A Clinical Study of Sorafenib Combined With Gefitinib for the Treatment of pNET

NCT06592989 | Recruiting

• 1 other identifier: 20240625030921977
• Study Type: observational
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The incidence rate of pancreatic neuroendocrine neoplasms (pNENs) is increasing year by year. According to the statistical results of the SEER (Surveillance, Epidemiology, and End Results) database, the incidence rate of pNENs increased from 0.27/100000 to 1/100000 from 2000 to 2016, with a median overall survival time of 68 months. The 5-year overall survival rates of localized, locally advanced, and metastatic pNENs were 83%, 67%, and 28%, respectively. pNENs are gradually gaining attention and importance from the medical community. The existing therapeutic drugs for neuroendocrine tumors include somatostatin analogues, recombinant human interferon injections, chemotherapy drugs, and molecular targeted drugs. Although these drugs can prolong patients' PFS to some extent, there is a common problem of low objective response rates. In recent years, sunitinib and everolimus have been approved for targeted therapy in patients with pancreatic neuroendocrine neoplasms , but their clinical efficacy is still limited. The study by Panzuto et al. showed that the median PFS for first-line treatment of advanced well differentiated pancreatic neuroendocrine neoplasms was 13.9 months, with an ORR of 14.9%. After imaging progression of the disease, the median PFS after second-line treatment was 15 months, and the ORR of only 5.5%. There is currently no effective treatment for patients with disease progression or drug resistance after undergoing existing treatment ways. Therefore, there is a huge clinical demand for the treatment of pNEN patients worldwide, and effective drugs are urgently needed to benefit these patients. Our previous research found that pathways in tumor were significantly affected in pNENs and liver metastases and EGFR tyrosine kinase inhibitor resistance and transcriptional dysregulation in tumor were unique to liver metastasis through KEGG pathway analysis; Meanwhile, GO Biological Processes analysis emphasizes those signaling pathways closely related to tyrosine phosphorylation, DNA repair, and cell cycle regulation, especially in liver metastases. Xiao et al. found that epidermal growth factor receptor (EGFR) was enriched in high glycosylation pNENs using RNA-seq. EGFR was expressed in 21.2% of pNENs using immunohistochemistry and associated with poor overall survival. Therefore, the study from Xiao et al. demonstrates that EGFR may be a potential therapeutic target for pNENs. This is consistent with our previous findings that the EGFR signaling pathway plays an important role in pNENs with liver metastases. Due to the heterogeneity and complexity of tumors, the efficacy of monotherapy or blocking a single signaling pathway may be limited or this treatment method may easily develop drug resistance. The existing anti-tumor targeted drugs block tumor angiogenesis by inhibiting vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Colony-stimulating factor 1 receptor (CSF1R) is an important signaling pathway associated with the survival and function of tumor associated macrophages (TAMs). Inhibiting CSF1R can regulate the activity of macrophages, improve the immune microenvironment, promote immune response, and activate the body's immune function. Sofantinib is a novel oral tyrosine kinase inhibitor which exerts dual effects of anti-tumor angiogenesis and immune regulation by targeting VEGFR, FGFR1, and CSF1R, resulting in synergistic anti-tumor activity. In December 2020 and June 2021, sorafenib was approved in China as a monotherapy for unresectable locally advanced or metastatic, well differentiated extrapancreatic and pancreatic neuroendocrine neoplasms. However, in a multicenter, single blind, open label, phase Ib/II clinical trial, the objective response rate for pNENs patients was only 19%. There is currently no effective treatment available for patients with disease progression or drug resistance after undergoing existing treatment regimens. Therefore, there is an urgent need to seek new treatment methods to improve the therapeutic effect of pNENs. Based on our previous research results and relevant literature reports, we speculate that the combination of sorafenib and EGFR inhibitor gefitinib may improve the therapeutic effect of pNENs patients.

Conditions

Pancreatic Neuroendocrine Neoplasm; Sorafenib; Gefitinib

Outcome Measures

Primary Outcomes (2)

• objective response rate

  Objective response rate refers to the proportion of patients whose tumor has shrunk to a certain extent and maintained it for a certain period of time, including cases of CR and PR. The RECIST 1.1 criteria are used to assess objective tumor response. The subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete response (CR), partial response (PR), stable disease(SD), and progressive disease (PD) according to the RECIST 1.1 criteria.

  Baseline examination, then every 8 weeks until 2 years

• progression free survival

  Progression free survival refers to the period from the date of treatment until the first occurrence of disease progression or death from any cause.

  Researchers conduct survival assessments every 12 weeks until 2 years.

Secondary Outcomes (1)

• Evaluate the safety and tolerability of the combination therapy of sorafenib and gefitinib.

  2 years.

Study Arms (1)

experimental group

This study is a single arm design, with only one experimental group set up. Medication plan and cycle: oral administration. Sorafenib: once a day, 250mg each time. Gefitinib: once a day, 250mg each time. Every 4 weeks is a treatment cycle.

Drug: sorafenib, gefitinib

Interventions

sorafenib, gefitinib DRUG

Sofantinib: 250mg, QD, oral; Gefitinib: 250mg, QD, oral.

Also known as: No.

experimental group

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with pancreatic neuroendocrine neoplasms diagnosed by histopathology or cytology show progression after previous treatments such as SSA, targeted therapy, chemotherapy, and so on.

You may qualify if:

• Patients must have a full understanding of this study and voluntarily sign an informed consent form;
• Age ≥ 18 years old and age ≤ 80 years old;
• Patients with pancreatic neuroendocrine tumors diagnosed by histopathology or cytology, who have progressed after previous treatments such as SSA, targeted therapy, and chemotherapy (all grades of pancreatic neuroendocrine tumors and neuroendocrine cancers are allowed to be included);
• According to the criteria for evaluating the efficacy of solid tumors (RECIST V1.1), there should be at least one measurable lesion;
• At least 7 days have passed since the end of the last systemic treatment, and palliative radiotherapy for localized areas is allowed. It has been completed for more than 4 weeks;
• Expected survival time ≥ 12 weeks;
• Researchers estimate that patients can benefit from it;
• The patients have sufficient organ and bone marrow function;
• Male or female patients with fertility voluntarily use effective contraceptive methods, such as double barrier contraception, condoms, oral or injectable contraceptives, intrauterine devices, etc., during the study period and within 6 months of the last study medication. All female patients will be considered to have fertility unless they have undergone natural menopause, artificial menopause, or sterilization surgery (such as hysterectomy, bilateral adnexectomy, or radiation ovarian irradiation).

You may not qualify if:

• Other malignant tumors have been diagnosed in the past 5 years, except for effectively treated skin basal cell carcinoma, skin squamous cell carcinoma, or effectively resected cervical carcinoma in situ, breast cancer;
• Simultaneously receiving other investigational drugs or approved or investigational anti-tumor treatments;
• Patients with contraindications to experimental drugs (such as active bleeding, ulcers, intestinal perforation, intestinal obstruction, uncontrolled hypertension, III-IV grade heart failure, within 30 days after major surgery, severe liver and kidney dysfunction, etc.);
• The patient currently has any diseases or conditions that affect drug absorption, or the patient is unable to take oral medication;
• Confirmed allergy to any component of the investigational drug and/or its excipients;
• Pregnant (positive pregnancy test before medication) or breastfeeding women;
• Patients with large amounts of pleural effusion or ascites requiring drainage;
• Any other disease with clinically significant metabolic abnormalities, physical examination abnormalities, or laboratory examination abnormalities. According to the researcher's judgment, it is suspected that the patient has a certain disease or condition that is not suitable for the use of the study drug (such as having seizures and requiring treatment), or that it will affect the interpretation of the study results, or put the patient in a high-risk situation;
• Have taken medication containing components of Hypericum perforatum within 3 weeks prior to the first study medication. Or have taken other strong inducers or inhibitors of CYP3A4 within the previous 2 weeks;

Sponsors & Collaborators

• Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine: lead

Study Sites (1)

Shanghai General Hospital

Shanghai, Shanghai Municipality, 200080, China

RECRUITING

Related Publications (12)

• Hofland J, Kaltsas G, de Herder WW. Advances in the Diagnosis and Management of Well-Differentiated Neuroendocrine Neoplasms. Endocr Rev. 2020 Apr 1;41(2):371-403. doi: 10.1210/endrev/bnz004.

  PMID: 31555796 RESULT

• Del Rivero J, Perez K, Kennedy EB, Mittra ES, Vijayvergia N, Arshad J, Basu S, Chauhan A, Dasari AN, Bellizzi AM, Gangi A, Grady E, Howe JR, Ivanidze J, Lewis M, Mailman J, Raj N, Soares HP, Soulen MC, White SB, Chan JA, Kunz PL, Singh S, Halfdanarson TR, Strosberg JR, Bergsland EK. Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline. J Clin Oncol. 2023 Nov 10;41(32):5049-5067. doi: 10.1200/JCO.23.01529. Epub 2023 Sep 29.

  PMID: 37774329 RESULT

• Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME; RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016 Mar 5;387(10022):968-977. doi: 10.1016/S0140-6736(15)00817-X. Epub 2015 Dec 17.

  PMID: 26703889 RESULT

• Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Blaker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. doi: 10.1200/JCO.2009.22.8510. Epub 2009 Aug 24.

  PMID: 19704057 RESULT

• Rinzivillo M, De Felice I, Magi L, Annibale B, Panzuto F. Octreotide long-acting release (LAR) in combination with other therapies for treatment of neuroendocrine neoplasia: a systematic review. J Gastrointest Oncol. 2021 Apr;12(2):845-855. doi: 10.21037/jgo-20-292.

  PMID: 34012671 RESULT

• Sonbol MB, Mazza GL, Mi L, Oliver T, Starr J, Gudmundsdottir H, Cleary SP, Hobday T, Halfdanarson TR. Survival and Incidence Patterns of Pancreatic Neuroendocrine Tumors Over the Last 2 Decades: A SEER Database Analysis. Oncologist. 2022 Jul 5;27(7):573-578. doi: 10.1093/oncolo/oyac049.

  PMID: 35348774 RESULT

• Panzuto F, Andrini E, Lamberti G, Pusceddu S, Rinzivillo M, Gelsomino F, Raimondi A, Bongiovanni A, Davi MV, Cives M, Brizzi MP, Persano I, Zatelli MC, Puliafito I, Tafuto S, Campana D. Sequencing Treatments in Patients with Advanced Well-Differentiated Pancreatic Neuroendocrine Tumor (pNET): Results from a Large Multicenter Italian Cohort. J Clin Med. 2024 Apr 3;13(7):2074. doi: 10.3390/jcm13072074.

  PMID: 38610840 RESULT

• Xu M, Yan J, Hu B, Wu C, Gu H, Qi Z, Chen T, Yang W, Zheng Y, Dong H, Sheng W, Long J. Evolutionary Trajectories of Primary and Metastatic Pancreatic Neuroendocrine Tumors Based on Genomic Variations. Genes (Basel). 2022 Sep 4;13(9):1588. doi: 10.3390/genes13091588.

  PMID: 36140756 RESULT

• Xiao Z, Xu H, Strosberg JR, Lu R, Zhu X, Deng S, Ding L, Ni Q, Warshaw AL, Yu X, Luo G. EGFR is a potential therapeutic target for highly glycosylated and aggressive pancreatic neuroendocrine neoplasms. Int J Cancer. 2023 Jul 1;153(1):164-172. doi: 10.1002/ijc.34499. Epub 2023 Mar 17.

  PMID: 36891979 RESULT

• Syed YY. Surufatinib: First Approval. Drugs. 2021 Apr;81(6):727-732. doi: 10.1007/s40265-021-01489-y.

  PMID: 33788183 RESULT

• Xu J, Li J, Bai C, Xu N, Zhou Z, Li Z, Zhou C, Jia R, Lu M, Cheng Y, Mao C, Wang W, Cheng K, Su C, Hua Y, Qi C, Li J, Wang W, Li K, Sun Q, Ren Y, Su W. Surufatinib in Advanced Well-Differentiated Neuroendocrine Tumors: A Multicenter, Single-Arm, Open-Label, Phase Ib/II Trial. Clin Cancer Res. 2019 Jun 15;25(12):3486-3494. doi: 10.1158/1078-0432.CCR-18-2994. Epub 2019 Mar 4.

  PMID: 30833272 RESULT

• Zhou Q, Xu CR, Cheng Y, Liu YP, Chen GY, Cui JW, Yang N, Song Y, Li XL, Lu S, Zhou JY, Ma ZY, Yu SY, Huang C, Shu YQ, Wang Z, Yang JJ, Tu HY, Zhong WZ, Wu YL. Bevacizumab plus erlotinib in Chinese patients with untreated, EGFR-mutated, advanced NSCLC (ARTEMIS-CTONG1509): A multicenter phase 3 study. Cancer Cell. 2021 Sep 13;39(9):1279-1291.e3. doi: 10.1016/j.ccell.2021.07.005. Epub 2021 Aug 12.

  PMID: 34388377 RESULT

MeSH Terms

Conditions

Adenoma, Islet Cell

Interventions

Sorafenib; Gefitinib

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Jiuliang Yan, M.D.

  Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

  PRINCIPAL INVESTIGATOR

• Jiang Long, M.D.

  Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

  STUDY DIRECTOR

Central Study Contacts

Jiuliang Yan, M.D.

CONTACT

+8613621670521; doctor_yjl@163.com

Jiang Long, M.D.

CONTACT

+8618017317460; jiang.long@shgh.cn

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Attending physician

Study Record Dates

• First Submitted: September 8, 2024
• First Posted: September 19, 2024
• Study Start: September 30, 2024
• Primary Completion: March 31, 2026
• Study Completion (Estimated): September 30, 2026
• Last Updated: January 10, 2025

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Throughout the entire research period.
• Access Criteria: Researchers studying pancreatic neuroendocrine tumors can apply to share relevant data. But the applicant's identification is required.

Locations

CN (1)