Toripalimab Combined With Surufatinib for Locally Advanced Thyroid Cancer: a Phase II Study

The Efficacy and Safety of Anti-PD-1 Antibody Toripalimab Combined With Surufatinib for Locally Advanced Thyroid Cancer: a Phase II Study

This study is designed to evaluate the efficacy and safety of the combination of Toripalimab and Surufatinib for Locally Advanced Thyroid Cancer.

Study Overview

• Status: Unknown
• Conditions: Thyroid Cancer
• Intervention / Treatment: Drug: Surufatinib; Drug: Toripalimab

Detailed Description

Surufatinib (HMPL-012, previously named sulfatinib) is a small-molecule inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptor 1 and colony-stimulating factor 1 receptor. A multi-center , opened, Phase II study have identified the efficacy and safety of Surufatinib in advanced medullary thyroid Carcinoma ( MTC) and iodine-refractory differentiated thyroid carcinoma (DTC).Toripalimab is a humanized immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed cell death 1 (programmed death-1; PD-1), with potential immune checkpoint inhibitory and antineoplastic activities. In the present study, we design a single-arm, single center Phase II trial to evaluate the efficacy and safety of the combination of Surufatinib wiht Toripalimab in locally advanced differentiated thyroid cancer as neoadjuvant therapy.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yu-Long Wang, MD; Phone Number: +86-18017317225; Email: yulongwang@fudan.edu.cn
• Study Contact Backup: Name: Qing-Hai Ji, MD; Email: headneck@126.com

Study Locations

• China
  • Shanghai, China, 200032
    • 270 Dongan Road, Fudan University Shanghai Cancer Center
    • Contact: Yu-Long Wang; Phone Number: +86-18017317225; Email: yulongwang@fudan.edu.cn
    • Contact: Qing-Hai Ji; Email: headneck@126.com

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. The patient volunteered to participate in the study and signed an informed consent form and shows good compliance;
2. Age ≥18 years, male or female;
3. Pathologically diagnosed locally advanced differentiated thyroid cancer, including papillary thyroid cancer and follicular thyroid cancer;
4. Diagnosis of locally advanced disease should meet at least one of the criteria:1)Unresectable locally advanced lesion; 2)Difficult to achieve R0/R1 resection during preoperative assessment; 3)AJCC T4 stage: Primary tumor with invasion or adhesion of at least one of the following structures / organs, including: trachea, esophagus, common carotid artery, larynx, anterior vertebral fascia, brachial plexus;
5. Have at least one measurable lesion (RECIST 1.1);
6. Eastern Cooperative Oncology Group (ECOG) score 0-2;
7. Expected survival time ≥ 12 weeks;
8. If the patient presents with distant metastasis, the value of local treatment should be assessed by the investigator;
9. The patient volunteered to receive tumor biopsy/surgery during rull-in and rull-out periods.
10. The main organ functions meet the following criteria within 7 days before treatment:1)Standard blood test (without blood transfusion within 14 days):Hemoglobin (HB) ≥90g / L; Absolute neutrophil value (ANC) ≥ 1.5 × 109 / L; Platelet (PLT) ≥80 × 109 / L; 2)Biochemical inspection must meet the following standards: Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal value (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 ULN, if with liver metastases, ALT and AST ≤ 5 ULN; Serum creatinine (Cr) ≤ 1.5 ULN or creatinine clearance (CCr)>50ml / min; 3)International normalized ratio (INR) ≤2.3 or prothrombin time (PT) prolongs less than 6 seconds; 4)Urine routine indicates urinary protein <++, and the 24-hour urine protein quantification is less than 1.0 g.
11. Women of childbearing age should agree to use contraceptives during the study; negative serum or urine pregnancy tests within 14 days before study enrollment.

Exclusion Criteria:

1. History of a second malignancy during the past 5 years before inclusion in the study or during participation in the study, with the exception of a dermal basal cell or squamous cell carcinoma or cervical carcinoma in situ, if these were curatively treated;
2. Use any anti-tumor treatment within 4 weeks (28 days) prior to the start of the study treatment, except for TSH suppression treatment;
3. Previously used any immune checkpoint inhibitors, including but not limited to pembrolizumab, nivolumab, camrelizumab, sintilimab and etc;
4. With other uncontrolled cardiac symptoms or disease;
5. Patients whose blood pressure is still unsatisfactory with a blood pressure medication (systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg) or a history of hypertensive encephalopathy or hypertensive crisis;
6. Those who have multiple factors (such as inability to swallow) that affect oral medication;
7. Patients with a gastrointestinal bleeding tendency including 1)Active peptic ulcer; 2)Fecal occult blood ≥ ++; 3)A history of hematemesis or melena within 3 months;
8. Coagulation disorder, such as INR greater than 1.5, or activated partial thromboplastin time (APTT) greater than 1.5 * ULN;
9. Significant hemoptysis within 2 months before screening, or the daily volume of hemoptysis reached half a teaspoon (2.5ml) or more;
10. Patients whose imaging showed that the tumor had invaded the important blood vessels or the researchers judged that the tumor was likely to invade important blood vessels during the subsequent study period and caused fatal bleeding;
11. Arterial / venous thrombosis events, such as cerebrovascular accidents (including transient ischemic attacks), deep vein thrombosis and pulmonary embolism within 6 months;
12. Patients suffering from interstitial pneumonia or ILD, or with a history of interstitial pneumonia or ILD requiring hormone therapy, or with other pulmonary fibrosis，organic pneumonia(e.g., obliterative bronchiolitis), pneumoconiosis, drug-induced pneumonia and idiopathic pneumonia that may interfere with the diagnosis and management of immune-related pulmonary toxicity; or patients with CT image indicating active pneumonia or severely impaired pulmonary function during screening. Radiation pneumonia is acceptable in the radiation field. Patients with active tuberculosis will be excluded;
13. Active autoimmune disease or history of autoimmune disease with recurrence potential (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis): Patients with skin diseases that do not require systemic treatment such as vitiligo, psoriasis, hair loss, controlled type I diabetes receiving insulin therapy; childhood asthma that is completely relieved, or those who do not need any intervention in adulthood can be included; Patients with asthma who undergo medical intervention such as bronchiectasis, cannot be included;
14. Use immunosuppressive agents or systemic hormone therapy within preceding 14 days before the study starts to achieve the purpose of immunosuppression (dose>10mg/day prednisone or hormones with equivalent effects);
15. Patients who received strong CYP3A4/CYP2C19 inducer including rifampin (and its analogs) and hypericum perforatum or strong CYP3A4/CYP2C19 inhibitor within preceding 14 days;
16. Patients who have a history of severe allergies to any monoclonal antibody or anti-angiogenic targeted drugs;
17. Patients who have severe uncontrolled infection during study screening;
18. Patients who are pregnant or lactating;
19. Patients who refuse to receive tumor biopsy during rule-in and rule-out period;
20. Other reasons according to the investigator's judgement.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A; Surufatinib 250mg will be taken orally once daily continuously through a 21-day cycle of study treatment. Toripalimab 240mg will be intravenously administered on Day 1 of each cycle. After neoadjuvant Toripalimab and Surufatinib treatment, the patients will receive operation treatment if the tumor is evaluated as resectable cases by clinical examination.	Drug: Surufatinib; Surufatinib is a tablet in the form of 50mg, oral, once a day.; Other Names: HMPL-012; Drug: Toripalimab; Toripalimab is an injection in the form of 240mg, intravenous, once three weeks.; Other Names: JS001
Experimental: Cohort B; Surufatinib 250mg will be taken orally once daily continuously through a 21-day cycle of study treatment. Toripalimab 240mg will be intravenously administered on Day 1 of each cycle. After neoadjuvant Toripalimab and Surufatinib treatment, the patients will receive further drug reatment, if the tumor is evaluated as unresectable cases and patients have potential benefits by clinical examination.	Drug: Surufatinib; Surufatinib is a tablet in the form of 50mg, oral, once a day.; Other Names: HMPL-012; Drug: Toripalimab; Toripalimab is an injection in the form of 240mg, intravenous, once three weeks.; Other Names: JS001
Experimental: Cohort C; Surufatinib 250mg will be taken orally once daily continuously through a 21-day cycle of study treatment. Toripalimab 240mg will be intravenously administered on Day 1 of each cycle. After neoadjuvant Toripalimab and Surufatinib treatment, the patients will be removed from the study, if the tumor is evaluated as unresectable cases and patients have no potential benefits by clinical examination.	Drug: Surufatinib; Surufatinib is a tablet in the form of 50mg, oral, once a day.; Other Names: HMPL-012; Drug: Toripalimab; Toripalimab is an injection in the form of 240mg, intravenous, once three weeks.; Other Names: JS001

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	Objective Response Rate	16 months after the last patient enrolled

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0/1 resection rate	R0 and R1 resection rate reviewed by operation team and pathologists	Within one week after operation
DCR	Disease Control Rate	16 months after the last patient enrolled
TTR	Time to objective response	16 months after the last patient enrolled
PFS	Progression Free Survival	16 months after the last patient enrolled
OS	Overall Survival	16 months after the last patient enrolled
AE	adverse events	From first dose to within 30 days after the last dose

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Qing-Hai Ji, MD, Fudan University; Principal Investigator: Yu-Long Wang, MD, Fudan University

Study record dates

Study Major Dates

• Study Start (Anticipated): October 1, 2020
• Primary Completion (Anticipated): April 30, 2022
• Study Completion (Anticipated): September 30, 2022

Study Registration Dates

• First Submitted: August 20, 2020
• First Submitted That Met QC Criteria: August 21, 2020
• First Posted (Actual): August 24, 2020

Study Record Updates

• Last Update Posted (Actual): August 24, 2020
• Last Update Submitted That Met QC Criteria: August 21, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Neoadjuvant therapy; Toripalimab; Surufatinib; Thyroid cancer
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms
• Other Study ID Numbers: Thca-NEO-ST

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No