Entacapone Combination With Imatinib for Treatment of GIST

NCT04006769 | Completed Early Phase 1

• 1 other identifier: gist-ent
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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.

Conditions

Gastrointestinal Stromal Tumor, Malignant

Keywords

entacapone; Imatinib mesylate; GIST; treatment

Outcome Measures

Primary Outcomes (1)

• Adverse Events (AE) And Serious Adverse Events(SAE)

  According to Criteria CTCAE5.0, the ratio of AE and SAE which were defined by the Common Terminology Criteria for Adverse Events, CTCAE.

  36 months or 31 days after last dose, which come first.

Secondary Outcomes (2)

• Objective Response Rate(ORR)

  36 Months

• Quality of Life(QOL)

  Difference between baseline and the timepoint of the best efficacy within 181 days.

Study Arms (1)

Entacapone & Imatinib mesylate

EXPERIMENTAL

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; Drug: Imatinib Mesylate

Interventions

Entacapone DRUG

Entacapone tablet

Also known as: Comtan, Comtess

Entacapone & Imatinib mesylate

Imatinib Mesylate DRUG

Imatinib Mesylate tablet

Also known as: Gleevec

Entacapone & Imatinib mesylate

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Able to provide written informed consent and can understand and comply with the requirements of the study and the schedule of assessments.
• 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).
• Expected life span \> 12 weeks.
• Histologically confirmed disease which is currently metastatic/unresectable gastrointestinal stroma tumor(GIST) of c-KIT E11 mutation genotype.
• 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.
• 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.
• 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.
• Eastern Cooperative Oncology Group-performance status(ECOG PS) ≤ 2,or 3(the symptoms were definitely caused by GIST itself).
• 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）.
• 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.

You may not qualify if:

• 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).
• Progression within the first 6 months of first-line imatinib treatment (primary imatinib resistance).
• 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.
• A known history of human immunodeficiency virus(HIV) infection.
• Malignancy other than GIST and still under the active treatment.
• Was administered a live vaccine ≤ 4 weeks before written informed consent.
• 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.
• History of severe hypersensitivity reactions to any ingredient of entacapone and imatinib.
• Pheochromocytoma or history of neuroleptic malignant syndrome(NMS) and/or non-traumatic rhabdomyolysis (NRML).
• 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.

Sponsors & Collaborators

• Xiangya Hospital of Central South University: lead

Study Sites (1)

Bin Li, MD

Changsha, Hunan, 410008, China

Location

Related Publications (5)

• 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.

  PMID: 12181401 BACKGROUND

• 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.

  PMID: 17046465 BACKGROUND

• 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.

  PMID: 15869870 BACKGROUND

• 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.

  PMID: 30996080 BACKGROUND

• 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.

  PMID: 19097774 BACKGROUND

MeSH Terms

Conditions

Gastrointestinal Stromal Tumors

Interventions

entacapone; Imatinib Mesylate

Condition Hierarchy (Ancestors)

Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Bin Li, MD

  Xiangya Hospital, Central South University, Changsha, Hunan,China,410008

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Center for molecular medicine, Xiangya hospital, Central South University

Study Record Dates

• First Submitted: June 27, 2019
• First Posted: July 5, 2019
• Study Start: October 30, 2020
• Primary Completion: August 31, 2022
• Study Completion: August 31, 2022
• Last Updated: October 18, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

CN (1)