Clinical Trials /

Fimepinostat in Treating Brain Tumors in Children and Young Adults

NCT03893487

Description:

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.

Related Conditions:
  • Anaplastic Astrocytoma
  • Diffuse Intrinsic Pontine Glioma
  • Glioblastoma
  • Malignant Glioma
  • Medulloblastoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Fimepinostat in Treating Brain Tumors in Children and Young Adults
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: 18086
  • SECONDARY ID: 18086
  • SECONDARY ID: PNOC016
  • NCT ID: NCT03893487

Conditions

  • Diffuse Intrinsic Pontine Glioma
  • Recurrent Anaplastic Astrocytoma
  • Recurrent Glioblastoma
  • Recurrent Malignant Glioma
  • Recurrent Medulloblastoma

Interventions

DrugSynonymsArms
FimepinostatCUDC-907Treatment (fimepinostat, tumor resection)

Purpose

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.

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (fimepinostat, tumor resection)ExperimentalPatients 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.
  • Fimepinostat

Eligibility 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 (DIPG) (World Health
                  Organization [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

               -  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

          -  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

          -  Strata B & C: Patients in the medulloblastoma and HGG strata will be allowed to have
             undergone prior therapy including surgery, chemotherapy, and radiation therapy.
             Patients in the DIPG stratum are not allowed to have prior therapy before the
             initiation of fimepinostat. 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
      
Maximum Eligible Age:39 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Penetration of fimepinostat across the blood brain barrier (BBB)
Time Frame:During surgery or biopsy
Safety Issue:
Description: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.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sabine Mueller, MD, PhD

Last Updated

November 15, 2019