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Fimepinostat in Treating Brain Tumors in Children and Young Adults (PNOC016)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03893487
Recruitment Status : Recruiting
First Posted : March 28, 2019
Last Update Posted : November 17, 2020
Sponsor:
Collaborators:
Pacific Pediatric Neuro-Oncology Consortium
Cannonball Kids' Cancer Foundation
Curis, Inc.
Information provided by (Responsible Party):
Sabine Mueller, MD, PhD, University of California, San Francisco

Brief Summary:
This trial studies how well fimepinostat works in treating patients with newly diagnosed diffuse intrinsic pontine glioma, or medulloblastoma, or high-grade glioma that have come back. Fimepinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Diffuse Intrinsic Pontine Glioma Recurrent Anaplastic Astrocytoma Recurrent Glioblastoma Recurrent Malignant Glioma Recurrent Medulloblastoma Drug: Fimepinostat Procedure: Therapeutic Conventional Surgery Early Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To confirm penetration of fimepinostat across the blood brain barrier (BBB) in children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG), recurrent medulloblastoma, or recurrent high-grade glioma (HGG) by measuring concentration of fimepinostat and metabolite in primary tumor tissue.

EXPLORATORY OBJECTIVES:

I. To assess pharmacokinetics (PK) of fimepinostat in plasma and tumor tissue of children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG.

II. To assess pharmacodynamics (PD) of fimepinostat in children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG as measured by phosphorylation and acetylation in tumor tissue.

III. To correlate acetylation and phosphorylation in tumor tissue with tissue and plasma PK levels.

IV. To assess the safety and tolerability of fimepinostat in children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG.

V. To assess preliminary efficacy of fimepinostat given as monotherapy after surgery in children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG, as based on progression-free survival (PFS) and objective response rate (ORR) as appropriate.

OUTLINE:

Patients receive fimepinostat orally (PO) once daily (QD) on days -2 to 0. Within 2 hours of receiving fimepinostat on day 0, patients undergo tumor resection.

MAINTENANCE PHASE: Patients receive fimepinostat by mouth, once daily for days 1-5 each week. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity for up to 12 months from the time treatment begins. Should patients continue to derive clinical benefit, and not experience excess toxicity or progression, patients can continue to receive drug for up to 24 months or longer pending discussion with study chairs and study sponsor.

After completion of study treatment, patients are followed up at 30 days, then every 3 months for up to 5 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Target Validation Study of Fimepinostat in Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG), Recurrent Medulloblastoma, or Recurrent High-Grade Glioma (HGG)
Actual Study Start Date : August 7, 2019
Estimated Primary Completion Date : June 1, 2022
Estimated Study Completion Date : June 1, 2027


Arm Intervention/treatment
Experimental: Treatment (fimepinostat, tumor resection)

Patients receive fimepinostat by mouth once daily, on Days -2 to 0. Within 2 hours of receiving fimepinostat on Day 0, patients undergo tumor resection or biopsy as part of their standard of care.

MAINTENANCE PHASE: Patients receive fimepinostat by mouth, once daily for days 1-5 each week. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity for up to 12 months from the time treatment begins. Should patients continue to derive clinical benefit, and not experience excess toxicity or progression, patients can continue to receive drug for up to 24 months or longer pending discussion with study chairs and study sponsor.

Drug: Fimepinostat
Fimepinostat capsules
Other Name: CUDC-907

Procedure: Therapeutic Conventional Surgery
Undergo surgery




Primary Outcome Measures :
  1. Penetration of fimepinostat across the blood brain barrier (BBB) [ Time Frame: During surgery or biopsy ]
    Will be analyzed using descriptive statistics from results of fimepinostat concentrations measured within the tumor tissue collected at the time of a standard of care surgery or biopsy. Within each strata, Simon's two-stage design will be used.



Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 39 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have one of the following histologically confirmed diagnoses (histologic confirmation from initial diagnosis acceptable, as appropriate):

    • Stratum A: Newly diagnosed diffuse intrinsic pontine glioma (WHO grade II-IV) - this stratum does not require tissue confirmation at time of enrollment, but diagnostic confirmation will be required to continue on study after biopsy. Patients with newly diagnosed DIPG will be eligible to enroll before or after standard of care radiation, but must be eligible for a biopsy. Newly diagnosed DIPG stratum should not have received prior therapy before the initiation of fimepinostat, with the exception of those patients who received temozolomide during radiation therapy or who previously received radiation as per standard of care and have not yet undergone a biopsy. All patients who have received therapy other than radiation and temozolomide should be discussed with study chair(s) prior to enrollment. Patients enrolling after standard of care radiation must be enrolled within 14 weeks of completion of radiotherapy.
    • Stratum B: Recurrent medulloblastoma (WHO grade IV), any molecular subtype
    • Stratum C: Recurrent high-grade glioma (HGG), including anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV)

      • Stratum B & C: Patients in the recurrent medulloblastoma or recurrent HGG arm can have locally recurrent or disseminated disease, provided resection/biopsy would still be clinically indicated. Disseminated disease can be diagnosed by imaging or Cerebrospinal fluid (CSF) cytology. Recurrent DIPG will be eligible for stratum C; however, eligibility requires biopsy/resection is feasible in a region of tumor outside of the pons (i.e. cerebellar extension or new metastatic site). These patients should be discussed with study chair(s) prior to enrollment
  • Patients must be able to swallow intact fimepinostat capsules or mini-tabs without chewing or crushing
  • Patients must have body surface area (BSA) >= 0.5 m^2
  • Patients must undergo tumor tissue collection as part of their standard of care

    • Minimum possible tissue collected must be equivalent to about 4-6 stereotactic core biopsies
  • Prior Therapy: Patients in the medulloblastoma and HGG strata will be allowed to have undergone prior therapy including surgery, chemotherapy, and radiation therapy. Patients in the newly diagnosed DIPG stratum should not have received prior therapy before the initiation of fimepinostat, with the exception of those patients who received temozolomide during radiation therapy or who previously received radiation as per standard of care and have not yet undergone a biopsy. All patients who have received therapy other than radiation and temozolomide should be discussed with study chair(s) prior to enrollment. Patients must have fully recovered from acute side effects related to previous anti-cancer therapies. Patients undergoing radiation during protocol therapy will not be permitted to receive other concomitant agents with radiation and pending initiation of maintenance with fimepinostat

    • Myelosuppressive chemotherapy: At least 21 days after last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
    • Hematopoietic growth factors: At least 14 days after last dose of a long-acting growth factor or 7 days after short-acting growth factor or beyond time during which adverse events are known to occur
    • Biologic (anti-neoplastic agent): At least 7 days after last dose of a biologic agent or beyond time during which adverse events are known to occur
    • Monoclonal antibodies: At least 21 days after last dose of monoclonal antibody
    • Radiotherapy:

      • At least 2 weeks after local palliative radiotherapy (XRT)
      • At least 3 months from craniospinal XRT, or XRT to > 50% pelvis
    • Surgery:

      • At least 21 days from major surgery (biopsy and central line placement/removal are not considered major)
  • Corticosteroids: Subjects who are receiving dexamethasone must be on a stable or decreasing dose for at least 7 days prior to enrollment
  • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
  • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 milliliters (mL)/minute (min)/1.73 m^2 or
  • A serum creatinine based on age/gender as follows:

    • Age: Maximum Serum Creatinine (mg/dL)
    • 3 to < 6 years: 0.8 (male), 0.8 (female)
    • 6 to < 10 years: 1 (male), 1 (female)
    • 10 to < 13 years: 1.2 (male), 1.2 (female)
    • 13 to < 16 years: 1.5 (male), 1.4 (female)
    • >= 16 years: 1.7 (male), 1.4 (female)
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) =< 110 U/L
  • Serum albumin >= 2 g/dL
  • Neurologic function:

    • Subjects with seizure disorder may be enrolled if well controlled
  • Gastrointestinal function:

    • Diarrhea < grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0
  • Metabolic function:

    • Non-fasting glucose < 125 mg/dL without the use of antihyperglycemic agents

      • If non-fasting glucose > 125 mg/dL, a fasting glucose should be done. If fasting glucose =< 160 mg/dL without the use of antihyperglycemic agents, patient will meet adequate metabolic function criteria
  • Cardiac function: corrected QT (QTc) < 480 msec
  • The effects of fimepinostat on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 30 days after completion of fimepinostat administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate

Exclusion Criteria:

  • Subjects who have not recovered from acute adverse events due to therapeutic agents administered more than 4 weeks earlier
  • Patients must not have received prior therapy with single-agent or combination histone deacetylase (HDAC) and Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors
  • Subjects who are receiving any other investigational agent
  • History of allergic reaction to compounds of similar chemical or biological composition to fimepinostat
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements
  • Patients with active human immunodeficiency virus (HIV) infection and with potential life-threatening consequences associated with immune-suppressive therapy
  • Patients with history of type 1 or 2 diabetes mellitus
  • Patients with gastrointestinal condition that could interfere with absorption or metabolism of fimepinostat

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03893487


Contacts
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Contact: Roisheen Doherty 415-502-1600 PNOC_Regulatory@ucsf.edu
Contact: Sabine Mueller, MD, PhD 877-827-3222 cancertrials@ucsf.edu

Locations
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United States, California
Rady Children's Hospital Recruiting
San Diego, California, United States, 92123
Contact: John Crawford, MD, MS    858-966-4939    jcrawford@rchsd.org   
Principal Investigator: John Crawford, MD, MS         
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Kelly Hitchner    415-502-1600    PNOC_Regulatory@ucsf.edu   
Contact: Sabine Mueller, MD, PhD    877-827-3222    cancertrials@ucsf.edu   
Principal Investigator: Sabine Mueller, MD, PhD         
United States, Florida
University of Florida Recruiting
Gainesville, Florida, United States, 32611
Contact: Sridharan Gururangan, FRCP    352-294-8347    Sridharan.Gururangan@neurosurgery.ufl.edu   
Principal Investigator: Sridharan Gururangan, FCRP         
United States, Maryland
Johns Hopkins Hospital Recruiting
Baltimore, Maryland, United States, 21231
Contact: Kenneth Cohen, MD, MBA    410-614-5055    kcohen@jhmi.edu   
Principal Investigator: Kenneth Cohen, MD, MBA         
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Susan N Chi, MD    617-632-4386    Susan_Chi@dfci.harvard.edu   
Principal Investigator: Susan N Chi, MD         
United States, Michigan
University of Michigan Hospital Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Andrea Franson, MD, MS       atflynn@med.umich.edu   
Contact: Carl Koschmann, MD       ckoschma@med.umich.edu   
United States, Minnesota
Children's Minnesota Research Institute Recruiting
Minneapolis, Minnesota, United States, 55404
Contact: Anne Bendel, MD    612-813-5940    anne.bendel@childrensmn.org   
Contact: Maggie Skrypek, MD    612-813-5940    maggie.skrypek@childrensmn.org   
United States, Missouri
Washington University in St Louis Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Joshua Rubin, MD, PhD    314-286-2790    rubin_j@kids.wustl.edu   
Principal Investigator: Joshua Rubin, MD, PhD         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Amar Gajjar, MD    901-595-2615    Amar.Gajjar@STJUDE.ORG   
Contact: Christopher Tinkle, MD    901-595-8735    Christopher.Tinkle@STJUDE.ORG   
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Holly Lindsay, MD    832-824-2146    hblindsa@txch.org   
Contact: Patricia Baxter, MD       pabaxter@txch.org   
United States, Utah
University of Utah, Children's Primary Recruiting
Salt Lake City, Utah, United States, 84113
Contact: Nicholas Whipple, MD, MPH    801-662-4700    Nicholas.whipple@hsc.utah.edu   
Principal Investigator: Nicholas Whipple, MD, MPH         
Sub-Investigator: Carol Bruggers, MD         
Switzerland
The University Children's Hospital in Zurich Recruiting
Zürich, Zurich, Switzerland, 8032
Contact: Nicolas Gerber, MD    +41 44 266 31 17      
Contact: Stephanie Mathes, PhD    +41 44 266 3726    PNOC_regulatory@ucsf.edu   
Principal Investigator: Nicolas Gerber, MD         
Sub-Investigator: Ana Guerreiro Stuecklin,, MD         
Sponsors and Collaborators
Sabine Mueller, MD, PhD
Pacific Pediatric Neuro-Oncology Consortium
Cannonball Kids' Cancer Foundation
Curis, Inc.
Investigators
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Principal Investigator: Sabine Mueller, MD, PhD University of California, San Francisco
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Responsible Party: Sabine Mueller, MD, PhD, Associate Adjunct Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03893487    
Other Study ID Numbers: 18086
NCI-2019-00144 ( Other Identifier: NCI Clinical Trials Reporting Program (CTRP) )
PNOC016 ( Other Identifier: Pacific Pediatric Neuro-Oncology Consortium )
First Posted: March 28, 2019    Key Record Dates
Last Update Posted: November 17, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Glioblastoma
Glioma
Astrocytoma
Medulloblastoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neuroectodermal Tumors, Primitive