Study of Surufatinib Combined With Toripalimab in Patients With Advanced Solid Tumors
Study of Surufatinib Combined With Toripalimab in Patients With Advanced Solid Tumors
This is a phase II, single arm, open-label, multicenter study to evaluate the efficacy and
 safety of Surufatinib combined with Toripalimab in patients with advanced solid tumors.
The study population is about 200 patients with advanced solid tumors, who fails or cannot
 tolerate standard therapies, or for whom no effective standard therapy is available, or who
 refuses standard therapies. Surufatinib 250 mg once a day (QD) will be orally administrated
 and Toripalimab 240mg will be intravenously administered every 3 weeks up to documented
 disease progression, development of unacceptable toxicity, participant request, or withdrawal
 of consent. For Toripalimab, the upper time limit for treatment is 2 years. The primary
 objective is safety of safety run-in (about 6 patients) and objective response rate (ORR) of
 Surufatinib combined with Toripalimab in patients with advanced solid tumors.
Inclusion Criteria:

 -  Adequately understand the study and voluntarily sign the Informed Consent Form;

 -  18-75 years old;

 -  Histologically or cytologically confirmed advanced solid tumors (focusing on
 neuroendocrine neoplasmas (NENs), biliary tract cancer, gastric cancer, thyroid
 cancer, small cell lung cancer, soft tissue sarcoma, endometrial cancer and esophageal
 squamous cell carcinoma, etc);

 -  Fail or cannot tolerate the standard therapies, or for whom no effective standard
 therapy is available, or refuse standard therapy;

 -  Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group
 (ECOG) scale;

 -  Have measurable lesions (according to RECIST 1.1);

 -  Agree to provide histology samples;

 -  Lab tests within 7 days before first dose:

 1. Absolute neutrophil count (ANC) ≥1.5×10^9/L, platelet count ≥100×10^9/L, and
 hemoglobin ≥9 g/dL;

 2. Serum total bilirubin <1.5 times the upper limit of normal (ULN);

 3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤ 1.5
 times the ULN without liver metastases; and ALT and AST ≤ 3 times ULN with liver
 metastases;

 4. Serum creatinine <1.5 times ULN and creatinine clearance ≥50 mL/min;

 5. Urine protein < 2+; if ≥2+, 24-hour urine protein <1 g;

 6. International Normalized Ratio (INR) ≤1.5 ULN and activated partial
 thromboplastin time (APTT) ≤1.5 ULN;

 -  Have expected survival of more than 12 weeks;

 -  Male or females patients with reproductive potential must agree to use an effective
 contraceptive method, for example, double-barrier device, condom, oral or injected
 birth control medication or intrauterine device, during the study and within 90 days
 after study treatment discontinuation. All female patients are considered to be
 fertile, unless the patient had natural menopause or artificial menopause or
 sterilization (such as hysterectomy, bilateral oophorectomy or ovarian irradiation).

 Exclusion Criteria:

 -  Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or 1
 (except for hair loss or Grade ≤ 2 peripheral neurotoxicity caused by oxaliplatin);

 -  Other malignancies diagnosed within the previous 5 years, except skin basal cell
 carcinoma or skin squamous cell carcinoma or cervical carcinoma in situ;

 -  Central nervous system metastases;

 -  Systematic anti-tumor therapy received within 4 weeks prior to first dose, including
 chemotherapy, biotherapy, targeted therapy, hormonotherapy, and anti-tumor Chinese
 medicine treatment;

 -  Radical radiotherapy within 4 weeks prior to first dose, radioactive seed implantation
 within 60 days prior to first dose, or Palliative radiotherapy for a bone metastasis
 lesion within 1 week prior to first dose;

 -  Functional NENs which need to be treated with long acting Somatostatin analogues
 (SSAs) to control disease related syndromes, such as insulinoma, gastrinoma,
 glucagonoma, somatostatinoma, ACTHoma, VIPoma, accompanied by carcinoid syndrome,
 Zollinger-Ellison syndrome or other active symptoms;

 -  Previously treated with anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody,
 anti-CTLA-4 antibody, any other antibody acting on the T cell stimulation or
 checkpoint pathway or Surufatinib;

 -  Previously received anti-VEGF/VEGFR targeted drugs and progressed during the treatment
 or within 4 months after these drugs;

 -  Thyroid dysfunction with symptoms or clinical significance when screening except
 hypothyroidism controlled only by thyroid hormone replacement therapy, the level of
 TSH in patients with iodine refractory differentiated thyroid cancer is more than 0.1
 mU/L (or other corresponding unit level) before the beginning of the study treatment;

 -  Previously received immunosuppressive drugs except locally or temporarily used
 glucocorticoids;

 -  Autoimmune disease with systematic treatment or autoimmune disease history within 2
 years;

 -  Previously received systematic immunologic stimulants within 4 weeks prior to the
 first dose;

 -  Inoculated with any live vaccine or attenuated live vaccine within 4 weeks or planed
 to inoculate during the study;

 -  Major surgery within 4 weeks or unhealed wound/ulcer/fracture;

 -  Uncontrolled malignant hydrothorax, ascites, or pericardial effusion;

 -  Under anti-hypertension treatment, still uncontrolled hypertension, defined as:
 systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg;

 -  Disease or situation that affects drug absorption, or unable to take drugs orally;

 -  Previously received CYP3A4 strong inducers or strong inhibitors within 1 week or 5
 half-life periods;

 -  Active gastric and duodenal ulcers, ulcerative colitis and other digestive disease,
 gastrointestinal tumor with active bleeding, or other gastrointestinal conditions that
 may cause bleeding or perforation by investigator's discretion;

 -  History or presence of a serious hemorrhage (>30 ml within 2 months), hemoptysis (>5
 ml blood within 4 weeks) within 2 months;

 -  History or presence of an artery thrombosis or deep venous thrombosis within 6 months,
 or a thromboembolic event (including transient ischemic attack) within 12 months;

 -  Clinically significant cardiovascular disease, including but not limited to, acute
 myocardial infarction within 6 months prior to first dose, severe/unstable angina
 pectoris or coronary artery bypass grafting, congestive heart failure according to the
 New York Heart Association (NYHA) classification ≥ 2; ventricular arrhythmias which
 needs drug treatment; left ventricular ejection fraction (LVEF) <50%;

 -  Severe electrolyte abnormalities with clinical significance by investigator's
 discretion;

 -  Any clinically significant active infection, or unknown reason fever prior to first
 dose (temperature > 38.5℃);

 -  Active tuberculosis, on treatment or previously received antituberculosis therapy
 within 1 year;

 -  History or presence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis,
 radiation pneumonitis, drug-related pneumonia or severely injured lung function except
 radiation pneumonia in the radiotherapy area;

 -  A positive immunodeficiency virus (HIV) test;

 -  History of clinically significant hepatic disease, including, but not limited to,
 known hepatitis B virus (HBV) infection with HBV DNA positive (copies ≥1×10^3/ml or >
 200 IU/ml); known Hepatitis C virus (HCV) infection with HCV RNA positive (copies
 ≥1×10^3/ml); or liver cirrhosis, etc.;

 -  Previously received investigational treatments unlisted in China within 4 weeks prior
 to first dose;

 -  Women who are pregnant or lactating;

 -  Previously allergic to any of the JS001 or Surufatinib ingredients, or monoclonal
 antibody;

 -  Any other conditions are inappropriate for the use of the investigational products by
 investigator's discretion.