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 (NET) (WD-NETs).
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
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. PRRT using 177Lu-DOTATATE(Lutathera®) will be offered to patients with
somatostatin receptor positive (SSTR+) tumors with Ki-67 index > 20% (well-differentiated
grade 3). Patients may have any number of liver and/or extrahepatic lesions with liver
parenchyma replacement by tumor < 75%. 200±20 millicurie (mCi) of 177Lu-DOTATATE will be
administered intravenously per treatment on outpatient basis. Patients will receive a total
of four treatments of 177Lu-DOTATATE, administered every 8±1 weeks
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
After completion of study treatment, patients are followed up at 30 days and then every 3-6
Subject Inclusion Criteria
1. Be willing and able to provide written informed consent for the trial.
2. Be >= 18 years of age on day of signing informed consent.
3. Have a histologically proven well-differentiated neuroendocrine tumor (WHO grade 1,
grade 2, or morphologically and/or clinically well-differentiated grade 3) of any
primary site, including unknown primary site.
a. For group 1, only well-differentiated grade 3 tumors that demonstrate somatostatin
receptor expression on Ga-68 DOTA or In-111 Octreoscans will be allowed.
4. Radiographic, biochemical, or clinical evidence of tumor progression over a period of
up to 12 months in at least one site.
1. Group 1: At least one symptomatic and/or progressive somatostatin receptor
positive (SSTR+) lesion over a period of up to 12 months or have at least one
measurable lesion based on RECIST v. 1.1.
2. Groups 2-4: At least one symptomatic and/or progressive liver lesion over a
period of up to 12 months or have at least two measurable lesions in the liver or
at least one measurable lesion in the liver and another measurable lesion
elsewhere, based on RECIST v. 1.1.
5. 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).
1. Patients with unsuccessful baseline biopsies may undergo an additional biopsy
attempt (at the same or a different site, determined by the investigator).
2. 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
6. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
7. Have a life expectancy of greater than 3 months.
8. Demonstrate adequate organ function.
1. Absolute neutrophil count (ANC) ≥1,500 /microliters (mcL).
2. Platelet count >75,000/mcL.
3. Hemoglobin > 9g/dLb (For group 1 only. There is no hemoglobin cut-off level for
4. Serum creatinine OR Measured or calculated a creatinine clearance (GFR can also
be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60
mL/min for subject with creatinine levels > 1.5 X institutional ULN.
5. Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with
total bilirubin levels > 1.5 ULN.
6. AST (SGOT) and ALT (SGPT) ≤ 5 X ULN.
7. Albumin >2.5 mg/dL.
8. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or partial thrombin time
(PTT) is within therapeutic range of intended use of anticoagulants.
9. Female subject of childbearing potential should have a negative urine or serum
pregnancy within 30 days 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
10. 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.
11. 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.
Subject Exclusion Criteria
1. Has had prior thermal ablation, embolotherapy, radioembolization, or external beam
radiation within 30 days of initiation of study therapy.
2. Has had prior peptide receptor radionuclide therapy (group 1 only).
3. Has had biliary tract intervention that resulted in compromise to the Ampulla of Vater
or a biliary-enteric anastomosis (groups 2-4 only).
4. Has greater than 75% liver parenchyma replacement by tumor (determined by radiologist
5. 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.
6. 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
7. Has a known history of active Tuberculosis (TB) (Bacillus Tuberculosis).
8. Hypersensitivity to pembrolizumab or any of its excipients.
9. 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.
10. 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.
1. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.
2. Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
3. 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.
11. 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.
12. 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.
13. 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.
14. Has a history of (non-infectious) pneumonitis that required steroids or current
15. Has an active infection requiring systemic therapy.
16. Has liver fibrosis either determined by imaging or laboratory testing (i.e. total
serum bilirubin > 1.5 times ULN, Aspartate Aminotransferase (AST) and alanine
aminotransferase (ALT) > 5 times ULN, INR >1.5 times ULN, albumin < 2.0mg/dl).
17. 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.
18. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
19. 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.
20. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
21. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
22. Has known active untreated Hepatitis B.
23. Has received a live vaccine within 30 days of planned start of study therapy. a. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live
attenuated vaccines, and are not allowed