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Entacapone Combination With Imatinib for Treatment of GIST

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

Tracking Information
First Submitted Date  ICMJE June 27, 2019
First Posted Date  ICMJE July 5, 2019
Last Update Posted Date July 5, 2019
Estimated Study Start Date  ICMJE July 2019
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 30, 2019)
  • Objective response rate(ORR) [ Time Frame: 30 days, 90days, 180days ]
    the total proportion of patients with reduction in tumor burden of a predefined amount. The ORR is the sum of complete response(CR)+partial responses(PR) per Response Evaluation Criteria in Solid Tumors(RECIST) v1.1
  • Disease control rate(DCR) [ Time Frame: 30 days, 90days, 180days ]
    the total proportion of patients who demonstrate a response to treatment. The DCR is the sum of complete response(CR)+partial responses(PR)+ stable disease(SD) per Response Evaluation Criteria in Solid Tumors(RECIST) v1.1
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Entacapone Combination With Imatinib for Treatment of GIST
Official Title  ICMJE Entacapone in Combination With Imatinib Mesylate for Treatment of Patients With Gastrointestinal Stromal Tumors(GIST) Following Failure of at Least Imatinib and Sunitinib
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Gastrointestinal Stromal Tumor, Malignant
Intervention  ICMJE
  • Drug: Entacapone
    Entacapone tablet
    Other Names:
    • Comtan
    • Comtess
  • Drug: Imatinib Mesylate
    Imatinib Mesylate tablet
    Other Name: Gleevec
Study Arms  ICMJE Experimental: Entacapone & Imatinib mesylate

Entacapone 200mg tablet by mouth, three times a day and then increasing to 400mg tablet by mouth, three times a day 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.

Interventions:
  • Drug: Entacapone
  • Drug: Imatinib Mesylate
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 30, 2019)
5
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2020
Estimated Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Zhi Li, PHD +86-1580265-4231 peries@csu.edu.cn
Contact: Lun-Quan Sun, PHD +86-13908454347 lunquansun@csu.edu.cn
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04006769
Other Study ID Numbers  ICMJE gist-ent
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Data will be available within 6 months of study completion.
Access Criteria: Data access requests will be reviewed by an external independent Review Panel. Requestors will be required to sign a Data Access Agreement.
Responsible Party Lun-Quan Sun, Xiangya Hospital of Central South University
Study Sponsor  ICMJE Xiangya Hospital of Central South University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Bin Li, MD Xiangya Hospital, Central South University, Changsha, Hunan,China,410008
PRS Account Xiangya Hospital of Central South University
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP