A Randomized, Controlled, Multi-center, Phase III Clinical Study to Investigate Recombinant Humanized PD-1 Monoclonal Antibody Injection (JS001) Versus Dacarbazine as the 1st-line Therapy for Unresectable or Metastatic Melanoma

• In the subjects who have clinical benefit evaluated by investigators and tolerate the study treatment, treatment will be considered to give after occurrence of progression defined by RECIST1.1 as evaluated by the initial investigators, these subjects must terminate the treatment when further progression is validated.
• The subjects in dacarbazine treatment group are allowed to be crossed to receive JS001 after progression of disease; however, they need to be re-evaluated if they meet the inclusion/exclusion criteria.

Subjects need to provide one tumor tissue specimen for archival or one newly acquired biopsy tissue from the site that is previously not irradiated for evaluation of PD-L1 expression status when they participate in the study. The PD-L1 expression status of specimen will be evaluated in the central laboratory using immunohistochemical (IHC) method. Subjects with positive or negative PD-L1 can be enrolled in this study, and the clinical activity in the two subgroups will be evaluated in accordance with the prespecified subgroup analysis.

Inclusion criteria

• Patients are eligible for participation in the trial only when they meet the following criteria:
• Age ≥18 years, male or female;
• Systemic treatment-naïve, histologically confirmed unresectable stage III or IV melanoma. Previous adjuvant or neoadjuvant therapy is allowed, however, it is required to be completed at least three weeks prior to the randomization, and all the relevant adverse events have been recovered to normal or CTC-AE grade 1;
• Measurable lesion (according to RECIST v1.1 criteria);
• ECOG score 0 or 1
• Tumor tissue has to be provided (FFPE archival or newly acquired tissue block or unstained slide from FFPE) for analysis of biomarkers;
• Previous radiotherapy must be completed at least two weeks prior to administration of investigational product;
• The laboratory data for screening must meet the following criteria and should be acquired within 14 days prior to the first dose:

• Peripheral hemogram: white blood cell (WBC) ≥3.0×109/L, neutrophil (ANC) ≥1.5×109/L, platelet (PLT) ≥100×109/L, hemoglobin (Hgb) ≥90g/L;
• Renal function: serum creatinine°≤1.5 x ULN or calculated creatinine clearance (CrCl) >40 mL/min (using Cockcroft Gault formula);
• Hepatic function: AST/ALT≤2.5 x ULN in subjects without hepatic metastasis, AST/ALT≤5 x ULN in those with hepatic metastasis;
• Total bilirubin ≤1.5 x ULN (except the subjects with Gilbert syndrome, the total bilirubin must be < 3.0mg/dL).
• Estimated survival ≥16 weeks;
• Men with reproductive capacity or women of childbearing potential must use highly effective contraceptive methods during the trial (e.g., oral contraceptives, intrauterine device, sexual abstinence or barrier method combined with spermicide), and continue contraception for 12 months after the end of treatment;
• Subject is willing to participate in the study, sign the informed consent form with good compliance and cooperation with follow-up;
• Re-enrollment: re-enrollment of subjects who discontinue the study for failure prior to the treatment (i.e., the subject has not been randomized/received any treatment yet) is allowed in this study. The subjects must re-sign the informed consent form if they are re-enrolled.

Exclusion criteria

• Patients will be excluded from the trial when they have any one of the following conditions:
• Previous treatment with anti-PD-1, anti-PD-L1or anti-PD-L2 therapy;
• Known allergy to recombinant humanized anti-PD-1 monoclonal antibody and its components;
• Presence of BRAF mutation, except unwillingness or inability to receive BRAF mutation inhibitor;
• Malignant melanoma originated from eyes or mucosa;
• Having received other anti-tumor therapy (including corticosteroids, immunotherapy) or participated in other clinical studies within 4 weeks prior to the start of treatment, or having not recovered from the previous toxicity (except grade 2 alopecia and grade 1 neurotoxicity);
• Pregnant or lactating women;
• HIV positive; HCV positive; positive HBV DNA copies detected simultaneously with HBsAg or HBCAb positive (quantitative detection limit 500 IU/ml);
• History of active pulmonary tuberculosis;
• Active autoimmune disease requiring systemic treatment in the past two years (e.g., use of disease-modulating drugs, corticosteroids or immunosuppressive drugs), relevant alternative therapy is allowed (e.g., thyroxine, insulin or physiological corticosteroid replacement therapy for renal or pituitary insufficiency);
• Other serious, uncontrollable concomitant diseases that may affect the compliance with protocol or interfere with interpretation of the results, including active opportunistic infection (serious) infection in progressive stage, uncontrollable diabetes, cardiovascular disease (grade Ⅲ or Ⅳ heart failure defined by New York Heart Association, degree Ⅱ and above cardiac block, myocardial infarction in the past 6 months, unstable arrhythmia or unstable angina pectoris, cerebral infarction within 3 months, etc.) or pulmonary disease (history of interstitial pneumonia, obstructive pulmonary disease and symptomatic bronchospasm);
• Subjects with active central nervous system (CNS) metastasis, active brain metastasis or leptomeningeal metastatic foci. For the subjects with brain metastasis, if they have received treatment and have no evidence of progressive disease on the nuclear magnetic resonance imaging (MRI) at least 8 weeks after completion of the treatment and within 28 days prior to the first dose, they are eligible to participate in the study. Meanwhile, it is required corticosteroid for systemic therapy at the dose of immunosuppressant (>10mg/day prednisone equivalent) must not be needed at least two weeks prior to administration of investigational product;
• Previously receiving hematopoietic stimulating factor within two weeks prior to the start of treatment, for example, colony stimulating factor, erythropoietin;
• Having been injected by live vaccine within 4 weeks prior to the start of treatment;
• Major surgery within 4 weeks prior to the start of treatment (not including diagnostic surgery);
• History of psychotropic drug abuse and inability to give up or history of mental disorder;
• Having other malignant tumors that have not been recovered in the past 5 years, not including obviously cured malignancies, or curable cancers, for example, basal cell carcinoma or squamous cell cutaneous carcinoma, superficial bladder cancer or carcinoma in situ of prostate, carcinoma in situ of cervix or carcinoma in situ of breast;
• Other severe, acute or chronic medical or mental diseases or abnormal laboratory findings that may increase the risk from participation in the study, or interfere with interpretation of study results according to investigators' opinion.

Eligibility criteria on cross-over to JS001 treatment period -inclusion criteria for the subjects who are previously randomized into DTIC:

• According to investigators' evaluation, the subjects must have documented radiological progression of disease during DTIC treatment;
• Previous anticancer therapy, including DTIC and palliative radiotherapy, must be completed at least three weeks prior to the dose of JS001;
• Adverse events related with DTIC or palliative radiotherapy must have been relieved to grade 1 or baseline at randomization;
• Any major surgery must be completed at least 28 days prior to the first dose of JS001;
• No previous treatment with anti-PD-1 or anti-PD-L1 therapy;
• The laboratory data on the eligibility for cross-over therapy must meet the following criteria and should be acquired within 14 days prior to the start of JS001 treatment:
• Peripheral hemogram: white blood cell (WBC) ≥3.0×109/L, neutrophil (ANC) ≥1.5×109/L, platelet (PLT) ≥100×109/L, hemoglobin (Hgb) ≥90g/L;
• Renal function: serum creatinine≤1.5 x ULN or calculated creatinine clearance (CrCl) >40 mL/min (using Cockcroft Gault formula);
• Hepatic function: AST/ALT≤2.5 x ULN in subjects with no hepatic metastasis, AST/ALT≤5 x ULN in those with hepatic metastasis;
• Total bilirubin≤1.5 x ULN (except the subjects with Gilbert syndrome, total bilirubin must be<3.0mg/dL).
• Men with reproductive capacity or women of childbearing potential must use highly effective contraceptive methods during the trial (e.g., oral contraceptives, intrauterine device, sexual abstinence or barrier method combined with spermicide), and continue contraception for 12 months after the end of treatment;
• Subjects are willing to participate in the study, sign the informed consent form with good compliance and cooperation with follow-up;