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)


Rationale for Study

Despite advances in neurosurgery, chemotherapy, and radiotherapy, outcomes remain poor for many pediatric brain tumors, such as DIPG, MYC-driven medulloblastoma, and HGG. Due to continued poor outcomes, many studies have investigated novel therapeutic approaches targeting molecular pathways that are active in pediatric brain tumors. Two common molecular pathways involved in pediatric brain tumors include those in regulation of chromatin and MYC, a transcription factor mediating cell survival, division, and apoptosis. A range of histone deacetylase (HDAC) inhibitors are currently being studied to address altered chromatin remodeling, while phosphatidylinositol 3-kinase (PI3K) inhibitors are being used to decrease MYC overexpression. 

A novel oral, potent dual pan-HDAC and PI3K inhibitor, fimepinostat, has shown broad antitumor activity in hematologic and solid tumors. Fimepinostat demonstrates greater inhibition of tumor growth in vitro and in vivo than single-target HDAC or PI3K inhibitors. Given the evidence of chromatin and PI3K-related activity among a range of pediatric brain tumors and the preclinical/clinical promise of fimepinostat, this drug holds promise as a successful treatment strategy for children and young adults with brain tumors.


Trial Requirement/Treatment

This study will include children and young adults (3-39 years of age) with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG who will undergo tissue collection as part of standard of care.  Patients will initiate drug prior to resection/biopsy and continue drug during a maintenance phase after resection/biopsy. Fimepinostat is a pan-HDAC and PI3K inhibitor. Fimepinostat will be given orally 2 days prior to resection/biopsy and the day of the resction/biopsy (for a total of 3 doses). Treatment with fimepinostat CUDC-907 will continue during a maintenance phase after resection/biopsy once daily for 5 daily doses every week. Patients will receive fimepinostat on study 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.


Primary Objectives

To confirm penetration of fimepinostat across the blood brain barrier (BBB) in children and young adults with newly diagnosed DIPG, recurrent medulloblastoma, or recurrent HGG by measuring concentration of fimepinostat in tumor tissue

Inclusion Criteria

  • Age ≥ 3 years and ≤ 39 years at time of enrollment.

  • 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.

    • Stratum B*: Recurrent medulloblastoma (WHO grade IV), any molecular subtype.

    • Stratum C*: Recurrent high-grade glioma, including anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV)

  • 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 m2.

  • Patients must undergo tumor tissue collection as part of their standard of care.

  • 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 nitrosurea).

  • 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 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.

  • Bone Marrow Function:

    • Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3

    • Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).

  • Renal Function:

    • Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m2 or

    • A serum creatinine based on age/gender as follows:



Maximum Serum

Creatinine (mg/dL)




3 to < 6 years



6 to < 10 years



10 to < 13 years



13 to < 16 years



≥ 16 years



The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.

  • Liver Function:

    • Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age.

    • SGPT (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 CTCAE v5.0.

  • 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 ≤ 160mg/dL without the use of antihyperglycemic agents, patient will meet adequate metabolic function criteria. 

  • Cardiac Function: 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 HDAC and 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 HIV infection and with potential life-threating 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.