Phase III Study of Surufatinib in Treating Advanced Extrapancreatic Neuroendocrine Tumors

• ClinicalTrials.gov Identifier: NCT02588170
• Recruitment Status: Completed
• First Posted: October 27, 2015
• Last Update Posted: March 30, 2023
• Sponsor: Hutchison Medipharma Limited
• Information provided by (Responsible Party): Hutchmed ( Hutchison Medipharma Limited )

Tracking Information

• First Submitted Date: October 26, 2015
• First Posted Date: October 27, 2015
• Last Update Posted Date: March 30, 2023
• Actual Study Start Date: December 7, 2015
• Actual Primary Completion Date: March 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 26, 2015)

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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 1, 2018)

• The objective response rate of the tumor (ORR) [ Time Frame: 9 months after the last patient enrolled ]
  the incidence of confirmed complete response or partial response
• The disease control rate (DCR) [ Time Frame: 9 months after the last patient enrolled ]
  the incidence of complete response, partial response and stable disease
• Duration of Response (DoR) [ Time Frame: 9 months after the last patient enrolled ]
  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
• Time to Response (TTR) [ Time Frame: 9 months after the last patient enrolled ]
  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).
• Overall survival [ Time Frame: 9 months after the last patient enrolled ]
  the time from the date of randomization to the date of death (all causes)
• adverse events evaluated by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 [ Time Frame: From first dose to within 30 days after the last dose ]
  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.

Original Secondary Outcome Measures (submitted: October 26, 2015)

• The objective response rate of the tumor (ORR) [ Time Frame: 9 months after the last patient enrolled ]
  the incidence of confirmed complete response or partial response
• The disease control rate (DCR) [ Time Frame: 9 months after the last patient enrolled ]
  the incidence of complete response, partial response and stable disease
• Duration of Response (DoR) [ Time Frame: 9 months after the last patient enrolled ]
  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
• Time to Response (TTR) [ Time Frame: 9 months after the last patient enrolled ]
  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).
• Overall survival [ Time Frame: 9 months after the last patient enrolled ]
  the time from the date of randomization to the date of death (all causes)
• adverse events evaluated by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 [ Time Frame: From first dose to within 30 days after the last dose ]
  The safety and tolerability of sulfatinib 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase III Study of Surufatinib in Treating Advanced Extrapancreatic Neuroendocrine Tumors
• Official Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Neuroendocrine Tumors

Intervention

• Drug: Surufatinib
  Surufatinib 300 mg once a day (QD) will be orally administrated on a 28-day cycle
  Other Names:

  • HMPL-012
  • Sulfatinib
• Other: Placebo
  Placebo 300 mg once a day (QD) will be orally administrated on a 28-day cycle

Study Arms

• Experimental: Surufatinib
  Surufatinib 300 mg, orally, once daily (QD)
  Intervention: Drug: Surufatinib
• Placebo Comparator: Placebo
  Placebo 300 mg, orally, once daily (QD)
  Intervention: Other: Placebo

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. 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.
• 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, Zhou Z, Li J, Bai C, Chi Y, Li Z, Xu N, Li E, Liu T, Bai Y, Yuan Y, Li X, Wang X, Chen J, Ying J, Yu X, Qin S, Yuan X, Zhang T, Deng Y, Xiu D, Cheng Y, Tao M, Jia R, Wang W, Li J, Fan S, Peng M, Su W. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Nov;21(11):1500-1512. doi: 10.1016/S1470-2045(20)30496-4. Epub 2020 Sep 20.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 29, 2023): 219
• Original Estimated Enrollment (submitted: October 26, 2015): 273
• Actual Study Completion Date: July 7, 2022
• Actual Primary Completion Date: March 31, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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) 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.
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 metastasis, 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. Neuroendocrine tumors with pancreatic origins
3. 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;
4. Have received anti-VEGF/VEGFR targeted drugs and progressed upon these drugs;
5. Urinalysis shows urine protein ≥ 2+ or 24-hour protein quantity test shows urinary protein ≥1 g;
6. Serum potassium, calcium (albumin-bound ionic or corrected) or magnesium exceed the normal range with clinical significance;
7. Under anti-hypertension treatment, still uncontrolled hypertension, defined as: systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg;
8. 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;
9. 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;
10. 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%;
11. Mean corrected QT interval (QTc) ≥ 480 msec;
12. Other malignancies diagnosed within the previous 5 years, except basal cell carcinoma or cervical carcinoma in situ after radical resection;
13. 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 ;
14. Palliative radiotherapy for a bone metastasis lesion within 2 weeks prior to the initiation of the investigational treatment;
15. 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);
16. Any clinically significant active infection, including, but not limited to, human immunodeficiency virus (HIV) infection;
17. 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.
18. Surgery (except biopsy) within 28 days prior to the initiation of investigational treatment or unhealed surgical incision;
19. Brain metastases and/or spinal cord compression not treated by surgery and/or radiotherapy, and with no clinical imaging evidence of disease stability;
20. Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or 1 (except for hair loss);
21. Received investigational treatments in other clinical studies within 4 weeks prior to enrollment;
22. Women who are pregnant or lactating;
23. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT02588170
• Other Study ID Numbers: 2015-012-00CH4
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hutchmed ( Hutchison Medipharma Limited )
• Original Responsible Party: Same as current
• Current Study Sponsor: Hutchison Medipharma Limited
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Songhua Fan, MD; Hutchison Medi Pharma

• PRS Account: Hutchmed
• Verification Date: March 2023