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Fimepinostat, Combination HDAC and Pi3-kinase Inhibitor Tumor-Directed Therapy for Cushing Disease

Primary Purpose

Cushing Disease

Status
Not yet recruiting
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Fimepinostat
Sponsored by
University of California, Los Angeles
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cushing Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria: Male and female patients at least 18 years old Patients with confirmed pituitary origin Cushing syndrome defined as 1, 2& 3 or 4 & 5 below: Persistent hypercortisolism defined as a mean of 3 consecutive 24h UFC at baseline assessment ≥ 1.3x ULN Normal or elevated plasma ACTH levels Pituitary adenoma > 4mm visible on MRI or inferior petrosal sinus sampling (IPSS) central to peripheral ACTH gradient >2 at baseline and/or >2 after DDAVP stimulation. Recurrent or persistent CD defined as pathologically confirmed previously resected pituitary ACTH-secreting tumor, and 24 hour UFC >ULN at least 4 weeks after pituitary surgery. Patients on medical treatment for CD. Washout periods will be completed as below before screening: Inhibitors of steroidogenesis (metyrapone, ketoconazole, osilodristat, Levo-ketoconazole): 2 weeks SRLs (pasireotide): 2 weeks Progesterone receptor antagonist (mifepristone): 2 weeks Dopamine agonists (cabergoline): 4 weeks CYP3A4 strong inducers or inhibitors: varies between drugs; minimum 5-6 times the half-life of drug Exclusion Criteria: Patients with compromised visual fields, or evidence of visual changes within past 6 months Patients with sellar tumor abutting or compressing the optic chiasm on MRI and normal visual fields Patients with Cushing's syndrome not due to an ACTH-secreting pituitary tumor Patients who have undergone major surgery including pituitary surgery within 1 month of screening or who have any major surgical procedures planned across the study period Patients with serum potassium < 3.5 mEq/L unless stably controlled on potassium supplementation Patients with poorly-controlled Diabetes mellitus evidenced by HbA1c levels >8 Patients with poorly controlled hypertension (i.e. blood pressure ≥ 160/100 mm Hg) Patients who have clinically significant cardiovascular impairment, as evidenced by the presence of bradycardia, ventricular tachycardia, history of myocardial infarction within past year, or any other cardiovascular impairment that may pose significant health risk in view of the investigator. Patients with liver disease or history of liver disease such as cirrhosis, chronic active hepatitis B and C, or chronic persistent hepatitis, or patients with ALT or AST >1.5 x ULN, serum total bilirubin >ULN, serum albumin <0.67 x LLN at screening Patients with renal disease or history of renal disease with creatinine clearance of 30 cm3/min or less and/or creatinine > 1.5 mg/dl at screening Patients not biochemically euthyroid. Patients receiving thyroid-replacement therapy must be on a stable dose for at least 3 months. Patients who are known to be positive for HIV, or any other condition that significantly compromises subject's immune system. History of alcohol abuse or illicit substance use within past year. Female patients who are pregnant or lactating or are of childbearing potential unless willing to practice acceptable method of birth control. Women participating in the trial must employ double barrier method through oral contraceptive or diaphragm with partner utilizing a condom. Abstinence is an acceptable form of birth control if routinely practiced. Male participants must utilize a condom with spermicidal cap/jelly and agree to not donate sperm for up to 3 months beyond main study period. Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or within 5 half-lives of the investigational treatment whichever is longer. Patients with concomitant treatment of strong CYP3A4 inducers or inhibitors. Patients who have received pituitary irradiation within the last 5 years prior to the baseline visit Patients with known hepatitis B surface antigen (HbsAg) positivity Patients with known hepatitis C antibody (anti-HCV) positivity

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Active Comparator

    Arm Label

    Fimepinostat 60mg

    Fimepinostat 30mg

    Arm Description

    two 30mg capsules once a day, 10 subjects

    single 30mg capsule daily in 10 subjects

    Outcomes

    Primary Outcome Measures

    Number of participants with mUFC ≤ 1.0xULN
    4 week UFC calculated as the mean of three 24h UFC specimens collected on consecutive days between day 24-28

    Secondary Outcome Measures

    Number of participants with normalization (values within normal limits) or >50% improvement from baseline in 24h UFC, plasma ACTH, serum and salivary cortisol levels
    4 week UFC calculated as the mean of three 24h UFC specimens collected on consecutive days between day 24-28
    body weight change from baseline
    body mass index change from baseline
    Systolic and Diastolic Blood Pressure Change from baseline
    Cushing Disease health-related quality of life questionnaire (CushingQoL) change from baseline
    The CushingQoL is scored using a total score ranging from 0 to 100 with lower scores indicating a greater impact on QoL
    Beck Depression inventory second edition (BDIII) change from baseline
    Beck Depression scale is scored as follows 1-10 These ups and downs are considered normal. 11-16 Mild mood disturbances. 17-20 borderline clinical depression. 21-30 Moderate depression. 31-40 Severe depression

    Full Information

    First Posted
    July 6, 2023
    Last Updated
    July 31, 2023
    Sponsor
    University of California, Los Angeles
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05971758
    Brief Title
    Fimepinostat, Combination HDAC and Pi3-kinase Inhibitor Tumor-Directed Therapy for Cushing Disease
    Official Title
    Fimepinostat, Combination HDAC and Pi3-kinase Inhibitor Tumor-Directed Therapy for Cushing Disease
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    July 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    January 2024 (Anticipated)
    Primary Completion Date
    January 2025 (Anticipated)
    Study Completion Date
    January 2025 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    University of California, Los Angeles

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Supported by the pre-clinical data (summarized in Research Strategy), the investigators propose that Fimepinostat is an ideal candidate drug in the treatment and intervention of patients with Cushing Disease. The investigators propose a pilot, short-term (4 weeks) phase II single-center study to demonstrate the safety and efficacy of Fimepinostat in the treatment of patients with de novo, persistent, and/or recurrent CD recruited at the University of California, Los Angeles. The trial will have a 2-arm design and will simultaneously examine two different doses of Fimepinostat. The study will allow the investigators to determine the efficacy and safety of these doses in the treatment of CD and guide dose selection for subsequent, larger studies.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Cushing Disease

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    20 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Fimepinostat 60mg
    Arm Type
    Active Comparator
    Arm Description
    two 30mg capsules once a day, 10 subjects
    Arm Title
    Fimepinostat 30mg
    Arm Type
    Active Comparator
    Arm Description
    single 30mg capsule daily in 10 subjects
    Intervention Type
    Drug
    Intervention Name(s)
    Fimepinostat
    Intervention Description
    The study will allow us to determine the efficacy and safety of these doses in the treatment of Cushing Disease (CD) and guide dose selection for subsequent, larger studies.
    Primary Outcome Measure Information:
    Title
    Number of participants with mUFC ≤ 1.0xULN
    Description
    4 week UFC calculated as the mean of three 24h UFC specimens collected on consecutive days between day 24-28
    Time Frame
    Baseline, 4 weeks
    Secondary Outcome Measure Information:
    Title
    Number of participants with normalization (values within normal limits) or >50% improvement from baseline in 24h UFC, plasma ACTH, serum and salivary cortisol levels
    Description
    4 week UFC calculated as the mean of three 24h UFC specimens collected on consecutive days between day 24-28
    Time Frame
    Baseline, 4 weeks
    Title
    body weight change from baseline
    Time Frame
    Baseline, Day 28
    Title
    body mass index change from baseline
    Time Frame
    Baseline, Day 28
    Title
    Systolic and Diastolic Blood Pressure Change from baseline
    Time Frame
    Baseline, Day 28
    Title
    Cushing Disease health-related quality of life questionnaire (CushingQoL) change from baseline
    Description
    The CushingQoL is scored using a total score ranging from 0 to 100 with lower scores indicating a greater impact on QoL
    Time Frame
    Baseline, Day 28
    Title
    Beck Depression inventory second edition (BDIII) change from baseline
    Description
    Beck Depression scale is scored as follows 1-10 These ups and downs are considered normal. 11-16 Mild mood disturbances. 17-20 borderline clinical depression. 21-30 Moderate depression. 31-40 Severe depression
    Time Frame
    Baseline, Day 28

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    Inclusion Criteria: Male and female patients at least 18 years old Patients with confirmed pituitary origin Cushing syndrome defined as 1, 2& 3 or 4 & 5 below: Persistent hypercortisolism defined as a mean of 3 consecutive 24h UFC at baseline assessment ≥ 1.3x ULN Normal or elevated plasma ACTH levels Pituitary adenoma > 4mm visible on MRI or inferior petrosal sinus sampling (IPSS) central to peripheral ACTH gradient >2 at baseline and/or >2 after DDAVP stimulation. Recurrent or persistent CD defined as pathologically confirmed previously resected pituitary ACTH-secreting tumor, and 24 hour UFC >ULN at least 4 weeks after pituitary surgery. Patients on medical treatment for CD. Washout periods will be completed as below before screening: Inhibitors of steroidogenesis (metyrapone, ketoconazole, osilodristat, Levo-ketoconazole): 2 weeks SRLs (pasireotide): 2 weeks Progesterone receptor antagonist (mifepristone): 2 weeks Dopamine agonists (cabergoline): 4 weeks CYP3A4 strong inducers or inhibitors: varies between drugs; minimum 5-6 times the half-life of drug Exclusion Criteria: Patients with compromised visual fields, or evidence of visual changes within past 6 months Patients with sellar tumor abutting or compressing the optic chiasm on MRI and normal visual fields Patients with Cushing's syndrome not due to an ACTH-secreting pituitary tumor Patients who have undergone major surgery including pituitary surgery within 1 month of screening or who have any major surgical procedures planned across the study period Patients with serum potassium < 3.5 mEq/L unless stably controlled on potassium supplementation Patients with poorly-controlled Diabetes mellitus evidenced by HbA1c levels >8 Patients with poorly controlled hypertension (i.e. blood pressure ≥ 160/100 mm Hg) Patients who have clinically significant cardiovascular impairment, as evidenced by the presence of bradycardia, ventricular tachycardia, history of myocardial infarction within past year, or any other cardiovascular impairment that may pose significant health risk in view of the investigator. Patients with liver disease or history of liver disease such as cirrhosis, chronic active hepatitis B and C, or chronic persistent hepatitis, or patients with ALT or AST >1.5 x ULN, serum total bilirubin >ULN, serum albumin <0.67 x LLN at screening Patients with renal disease or history of renal disease with creatinine clearance of 30 cm3/min or less and/or creatinine > 1.5 mg/dl at screening Patients not biochemically euthyroid. Patients receiving thyroid-replacement therapy must be on a stable dose for at least 3 months. Patients who are known to be positive for HIV, or any other condition that significantly compromises subject's immune system. History of alcohol abuse or illicit substance use within past year. Female patients who are pregnant or lactating or are of childbearing potential unless willing to practice acceptable method of birth control. Women participating in the trial must employ double barrier method through oral contraceptive or diaphragm with partner utilizing a condom. Abstinence is an acceptable form of birth control if routinely practiced. Male participants must utilize a condom with spermicidal cap/jelly and agree to not donate sperm for up to 3 months beyond main study period. Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or within 5 half-lives of the investigational treatment whichever is longer. Patients with concomitant treatment of strong CYP3A4 inducers or inhibitors. Patients who have received pituitary irradiation within the last 5 years prior to the baseline visit Patients with known hepatitis B surface antigen (HbsAg) positivity Patients with known hepatitis C antibody (anti-HCV) positivity

    12. IPD Sharing Statement

    Learn more about this trial

    Fimepinostat, Combination HDAC and Pi3-kinase Inhibitor Tumor-Directed Therapy for Cushing Disease

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