Inclusion Criteria:
1.18 and 75 years; Eastern Cooperative Oncology Group (ECOG) performance status score of 0
or 1; Life expectancy ≥ 3 months.
2.Histologically or cytologically confirmed unresectable locally advanced or metastatic
acral malignant melanoma.
3.At least one measurable lesion, as defined by RECIST v1.1, that has not been irradiated.
New lesions that have developed in a previously irradiated field may be used as sites of
measurable disease assuming all other criteria are met.
4. Providing tumor specimen obtained by biopsy or surgical sample within 2 years 5.No prior
systemic therapy or has received at least first-line treatment but appeared disease
progression or intolerance.
6.The main organs function are normally. Adequate bone marrow, hepatic, and renal function
documented within 4 weeks prior to treatment as documented by:absolute neutrophil count ≥
1.5*10^9/L; platelets ≥ 100 x 10^9/ L; hemoglobin ≥ 90 g/L(no blood transfusion within 14
days before enrollment) serum creatinine ≤1.5×ULN，total bilirubin ≤ 1.5 x upper limit of
normal (ULN); aspartic transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN ,
unless there are liver metastases in which case AST and ALT ≤5.0 x ULN;INR, aPTT, PT≤1.5 x
ULN; left ventricular ejection fraction (LVEF) ≥50%. serum creatinine ≤1╳ULN，creatinine
clearance >50 umol/L；urinary protein <2+ by urine dipstick. If dipstick is ≥2+ then a
24-hour urine collection can be done and the patient may enter only if urinary protein is
<2 g per 24 hours；Women of childbearing potential must have a negative serum or urine
pregnancy test are received within 7 days before the randomization. Women of non
childbearing age are defined as having been postmenopausal for at least 1 year, or having
undergone sterilization or hysterectomy.Male or female subjects should agree to use an
adequate method of contraception starting with the first dose of study therapy through 1
year after the last dose of study with an annual failure rate of less than 1% (such as
intrauterine devices , contraceptives or condoms) .
7.Written and voluntary informed consent. 8.No evidence of preexisting uncontrolled
hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour
apart. The baseline systolic blood pressure readings must be ≤140, and the baseline
diastolic blood pressure readings must be ≤90. Patients whose hypertension is controlled by
antihypertensive therapies are eligible.
Exclusion Criteria:
1. Any component of this study was not tolerated in the past.
2. Participated in other clinical trials within 4 weeks. 3. Hypersensitivity to recombinant humanized anti-PD-1 monoclonal Abm or its components.
4. Has received chemotherapy, surgery, radiotherapy, the last treatment from the first
dose less than 4 weeks, or oral targeted drugs for less than 5 half-lives, or oral
fluorouracil pyridine drugs for less than 14 days, mitomycin C and nitrosourea for
less than 6 weeks.
5. Prior therapy with VEGFR-target TKI included anlotinib or an anti-programmed cell
death (PD)-1, anti-PD-L1, anti-PD-L2, anti-tumor necrosis factor CD137, or
anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody ,or any other
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
Previous treatment with anti-angiogenesis agents including thalidomide, or inhibitors
of epidermoid growth factor (EGF), platelet derived growth factor (PDGF), or
fibroblast growth factors (FGF) receptors.
6. Any other form of systemic or local antitumor therapy is planned for the duration of
the study.
7. Immunosuppressive therapy with immunosuppressive agents or systemic or absorbable
local hormones (dosage > 10 mg/day prednisone or other therapeutic hormones) is
required for the purpose of immunosuppression, and is still in use for 2 weeks after
the first administration.
8. Has diagnosed and/or treated additional malignancy within 5 years prior to
randomization. Exceptions include cured basal cell carcinoma of skin and carcinoma in
situ of cervix.
9. Has brain metastasis and cancerous meningitis during screening . Active autoimmune
disease（Such as the following, but not limited to: autoimmune hepatitis interstitial
pneumonia enteritis vasculitis, nephritis。Subjects with asthma requiring
bronchodilators for medical intervention were not included） requiring systemic
treatment（Such as the use of palliative drugs, corticosteroids, or immunosuppressants）
occurred within 2 years prior to initial administration.
Abnormal coagulation function (INR > 1.5 or PT > 1.2uln or PTT > 1.2 ULN), bleeding
tendency or undergoing thrombolytic or anticoagulant therapy; treated with
anticoagulants or vitamin K antagonists such as warfarin, heparin or similar drugs;
10. Has any bleeding or bleeding events ≥ grade 3 or with unhealed wounds, ulcerative , or
fractures within 4 weeks prior to the first administration.
11. Received major surgical treatment or significant traumatic injury within Random 28
days prior. 12. Subjects with poor blood pressure control (systolic≥ 150 mmHg or diastolic ≥100mmHg)
13. Has multiple factors affecting oral medication or malabsorption syndromes.
14. Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring
recurrent drainage procedures.
15. A serious uncontrolled medical disorder or active infection that would impair their
ability to receive study treatment. liver cirrhosis,active hepatitis*;*active
hepatitis(Hepatitis B reference: HBsAg positive, and HBV DNA test value exceeds the
normal valueHepatitis C reference: HCV antibody positive, and HCV virus titer
detection value exceeds the upper limit of normal value.HIV infected.
16. Has vaccinated with vaccines or attenuated vaccines within 4 weeks prior to first
dose. Has received granulocyte colony stimulating factor(G -CSF)，or Granulocyte
macrophage colony stimulating factor (GM-CSF) within 2 weeks prior to first dose. 17. Subjects with a history of psychotropic substance abuse and being unable to get rid of
it or with mental disord. 18. Women who are pregnant or breast-feeding.
19. According to the judgement of the researchers, there are other factors that may lead
to the termination of the study. For example, other serious diseases including mental
disorders need to be treated together, serious laboratory abnormalities, accompanied
by family or social factors, which will affect the safety of the subjects, or the
collection of data and samples.
