Pembrolizumab and Liver-Directed Therapy in Treating Patients With Well-Differentiated Neuroendocrine Tumors and Symptomatic and/or Progressive Liver Metastases

PRIMARY OBJECTIVES:

I. To evaluate the best observed overall response rate (ORR) in lesion(s) not targeted for
liver-directed therapy (abscopal effect) to pembrolizumab plus liver-directed therapy
according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for patients with
metastatic well-differentiated (World Heath Organization [WHO] grade 1 or 2) neuroendocrine
tumors (WD-NETs).

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of pembrolizumab in combination with
liver-directed therapies in this patient population.

II. To evaluate duration of response (DOR) in patients receiving pembrolizumab in combination
with liver-directed therapies.

III. To evaluate progression free survival (PFS) in subjects treated with pembrolizumab in
combination with liver-directed therapies.

IV. Best observed radiographic ORR per modified RECIST (mRECIST) in lesions targeted for
liver-directed therapy.

V. Duration of response in lesions targeted for liver-directed therapy by mRECIST.

OUTLINE: Patients are assigned to 1 of 4 groups.

GROUP I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1.
Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or
unacceptable toxicity. Patients with up to 6 liver lesions, largest being no larger than 4 cm
who have < 25% liver parenchyma replacement by tumors, undergo computed tomography
(CT)-guided radiofrequency ablation (RFA) over 2-3 hours, 3-7 days following the first dose
of pembrolizumab.

GROUP II: Patients receive pembrolizumab as in Group I. Patients with any number of liver
lesions, largest being no larger than 5 cm, who have < 75% liver parenchyma replacement by
tumors, undergo transarterial embolization (TAE) over 2-3 hours, 3-7 days following the first
dose of pembrolizumab.

GROUP III: Patients receive pembrolizumab as in Group I. Patients with any number of liver
lesions, largest measuring more than 5 cm, who have < 75% liver parenchyma replacement by
tumors, undergo yttrium-90 microsphere radioembolization (RE) 3-15 days following the first
dose of pembrolizumab.

GROUP IV: Patients receive pembrolizumab as in Group I. Patients with up to 6 liver lesions,
largest being no larger than 4 cm who have < 25% liver parenchyma replacement by tumors,
undergo CT-guided cryoablation over 2-3 hours, 3-7 days following the first dose of
pembrolizumab.

After completion of study treatment, patients are followed up at 30 days and then every 3-6
months thereafter.

Inclusion Criteria:

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

- Have a histologically proven well-differentiated neuroendocrine tumor

- Radiographic, biochemical, or clinical evidence of tumor progression over a period of
up to 12 months in at least one site

- At least one symptomatic and/or progressive liver lesion over a period of up to 12
months

- Have at least one measurable lesions in the liver or at least one measurable lesion in
the liver and another measurable lesion elsewhere, based on RECIST version (v.) 1.1

- Patients must agree to have a biopsy of metastatic tissue at baseline and
on-treatment, and there must be a lesion that can be biopsied with acceptable clinical
risk (as judged by the investigator)

- Patients with unsuccessful baseline biopsies may undergo an additional biopsy
attempt (at the same or a different site, determined by the investigator)

- For patients with an intact primary and no metastatic site that can be safely
biopsied, biopsy of the primary is acceptable, but must be approved by the
principal investigator

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

- Have a life expectancy of greater than 3 months

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

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

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

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

- Albumin >= 2.5 mg/dL, should be 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 partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants, should be
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, should be 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 should 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; subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year

- Male subjects should 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

Exclusion Criteria:

- Has had prior thermal ablation, embolotherapy, radioembolization, or external beam
radiation

- Has greater than 75% liver parenchyma replacement by tumor

- 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

- 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

- 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

- Concurrent somatostatin analog therapy is allowed (for control of hormone excess)
provided patient has been on stable dose for at least two months and tumor
progression has been documented

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

- Has an active infection requiring systemic therapy

- Has liver fibrosis either determined by imaging or laboratory testing (i.e. total
serum bilirubin > 1.5 times ULN, AST and ALT > 2.5 times ULN, INR > 1.5 times ULN,
albumin < 2.5 mg/dl)

- 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 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)

- 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