Entacapone Combination With Imatinib for Treatment of GIST

• ClinicalTrials.gov Identifier: NCT04006769
• Recruitment Status: Active, not recruiting
• First Posted: July 5, 2019
• Last Update Posted: December 8, 2021
• Sponsor: Xiangya Hospital of Central South University
• Information provided by (Responsible Party): Lun-Quan Sun, Xiangya Hospital of Central South University

Study Description

Brief Summary:

This study evaluates the combination of entacapone and imatinib in the treatment of gastrointestinal stromal Tumors who have progressed on the setting of at least Imatinib and Sunitinib. 5 participants will be included in this open-label observatory study.

Condition or disease	Intervention/treatment	Phase
Gastrointestinal Stromal Tumor, Malignant	Drug: Entacapone; Drug: Imatinib Mesylate	Early Phase 1

Detailed Description:

Most patients with Metastatic/unresectable Gastrointestinal stromal tumors will progress on the treatment of tyrosine kinase inhibitor(TKI) including Imatinib and Sunitinib.

Entacapone and imatinib can each inhibit the role of v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog(KIT) which is a kind of transmembrane receptor tyrosine kinase promoting the clonal proliferation and growth of GIST cells, but they do so by different mechanisms.

Entacapone has been approved from China Food and Drug Administration(cFDA) for controlling the symptom of Parkinson' s disease in the combination with levodopa. Recently, entacapone was identified to be an inhibitor of Fat mass and obesity-associated protein(FTO) enzyme, which was reported as the first N6-methyladenosine (m6A) demethylase of eukaryotic messenger RNA(mRNA). Entacapone can inhibit the transcriptional level of KIT mRNA leading to the decreased expression of KIT protein.

Imatinib mesylate, an oral multiple TKI targeting the KIT-oncoprotein, was the standard first-line therapy of c-KIT-mutated GISTs. Imatinib can prohibit the activation of mutated c-KIT tyrosine kinase and then impede the kinase cascade of c-KIT signal pathway.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Entacapone in Combination With Imatinib Mesylate for Treatment of Patients With Gastrointestinal Stromal Tumors(GIST) Following Failure of at Least Imatinib and Sunitinib
• Actual Study Start Date: October 30, 2020
• Actual Primary Completion Date: June 13, 2021
• Estimated Study Completion Date: January 1, 2025

Arms and Interventions

Arm

Intervention/treatment

Experimental: Entacapone & Imatinib mesylate; Entacapone 200mg tablet (Orion pharma,Switzerland) by mouth, three times a day and then escalated to final dose of 1.0 grams three times per day within one week, until disease progression, intolerable toxicity, or withdrawal of informed consent, whichever occurs first. And Imatinib mesylate 400mg tablet by mouth, once a day until disease progression, intolerable toxicity, or withdrawal of informed consent, whichever occurs first.

Drug: Entacapone; Entacapone tablet; Other Names: Comtan; Comtess; Drug: Imatinib Mesylate; Imatinib Mesylate tablet; Other Name: Gleevec

Outcome Measures

Primary Outcome Measures :

1. Objective response rate(ORR) [ Time Frame: day 30, day 90, day 180. ]
   The ORR is the proportion of the patients who achieved complete response (CR) or partial responses(PR) according to CHOI criteria or Response Evaluation Criteria in Solid Tumors(RECIST) v1.1
2. Disease control rate(DCR) [ Time Frame: day 30, day 90, day 180. ]
   The ORR is the proportion of the patients who achieved complete response (CR) or partial responses(PR) and stable disease(SD) according to CHOI criteria or Response Evaluation Criteria in Solid Tumors(RECIST) v1.1

Secondary Outcome Measures :

1. Adverse events（AE) and serious adverse events(SAE) [ Time Frame: day 30, day 60, day 90, day 120, day 150, day 180. ]
   The ratio of AE and SAE which were defined by the Common Terminology Criteria for Adverse Events,CTCAE)
2. Quality of Life(QOL) [ Time Frame: day 30, day 90, day 180. ]
   The data was collected using EORTC QLQ-C30 V3.0 questionnaire

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Able to provide written informed consent and can understand and comply with the requirements of the study and the schedule of assessments.
2. Age ≥ 18 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place).
3. Expected life span > 12 weeks.
4. Histologically confirmed disease which is currently metastatic/unresectable gastrointestinal stroma tumor(GIST) of c-KIT E11 mutation genotype.
5. Patients received imatinib as the first-line treatment and no progression within the first 6 months(no primary resistance to imatinib ). With disease progression following treatment with at least imatinib and sunitinib.
6. Patients must be able to provide archival tumor tissues (approximately 4 [at least 2] unstained Formalin Fixed and Paraffin Embedded Tissues （FFPET）slides) for biomarker analysis to assess the expression of FTO and c-KIT protein.
7. At least 1 measurable lesion (the longest diameter≥ 10mm). Note: Computed Tomography（CT） abdomen and pelvis with contrast including peritoneum, or positron emission tomography/computed tomography(PET/CT) performed skull base to knees or whole body before the first day of entacapone.
8. Eastern Cooperative Oncology Group-performance status(ECOG PS) ≤ 2,or 3(the symptoms were definitely caused by GIST itself).

9. Adequate hematologic and end-organ function, as defined by the following laboratory results (obtained ≤ 28 days prior to the first day of entacapone):

   • Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 /L, hemoglobin ≥ 80 g/L and platelets ≥80 × 10 9 /L.
   • Total serum bilirubin ≤ 2.5 × upper limit of normal (ULN); Aspartate and alanine aminotransferase (AST and ALT) ≤ 2.5× ULN.
   • Estimated creatinine clearance rate≥ 60 mL/min（According to the formula of Cockcroft-Gault）.
10. Females of childbearing potential must be willing to practice highly effective method of birth control for the duration of the study, and at least 120 days after the last dose of entacapone or imatinib. Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and at least 120 days after the last dose of entacapone or imatinib.

Exclusion Criteria:

1. Age < 18 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place).
2. Progression within the first 6 months of first-line imatinib treatment (primary imatinib resistance).

3. Patients with active/symptomatic carrier or chronic hepatitis B virus (HBV) whose HBV DNA ≥ 1×104 copies/mL should be excluded. Note: Patients with detectable hepatitis B surface antigen(HBsAg) or HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at screening should have been treated for ≥2 weeks prior to written informed consent and should continue treatment for 6 months after study drug treatment discontinues.

   Note: Patients with active hepatitis C may enroll and those with detectable hepatitis C virus(HCV) RNA who are receiving antiviral therapy at time of screening should remain on continuous, effective antiviral therapy during the study.

4. A known history of human immunodeficiency virus(HIV) infection.
5. Malignancy other than GIST and still under the active treatment.
6. Was administered a live vaccine ≤ 4 weeks before written informed consent.
7. Any of the following medical conditions may threaten the safety of patients or affect the trial obedience including symptomatic heart failure requiring systematic treatment, unstable angina , acute myocardial infarction and severe chronic or active infections (including tuberculosis infection) requiring systemic antibacterial, antifungal, or antiviral therapy.
8. History of severe hypersensitivity reactions to any ingredient of entacapone and imatinib.
9. Pheochromocytoma or history of neuroleptic malignant syndrome(NMS) and/or non-traumatic rhabdomyolysis (NRML).
10. Female in pregnancy or lactation(Urine or serum pregnancy test and documented as negative within 7 days prior to the first dose of entacapone for the female with fertility expectation or sexual intercourse.

Contacts and Locations

Locations

China, Hunan

Bin Li, MD

Changsha, Hunan, China, 410008

Sponsors and Collaborators

Xiangya Hospital of Central South University

Investigators

• Principal Investigator: Bin Li, MD; Xiangya Hospital, Central South University, Changsha, Hunan,China,410008

More Information

Publications:

Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002 Aug 15;347(7):472-80. doi: 10.1056/NEJMoa020461.

Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006 Oct 14;368(9544):1329-38. doi: 10.1016/S0140-6736(06)69446-4.

Tabone S, Theou N, Wozniak A, Saffroy R, Deville L, Julie C, Callard P, Lavergne-Slove A, Debiec-Rychter M, Lemoine A, Emile JF. KIT overexpression and amplification in gastrointestinal stromal tumors (GISTs). Biochim Biophys Acta. 2005 Jun 30;1741(1-2):165-72. doi: 10.1016/j.bbadis.2005.03.011. Epub 2005 Apr 13.

Peng S, Xiao W, Ju D, Sun B, Hou N, Liu Q, Wang Y, Zhao H, Gao C, Zhang S, Cao R, Li P, Huang H, Ma Y, Wang Y, Lai W, Ma Z, Zhang W, Huang S, Wang H, Zhang Z, Zhao L, Cai T, Zhao YL, Wang F, Nie Y, Zhi G, Yang YG, Zhang EE, Huang N. Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1. Sci Transl Med. 2019 Apr 17;11(488):eaau7116. doi: 10.1126/scitranslmed.aau7116.

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

• Responsible Party: Lun-Quan Sun, Director of Center for molecular medicine, Xiangya hospital, Central South University, Xiangya Hospital of Central South University
• ClinicalTrials.gov Identifier: NCT04006769
• Other Study ID Numbers: gist-ent
• First Posted: July 5, 2019
• Last Update Posted: December 8, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be made available.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: Data will be available starting at the 6 months after publication.
• Access Criteria: Data access requests will be reviewed by an external independent Review Panel. Requestors will be required to sign a Data Access Agreement.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Lun-Quan Sun, Xiangya Hospital of Central South University:

entacapone; Imatinib mesylate; GIST; treatment

Additional relevant MeSH terms:

Gastrointestinal Stromal Tumors; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Imatinib Mesylate; Entacapone; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antiparkinson Agents; Anti-Dyskinesia Agents; Catechol O-Methyltransferase Inhibitors