Phase III Study of Surufatinib in Treating Advanced Pancreatic Neuroendocrine Tumors

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 Pancreatic Neuroendocrine Tumors

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 pancreatic neuroendocrine tumors.

Study Overview

• Status: Completed
• Conditions: Neuroendocrine Tumors
• Intervention / Treatment: Drug: Surufatinib; Other: Placebo

Detailed Description

195 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 sulfatinib will be offered to the control arm patients who are still on treatment until disease progression or intolerable toxicity.

• Study Type: Interventional
• Enrollment (Anticipated): 195
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100142
      • Beijing Cancer Hospital
    • Beijing, Beijing, China, 100032
      • Peking Union Medical College Hospital
    • Beijing, Beijing, China, 100071
      • the 307 Hospital of People's Liberation Army
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Sun Yat-Sen University Cancer Center
  • Sichuan
    • Chengdu, Sichuan, China, 610047
      • West China Hospital, Sichuan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adequately understand the study and voluntarily sign the Informed Consent Form;
2. Be at least 18 years old;
3. 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) PNET. 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. If the mitotic ratio and Ki-67 index correspond to different grade, the higher grade should be used to assign classification.
4. 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;
5. Patients must have radiological documentation of progression of disease within 12 months prior to randomization.
6. Have measurable lesions (according to RECIST 1.1);
7. Absolute neutrophil count (ANC) of ≥1.5×109/L, platelet count of ≥100×109/L, and hemoglobin ≥9 g/dL;
8. Serum total bilirubin <1.5 times the upper limit of normal (ULN);
9. 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 metastatic, with ALT and AST ≤ 5 times ULN.
10. Serum creatinine <1.5 times ULN and creatinine clearance ≥60 ml/min;
11. International Normalized Ratio (INR) ≤1.5 ULN and activated partial thromboplastin time (APTT) ≤1.5 ULN.
12. Have a performance status (PS) of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale;
13. Have expected survival of more than 12 weeks;
14. 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:

1. High grade (G3) neuroendocrine cancer, adenocarcinoid, pancreatic islet cell carcinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma;
2. 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;
3. Have received anti-VEGF/VEGFR targeted drugs and progressed upon these drugs;
4. Urinalysis shows urine protein ≥ 2+ or 24-hour protein quantity test shows urinary protein ≥1 g;
5. Serum potassium, calcium (albumin-bound ionic or corrected) or magnesium exceeds the normal range with clinical significance;
6. Under anti-hypertension treatment, still uncontrolled hypertension, defined as: systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg;
7. 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;
8. 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;
9. 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%;
10. Mean corrected QT interval (QTc) ≥ 480 msec;
11. Other malignancies diagnosed within the previous 5 years, except basal cell carcinoma or cervical carcinoma in situ after radical resection;
12. Anti-tumor therapy received within 4 weeks prior to the initiation of the investigational treatment, including, but not limited to, chemotherapy, radical radiotherapy, targeted therapy, immunotherapy and anti-tumor Chinese medicine treatment, hepatic chemoembolization, cryoablation and radiofrequency ablation ;
13. Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to the initiation of the investigational treatment;
14. Drugs containing St John's wort taken within 3 weeks prior to the first study treatment, or other strong inducers with CYP3A4 or strong inhibitors taken within two weeks prior to the first study treatment (see appendix 3);
15. Any clinically significant active infection, including, but not limited to, human immunodeficiency virus (HIV) infection;
16. History of clinically significant hepatic disease, including, but not limited to, known hepatitis B virus (HBV) infection with HBV DNA positive (copies ≥1×104/ml); known Hepatitis C virus infection with HCV RNA positive (copies ≥1×103/m); or liver cirrhosis, etc.
17. Surgery (except biopsy) within 28 days prior to the initiation of investigational treatment or unhealed surgical incision; 18 Brain metastases and/or spinal cord compression not treated by surgery and/or radiotherapy, and with no clinical imaging evidence of disease stability;

19. Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or 1 (except for hair loss); 20. Received investigational treatments in other clinical studies within 4 weeks prior to enrollment; 21. Women who are pregnant or lactating; 22. Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other conditions are inappropriate for the use of the investigational product or affect interpretation of study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Surufatinib; Surufatinib 300 mg, orally, once daily (QD)	Drug: Surufatinib; Surufatinib 300 mg once a day (QD) will be orally administrated on a 28-day cycle; Other Names: HMPL-012; Sulfatinb
Placebo Comparator: Placebo; Placebo 300 mg, orally, once daily (QD)	Other: Placebo; Placebo 300 mg once a day (QD) will be orally administrated on a 28-day cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	the duration between the randomization date and the first disease progression (PD) or death (whichever comes first).	7 months after the last patient enrolled

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The objective response rate of the tumor (ORR)	the incidence of confirmed complete response or partial response	7 months after the last patient enrolled
The disease control rate (DCR)	the incidence of complete response, partial response and stable disease	7 months after the last patient enrolled
Duration of Response (DoR)	the duration between the date the criteria for complete response or partial response was first measured (first record shall prevail) and the date of disease recurrence or progression as objectively recorded	7 months after the last patient enrolled
Time to Response (TTR)	the period from the date of randomization to the date when the criteria for complete response or partial response was first measured (first record shall prevail).	7 months after the last patient enrolled
Overall survival (OS)	the time from the date of randomization to the date of death (all causes)	7 months after the last patient enrolled
•adverse events evaluated by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03	The safety and tolerability of Surufatinib will be evaluated based on adverse events data. Other safety parameters include physical examination, vital signs, laboratory test results (i.e., hematology, chemistry panel, and urinalysis), 12-lead electrocardiogram, and ultrasonic cardiogram.	From first dose to within 30 days after the last dose

Collaborators and Investigators

• Sponsor: Hutchison Medipharma Limited
• Investigators: Study Director: Songhua Fan, MD, Hutchison Medi Pharma

Publications and helpful links

General Publications

• Li J, Cheng Y, Bai C, Xu J, Shen L, Li J, Zhou Z, Li Z, Chi Y, Yu X, Li E, Xu N, Liu T, Lou W, Bai Y, Yuan X, Wang X, Yuan Y, Chen J, Guan S, Fan S, Su W. Treatment-related adverse events as predictive biomarkers of efficacy in patients with advanced neuroendocrine tumors treated with surufatinib: results from two phase III studies. ESMO Open. 2022 Apr;7(2):100453. doi: 10.1016/j.esmoop.2022.100453. Epub 2022 Mar 25.
• Xu J, Shen L, Bai C, Wang W, Li J, Yu X, Li Z, Li E, Yuan X, Chi Y, Yin Y, Lou W, Xu N, Bai Y, Zhang T, Xiu D, Wang X, Yuan Y, Chen J, Qin S, Jia R, Lu M, Cheng Y, Zhou Z, Li J, He J, Su W. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Nov;21(11):1489-1499. doi: 10.1016/S1470-2045(20)30493-9. Epub 2020 Sep 20.
• Li J, Cheng Y, Bai C, Xu J, Shen L, Li J, Zhou Z, Li Z, Chi Y, Yu X, Li E, Xu N, Liu T, Lou W, Bai Y, Yuan X, Wang X, Yuan Y, Chen J, Guan S, Fan S, Su W. Health-related quality of life in patients with advanced well-differentiated pancreatic and extrapancreatic neuroendocrine tumors treated with surufatinib versus placebo: Results from two randomized, double-blind, phase III trials (SANET-p and SANET-ep). Eur J Cancer. 2022 Jul;169:1-9. doi: 10.1016/j.ejca.2022.03.027. Epub 2022 Apr 28. Erratum In: Eur J Cancer. 2023 Jan;178:247-248.

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2015
• Primary Completion (Actual): November 11, 2019
• Study Completion (Actual): July 7, 2022

Study Registration Dates

• First Submitted: October 26, 2015
• First Submitted That Met QC Criteria: October 26, 2015
• First Posted (Estimate): October 28, 2015

Study Record Updates

• Last Update Posted (Actual): March 30, 2023
• Last Update Submitted That Met QC Criteria: March 29, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors
• Other Study ID Numbers: 2015-012-00CH3