Sovantinib is an orally administered small molecule targeted drug that inhibits VEGFR1, 2, 3 and FGFR kinase activities and inhibits VEGFR2 phosphorylation and its downstream signaling, thereby achieving inhibition of tumor vasculature. After years of phase I and phase II clinical studies confirming the efficacy of soventinib in neuroendocrine tumors, a phase III clinical trial is being conducted to recruit patients with neuroendocrine tumors.
Major criteria for enrollment.
Mainly enrolled neuroendocrine tumors of different sites (G1/G2) with at least one measurable lesion and basically normal liver and kidney function and blood picture.
Enrollment was free of charge for treatment with sovalteinib or placebo (sovalteinib: placebo = 2:1) and free of charge for some tests and examinations.
195 cases enrolled in the national program for pancreatic NET
273 cases of non-pancreatic NETs are planned to be enrolled nationwide.
Specific entry criteria are as follows.
Enrollment criteria
1. Fully informed about the study and voluntarily signed the informed consent form;
2. Age > 18 years;
3. Patients with low- or intermediate-grade (G1 or G2) advanced (locally advanced or distant metastases that cannot be surgically resected) NET diagnosed by histopathology. For NET of pancreatic or gastrointestinal origin, low grade (G1) is defined as nuclear schizograms <2/10 high magnification field [HPF] and/or Ki-67 differentiation index <3%; intermediate grade (G2) is defined as nuclear schizograms 2-20/10 high magnification field [HPF] and/or Ki-67 differentiation index 3-20%.
If nuclear schizograms and Ki-67 indices corresponded to different grades of the same tumor tissue, the higher grade was followed. For NETs of lung and thymic origin, G1 is defined as nuclear schizograms <2/10 high magnification fields [HPF] without necrotic foci; G2 is defined as nuclear schizograms 2-10/10 high magnification fields [HPF] with or without necrotic foci. NET of other origin or unknown origin can refer to the grading criteria for NET of pancreatic or gastrointestinal origin. (Subject to central pathology audit results);
4, Previous treatment with ≤2 systemicAnti-tumor Therapy (SystemicAnti-tumor Therapy), either long-acting growth inhibitor analogs, interferon, PRRT (peptide receptor radionuclide therapy), mTOR inhibitors or chemotherapy; patients with advanced primary treatment who cannot receive or refuse to receive the above treatments can also be enrolled;
5. Patients need to have imaging-confirmed tumor disease progression within 12 months prior to randomization;
6. Patients with measurable lesions (according to RECIST 1.1 criteria);
7, absolute neutrophil count (ANC) ≥ 1.5×109/L, platelets ≥ 100×109/L and hemoglobin ≥ 9g/dL;
8, the patient’s total serum bilirubin ≤ 1.5 times the upper limit of the reference range of normal values (ULN);
9, in the absence of supportive therapy, without liver metastases, glutamic aminotransferase (ALT), glutamic aminotransferase (AST) and alkaline phosphatase (ALP) ≤ 2.5 times ULN; liver metastases ALT, AST and ALP ≤ 5 times ULN;
10.Serum creatinine ≤1.5 times ULN and creatinine clearance ≥60ml/min;
11, International normalized ratio (INR) ≤ 1.5 times ULN and partial activation prothrombin time (APTT) ≤ 1.5 times ULN;
12.ECOG physical status 0 or 1 point;
13, Expected survival more than 12 weeks;
14, Male or female patients of childbearing potential voluntarily use an effective contraceptive method, such as a double barrier method, condom, oral or injectable contraceptive medication, IUD, etc., during the study period and within 90 days of the last study dose. All female patients will be considered fertile unless the female patient is spontaneously menopausal, has undergone artificial menopause or sterilization (e.g., hysterectomy, bilateral adnexal resection or radiation ovarian irradiation).
Exclusion criteria
1. High-grade (G3) neuroendocrine carcinoma, carcinoid tumor, pancreatic islet cell carcinoma, cupular cell carcinoid tumor, large cell neuroendocrine carcinoma and small cell carcinoma;
2. Functional NETs that require long-acting growth inhibitor analogs for symptom control, such as insulinoma, gastrinoma, glucagonoma, growth inhibitor tumor, ACTH tumor, VIP tumor, with carcinoid syndrome, Zoe’s syndrome, or disease-specific active symptoms;
3. Patients who have previously received anti-VEGF/VEGFR targeted drugs and have disease progression during treatment;
4, urine routine shows urine protein ≥ 2+ or 24-hour urine protein quantitative test shows urine protein ≥ 1 gram;
5, serum potassium, calcium (ionized or albumin-bound corrected) or magnesium are outside the normal range and are clinically significant;
6, hypertension not stably controlled by medication, specified as: systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg;
7, GI disease or condition that, in the judgment of the investigator, may affect drug absorption, including but not limited to active gastric and duodenal ulcers, ulcerative colitis or unresected GI tumors with active bleeding, or other conditions that, in the judgment of the investigator, may cause GI bleeding or perforation;
8, previous or current severe bleeding (bleeding >30 ml within 3 months), coughing up blood (>5 ml of fresh blood within 4 weeks) or thromboembolic events (including transient ischemic attack) within 12 months;
9, clinically significant cardiovascular disease, including but not limited to acute myocardial infarction, severe/unstable angina or coronary artery bypass grafting within 6 months prior to enrollment; congestive heart failure New York Heart Association (NYHA) classification ≥ grade 2; ventricular arrhythmia requiring pharmacological treatment; left ventricular ejection fraction (LVEF).
10, electrocardiogram (ECG) showing QT interval ≥ 480 milliseconds (ms);
11, other malignancies within the past 5 years, except for basal or squamous cell carcinoma of the skin after radical surgery, or carcinoma in situ of the cervix;
12. Anti-tumor therapy, including but not limited to chemotherapy, radical radiotherapy, biologic targeted therapy, immunotherapy, anti-tumor herbal therapy, hepatic artery interventional embolization, cryoablation of liver metastases or radiofrequency ablation, within 4 weeks prior to the start of study treatment;
13. Received palliative radiotherapy for bone metastases within 2 weeks prior to the start of study treatment;
14, have taken a drug containing onychomycin within 3 weeks prior to the first study dose, or have taken other strong inducers or inhibitors of CYP3A4 within the previous 2 weeks;
15, Any clinically significant active infection, including but not limited to human immunodeficiency virus (HIV) infection;
16, known history of significant liver disease, including but not limited to known hepatitis B virus (HBV) infection with positive HBV DNA (≥1×104/ml); known hepatitis C virus infection (HCV) with positive HCV RNA (≥1×103/ml), or cirrhosis;
17. Surgical procedure (except biopsy) performed within 28 days prior to enrollment in this study or surgical incision not fully healed;
18. Brain metastases or spinal cord compression without surgery and/or radiation therapy, or previously treated brain metastases or spinal cord compression without clinical imaging evidence of stable disease;
19. Toxic response to previous anticancer treatment has not returned to grade 0 or 1 level (except for alopecia);
20.Participated in clinical trials of other drugs within the past 4 weeks and treated with the corresponding trial drug;
21.Pregnant (positive pregnancy test before drug administration) or breastfeeding women;
22, any other disease, metabolic abnormality, physical examination abnormality or laboratory test abnormality that, in the judgment of the investigator, gives reason to suspect that the patient has a disease or condition that is inappropriate for the use of the study drug or that would affect the interpretation of the study results.