| Eligibility |
Inclusion criteria:
1. Fully understand and be willing to provide written informed consent;
2. Male or female with age = 18 years and =75 years (At part B age =18 years);
3. The expected survival is = 3 months;
4. ECOG PS 0 or 1;
5. Advanced tumor patients who have failed standard treatment (including PD-1/PD-L1),
cannot tolerate standard treatment, OR refused/have no standard treatment (note:
Patients with hepatocellular carcinoma, lung cancer and urothelial carcinoma that have
failed PD-1 or PD-L1 treatment are preferred, and other types of the advanced tumor
patients without standard treatment can be enrolled according to initial efficacy);
6. Having at least one measurable disease per RECIST 1.1.
7. Agree to provide tumor tissue samples (fresh biopsy samples before treatment should be
provided as far as possible; for patients who cannot provide fresh biopsy samples
before treatment, archived samples can be provided within 2 years; for some patients
who cannot provide qualified tumor tissue samples, they can also be included in the
group after discussion and agreement between the investigator and the sponsor);
8. The results of laboratory tests during the screening period indicate that the patient
has good organ function:
a) Hematology (no blood transfusion within 14 days and no treatment with blood
components or granulocyte colony cytokines): i. Absolute neutrophil count ANC =
1.5×109/L(1,500/mm3) ii. Platelets = 100×109/L(Part B: = 75×109/L) (100,000/mm3) iii.
Hemoglobin = 10.0g/dL (Part B: = 9.0g/dL) b) Hepatic function: i. Serum total
bilirubin(TBil) =1.5×ULN ; For patients with primary liver cancer, liver metastasis,
or proven/suspected Gilbert's disease, TBil = 2×ULN ii. AST and ALT =2.5 × ULN; =5×ULN
in those with hepatic metastasis or primary liver cancer.
c) Renal function: i. Creatinine clearance(CrCl) =50mL/min(Cockcroft-Gault formula);
ii. Urine protein = 2+ (if the urine protein is 2+, the 24-h urine protein test will
be performed, and only patients with =2g are eligible).
d) Coagulation function: International standardized ratio (PT/INR) and activated
partial thrombin time (APTT) =1.5×ULN (for those receiving anticoagulant therapy, such
as low molecular weight heparin or warfarin, the anticoagulant dose is required to be
stable for at least 4 weeks without dose adjustment, and the coagulation parameters
INR and APTT at screening are within the expected range of anticoagulant therapy) e)
Endocrine function: Thyroid stimulating hormone (TSH) normal, or abnormal TSH but
normal FT3 and/or FT4 (for patients with hypothyroidism with abnormal TSH but normal
FT4) f) Cardiac function: QTc interval = 460 ms for male and = 480 ms for female,
which is calculated according to Fridericia formula.
9. Men or women patients of childbearing potentials agree to use an effective method of
contraception (e.g., oral contraceptives, intrauterine devices, or barrier
contraception combined with spermicide) and continued to use contraception for 6
months after treatment.
10. Good compliance and follow-up.
Exclusion criteria:
1. A history of malignancies other than the tumors described in this study within 5
years, with the exception of early malignancies that have been completely cured (no
recurrence within 5 years), including but not limited to adequately treated thyroid
cancer, carcinoma in situ of the cervix, basal or squamous cell skin cancer, and
ductal carcinoma in situ after the radical mastectomy);
2. The patients received systemic antitumor drugs(chemotherapy, small molecular targeted
drug therapy, hormone therapy, immunotherapy or biological treatment, etc.), local
anti-tumor therapy (e.g., patients accepted palliative radiotherapy for bone
metastases are eligible, in which the radiotherapy is performed more than 2 weeks
before the baseline tumor assessment ), or clinical research drug/treatment instrument
within 4 weeks prior to first dose;
3. Patients who have previously received PCKS9 inhibitor therapy;
4. Adverse reactions caused by previous treatment have not recovered to GRADE 1 or below
per CTCAE (version 5.0) (except alopecia and neurotoxicity, which investigator judged
could not be recovered for a long time);
5. Previous allogeneic hematopoietic stem cell transplantation or solid organ
transplantation;
6. Having untreated central nervous system metastasis, or meningeal metastasis. Patients
who has received treatment for brain metastases are eligible if meet all the following
criterion; stable condition is observed at least 3 months; no radiological progression
is identified within 4 weeks prior to first dose; all the nervous system symptoms have
returned to baseline levels; no new evidence or expanded brain metastases; has stopped
radiotherapy, surgery or steroid therapy at least 28 days prior to first dose;
7. Autoimmune diseases, including but not limited to systemic lupus erythematosus,
rheumatoid arthritis, inflammatory bowel disease, etc., diagnosed within 2 years are
ineligible, except for type I diabetes controlled by replacement therapy, skin
diseases that do not require systemic treatment (e.g., psoriasis and vitiligo),
endocrine diseases controlled by hormone replacement therapy (e.g., hypothyroidism);
8. Patients with associated clinical symptoms (dyspnea, wheezing, abdominal distension,
etc.), uncontrolled or repetitive drainage of pleural/abdominal effusion or
pericardial effusion. The patients with pleural/abdominal effusion are not allowed to
accept intrapleural/intraperitoneal injection of anti-tumor agents accordingly;
9. Have serious cardiovascular and cerebrovascular diseases, such as poorly controlled
hypertension (systolic blood pressure > 150mmHg and/or diastolic blood pressure >
100mmHg) or pulmonary hypertension as judged by the investigator; Unstable angina or
myocardial infarction, coronary artery bypass grafting or stenting within 6 months
prior to study use; Chronic heart failure with heart function grade 2 or greater
(NYHA); Degree ? or higher heart block; Grade =2 supraventricular or ventricular
arrhythmias; Left ventricular ejection fraction (LVEF) < 50%; Cerebrovascular accident
(CVA) or transient ischemic attack (TIA) occurred within 6 months prior to medication;
10. History of pulmonary disease: drug-induced interstitial lung disease or pneumonia,
obstructive pulmonary disease that severely affects lung function, and symptomatic
bronchospasm;
11. Has an active infection requiring systemic treatment;
12. Human immunodeficiency virus (HIV) antibody test positive;
13. Patients with non-alcoholic steatohepatitis, alcoholic/drug-related/autoimmune
hepatitis or uncontrolled active hepatitis B virus (HBV), or hepatitis C virus (HCV):
1. Active HBV infection is defined as patients with surface antigen (HBsAg) positive
and detectable DNA higher than the upper limit of the reference in each research
center, accompanied with increased ALT; active HCV infection is defined as
patients with positive HCV antibody and positive HCV RNA.
2. Patients with active HBV can take antiviral drugs, such as nucleoside (acid)
analogues (NAs), as recommended in the Guidelines for the Prevention and
Treatment of Chronic Hepatitis B (2019 edition). Prior to the first dose,
patients with HBV DNA < 2000 IU/ mL can participate in this study.
3. Patients who test positive for HCV antibodies can only be enrolled in this study
if the polymerase chain reaction (PCR) test is negative for HCV RNA. D) If the
patients were receiving antiviral therapy at the time of enrollment and were
required to maintain stable antiviral therapy throughout the study, any patients
with compliance concerns were excluded from enrollment.
14. Active tuberculosis (TB) is known to exist. Patients suspected of having active TB
should be examined for chest X-rays, sputum cytology, and clinical signs and symptoms.
15. Received systemic corticosteroids (prednisone > 10mg/ day or equivalent) or other
immunosuppressive drugs within 14 days prior to the first dose;
16. Have received broad-spectrum antibiotics that may affect gut microbiota within 14 days
prior to the first administration;
17. Receiving live or attenuated live vaccine within 4 weeks prior to the first
administration;
18. Major surgical procedures (as defined by the investigator, e.g., open biopsy and
severe trauma) were performed within 4 weeks prior to the first dose. Note:
Intravenous drip replacement is acceptable. Patients who plan to accept major surgery
within 30 days after the first dose or not yet fully recovered from previous surgery.
Patients with local surgery (e.g., core needle biopsy and prostate biopsy) performed
at least 24 h before the first administration are eligible;
19. Those who have a history of psychotropic drug abuse and cannot get rid of it or have a
history of mental disorders;
20. Pregnant or lactating women;
21. Patients are allergic to JS002 or Toripalimab and their active ingredients or
excipient;
22. Other severe, acute or chronic medical or psychiatric conditions or laboratory
abnormalities that, in the investigator's judgment, may increase the risk associated
with study participation or may interfere with the interpretation of study results.
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