Inclusion Criteria:
- - Patients who included in this study must fulfil all of the following criteria:
1.
Fully aware of this study and voluntary to sign the informed consent form (the
informed consent form must be signed before any trial-specific procedure is
performed);
2. Aged 18-75 (inclusive);
3. Histologically or cytologically confirmed patients with inoperable or metastatic
high-grade neuroendocrine neoplasm (Ki67 index > 20% or with mitotic count of
more than 20 mitoses per high power field);
4. Patients who failed to receive standard treatment (Have progressed on previous
treatment, or treatment toxicity and side effects are not tolerated), or cannot
receive standard treatment (including patients who are intolerant to standard
treatment, who are judged by the investigator to be unsuitable for standard
treatment or who refuse to receive standard treatment), or who have no standard
treatment plan;
5. Having clear measurable lesions (according to RECIST 1.1). If the lesion is the
only one that has received previous local treatment (radiotherapy, ablation,
vascular intervention, etc.), there must be clear imaging evidence of disease
progression in that lesion;
6. Agree to provide tumor specimens (for further diagnosis of pathological grade,
detection of PD-L1 expression and lymphocyte infiltration);
7. ECOG performance status of 0 or 1;
8. Brain metastases are asymptomatic or stable after local treatment are allowed to
be enrolled as long as they meet the following conditions:
1) Measurable lesions are outside of the central nervous system 2) No central nervous
system symptoms or no exacerbation of symptoms for at least 2 weeks 3) No
glucocorticoid treatment or discontinuation of glucocorticoid treatment within 7 days
before first dose of study treatment.
9. Patients were allowed to receive palliative radiation therapy, but it ended 14 days
before the first dose of study treatment, and the radiation-related toxicity returned
to grade 1 or less (CTCAE5.0); 10. Predicted survival ≥ 3 months; 11. Patients with
adequate organ functions whose laboratory tests within 7 days before the first dose
meet the following requirements:
1. Absolute neutrophil count (ANC) ≥1.5x109/L within 14 days, without use of
granulocyte colony-stimulating factor or other hematopoietic stimulating factor.
2. Platelet count ≥100×109/L within 14 days, without blood transfusion or use of
blood product.
3. Hemoglobin ≥ 9 g/dL within 14 days, without blood transfusion or erythropoietin.
4. Total bilirubin ≤1.5 × upper limit of normal (ULN); Such as total bilirubin >
1.5×ULN, but direct bilirubin ≤ ULN was also allowed.
5. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5×ULN (ALT or
AST ≤5×ULN in patients with liver metastasis).
6. Serum creatinine ≤1.5×ULN and creatinine clearance rate ≥60 mL /min (calculated
according to the Cockcroft-Gault formula).
7. Good coagulation function, defined as International normalized ratio (INR) or
prothrombin time (PT) ≤1.5 ULN;
8. Normal thyroid function, defined as thyroid stimulating hormone (TSH) within the
normal range. If the baseline TSH is outside the normal range, subjects with
total T3 (or FT3) and FT4 within the normal range can be enrolled; Hypothyroidism
that can be controlled only by thyroid hormone replacement therapy can be
enrolled;
9. The myocardial enzyme profile is within the normal range (if the investigator
comprehensively determines that the simple laboratory abnormality is not
clinically significant, the patients is allowed to be enrolled); 12. Females of
childbearing potential must have a negative urine or serum pregnancy test within
3 days prior to the first dose (Day 1 of Cycle 1). If a urine pregnancy test
result cannot be confirmed as negative, a blood pregnancy test is requested. All
female patients will be considered to be of childbearing potential unless they
are naturally postmenopausal, underwent artificial menopause, or are surgically
sterile (e.g., hysterectomy, bilateral adnexectomy).
13. If there is a risk of conception, Male or female patients of childbearing
potential volunteer to use effective contraceptive methods (failure rate ≤ 1%) during
the study and within 120 days after last administration of the study drug.
Exclusion Criteria:
- - Subjects must be excluded from this study when any one of the following criteria is
met:
1.
Presence of other malignancies in the past 5 years (except for basal cell
carcinoma or squamous cell carcinoma of the skin and carcinoma in situ of the
cervix, which were effectively controlled);
2. Currently participate in an interventional clinical study, or have been treated
with another study drug or medical equipment within 4 weeks prior to the first
dose;
3. Previous use of anti (PD-1), anti-PD-L1, anti-PD-L2 or CTLA-4 antibody or any
other antibody acting on T cell co-stimulatory or checkpoint pathways (including
but not limited to OX-40, CD137, etc.), anti-VEGF/VEGFR-targeted drugs;
4. Having abnormal thyroid function with symptoms ongoing or requiring treatment at
screening (only hypothyroidism that can be controlled by thyroid hormone
replacement therapy can be included);
5. Received systemic therapy with anti-neuroendocrine tumor of proprietary Chinese
medicines or immunomodulatory drugs (including thymosin, interferon and
interleukin, except for local control of pleural effusion) within 2 weeks prior
to the first dose;
6. Patients with any active autoimmune disorders requiring systematic treatment
(e.g., palliative drugs, glucocorticoids, or immunosuppressants) or a history of
autoimmune disease in the past 2 years. Alternative therapies (e.g. thyroxine,
insulin, or physiologic glucocorticoids for adrenal or pituitary dysfunction) are
not considered systemic;
7. Use of immunosuppressant within 7 days prior to the first dose, not including
local glucocorticoid via nasal spray, inhalation or other routes or systemic
glucocorticoid at physiological dose. Note: Physiological doses of
glucocorticoids (≤10 mg/ day of prednisone or equivalent dose) are permitted;
8. Uncontrollable malignant hydrothorax, ascites or pericardial effusion (patients
who do not need drainage effusion or who stop drainage for 3 days without
significant increase in effusion can be included in the group);
9. Use of CYP3A potent or moderate inducers during the administration of concomitant
medications or within 1 weeks or 5 half-lives (whichever is longer) prior to the
first dose (Appendix 3);
10. Patients who currently have gastric and duodenal active ulcer, ulcerative
colitis, or active bleeding in the unresected tumor, or serious gastrointestinal
disorders, or other conditions that may cause haemorrhage of digestive tract or
perforation;
11. Patients with evidence or history of obvious bleeding tendency within 2 months
prior to the first dose. (bleeding within 2 months > 30 mL, hematemesis, black
feces), hemoptysis (within 4 weeks > 5 mL of fresh blood);
12. Allogeneic organ transplantation (except corneal transplantation) or allogeneic
hematopoietic stem cell transplantation;
13. A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to the study drugs (Sintilimab, IBI310, Surufatinib), or a
prior history of severe allergy to any other monoclonal antibody.
14. Patients with multiple factors affecting oral medication (such as inability to
swallow, post-gastrointestinal resection, chronic diarrhea and intestinal
obstruction);
15. Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or
1 (except for hair loss);
16. Human immunodeficiency virus (HIV) antibody positive;
17. Untreated active hepatitis B (defined as HBsAg positive with HBV-DNA copy number
greater than the upper limit of the normal value in the laboratory department of
the research center);
Note: Hepatitis B subjects who meet the following criteria can also be enrolled:
1) HBV viral load before initial administration < 1000 copies/mL (200 IU/ml). Subjects
should receive anti-HBV therapy to avoid virus reactivation 2) For patients with HBc
(+), HBsAg (-), anti-HBS (-), and HBV viral load (-), prophylactic anti-HBV therapy is
not required, but rigorous monitoring of virus reactivation is required;
18. Patients with known positive hepatitis C virus antibody (HCV Ab) and HCV RNA > 1 ×
103 copies/mL;
19. Vaccination of any live or attenuated live vaccine within 4 weeks prior to the
first dose or during the study; Note: Acceptance of injectable inactivated virus
vaccine against seasonal influenza is permitted within 30 days prior to first dose;
Intranasally administered live attenuated flu vaccines are not allowed;
20. Pregnant (positive pregnancy test prior to administration) or lactating women;
21. Presence of any serious or uncontrollable systemic illness;
22. Other disease, metabolic disorder, physical examination anomaly, abnormal
laboratory result, or any other condition that investigators suspect may prohibit use
of the investigational product, affect interpretation of study results, or put the
patient at high risk.
