| Eligibility |
Inclusion Criteria:
- Confirmed G3 NENs originated in the gastroenteropancreatic tract (WHO 2010
classification). Patients with a G3 NEN of unknown primary will also be eligible for
this trial.
- Ki-67 >20% or mitotic rate > 20 per 10 HPF.
- Metastatic or locally advanced unresectable disease not amenable to treatment with
curative intent.
- No prior systemic treatment for advanced disease nor as adjuvant therapy.
- Availability of fresh or archive formalin-fixed, paraffin-embedded tumor tissue for
biomarker assessment.
- Patients must have clinically and/or radiographically documented measurable disease.
At least one site of disease must be unidimensionally measurable as per RECIST 1.1.
- Adequate organ function as defined by the following criteria (within 7 days prior to
enrollment):
1. absolute neutrophil count (ANC) =1500 cells/mm3
2. platelets =100,000 cells/mm3
3. hemoglobin =9.0 g/dL
4. AST and ALT =2.5 x upper limit of normal (ULN); in patients with liver metastases
AST and ALT =5.0 x ULN
5. total bilirubin =1.5 x ULN
6. serum creatinine =1.5 x ULN or calculated creatinine clearance =60 mL/min.
- Male or female, age =18 years.
- ECOG performance status of 0-2.
- Life expectancy of =12 weeks.
- Women of childbearing potential must have a negative serum or urine pregnancy test
within 7 days prior to treatment initiation.
- Highly effective contraception (i.e. methods with a failure rate of less than 1 % per
year) for both fertile, sexually active male and female subjects. Highly effective
contraception must be used 28 days prior to first trial treatment administration, for
the duration of trial treatment, and at least for 60 days after stopping trial
treatment.
- Signed and dated informed consent document must be given according to ICH/GCP, and
national/local regulations indicating that the patient (or legally acceptable
representative) has been informed of all pertinent aspects of the trial prior to
enrolment.
Exclusion Criteria:
- The following endocrine tumor types may not be included: paraganglioma, adrenal,
thyroid parathyroid or pituitary endocrine tumors. Large or small cell lung
neuroendocrine carcinoma of the lung will also be excluded.
- Prior therapy with any immune checkpoint inhibitor.
- Major surgery, except diagnostic biopsy, in <4 weeks or radiation therapy <2 weeks
prior to starting study treatment. Prior palliative radiotherapy to metastatic
lesion(s) is permitted, provided there is at least one measurable lesion that has not
been irradiated.
- Prior organ transplantation, including allogeneic stem-cell transplantation.
- Prior history of non-infectious pneumonitis requiring steroids or current pneumonitis.
- Systemic chronic steroid therapy (> 10 mg/day prednisone or equivalent) or other
immunosuppressive agents or use of any investigational drug within 28 days before the
start of trial treatment. Short-term administration of steroids for allergic reactions
or management of immune-related adverse events is allowed. Topical, inhaled, nasal and
ophthalmic steroids are also allowed.
- Use of any live vaccines against infectious diseases within 4 weeks of initiation of
study treatment.
- Known history of positive testing for Human Immunodeficiency Virus (HIV) infection,
known history of or positive tests for Hepatitis B virus surface antigen (HBVsAg) or
Hepatitis C ribonucleic acid (HCV RNA) indicating acute or chronic infection or other
significant acute or chronic infections requiring medication at study entry.
- Active, known or suspected autoimmune disease or a documented history of autoimmune
disease, including ulcerative colitis and Crohn's disease. (Patients with vitiligo,
type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only
requiring hormone replacement, psoriasis not requiring systemic treatment, or
conditions not expected to recur in the absence of an external trigger are permitted
to enroll).
- Active seizure disorder or evidence of brain metastases, spinal cord compression, or
carcinomatous meningitis.
- A serious uncontrolled medical disorder or active infection that would impair their
ability to receive study treatment will not be allowed to enter the study. Any of the
following within the 12 months prior to study drug administration: myocardial
infarction, uncontrolled angina, coronary/peripheral artery bypass graft, NYHA class >
III congestive heart failure, cerebrovascular accident or transient ischemic attack
and 6 months for deep vein thrombosis or pulmonary embolism.
- Known hypersensitivity reactions to monoclonal antibodies (= grade 3 according to NCI
Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 [xliii] or any past
medical history of anaphylaxis or uncontrolled asthma (i.e., 3 or more asthma
characteristics partially controlled).
- Any other prior malignancy within 5 years of study entry, with the exception of
adequately treated in-situ carcinoma of the cervix, breast or uteri, or
non-melanomatous skin cancer.
- Any psychological, familial, sociological or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule; those conditions
should be discussed with the patient before registration in the trial.
- Dementia or significantly altered mental status that would prohibit the understanding
or rendering of informed consent and compliance with the requirements of this
protocol.
- Female patients who are pregnant or lactating, or men and women of reproductive
potential not willing or not able to employ an effective method of birth
control/contraception to prevent pregnancy during treatment and for 6 months after
discontinuing study treatment The definition of effective contraception should be in
agreement with local regulation and based on the judgment of the principal
investigator or a designated associate.
- Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and in
the judgment of the investigator would make the patient inappropriate for study entry.
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