A Randomized, Double-blind, Multi-center Phase III Clinical Study to Assess the Efficacy and Safety of Surufatinib Compared to Placebo in Patients With Advanced Extrapancreatic Neuroendocrine Tumors
Overview
- Phase
- Phase 3
- Intervention
- Surufatinib
- Conditions
- Neuroendocrine Tumors
- Sponsor
- Hutchison Medipharma Limited
- Enrollment
- 219
- Locations
- 5
- Primary Endpoint
- Progression Free Survival (PFS)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
A randomized, double-blind, placebo controlled, multi-center Phase III study to assess the efficacy of Surufatinib 300 mg once a day in treating advanced extrapancreatic neuroendocrine tumors.
Detailed Description
273 patients will be randomly assigned (in 2:1 ratio) to the Surufatinib or Placebo treatment group based on interactive web response system（IWRS).The patients will receive continuous oral treatment, every 28-day treatment cycle until progression of disease occurs, intolerable toxicity or other protocol specified end-o-treatment criteria is met. The tumor should be assessed every 8 weeks (+/-3 days) within the first year and every 12 weeks (+/-3 days) after the patient has been treated for one year. A Blinded Independent Image Review Committee (BIIRC) will subsequently provide a central review of the oncologic imaging materials from the patients. An independent Data Monitoring Committee (IDMC) will be assembled to monitor safety and efficacy data, and evaluate interim analysis. If the interim analysis demonstrates overwhelming efficacy of the treatment arm with respect to PFS (primary endpoint) versus control arm, IDMC could recommend terminating and to unblinding the study and Surufatinib will be offered to the control arm patients who are still on treatment until disease progression or intolerable toxicity.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Adequately understand the study and voluntarily sign the Informed Consent Form;
- •Be at least 18 years old;
- •Based on central pathology review results，patients have a confirmed histologically pathology diagnosis of low- or intermediate grade (G1 or G2) advanced (unresectable or distant metastatic) extrapancreatic NETs with origins including, but not limited to, the lung, thymus, the gastrointestinal tract (stomach, duodenum, liver, jejunum, ileum, colon, cecum, appendix, rectum) and unknown origin etc. For Gastrointestinal neuroendocrine tumors (GI-NETs), G1 is defined as \< 2 mitoses /10 high-power field［HPF］and/or \<3% Ki-67 index; G2 is defined as 2-20/10 HPF and/or 3-20% Ki-67 index; for NETs originating from the lung and thymus gland, G1 is defined as \<2 mitoses/10 HPF and no necrosis; G2 is defined as 2-10/10 HPF and/or foci of necrosis. NETs from origin other than GI-NET, lung and thymus, or from unknown origins should be graded according to the GI-NET grading criteria. If the mitotic ratio and Ki-67 index correspond to different grade, the higher grade should be used to assign classification.
- •Have previously progressed on no more than two types of systemic anti-tumor therapy, including long-acting somatostatin analogs (SSAs), interferon, PRRT(peptide receptor radionuclide therapy), mTOR inhibitors or chemotherapy(chemotherapies were considered as one kind of regimen, regardless of medications and cycles); patients who are unable or unwilling to receive such treatments are also eligible;
- •Patients must have radiological documentation of progression of disease within 12 months prior to randomization.
- •Have measurable lesions (according to RECIST 1.1);
- •Absolute neutrophil count (ANC) of ≥1.5×109/L, platelet count of ≥100×109/L, and hemoglobin ≥9 g/dL;
- •Serum total bilirubin \<1.5 times the upper limit of normal (ULN);
- •Patients who do not have liver metastasis, with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels ≤ 2.5 times the ULN; and who do have liver metastasis, with ALT and AST ≤ 5 times ULN.
- •Serum creatinine \<1.5 times ULN and creatinine clearance ≥60 ml/min;
Exclusion Criteria
- •High grade (G3) neuroendocrine cancer, adenocarcinoid, pancreatic islet cell carcinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma;
- •Neuroendocrine tumors with pancreatic origins
- •Functional NETs which need to be treated with long acting 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;
- •Have received anti-VEGF/VEGFR targeted drugs and progressed upon these drugs;
- •Urinalysis shows urine protein ≥ 2+ or 24-hour protein quantity test shows urinary protein ≥1 g;
- •Serum potassium, calcium (albumin-bound ionic or corrected) or magnesium exceed the normal range with clinical significance;
- •Under anti-hypertension treatment, still uncontrolled hypertension, defined as: systolic blood pressure \>140 mmHg or diastolic blood pressure \>90 mmHg;
- •Gastrointestinal disease or condition that investigators suspect may affect drug absorption, including, but not limited to, 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 3 months), hemoptysis (\>5 ml blood within 4 weeks) 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 enrollment, 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; LVEF (LVEF) \<50%;
Arms & Interventions
Surufatinib
Surufatinib 300 mg, orally, once daily (QD)
Intervention: Surufatinib
Placebo
Placebo 300 mg, orally, once daily (QD)
Intervention: Placebo
Outcomes
Primary Outcomes
Progression Free Survival (PFS)
Time Frame: 9 months after the last patient enrolled
the duration between the randomization date and the first disease progression (PD) or death (whichever comes first).
Secondary Outcomes
- The disease control rate (DCR)(9 months after the last patient enrolled)
- The objective response rate of the tumor (ORR)(9 months after the last patient enrolled)
- Duration of Response (DoR)(9 months after the last patient enrolled)
- Overall survival(9 months after the last patient enrolled)
- adverse events evaluated by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03(From first dose to within 30 days after the last dose)
- Time to Response (TTR)(9 months after the last patient enrolled)