 8 weeks or minor surgery within the past 4 weeks

- Has gastrointestinal bleeding or any other hemorrhage/bleeding event Common
Terminology Criteria for Adverse Events (CTCAE) grade > 3 within 6 months of start of
study drug

- Has greater than 1+ proteinuria on a urine dipstick or equivalent routine laboratory
analysis will require further testing with a urine protein to creatinine ratio (UPCR);
UPCR must be calculated as follows: UPCR = protein concentration (mg/dL)/creatinine
(mg/dL); if the UPCR >= 1, then the patient will not be eligible for study entry;
however, if urinalysis or equivalent routine laboratory analysis shows no protein,
then UPCR testing is not required

- Has a history of non-healing wounds or ulcers, or bone re-fractures within 3 months of
fracture

- Has a history of arterial thromboembolism within 12 months of start of study drug

- Has inadequately controlled hypertension (defined as systolic blood pressure greater
than 150 mm Hg or diastolic blood pressure greater than 95 mm Hg); the use of
antihypertensive medications to control blood pressure is permitted

- Has a history of hypertensive crisis or hypertensive encephalopathy within 6 months
prior to planned start of study drug

- Has had clinically significant cardiovascular disease within 12 months of planned
start of study drug, including myocardial infarction, unstable angina, grade 2 or
greater peripheral vascular disease, cerebrovascular accident, transient ischemic
attack, congestive heart failure, or arrhythmias not controlled by outpatient
medication, percutaneous transluminal coronary angioplasty/stent

- Has a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to planned start of study drug

- Known reversible posterior leukoencephalopathy syndrome (RPLS)

- Difficulty swallowing, malabsorption, active partial or complete bowel obstruction, or
other chronic gastrointestinal disease or conditions that may hamper compliance and/or
absorption of capecitabine

- 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 are not allowed