| Eligibility |
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:
1. 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;
2. Renal function: serum creatinine°=1.5 x ULN or calculated creatinine clearance
(CrCl) >40 mL/min (using Cockcroft Gault formula);
3. Hepatic function: AST/ALT=2.5 x ULN in subjects without hepatic metastasis,
AST/ALT=5 x ULN in those with hepatic metastasis;
4. 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 ? or ? heart failure defined by New York Heart
Association, degree ? 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;
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